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The woman who should have got Alzheimers by 50, but didnt – The Irish Times

The womans genetic profile showed she would develop Alzheimers by the time she turned 50.

She, like thousands of her relatives, going back generations, was born with a gene mutation that causes people to begin having memory and thinking problems in their 40s and deteriorate rapidly towards death around age 60.

But remarkably, she experienced no cognitive decline at all until her 70s, nearly three decades later than expected.

How did that happen?

New research provides an answer, one that experts say could change the scientific understanding of Alzheimers disease and inspire new ideas about how to prevent and treat it.

In a study published in the journal Nature Medicine, researchers say the woman, whose name they withheld to protect her privacy, has another mutation that has protected her from dementia, even though her brain has developed a major neurological feature of Alzheimers disease. This ultra-rare mutation appears to help stave off the disease by minimising the binding of a particular sugar compound to an important gene. That finding suggests that treatments could be developed to give other people that same protective mechanism.

A drug or gene therapy would not be available any time soon because scientists first need to replicate the protective mechanism found in this one patient by testing it in laboratory animals and human brain cells. Still, this case comes at a time when the Alzheimers field is craving new approaches after billions of dollars have been spent on developing and testing treatments and some 200 drug trials have failed. It has been more than 15 years since the last treatment for dementia was approved, and the few drugs available do not work very well for very long.

The woman is entering her late 70s now and lives in Medelln, the epicentre for the worlds largest family to experience Alzheimers. It is an extended Colombian family of about 6,000 people whose members have been plagued with dementia for centuries, a condition they called La Bobera the foolishness and attributed to superstitious causes.

Decades ago Colombian neurologist Dr Francisco Lopera began painstakingly collecting the familys birth and death records in Medelln and remote Andes mountain villages. He documented the sprawling family tree and took dangerous risks in guerrilla and drug-trafficking territory to cajole relatives of people who died with dementia into giving him their brains for analysis.

Through this work, Dr Lopera, whose brain bank at the University of Antioquia now contains 300 brains, helped discover that their Alzheimers was caused by a mutation on a gene called Presenilin 1. Although this type of hereditary early-onset dementia accounts for only a small proportion of the roughly 30 million people worldwide with Alzheimers, it is important because, unlike most forms of the disease, the Colombian version has been traced to a specific cause and a consistent pattern. So Dr Lopera and a team of American scientists have spent years studying the family, searching for answers both to help the Colombians and to address the mounting epidemic of the more typical old-age Alzheimers disease.

When they found that the woman had the Presenilin 1 mutation, but had not yet even developed a pre-Alzheimers condition called mild cognitive impairment, the scientists were mystified. We have a single person who is resilient to Alzheimers disease when she should be at high risk, said Dr Eric Reiman, executive director of the Banner Alzheimers Institute in Phoenix and a leader of the research team.

The woman was flown to Boston, where some of the researchers are based, for brain scans and other tests. Those results were puzzling, said Yakeel Quiroz, a Colombian neuropsychologist who directs the familial dementia neuroimaging lab at Massachusetts General Hospital.

The womans brain was laden with the foremost hallmark of Alzheimers: plaques of amyloid protein. She had the highest levels of amyloid that we have seen so far, said Quiroz, adding that the excessive amyloid probably accumulated because the woman had lived much longer than other family members with the Alzheimers-causing mutation.

But the woman had few other neurological signs of the disease not much of a protein called tau, which forms tangles in Alzheimers brains, and little neurodegeneration or brain atrophy. Her brain was functioning really well, said Quiroz, who, like Dr Reiman, is a senior author of the study. Compared to people who are 45 or 50, shes actually better.

She said the woman, who raised four children, had only one year of formal education and could barely read or write, so it was unlikely her cognitive protection came from educational stimulation. She has a secret in her biology, Dr Lopera said. This case is a big window to discover new approaches.

Quiroz consulted Dr Joseph Arboleda-Velasquez, who, like her, is an assistant professor at Harvard Medical School (he is also Quirozs husband). Dr Arboleda-Velasquez, a cell biologist at Massachusetts eye and ear, conducted extensive genetic testing and sequencing, determining that the woman had an extremely rare mutation on a gene called APOE.

APOE is important in general-population Alzheimers. It has three variants. One, APOE4, greatly increases risk and is present in 40 per cent of people with Alzheimers. The Colombian woman has two copies of APOE3, the variant that most people are born with but both copies have a mutation called Christchurch (for the New Zealand city where it was discovered). The Christchurch mutation is extremely rare, but several years ago, Reimans daughter Rebecca, a technologist, helped determine that a handful of Colombian family members have that mutation on one of their APOE genes. They developed Alzheimers as early as their family members typically did. The fact that she had two copies, not just one, really kind of sealed the deal, Dr Arboleda-Velasquez said.

Dr Guojun Bu, chairman of the neuroscience department at the Mayo Clinic in Jacksonville, Florida, who studies APOE, said that while the findings involved a single case and more research was needed, the implications could be profound.

When you have delayed onset of Alzheimers by three decades, you say wow. New York Times

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The woman who should have got Alzheimers by 50, but didnt - The Irish Times

Recommendation and review posted by Bethany Smith

Edited Transcript of SRPT earnings conference call or presentation 7-Nov-19 9:30pm GMT – Yahoo Finance

BOTHELL Nov 8, 2019 (Thomson StreetEvents) -- Edited Transcript of Sarepta Therapeutics Inc earnings conference call or presentation Thursday, November 7, 2019 at 9:30:00pm GMT

* Alexander G. Cumbo

Sarepta Therapeutics, Inc. - Executive VP & Chief Commercial Officer

* Douglas S. Ingram

Sarepta Therapeutics, Inc. - President, CEO & Director

Sarepta Therapeutics, Inc. - Executive VP of R&D and Chief Medical Officer

* Ian M. Estepan

Sarepta Therapeutics, Inc. - Senior VP of Corporate Affairs & Chief of Staff

Sarepta Therapeutics, Inc. - SVP of Gene Therapy

Sarepta Therapeutics, Inc. - Executive VP, CFO & Chief Business Officer

Robert W. Baird & Co. Incorporated, Research Division - Senior Research Analyst

* Christopher N. Marai

Nomura Securities Co. Ltd., Research Division - MD & Senior Analyst of Biotechnology

* Debjit D. Chattopadhyay

H.C. Wainwright & Co, LLC, Research Division - MD of Equity Research & Senior Healthcare Analyst

BTIG, LLC, Research Division - MD and Specialty Pharmaceutical & Biotechnology Research Analyst

Janney Montgomery Scott LLC, Research Division - Equity Research Analyst & Director of Biotechnology Research

Good day, ladies and gentlemen, and welcome to the Sarepta Therapeutics Third Quarter 2019 Earnings Call. (Operator Instructions) As a reminder, today's call is being recorded.

And now I'd like to introduce your host for today's program, Ian Estepan, Senior Vice President, Chief of Staff and Corporate Affairs.

Ian M. Estepan, Sarepta Therapeutics, Inc. - Senior VP of Corporate Affairs & Chief of Staff [2]

Thank you, Michelle, and thank you all for joining today's call. Earlier today, we released our financial results for the third quarter of 2019. The press release is available on our website at, and our 10-Q was filed with the SEC earlier this afternoon. Joining us on the call today are Doug Ingram, Sandy Mahatme; Bo Cumbo, Dr. Gilmore O'Neill; and Dr. Rodino-Klapac. After our formal remarks, we'll open up the call for questions.

I'd like to note that during this call, we'll be making a number of forward-looking statements. Please take a moment to review our slide on the webcast which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta's control. Actual results could materially differ from these forward-looking statements, and any such risks can materially and adversely affect the business, the results of operations and the trading prices of Sarepta's common stock.

For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q filed with the Securities and Exchange Commission as well as the company's other SEC filings. The company does not undertake any obligation to publicly update its forward-looking statements, including any financial projections provided today, based on subsequent events or circumstances.

And with that, let me turn the call over to our CEO, Doug Ingram, who will provide an overview on our recent progress. Doug?


Douglas S. Ingram, Sarepta Therapeutics, Inc. - President, CEO & Director [3]


Thank you, Ian. Good afternoon and evening, and thank you all for joining us for Sarepta Therapeutics Third Quarter 2019 Conference Call.

Our ambitious strategy involving one of the deepest multi-platform genetic medicine pipelines in biotech has required focused execution over the course of 2019. To remind you, we have more than 25 active programs across our RNA and gene therapy platforms, and we're either actively in or in late-stage planning for some 9 human clinical trials to advance our plans. I am pleased to say that over the course of 2019 and in the third quarter specifically, we have made very significant strides in advancing our programs and our strategic vision, and I'm excited to discuss those advancements. However, while doing so, I must also acknowledge what we all know that we had a setback in the third quarter. And rather than burying it among or after a discussion of our successes, I will begin by commenting on a CRL disappointment that occurred in August.

Having worked diligently on our submission for VYONDYS 53, the generic name of that is golodirsen, for well over a year and based on all of our interactions with the Division of Neurology Products, we were very confident that we would obtain an approval on our PDUFA date, which was August 19. Instead, as you know, we were surprised to have received a complete response letter, also known as a CRL, signed by the Office of Drug Evaluation I. Our disappointment extends beyond Sarepta to the 8% of exon 53 amenable DMD patients in the United States who degenerate every day while they await access to this therapy.

When I joined Sarepta, I made some commitments externally and to the Division of Neurology, that we intended to build a positive relationship with the Division of Neurology, one founded on transparency and on solid evidence-based science. And consistent with that commitment, we will work with the agency to address the reasons for the CRL and determine a pathway for a potential approval if one is possible.

I've heard from those who would prefer that I speak more often and more publicly on this issue and/or that I would attempt to engage the patient community or others to assist, for instance, in applying external pressure to bring this therapy along faster. I have no intention of doing either of those things. If we can win the day with this therapy and with this issue, we will have done so on the science and on the regulations and in collaborative evidence-based discussions with our reviewers at the FDA.

Now I've also heard some speculation about the implications of the CRL. So let me take a moment to address these as well. First, the VYONDYS CRL does have implications for our submission for our next PMO, casimersen. As they are closely related, we will await clarity on the VYONDYS matter before we submit for casimersen in the United States. But let me [just dissuade] anyone who might have concerns for our other programs. The CRL does not have any read-through to our micro-dystrophin gene therapy program. The CRL involves 2 safety signals in connection with an application for an accelerated approval. Our micro-dystrophin program is overseen by a different part of the FDA, CBER, and we are not seeking accelerated approval there. There is simply no overlap in either substance or personnel.

Secondly, to those who may believe that the CRL suggests some sort of bias on behalf of the Division of Neurology towards Sarepta, I would unequivocally and emphatically disagree. Let me reiterate that I remain convinced that we were treated very fairly and professionally by the Division of Neurology. Also, I'm very proud of the Sarepta team and how they comported themselves during this review. From my perspective, we have gone a long way in the last 2.5 years in forging a positive evidence-based working relationship with the division. We will work diligently to address the VYONDYS CRL. But with that, I do not intend to provide a prediction on outcome or on timing or to provide interviews during the process. However, I will provide an update to the patient, physician and investment communities once we have definitive clarity on the outcome of those discussions.

Now moving to our positive achievements in the quarter. We have made some enormous amount of progress in this third quarter. EXONDYS continues to perform well with third quarter sales above consensus at $99 million. That is a 26% increase over the same quarter last year. Commenting for a moment on a confirmatory trial for EXONDYS, to remind you, this trial comprises 3 arms: one with EXONDYS at 100 mg per kg and another at 200 mg per kg versus our current dose at 30 mg per kg. The trial design, which was an FDA requirement, will answer whether higher doses of EXONDYS provide even more benefit than the currently approved dose. Now since the comparator arms involve higher doses than the currently approved dose, we were required to begin our confirmatory trial with a healthy human volunteer study. We have completed this trial, and based on the results, we have initiated the main confirmatory trial. We will begin dosing this quarter.

Staying on our RNA franchise. We have moved to our multi-ascending dose trial for our next-generation RNA platform, the PPMO, and we are dosing trial participants now. We will have safety and dosing insight in 2020. If our PPMO shows encouraging results, in addition to SRP-5051, that's the construct that we're currently in a multi-ascending dose regarding, we have 5 additional constructs that have already been built, which in total have the potential to treat as much as 43% of the DMD community. We are also conducting research now on new therapeutic targets that could be served by our PPMO platform.

Moving next to our gene therapy platform. As you know, we are spending enormous resource and energy to build out our vision of an enduring gene therapy engine. Between our research and clinical-stage programs, we have more than 14 therapeutic candidates advancing through research and development. We have made great progress thus far this year and quarter, led by our most advanced program, SRP-9001, for DMD, which, at least to my knowledge, is the highest-potential late-stage gene therapy program currently in biotech. As you should be aware, our double-blind, placebo-controlled SRP-9001 micro-dystrophin trial, the trial that we call Study 2, was fully dosed by midyear, but we took advantage of the availability of additional study material and previously announced that we had increased the study n from 24 patients to 40 patients, significantly increasing the study power and confidence in this study. In addition to our initial site with Dr. Jerry Mendell at Nationwide Children's Hospital, we have added a second site at UCLA with Dr. Perry Shieh. And I'm very proud to be associated with that clinician and investigator. Both sites are actively dosing patients, and we remain on target to complete our dosing by year-end.

Micro-dystrophin manufacturing is progressing well. From a capacity perspective, Brammer has now completed the buildout of our single-use micro-dystrophin manufacturing facility in Lexington, Massachusetts. We also have dedicated suites with Paragon in Maryland with actually substantially greater capacity than our dedicated Lexington facility, which means we have robustly secured capacity well in advance of launch.

Our analytical development work proceeds well, and we continue to make progress on process development and yield optimization. Given our recent capacity, analytical development and process development progress, we remain on track to commence our next trial, Study 301, with commercial development supply by mid-2020. Now Study 2 is being conducted with clinical material from Nationwide Children's Hospital. Study 301 will be a multicenter, multi-country, placebo-controlled trial using commercial process material from our hybrid manufacturing model with Brammer and Paragon. The main study will include DMD patients ages 4 to 7, but we are also planning a separate study for older and non-ambulatory patients as well.

Commenting on a few of our other gene therapy programs. Following exceptional expression and biomarker results in our first 3-patient cohort dosed with our construct for limb-girdle 2E, in October, we announced positive 9-month functional results in that same cohort. Consistent with robust expression of the native beta-sarcoglycan protein, that is the cause of the disease, all patients improved on every functional endpoint by the 9-month time point. Consistent with the protocol, we will treat an additional 3-patient cohort with a higher dose, and then in early 2020, we will decide on the dose for what we hope to be the pivotal trial. These results will help inform dosing not only of our 2E program but also on the other limb-girdle programs in our pipeline. We will also meet with the FDA in the near term to discuss the development pathway for our limb-girdle programs. And informed by this and further work on manufacturing, we will provide an update on the clinical pathway and the timing for our limb-girdle portfolio in 2020.

Next, led by our partner Lysogene, the AAVance gene therapy study for MPS IIIA, also known as Sanfilippo Syndrome Type A, is proceeding well with 13 patients having been dosed to date. MPS IIIA is a rare autosomal recessive lysosomal storage disease that primarily affects the brain and the spinal cord, causing severe cognitive decline, motor disease, behavioral decline and unfortunately death at a young age. AAVance is a single-arm trial evaluating the safety and efficacy of an rh10-mediated gene therapy to deliver the missing SGSH gene with the goal of robustly expressing the missing enzyme in the brain that is the cause of MPS IIIA.

Moving to Charcot-Marie-Tooth, or CMT. Dr. Zarife Sahenk of Nationwide Children's Hospital intends to commence dosing of the proof-of-concept study for CMT 1A subject only to obtaining final release of trial material for that study. CMT is the largest inherited neuromuscular disease in the world. And CMT 1A, a devastating peripheral nerve disease, is also the most prevalent form of CMT. Dr. Sahenk's gene therapy is an AAV 1-mediated construct to deliver the neurotrophic factor-3, NT-3. In animal models, NT-3 has been shown to promote nerve regeneration, improved motor function, histopathology and electrophysiology of peripheral nerves. And in early proof-of-principle studies, NT-3 has shown markers of clinical benefits in patients with CMT 1A when administered subcutaneously.

In summary, we have made great progress in the third quarter and over the course of 2019 toward our ambitions, advancing our RNA and gene therapy platforms, advancing our many development programs, building out our gene therapy manufacturing capacity and building out our tower. As with any ambitious strategy, our progress this quarter was met with an obstacle in the form of VYONDYS CRL. The breadth of our ambition inevitably comes with challenges and obstacles to address and to overcome. But to those who might at times feel discouraged or disheartened by the need to overcome the occasional barrier, we should keep top of mind what we are doing with all of this. If we are successful in our mission, we will not merely be among the most significant gene therapy and genetic medicine biotechnology companies in existence, but we will have, more importantly, extended, improved and saved the lives of countless patients who would otherwise have been left hopeless.

And with that, I will turn the call over to Sandy to provide an update on the financials. Sandy?


Sandesh Mahatme, Sarepta Therapeutics, Inc. - Executive VP, CFO & Chief Business Officer [4]


Thanks, Doug. Good afternoon, everyone. Let me start by saying that we had another strong quarter both in terms of financial performance and in progress towards the pipeline and manufacturing capabilities. With a current top line run rate of approximately $400 million and a cash balance over $1 billion, we are in a strong position to continue to accelerate our strategic imperatives and invest in the growth of Sarepta. Net product revenue for the third quarter of 2019 was $99 million compared to $78.5 million for the same period of 2018. The increase primarily reflects higher demand for EXONDYS 51.

On a GAAP basis, the company reported a net loss of $126.3 million and $76.4 million or approximately $1.70 and $1.15 per share for the third quarter of 2019 and 2018, respectively. We reported a non-GAAP net loss of $84.4 million or $1.14 per share compared to non-GAAP net loss of $37.1 million or $0.56 per share in the third quarter of 2018.

In the third quarter of 2019, we recorded approximately $13 million in cost of sales compared to $8.7 million in the same period of 2018. The increase was primarily driven by inventory costs related to higher demand for EXONDYS 51 during the third quarter of 2019 as well as accrued royalty payments to BioMarin and the University of Western Australia.

On a GAAP basis, we recorded $133.9 million and $86.6 million of R&D expenses for the third quarters of 2019 and 2018, respectively, which is a year-over-year increase of $47.3 million. R&D expenses were $110.5 million for the third quarter of 2019 compared to $64.2 million for the same period of 2018, an increase of $46.3 million. The year-over-year growth in non-GAAP R&D expense was driven primarily due to continuing ramp-up of our micro-dystrophin program, our ESSENCE program and initiation of certain post-marketing studies for EXONDYS 51.

Turning to SG&A. On a GAAP basis, we recorded $75.4 million and $53 million of expenses for the third quarters of 2019 and '18, respectively, a year-over-year increase of $22.4 million. On a non-GAAP basis, the SG&A expenses were $59.6 million for the third quarter of 2019 compared to $42.5 million for the same period of 2018, an increase of $17.1 million. The year-over-year increase was primarily driven by significant organizational growth and continued expansion to support a commercial launch -- to support our commercial launch plans globally and almost 30 therapies in various stages of development across several therapeutic modalities.

On a GAAP basis, we recorded $2.5 million in other expenses for the third quarter of 2019 compared to $7 million for the same period of 2018. The favorable change is primarily driven by the payoff of certain debt instruments during the third quarter of 2018 as well as a higher return on investments over the third quarter of 2019.

We had approximately $1.1 billion in cash, cash equivalents and investments as of September 30, 2019.

With that, I'd like to turn the call over to Bo for a commercial update. Bo?


Alexander G. Cumbo, Sarepta Therapeutics, Inc. - Executive VP & Chief Commercial Officer [5]


Thank you, Sandy. Good afternoon, everyone. To begin, we are pleased with the continued strong performance of EXONDYS 51 in the third quarter. Total revenues reached $99 million. We were also pleased to be in a position to increase our 2019 revenue guidance range from $365 million to $375 million to a range of $370 million to $380 million for EXONDYS 51. Sales have increased quarter-over-quarter for over 3 years now, and we continue to see consistent demand for EXONDYS 51 as we speak today.

Compliance and adherence have remained high and stable since launch and to date continue to remain steady. It should be noted that in the past 2 years, we've experienced ordering volatility at the end of the year and suspect that we could see a change in ordering patterns with both Christmas and New Year's falling in the middle of the week. Internally, we are assuming the pattern from previous years could be more extreme this year due to both holidays falling midweek. With that said, we feel comfortable with the guidance provided.

The success we achieved this year reflects the impact EXONDYS 51 continues to have on patient lives. We remain the leading voice with KOLs and payers across the world in support of Duchenne patients and are recognized as the leader in RNA and gene therapies within the Duchenne field. Our strategy to advance the very best science, build awareness and appreciation for Duchenne and pave new pathways so Duchenne patients gain access to therapy have resulted in the successful trajectory of EXONDYS 51 since its approval just over 3 years ago and will play a role for future therapies.

As for golodirsen, if approved, we will be ready to launch, leveraging our knowledge and experience to facilitate rapid access to individuals amenable to exon 53. Our work is focused on delivering, and grounding us in all we do is the patient. That journey begins with identifying patients in our core therapeutic areas: Duchenne, the limb-girdle muscular dystrophy and MPS IIIA. Patient identification will be central to the commercial organization for the balance of 2019 and leading into 2020 and beyond. The genetic testing program, Decode Duchenne, which we started with PPMD many years ago, consistently identifies patients. We are also in the process of building genetic testing programs for our other disease states we are working on as well. We believe patient identification will always be one of our primary commercial goals, and we will continue to place resources on these programs.

Another important goal will be gene therapy site readiness. We are already working on global site readiness for our DMD micro-dystrophin program and working with many of the Zolgensma and Spinraza sites treating SMA. Based on the very strong results Novartis demonstrated with their recent launch of Zolgensma and understanding the label and the differences in patient population sizes between the 2 disease states, we believe having a strong network of sites ready and trained to handle gene therapies will be critical. We will continue to focus on this as we move through worldwide development and, if successful, commercialization.

We also believe it is critical to focus on access and reimbursement as early as possible. We're already speaking to and educating large to midsized insurance plans as well as CMS and Medicaid providers on the differences between chronic therapies and onetime gene therapies and the importance of quickly gaining access to these therapies for diseases like Duchenne. We have built constructive relationships with payers over time and look forward to continuing to work with them to support broad access.

In the limb-girdle muscular dystrophy, we are focused on disease education and identifying patients. The limb-girdle muscular dystrophies are a family of diseases, over 30 subtypes in all. Therefore, patient identification is of critical importance. Our plan is to leverage our knowledge and experience to ensure that we're able to serve these communities as we have in Duchenne. We've already attended limb-girdle muscular dystrophy conferences, held educational symposiums at major neuromuscular conferences, held advisory boards to understand how physicians identify and treat patients and already have a digital presence within the community. All of this will help us prepare for the potential to support multiple launches in the years to come.

Sarepta's prospects to transform the lives of patients with rare diseases is unparalleled in the industry. We have the largest neuromuscular RNA and gene therapy pipeline in the industry, and we understand the responsibility that comes with such an important mission.

With that, I will turn the call back to Doug for closing remarks.


Douglas S. Ingram, Sarepta Therapeutics, Inc. - President, CEO & Director [6]


Thank you, Bo. So looking forward, we have a number of significant milestones to achieve over the rest of 2019 and through 2020. First, we intend to complete dosing of our SRP-9001 Study 2, that's our micro-dystrophin study, by year-end with functional readout 48 weeks thereafter. We soon intend to launch process development for SRP-9001, not manufacturing for purposes of conducting our next clinical trial, gain insight from the agency on CMC and on our trial itself and then to commence Study 301 by mid-2020. We intend to dose an additional high-dose cohort for limb-girdle 2E and then make a dose selection. We intend to gain regulatory and manufacturing insight and to present an update on the development pathway and time line for our entire limb-girdle program in 2020. Dr. Sahenk intends to commence a proof-of-concept study for CMT gene therapy, NT-3. And we intend to obtain safety and dosing insight for our PPMO program in the first half of 2020. So we obviously have a lot to do but a lot of milestones as well over the coming months and quarters.

Thank you all for joining us tonight, and I'll open up the line for questions now.


Questions and Answers


Operator [1]


(Operator Instructions) Our first question comes from Alethia Young of Cantor Fitzgerald.


Alethia Rene Young, Cantor Fitzgerald & Co., Research Division - Head of Healthcare Research [2]


Congrats on all the progress over the quarter. This may be a simple one, but I was just curious to get your perspective around Zolgensma partial hold. And like should we -- is there any -- are there any reads to potentially make thinking about other gene therapy programs?


Douglas S. Ingram, Sarepta Therapeutics, Inc. - President, CEO & Director [3]


Thank you for that question, Alethia. Okay. So well, first, let me say this. Let's make sure we're all on the same page. For those of you maybe unaware, I expect everyone is aware, Novartis recently announced that their clinical trial for their AAV9-mediated SMA gene therapy for intrathecal administration was placed on a partial clinical hold due to neurotoxicity that was seen in animal models. So first, understand this, we do not have a unique insight into the Zolgensma clinical hold itself or the Zolgensma program. Certainly, one should look at Novartis to gain accurate insight on that program and those issues.

So with that said, I should tell you, we see no read-through to our program, and there's a host of reasons for that. First, understand that we are dosing peripherally with IV administration. We're not dosing intrathecally as was the issue, as announced by Novartis, regarding that partial clinical hold. And second of all, understand that we're not using AAV9. Dr. Louise Rodino-Klapac who is with us tonight and Dr. Jerry Mendell chose rh74 for a number of specific attributes. One of the significant ones was that rh74, unlike AAV9 as an example, does not promiscuously cross the blood-brain barrier. And unlike SMA where that would be of value, there is absolutely no value to these micro-dystrophin constructs in the CNS at all. They have promoters that wouldn't turn on in the CNS, so there would be no value there. So this seems to have been a very wise choice.

And also note this, that we have an enormous amount of preclinical and animal model evidence with respect to rh74. And even at doses that are multiples higher than we're using in our clinical trial, we have never seen evidence of neurotoxicity as relates to AAVrh74.


Operator [4]


Our next question comes from Whitney Ijem of Guggenheim.


Whitney Glad Ijem, Guggenheim Securities, LLC, Research Division - Senior Analyst of Biotechnology [5]


Congrats on all the progress. I'll ask a question on the original 4 micro-dystrophin patients. Curious if we'll get an update on them in 2020 either in an update from you or possibly a publication from Dr. Mendell.


Douglas S. Ingram, Sarepta Therapeutics, Inc. - President, CEO & Director [6]


Yes. Thanks for that question. Thank you for your comments. So yes, Dr. Mendell has always had a keen interest in publishing the 1-year data on the 4 patients, and he is working on the manuscript even as we speak. So I feel very confident that we'll have a publication in 2020 on the first 4 patients.

Original post:
Edited Transcript of SRPT earnings conference call or presentation 7-Nov-19 9:30pm GMT - Yahoo Finance

Recommendation and review posted by Bethany Smith

Orchard Therapeutics to Present New Registrational Data of Investigational Gene Therapies at the 61st American Society of Hematology Annual Meeting -…

Registrational Trial for Wiskott-Aldrich Syndrome Met Key Primary and Secondary Endpoints at Three Years; Data from Integrated Analysis Reinforce Treatment Benefits of Gene Therapy and Durability of Effect in Additional Patients

Similar Profiles Reported Between Cryopreserved and Fresh Formulations of OTL-101, Further Supporting Upcoming Regulatory Filing and Broad Patient Availability

BOSTON and LONDON, Nov. 06, 2019 (GLOBE NEWSWIRE) -- Orchard Therapeutics (ORTX), a leading commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies, today announced the upcoming presentation of registrational data from multiple programs at the 61st American Society of Hematology (ASH) Annual Meeting in Orlando, FL.

Investigators will describe ongoing clinical progress for two lead development programs in the companys primary immune deficiencies portfolio: OTL-103, an investigational gene therapy in development for the treatment of Wiskott-Aldrich syndrome (WAS) at theSan Raffaele-Telethon Institute for Gene Therapy(SR-Tiget) inMilan, Italy; and OTL-101, an investigational gene therapy in development for the treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID).

In addition, investigators will deliver an oral presentation featuring updated data from the ongoing proof-of-concept study of OTL-203, an investigational gene therapy in development for the treatment of mucopolysaccharidosis type I (MPS-I) atSR-Tiget.

This growing body of positive data, from dozens of patients across multiple diseases, provides a solid foundation as we advance each program toward its next phase of development, including upcoming regulatory submissions for ADA-SCID and WAS, saidMark Rothera, president and chief executive officer ofOrchard Therapeutics. We now have two supportive data sets one from our OTL-101 program in ADA-SCID and one from our OTL-200 program in metachromatic leukodystrophy that demonstrate cryopreserved formulations are engrafting as expected, similar to the fresh formulation. This supports our strategy for making these therapies, if approved, broadly available to patients in need throughout the world.

We are extremely pleased with our continued clinical progress, including the duration of benefits seen in our WAS trial, which is the longest published follow-up of hematopoietic stem cell gene therapy durability to date using lentiviral vector transduction, said Bobby Gaspar, M.D., Ph.D., chief scientific officer of OrchardTherapeutics. The totality of these data underscores the broad applicability of our gene therapy platform approach and the opportunity we have to deliver potentially curative treatments for a variety of devastating and rare genetic disorders.

Full presentation details are below:

Poster Presentation Details

Lentiviral Hematopoietic Stem and Progenitor Cell Gene Therapy for Wiskott-Aldrich Syndrome (WAS): Up to 8 Years of Follow up in 17 Subjects Treated Since 2010Publication Number: 3346Session: 801. Gene Therapy and Transfer: Poster IIDate and time:Sunday, December 8, 6:00-8:00pm ET

This presentation includes results from an integrated analysis of 17 patients treated with OTL-103 for the treatment of WAS, including the complete data set for the eight patients from the registrational study and nine who received OTL-103 as part of an expanded access program (EAP). Participants have been followed for a median of three years.

In the eight-patient registrational trial, investigators reported that the study achieved its key primary and secondary endpoints at three years, including the elimination of severe bleeding episodes and a significant reduction in the frequency of moderate bleeding episodes. Successful engraftment was observed within three months, leading to an increase in WAS protein expression and a vector copy number that has been maintained for up to eight years. Nine months post-administration, all patients stopped receiving platelet transfusions, and no severe bleeding events were reported. A significant reduction in the rate of severe infections was also observed and all patients were able to stop immunoglobin replacement therapy (IgRT), suggesting a complete reconstitution of immune function with durability of effect of up to eight years of follow-up post-gene therapy.

Story continues

Similar clinical results were seen in the integrated analysis of 17 patients and overall survival was 94% (16/17). One death occurred among the EAP cohort that was considered by the investigator to be unrelated to OTL-103.

Across the original and integrated data sets, there were no adverse events considered to be related to OTL-103, including no evidence of oncogenesis, replication competent lentivirus or abnormal clonal proliferation. Clinical benefit was also attained in patients older than five years of age, a group considered at higher risk when treated with allogeneic hematopoietic stem cell transplantation (HSCT).

Lentiviral Gene Therapy with Autologous Hematopoietic Stem and Progenitor Cells (HSPCs) for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (ADA-SCID): Results in an Expanded CohortPublication Number: 3345Session: 801. Gene Therapy and Transfer: Poster IIDate and time: Sunday, December 8, 6:00-8:00pm ET

This presentation details the safety and efficacy of OTL-101 in 30 individuals with ADA-SCID, treated with either fresh (n=20) or cryopreserved (n=10) formulations. Patients were followed for a median of 24 months (range 12-24 months overall and 12-18 months for patients treated with the cryopreserved formulation), and results were compared with a historical cohort of 26 ADA-SCID patients treated with allogeneic hematopoietic stem cell transplantation (HSCT), including HSCT both with, and without, a matched related donor.

Results showed engraftment of genetically modified hematopoietic stem cells in 29 of 30 OTL-101 patients by six to eight months, which persisted through follow-up in both studies. Analysis of both the vector copy number in granulocytes (a measure of engraftment) and T-cell reconstitution (a relevant measure of immune recovery) showed consistent performance across the fresh and cryopreserved-treated patients.

In the OTL-101 treated patients, overall survival was 30/30 (100%) and event-free survival was 29/30 (97%). One of the 30 patients restarted treatment with enzyme replacement therapy (ERT) and subsequently withdrew from the study and received a rescue HSCT. In the historical control population, 42% of HSCT patients required re-initiation of ERT, rescue HSCT or other intervention, or died. As expected, there was no incidence of graft versus host disease in the OTL-101 group, compared with eight patients who received HSCT.

Eighteen of 20 patients (90%) in the fresh formulation study stopped immunoglobin replacement therapy (IgRT) after two years, compared to 52% of HSCT patients. Of the seven patients treated with the cryopreserved formulation with 18 months of follow-up, five had discontinued IgRT (71%), which is comparable to the 18-month data for patients treated with the fresh formulation.

Oral Presentation Details

Extensive Metabolic Correction of Hurler Disease by Hematopoietic Stem Cell-Based Gene Therapy: Preliminary Results from a Phase I/II TrialPublication Number: 607Session: 801. Gene Therapy and Transfer: Gene Therapies for Non-Malignant DisordersDate and time:Monday, December 9, 7:00am ET

Investigators will present updated analyses from the ongoing proof-of-concept trial of OTL-203 for mucopolysaccharidosis type I (MPS-I).

About ADA-SCID and OTL-101Severe combined immune deficiency due to adenosine deaminase deficiency (ADA-SCID) is a rare, life-threatening, inherited disease of the immune system caused by mutations in the ADA gene resulting in a lack of, or minimal, immune system development.1-4The first symptoms of ADA-SCID typically manifest during infancy with recurrent severe bacterial, viral and fungal infections and overall failure to thrive, and without treatment the condition can be fatal within the first two years of life. The incidence of ADA-SCID is currently estimated to be one in 500,000 live births inthe United Statesand between one in 200,000 and one in 1 million inEurope.3OTL-101 is an autologous,ex vivo,hematopoietic stem cell-based gene therapy for the treatment of patients diagnosed with ADA-SCID being investigated in multiple clinical trials inthe United StatesandEurope, including a registrational trial at theUniversity of California, Los Angeles(UCLA). OTL-101 has received orphan drug designation from theU.S. Food and Drug Administration(FDA) and the European Medicines Agency (EMA) for the treatment of ADA-SCID, and Breakthrough Therapy Designation from theFDA.

About WAS and OTL-103Wiskott-Aldrich Syndrome (WAS) is a life-threatening inherited immune disorder characterized by autoimmunity and abnormal platelet function and manifests with recurrent, severe infections and severe bleeding episodes, which are the leading causes of death in this disease. Without treatment, the median survival for WAS patients is 14 years of age. Treatment with stem cell transplant carries significant risk of mortality and morbidities. OTL-103 is anex vivo,autologous, hematopoietic stem cell-based gene therapy developed for the treatment of WAS that Orchard acquired from GSK in April 2018 and has been developed at theSan Raffaele-Telethon Institute for Gene Therapy(SR-Tiget) inMilan, Italy. The global incidence of WAS is estimated to be about 100-260 births per year, with a global prevalence of 2,900-4,700 patients.

About MPS-I and OTL-203Mucopolysaccharidosis type I (MPS-I) is a rare inherited neurometabolic disease caused by a deficiency of the IDUA (alpha-L-iduronidase) lysosomal enzyme required to break down glycosaminoglycans (also known as GAGs or mucopolysaccharides). The accumulation of GAGs across multiple organ systems results in the symptoms of MPS-I including neurocognitive impairment, skeletal deformity, loss of vision and hearing, hydrocephalus, and cardiovascular and pulmonary complications. MPS-I occurs at an overall estimated frequency of one in every 100,000 live births.5There are three subtypes of MPS-I; approximately 60 percent of MPS-I patients have the severe Hurler subtype and, when untreated, these patients rarely live past the age of 10.IdTreatment options for MPS-I include hematopoietic stem cell transplant and chronic enzyme replacement therapy, both of which have significant limitations. Though early intervention with enzyme replacement therapy has been shown to delay or prevent some clinical features of the condition, it has only limited efficacy on neurological symptoms. OTL-203 is anex vivo, autologous, hematopoietic stem cell-based gene therapy being studied for the treatment of MPS-I. Orchard was granted an exclusive worldwide license to intellectual property rights to research, develop, manufacture and commercialize the gene therapy program for the treatment of MPS-I developed by theSan Raffaele-Telethon Institute for Gene TherapyinMilan, Italy.

About Orchard Orchard Therapeuticsis a fully integrated commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies.

Orchards portfolio ofex vivo, autologous, hematopoietic stem cell (HSC) based gene therapies includes Strimvelis, a gammaretroviral vector-based gene therapy and the first such treatment approved by theEuropean Medicines Agencyfor severe combined immune deficiency due to adenosine deaminase deficiency (ADA-SCID). Additional programs for neurometabolic disorders, primary immune deficiencies and hemoglobinopathies are all based on lentiviral vector-based gene modification of autologous HSCs and include three advanced registrational studies for metachromatic leukodystrophy (MLD), ADA-SCID and Wiskott-Aldrich syndrome (WAS), clinical programs for X-linked chronic granulomatous disease (X-CGD), transfusion-dependent beta-thalassemia (TDT) and mucopolysaccharidosis type I (MPS-I), as well as an extensive preclinical pipeline. Strimvelis, as well as the programs in MLD, WAS and TDT were acquired by Orchard from GSK inApril 2018and originated from a pioneering collaboration between GSK and theSan Raffaele Telethon Institute for Gene TherapyinMilan, Italyinitiated in 2010.

Orchard currently has offices in the UK and the U.S., including London, San Francisco and Boston.

Forward-Looking StatementsThis press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, intends, projects, and future or similar expressions that are intended to identify forward-looking statements.Forward-looking statements include express or implied statements relating to, among other things, the therapeutic potential of Orchards product candidates, including the product candidate or candidates referred to in this release, Orchards expectations regarding the timing of regulatory submissions for approval of its product candidates, including the product candidate or candidates referred to in this release, the timing of announcement of clinical data for its product candidates and the likelihood that such data will be positive and support further clinical development and regulatory approval of these product candidates, including any cryopreserved formulations of such product candidates, and the likelihood of approval of such product candidates by the applicable regulatory authorities. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, the risks and uncertainties include, without limitation: the risk that any one or more of Orchards product candidates, including the product candidate or candidates referred to in this release, will not be successfully developed or commercialized, the risk of cessation or delay of any of Orchards ongoing or planned clinical trials, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates, the delay of any of Orchards regulatory submissions, the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates, the receipt of restricted marketing approvals, and the risk of delays in Orchards ability to commercialize its product candidates, if approved.Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards annual report on Form 20-F for the year endedDecember 31, 2018as filed with theU.S. Securities and Exchange Commission(SEC) onMarch 22, 2019, as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

1Orphanet. SCID due to ADA deficiency.2Whitmore KV, Gaspar HB. Front Immunol. 2016;7:314.3Kwan A, et al. JAMA. 2014;312:729-738.4Sauer AV, et al. Front Immunol. 2012;3:265. 5Beck et al. The Natural History of MPS I: Global Perspectives from the MPS I Registry. Genetics in Medicine 2014, 16(10), 759.


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MediaMolly CameronManager, Corporate Communications+1

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Orchard Therapeutics to Present New Registrational Data of Investigational Gene Therapies at the 61st American Society of Hematology Annual Meeting -...

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Her daughter may die by age 10, but this mom keeps fighting to cure her rare disease – GMA

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Edited Transcript of OTIC earnings conference call or presentation 5-Nov-19 9:30pm GMT – Yahoo Finance

SAN DIEGO Nov 10, 2019 (Thomson StreetEvents) -- Edited Transcript of Otonomy Inc earnings conference call or presentation Tuesday, November 5, 2019 at 9:30:00pm GMT

Otonomy, Inc. - President, CEO & Director

* Paul E. Cayer

Otonomy, Inc. - Chief Financial & Business Officer

H.C. Wainwright & Co, LLC, Research Division - MD & Senior Healthcare Analyst

* Tara A. Bancroft

Good afternoon, ladies and gentlemen, and welcome to the Q3 2019 Otonomy, Inc. Earnings Conference Call.

I would now like to turn the conference over to your host, Mr. Stephen Jasper from Westwicke Partners, please go ahead.

Good afternoon and welcome to Otonomy's Third Quarter 2019 Financial Results and Business Update Conference Call. Joining me on the call from Otonomy are Dr. David Weber, President and Chief Executive Officer; and Paul Cayer, Chief Financial and Business Officer.

Before I turn the call over to Dr. Weber, I would like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Such statements include but are not limited to timing of results, patient's recruitment and enrollment plans for and designing conduct of the Phase III clinical trial for OTIVIDEX, the Phase I/II clinical trial for OTO-313 and the Phase I/II clinical trial for OTO-413. Expectations regarding preclinical development, including but not limited to the potential benefits of activities under the collaboration agreement between AGTC and Otonomy, expectations regarding the benefits and value potential of Otonomy's programs, expectations regarding funding of clinical development program advancement and company operations into 2021 and expectations regarding financial guidance, including operating expenses for 2019 and 2020.

Please refer to Otonomy's filings with the SEC, which are available from the SEC or on the Otonomy website for information concerning the risk factors that could affect the company.

I will now turn the call over to Dave Weber, President and CEO of Otonomy.

David Allen Weber, Otonomy, Inc. - President, CEO & Director [3]

Thank you, Stephen. Good afternoon, everyone and thank you for joining us on this call to discuss Otonomy's business updates and third quarter 2019 financial results.

We made significant progress in the third quarter toward our goal of reporting results from 3 clinical trials in 2020. Most importantly, we advanced enrollment in the Phase III trial of OTIVIDEX in Mnire's disease with all participating countries actively enrolling patients. For OTO-313, we successfully completed the initial safety cohort and initiated enrollment in the exploratory efficacy cohort of the Phase I/II trial in tinnitus patients.

And finally, we received FDA clearance to initiate the Phase I/II trial of OTO-413 in patients with hearing loss, which was an important milestone for this innovative program. The successful completion of these trials is our highest priority and greatest focus. In parallel, we continue to advance multiple preclinical programs addressing important unmet needs in neurotology, including a recently announced gene therapy collaboration targeting the most common cause of congenital hearing loss. I'll provide an update on our clinical programs and an overview of this collaboration in my brief comments.

I will also highlight the financial results from the quarter and lower spending guidance for the year. It is important to note that our existing capital will fund the company through the 3 clinical catalysts next year and into 2021. I plan to keep my remarks brief, and we can then open up the call for any questions.

Beginning with the OTIVIDEX Phase III trial in Mnire's disease, we updated the timing in our earnings release today. We expect results in the third quarter of 2020, which is a slight adjustment from our original timing of data late in the first half of 2020. We are pleased with the progress we have made on enrollment of the trial and the timing reflects the care and methodical approach we've taken in site selection and patient recruitment. We have 60 sites enrolling patients across all participating countries. As a reminder, the conduct and design of this study is based on the successful AVERTS-2 trial, and we plan to enroll approximately 160 patients in the United States and Europe.

The next product candidate in our clinical development pipeline is OTO-313, a sustained exposure formulation of the NMDA receptor antagonist gacyclidine in development for the treatment of tinnitus. We have successfully completed the initial safety cohort of the Phase I/II trial and are now enrolling patients in the second cohort, which is the exploratory efficacy part of the study.

Cohort 2 will enroll approximately 50 patients with persistent tinnitus who will be assessed across a number of endpoints, including the Tinnitus Functional Index or TFI, which is a validated clinical instrument that measures tinnitus severity and its impact on patients. Importantly for entry into cohort 2, patients must have a TFI score that exceeds a specified level to ensure adequate disease severity at baseline.

Patients in cohort 2 receive a single intratympanic injection of OTO-313 or placebo, randomized 1:1 and are followed for 2 months. We expect results in the second quarter of 2020.

Our third clinical stage program is OTO-413, a sustained exposure formulation of brain-derived neurotrophic factor or BDNF that we are developing for the repair of cochlear synaptopathy. Recent research has identified damage to synaptic connections as the underlying pathology in noise and age-related hearing loss that manifests as speech-in-noise hearing difficulty. Neurotrophic factors, including BDNF have potential therapeutic effects in the cochlea by promoting the survival of spiral ganglion neurons, increasing neurite outgrowth and reconnecting neurons with cochlea hair cells after damage.

As I mentioned in my opening comments, we have recently initiated a Phase I/II clinical trial and expect to have results in the second half of 2020. This is an ascending dose safety and exploratory efficacy study that will enroll up to 40 patients with speech-in-noise hearing difficulty. Patients will receive a single intratympanic injection of OTO-413 or placebo and be followed for 3 months. A number of efficacy endpoints will be evaluated, including electrophysiological measurements of hearing function and speech-in-noise hearing test.

We are excited to be the first company conducting a clinical trial of a therapeutic for synaptopathy, which has been an active area of neurotology research during the past decade. We believe that OTO-413 will not only provide clinical benefits for the many patients with impaired hearing in a noisy environment but more generally for the large population of patients with loss of hearing function due to aging or noise exposure.

In addition to OTO-413 for synaptopathy, we have -- I have also have ongoing preclinical development for OTO-6XX, which is our hair cell regeneration program to treat patients with severe hearing loss. Cochlea hair cells play a central role in hearing by converting sound waves into electrical signals that are then transmitted to the brain via auditory nerves. It is well-established that damage to hair cells through aging, excessive noise or exposure to ototoxic chemicals leads to hearing loss. Unfortunately for humans, we cannot naturally regenerate hair cells like non-mammalian species, such as birds and chickens. However, it is possible to activate regenerative path waves via drug intervention, thereby providing an approach to treat this pathology.

We have demonstrated hair cell regeneration in a nonclinical proof-of-concept model using a class of small molecules and have identified a candidate for further development. Between our OTO-413 and OTO-6XX programs, we addressed 2 of the critical pathologies believed to underlie acquired forms of hearing loss, and with our recently announced strategic collaboration with AGTC, we extend the reach of our pipeline to now also include genetic hearing loss.

The goal of this program is to develop an AAV based gene therapy to restore hearing in patients with sensorineural hearing loss caused by mutation in the gap junction protein beta 2 gene, otherwise known as GJB2. Mutations in this gene are the most common cause of congenital hearing loss, accounting for approximately 30% of all genetic hearing loss cases. Patients born with this mutation can have severe to profound deafness in both ears as identified in screening test now performed routinely in newborns.

The collaboration leverages the expertise, technology and capabilities of each partner, allowing each of us to do what we do best. In addition, the structure is highly cost efficient by utilizing each partner's existing resources, sharing the workload and splitting the cost. We look forward to sharing more information about this program in the future.

Taken together, our clinical and preclinical programs comprise the broadest and most advanced product pipeline in the emerging field of neurotology, and we have the cash on hand to support the rich advancement. As you all know from our financial statements in the earnings release and 10-Q, we finished the third quarter with $68 million in cash and short-term investments. We continue to manage our spending levels carefully and are in fact lowering our non-GAAP operating expense guidance by $5 million for full year 2019.

We also expect as we previously stated that 2020 operating expenses will be lower than 2019 and that our current capital will fund the company's operation through the 3 clinical trial readouts and into 2021.

In summary, we have positioned Otonomy for a breakout year in 2020. The OTIVIDEX Phase III trial, OTO-313 Phase I/II trial and OTO-413 Phase I/II trial provide multiple value creation catalysts for the company, and we are laser focused on their successful completion. We look forward to bringing this message to investors through an expanded set of outreach activities beginning this quarter and continuing into 2020.

To this point, we will be attending the Piper Jaffray Health Care Conference on December 3 in New York and participating in a hearing loss panel at investor meetings at the Evercore ISI Conference in Boston on December 4.

Operator, we are now ready for questions.


Questions and Answers


Operator [1]


(Operator Instructions) Your first question comes from line of Tyler Van Buren from Piper Jaffray.


Tara A. Bancroft, Piper Jaffray Companies, Research Division - Research Analyst [2]


This is Tara on for Tyler. So in thinking ahead to the OTIVIDEX Phase III readout, can you kind of set the bar for us as far as expectations and what are meaningful changes in these patients? Should we expect a similar vertigo day benefit like we saw on AVERTS-2? And what about percent of vertigo decrease?


David Allen Weber, Otonomy, Inc. - President, CEO & Director [3]


Thank you, Tara. Yes, what you can expect is similar to what we reported for AVERTS-2 and the Phase IIb trial that's in our corporate deck. We continue to focus in the primary outcome, is on definitive vertigo days, and change in definitive vertigo days. And importantly, achieving the p value that we've discussed with the agency. We have, as you know, one successful trial with AVERTS-2. So it really is duplicating that trial to provide two separate successful Phase III trials for submission of the NDA. So the data would be consistent with what we've shown previously, the trail design is the same, the endpoints are the same, and the data that we would expect to present both to investors and to the FDA are the same as AVERTS-2.


Tara A. Bancroft, Piper Jaffray Companies, Research Division - Research Analyst [4]


Okay. Can I ask then similarly for the Phase II and 313. Can you explain more about how the TFI questionnaire will maybe inform future registration endpoints and approval? Like what specifics are you looking for regarding changes in hearing quality there?


David Allen Weber, Otonomy, Inc. - President, CEO & Director [5]


Yes, thank you. So the TFI is a validated -- considered a validated instrument. It was actually developed by a consortium of researchers and it plays out in that testing, which is represented by 25 questions that cover things like intrusiveness of the tinnitus, a sense of control that the patients have, their cognition, their ability to sleep, their auditory function and more quality of life like their emotional state is in that TFI through those 25 questions. It's established through the validation of that work of what represents generally a meaningful change is 13 points and based on the work that has been done there, and we also understand the classification of patients. So patients that typically are less than 25 on the TFI score are considered mild, whereas 25 to 50 are moderate, and higher than that are 50 and severe. Generally, physicians consider any patient that has 25 and higher to be patients in need of treatment. That will be our primary outcome because we do believe that, as I've said, a very measurable and validated instrument, we are also assessing separately other types of rating scales, such as tentative loudness and annoyance and then also a patient global impression of change, basically where we are asking the patients of how they perceive their tinnitus since the beginning of the study to understand their overall perception of change.


Tara A. Bancroft, Piper Jaffray Companies, Research Division - Research Analyst [6]


Yes, that's super helpful. If I can ask one more question about the gene therapy pipeline?


David Allen Weber, Otonomy, Inc. - President, CEO & Director [7]




Tara A. Bancroft, Piper Jaffray Companies, Research Division - Research Analyst [8]


Okay. So you mentioned in the press release regarding the AGTC collaboration that you are targeting the patients with GJB2 mutation that has been identified from the routine hearing screens in newborns. So I'm assuming your target population will include like newborns and infants with hearing loss due to that mutation, but we also know that the same genes that are responsible for homogenic deafness may also contribute to environmental hearing loss due to like drug exposure, noise and aging. So will those patient also be included in your target population for this gene therapy?


David Allen Weber, Otonomy, Inc. - President, CEO & Director [9]


No, not initially at least. This will be focused more on the pediatric population because they are the most severely threatened with hearing loss and progressive hearing loss. So typically, this can be picked up on newborn screening and patients will continue to progress from there. So it's very important to catch them at an early stage and so that will be our initial focus for the gene therapy.


Operator [10]


Your next question comes from the line of Oren Livnat from H.C. Wainwright.


Oren Gabriel Livnat, H.C. Wainwright & Co, LLC, Research Division - MD & Senior Healthcare Analyst [11]


I have a few. With the OTIVIDEX Phase III that's enrolling little bit slower than we had modeled, can you just remind us what you're doing differently in this trial maybe from AVERTS-1 such that a more deliberate enrollment speed is potentially an indicator of improved likelihood of success? And I have a couple of others.


David Allen Weber, Otonomy, Inc. - President, CEO & Director [12]


Yes, thanks Oren. I'm taking one at a time, that's fine. So great question, and that actually is the key, as we are very focused on being very careful here, and very deliberate in our enrollment. We think that its very key to the success of the trial based on our learnings from AVERTS-1. As we've discussed previously, the real learnings was around AVERTS-1 so as to control the placebo response and manage the patient expectation bias. And that was really kind of focused on 3 major areas and one of those was careful site selection. So we have gone through, obviously, now we have 60 centers enrolling across all participating countries, that took time. We needed to make sure we got it right, the right clinical centers, and right investigators, and we feel very confident in the group that we've assembled that are now all participating and enrolling. So that was the first.

From there it's really careful selection of the patients. In this case, there are no -- there is no advertising going on direct to patients, unlike with the AVERTS-1, where there were investigators who were reaching out in the general population. This is all very controlled and targeted patient enrollment and so it's very -- in that regard, it does take time and it is important that investigators are identifying these patients and carefully selecting them.

So we're not putting pressure on the investigators in terms of trying to advertise or increase the enrollment, we want to be very deliberate in that patient population. So we think that the few weeks to few months that we're talking about here in extending is just a safeguard to make sure we get -- ultimately are able to deliver a successful trial as well step.


Oren Gabriel Livnat, H.C. Wainwright & Co, LLC, Research Division - MD & Senior Healthcare Analyst [13]


All right. And just a follow-up on the tinnitus question. You mentioned that the TFI improvement of more than 13 is believed to be clinically meaningful. Is that what you're targeting? Are you expecting any statistical significance in this small study? Or are you just looking for any signal? And if so, if you do see a signal, what do you think the next steps are? Should we expect another Phase II before jumping into the more advanced?


David Allen Weber, Otonomy, Inc. - President, CEO & Director [14]


Well, let's take that one at a time there. In terms of Phase II to Phase III, but I think first of all, this is not size for power. It is the exploratory efficacy trial because it is the first of its kind. We have no prior clinical data to base sizing and powering on, it is what we consider exploratory and so we are looking for signals through these different endpoints, including the TFI. The TFI, as I mentioned, when the instrument was developed and validated by the consortium, they identified 13 point difference as being clinically meaningful, but I should point out that's in the absence of a therapeutic that really is through other types of both behavioral treatment of tinnitus and even some devices that have been tried in tinnitus. So I think it'll be up to -- as we look at the data to understand what do we see with the TFI but clearly that gives us the benchmark at least based on some prior work, even if it was in a pharmaceutical treatment. I think clearly the patient global impression of change and the other endpoints that I mentioned of loudness perception and annoyance perception are also very key to these patients given that it is the loudness and that annoyance that is the most debilitating for them in this disorder. So that's how we look at the study, and we would look to utilize the Phase I/II trial for then powering the future study. With regards to Phase II, additional Phase II, Phase III, I think that is something that we will consider based on that data.

One of the things -- so clearly with very strong signals, the opportunity is to do what I will call a larger Phase II type Phase III trial or obviously based on the data if we had confidence to go into a Phase III from there, I think one of the things that we also will want to look at, however, in addition to this patient population we are currently studying is to look at bilateral patients as well. So it's something that we're interested in because there are many patients that have bilateral tinnitus and that potentially be eligible, but that is something we want to look at probably in a separate study before including those patients.

Currently, we're focused on unilateral patients and that is because there has been concern clinically and working with our KOLs of whether patients can really tell the difference if they have bilateral, can they really talk and understand the difference in their tinnitus between one ear and the other or is there a confusion there because of both ears. And so that's why we're being very careful here using unilateral patients, but I think one of the things you can probably expect from us in future work is to also include some bilateral patients to look at the ability to detect changes in those patients as well. I'd say detect because I think that's the key. We and our KOLs all believe that showing an effect in a single ear will equate to treatment of both ears, ultimately that you'd be able to treat both ears mechanistically. It's more ability to differentiate the signaling for their patient reported outcome here. Can they report the outcome very carefully between one ear versus the other is something I think we have to look at clinically if that makes sense.


Oren Gabriel Livnat, H.C. Wainwright & Co, LLC, Research Division - MD & Senior Healthcare Analyst [15]


All right. And at the risk of abusing my time, it was lost to me that there was a recent IPO of Frequency Therapeutics and other therapeutic company working I think on hair cell regeneration, and I'm just curious, obviously you can't speak too much to what they're doing but maybe you can just highlight how similar or different your approaches are? And if you think that there will be any key learnings from what they are doing?


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Edited Transcript of OTIC earnings conference call or presentation 5-Nov-19 9:30pm GMT - Yahoo Finance

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Russs Ravings: One Slip, And Youre Toast – Westfield, NJ Patch

Editor's note: The following is Patch Field Editor Russ Crespolini's, hopefully, weekly column. It is reflective of his opinion alone.

"One slip, and you're toast."

A doctor said this to describe a test my endocrinologist said I needed to get more answers about my brain tumor.

For those of you who have been following along at home, I have been documenting in my column my ongoing medical issue that included a myriad of tests all leading to the conclusion that I have a pair of tumors. One in my brain, attached to my pituitary gland and one somewhere else in the body, most likely in my lungs.

It, or they, are causing a biochemical imbalance known as cushing syndrome or disease.

The next step for me is an inferior petrosal sinus sampling (IPSS). The IPSS is an invasive procedure in which adrenocorticotropic hormone (ACTH) levels are sampled from the veins that drain the pituitary gland. This is done through what is apparently a really painful catheterization process. So, good times. They send the probes up into the brain through the groin to grab the samples.

They then compare the ACTH levels in the peripheral blood to determine whether the pituitary tumor is causing my issues. If it is NOT the culprit and it is an incidental finding, then we begin a hunt for an ectopic (mostly benign) tumor...or a malignancy.

In the interim, I went to my primary care physician for a physical and they suggested that I get a second opinion. So I went to see a second endocrinologist who reviewed my results, and described the IPSS test to me and followed it up by telling me that the test is dangerous because one slip and I am toast.

As in dead.


He said it with no malice, he was just trying to make a point of the seriousness of what I was facing. Which I appreciate. But what he didn't appreciate was one of the things that had kept me sane over the past few weeks was the thought I was heading towards some kind of consensus and some kind of a resolution. Having that questioned left me feeling more lost and hopeless than I can remember feeling in a very long time.

Because now I was being torn between two completely different schools of thought. One was saying I needed to undergo this test, which came with risks and the other was that I just needed to keep repeating more conservatives tests every month.

In neither plan, was a path to treating my symptoms.

So I spent the weekend trying to figure out what to do next. My first endocrinologist was trying to find me a place to get the IPSS and the second doctor had me second-guessing the wisdom of that decision. And not matter how hard I tried to rationalize and explain it away, "one slip and you're toast" still kept repeating over in my internal monologue.

And then I made an accidental discovery. One of my earlier columns, a couple in fact, had been picked up by the an organization called the Pituitary Network Association. The PNA is an international non-profit organization for patients with pituitary tumors and disorders, their families, loved ones, and the physicians and health care providers who treat them.

PNA was founded in 1992 by a group of acromegalic patients in order to communicate and share their experiences and concerns. PNA has rapidly grown to become the world's largest and fastest growing patient advocacy organization devoted to the treatment and cure of pituitary disorders. This was a nice discovery because my thoughts were being shared with other people who were going through something similar. It also showed me the power of this Patch network. But I also discovered that their network included experts.

I reached out to them and immediately got a response back that walked me through why I needed to find a specialist in this area and then gave me the name of one at Sloan Kettering in New York. The next morning, my doctor messaged me to tell me she found a specialist that can help me with this test and what comes after.

It was the same name.

So now I know where I am headed next. Sure, one slip and I might be toast. But I need to trust that these specialists won't slip.

Russ Crespolini is a Field Editor for Patch Media, adjunct professor and college newspaper advisor. His columns have won awards from the National Newspaper Association and the New Jersey Press Association.

He writes them in hopes of connecting with readers and engaging with them. And because it is cheaper than therapy. He can be reached at

Russs Ravings: One Slip, And Youre Toast - Westfield, NJ Patch

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13 Unexpected Reasons Why You Might Have A Fever – HuffPost

Feeling a little heated? Its typically nothing to worry about especially if youre sick. However, other issues can cause your temperature to rise.

A normal body temp is typically around 98.6 degrees Fahrenheit (37 degrees Celsius) but can vary slightly for each individual, and even fluctuate depending on the time of day.

It can be lower in the morning and higher in the late afternoon and evening, said Michael Hall, a physician based in Miami. But when your temperature gets to 100.4 degrees Fahrenheit or higher, and lasts more than a few hours, youre getting into fever territory something that can be caused by a number of conditions.

Most of my patients understand that a fever is a common symptom of cold and flu, said Christopher Dietz, an area medical director at MedExpress Urgent Care. However, what some people might not realize is that a fever isnt always just a sign that youre coming down with something.

Heres what could also be at play, according to medical experts:

PhotoAlto/Frederic Cirou via Getty Images


If you are looking for the reason behind your elevated temperature, start here. Experts note that infections are commonly associated with a fever.

When the immune system detects a threat such as bacteria or virus, a substance known as pyrogens is released into the bloodstream to reach the hypothalamus, which regulates body temperature, said Diana Gall, a general practitioner with Doctor4U in the U.K. When the hypothalamus detects pyrogens, it raises body temperature and causes fever in an attempt to kill off bacteria and viruses.

She noted that a high fever is one of the ways your body is responding and fighting the infection but a body temperature that is too high can also be dangerous.

If the fever is persistent and isnt coming down with home remedies, you should see a doctor, particularly if the fever is accompanied by a severe headache, difficulty breathing, blood in your urine or stool, redness of the skin or rash, or vomiting, etc. The infection may be serious and your body temperature may not reduce without medical treatment, she said.

Overexerting yourself outdoors

Hot outdoor temperatures and internal heat generation from exercise and mechanical movement of the body can heat you up, said Phil Mitchell, national medical director at DispatchHealth.

Under normal circumstances, your body will function well enough to cool you down through sweating and dilation of blood vessels. But if these basic systems are overcome and you cannot cool down, your body will continue to increase in temperature.

This typically does not happen from exercise alone, but exertion in a hot environment can cause this under the right circumstances, Mitchell said. He noted that you should immediately remove yourself from the heat and try other methods to cool your body down if this is the case.

Heatstroke can occur if heat exhaustion is not treated promptly. You need immediate medical attention if you become confused, lose consciousness or if you have an elevated temperature in this situation, said Steven Reisman, a cardiologist and director of New York Cardiac Diagnostic Center.


Vaccines to prevent a bacterial or viral infection prepare your body to come in contact with that infection later, said Erik A. Larsen, assistant director of EMS and emergency preparedness at White Plains Hospital in New Yorks Westchester County.

So when you get the vaccine, your bodys immune response is stimulated and the body says, Whoa, what is this? It then mounts a fever, he said.

Larsen added that when you get a vaccine, youre not really invaded by an active infection, but it tips your body off that sometime in the future you may come across this.

tommaso79 via Getty Images

Alcohol withdrawal

Low-grade fevers can occur during the first few days of alcohol withdrawal as the central nervous system, which has been suppressed by alcohol, readjusts, said Holly Phillips, a board-certified general internist in New York and a medical expert for RxSaver.

Alcohol withdrawal also causes tremors, which can affect your heat, Larsen said.

The body is reacting to the loss of not receiving alcohol, which creates muscle contractions. This makes the body shake like a tremor, and it raises the bodys temperature, he said.

Inflammatory conditions

Certain inflammatory conditions, like rheumatoid arthritis and lupus, can cause fevers, said Lisa Alex, a physician at Medical Offices of Manhattan. This also occurs because the body is producing pyrogens, which raises your temperature. So if you have underlying inflammatory conditions and have a flare-up of any sort, the result may be a fever.

Certain medications

Many medications like antibiotics [and] antimalarials can also cause drug-induced fever. Anticonvulsants and some herbal medications can also do the trick, said Soma Mandal, a New Jersey-based physician.

You should monitor your bodys reaction when taking any new medication.

Look for a fever that starts a week after starting a new medication and goes away once you stop taking the drug, said J. David Gatz, an assistant medical director of the emergency department at the University of Maryland Medical Center.

Blood clots

Blood clots are an under-discussed source of fevers, according to Nate Favini, medical lead at preventative primary care service Forward.

If youre experiencing fever along with pain, swelling and redness in your leg or shortness of breath, that could be a sign of a blood clot, he said.


While rare, several of my patients have had fever and flu-like symptoms every month at the start of their periods, likely due to severe pelvic inflammation caused by chronic bleeding into the stomach from wide-spread endometriosis, said Kenneth Ward, director of Predictive Laboratories and a scientific advisor for Predictive Technology Group in Salt Lake City.

If you experience this, Ward suggested making an appointment with your physician to get screened for the condition. Additional symptoms can include debilitating cramps during your period or pain with sex, urination or bowel movements.

Recent surgery

If youve recently gone under the knife, especially for a chest or abdominal procedure, you may experience an elevation in temperature in the days to follow, known as postoperative fever.

The body produces inflammatory proteins in response to the trauma surgery ... This causes fever as a reaction for the first few days post-operatively, said Laurence Gerlis, CEO and lead clinician at SameDayDoctor in London.

Studies show that this is a common side effect from surgeries, with up to 90% of patients reporting elevated temperature after the fact. In most cases, this resolves on its own.

Fevers could also be a side effect to anesthesia, although thats more rare, said Erin Nance, an orthopedic surgeon and hand and upper extremity specialist in New York. This is called malignant hyperthermia.

When this happens, according to Nance, its because of your bodys response to common anesthetic agents used during surgery. This can present as a high fever, muscle rigidity and rapid heart rate. The condition can be fatal and is treated with a medication called Dantrolene and ice packs.

If you have a family history of malignant hyperthermia, it is critical to tell your anesthesiologist before proceeding with surgery, she said.


Rina Allawh, a board-certified dermatologist with Montgomery Dermatology LLC in Pennsylvania, said that certain sexually transmitted infections may cause a higher-than-normal temperature.

Initially, syphilis presents with a non-tender chancre (i.e. an ulcer). However, if left untreated, may result in high fevers, joint pain, lymph node enlargement and fatigue, he said.

Gonorrhea, if left untreated, may result in high fevers associated with a rash, Allawh said. To prevent life-threatening consequences, prompt recognition and treatment of the condition is essential, he said. Additionally, practicing safe sexual practices and sexual-transmitted disease testing is equally as important.

Traveling to another country

Depending on the area of travel, a rise in body temperature can often be attributed to tropical bacteria and protozoa not often seen in developed countries, said Amna Husain, a board certified pediatrician and founder of Pure Direct Pediatric in New Jersey.

For this reason, I recommend travelers consult with their physicians and refer to the (Centers for Disease Control) guidelines for safe food and water recommendations, she said.

laflor via Getty Images

Hormone disorders or changes

Hyperthyroidism itself does not cause a fever, but we can see a very dangerous and fatal disorder associated with a large influx of thyroid hormone into the body called a thyroid storm, which does have fever, along with rapid heartbeat, fluctuations in blood pressure, and tremors associated with it, Husain said.

She noted that thyroid storm can occur because of a major stressor such as trauma, heart attack, delivery of a baby or because of an infection in people with uncontrolled hyperthyroidism.

In rare cases, it can be caused by treatment of hyperthyroidism with radioactive iodine therapy for Graves disease, she said.

Hormonal changes that occur during menopause can also cause you to feel warmer than normal, which are typically known as hot flashes.


Keep in mind that a fever isnt necessarily the first sign or a major sign of cancer. However, it could be one of many symptoms.

Several cancers are associated with fever, which are most commonly leukemias and lymphomas, although other cancers can cause this as well, said Timothy S. Pardee, chief medical officer at Rafael Pharmaceuticals and an oncologist and director of Leukemia Translational Research at Wake Forest Baptist Health in North Carolina.

Pardee said this occurs because, in some cases, cancer cells create an inflammatory response, which then causes the body to respond with a fever. In other cases, the cancer cells themselves secrete cytokines or substances in the body that can cause a fever. And, according to Pardee, cancers like leukemia can impair your bodys ability to fight off infections resulting in prolonged illnesses and fevers.

Additional symptoms to look for are unintended weight loss and drenching night sweats (where you have to change your shirt or sheets when you wake up). These symptoms should prompt a call to your doctor for further evaluation, he added.

When you should be concerned about a fever

A fever may not be cause for alarm, unless there are some specific situations, said David Cutler, a family medicine physician at Providence Saint Johns Health Center in Santa Monica, California.

He added that medication to reduce fever when there is an infection like a cold, flu or pneumonia can help minimize bothersome symptoms like headache, body aches and dehydration from excessive sweating.

But if the fever is caused by hormonal effects, such as menopausal hot flashes or muscular activity like strenuous exercise, these medications will not be effective. In these instances, Cutler said to use measures like cooling fans to lower the bodys temperature.

According to Amesh A. Adalja, senior scholar at Johns Hopkins Center for Health Security in Maryland, a person should be concerned for fever above 101 degrees Fahrenheit (38.3 degrees Celsius) when it is unremitting, when it is associated with other symptoms such as dehydration, extreme fatigue, shortness of breath and severe rash.

Additionally, someone suffering who has a compromised immune system should have a low threshold for seeking medical attention. Same goes for those who are pregnant, have heart or lung disease, or who are very young, he said.

That said, if youre ever concerned about a fever, its always worth it to call your doctor. Thats what theyre there for, after all.

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13 Unexpected Reasons Why You Might Have A Fever - HuffPost

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Nutrition Break: Take diabetes to heart | Advice – Grand Island Independent

November is National Diabetes Month.

Diabetes is a serious condition that happens when your body cannot make enough of a hormone called insulin or cannot properly use the insulin it has. Insulin helps your body digest sugars that come from what you eat and drink. Without enough insulin, sugar builds up in your blood. Over time, having too much sugar or glucose in your blood can cause health problems.

More than 30.3 million Americans have diabetes, or about 9.4 percent of the population. About 1 in 4 people with diabetes do not know they have the disease. Another 84.1 million have pre-diabetes, a condition in which a persons blood sugar is high, but not high enough to trigger diabetes.

According to the National Heart, Lung and Blood Institute, adults with diabetes are nearly twice as likely to die from heart disease or stroke as people without diabetes. This is because over time, high blood glucose from diabetes can damage your blood vessels and the nerves that control your heart. The good news is that steps taken to manage diabetes can also help lower the risk of having heart disease or a stroke.

Manage your A1C, blood pressure and cholesterol levels. Ask your health care team what your goals should be.

Develop or maintain healthy lifestyle habits. Follow a healthy eating plan and make physical activity part of your routine. To reduce stress, try gardening, taking a walk or listening to favorite music.

Stop smoking or using other tobacco products. If you have diabetes and use tobacco, your risk of heart problems is even greater. Both tobacco use and diabetes narrow blood vessels, so your heart has to work harder.

Take medicine as directed. It is important that those with diabetes take any medicine as prescribed by a physician. Talk with your doctor if you have questions about your medicines and do not stop taking them without checking with your doctor first.

Skillet Zucchini and Mushrooms

In a large skillet, heat oil. Saut green pepper and onion. Add zucchini and cook, covered until tender. Add mushrooms and heat through.

Spoon into a 2-quart baking dish. Sprinkle with cheese. Cover and let stand for 5 minutes or until cheese is melted. Serve hot.

Makes 6 servings.

Nutrition information per serving: 70 calories, 4g fat, 60 mg sodium, 5 g carbohydrates 1 g fiber.

Cami Wells is an Extension Educator for Nebraska Extension in Hall County. Contact her at (308) 385-5088 or at Visit the Hall County website at

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Nutrition Break: Take diabetes to heart | Advice - Grand Island Independent

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Households are awash in ‘forever chemicals’ – Press Herald

AUGUSTA As Maine compiles thousands of test results for soil and water contamination from an emerging class of toxic substances, consumers need look no further than their own homes for the most immediate and persistent exposure to these forever chemicals.

You wont find them listed on many labels, but the chemicals known as PFAS are literally everywhere in the modern household.

From the moment that we wake up in the morning to the moment we go to bed, we are encountering products that contain these chemicals, said Mike Schade, who tracks PFAS and other chemicals in consumer products for the nonprofit Safer Chemicals, Healthy Families Mind the Store campaign.

They are in cosmetics, shampoos and dental floss. Grabbing pizza, a burger or hot-and-ready dinner from a grocery store? Your food may come with a side order of PFAS-laced packaging.

From the Gore-Tex jacket or boots that keep you cozy in winter, to the stain-resistant couches and nonstick cookware that make life less messy, many of the modern products so common in American households are made with a diverse class of chemical now at the center of a growing health concern.

Studies have linked two specific types of the chemical PFOA and PFOS to cancer, kidney disease and other serious aliments. But while the chemical industry says newer varieties are safer, medical and public health experts say the developing science strongly suggests otherwise.

These are serious concerns about human health across the population, said Dr. Leonardo Trasande, director of New York University School of Medicines environmental pediatrics program and author of the book Sicker Fatter Poorer on hormone-disrupting chemicals. The reality is we always have gaps in our understanding, but at the same time there is enough data for us to take action.


The term PFAS refers generally to a broad category of synthetic chemicals, per- and polyfluoroalkyl substances, the first of which were developed in the 1940s by companies such as Dupont and 3M.

The chemicals helped usher in a new era of consumer convenience, perhaps best illustrated by the revolutionary nonstick cookware coated by Teflon. Dubbed the slickest substance known to man, the key chemical component in Teflon, polytetrafluoroethylene or PTFE, and another chemical PFOA work by essentially preventing water and water-based substances from penetrating.

Those hydrophobic qualities have made the two chemicals and thousands of subsequent varieties extremely popular with manufacturers. In addition to creating nonstick surfaces on frying pans, types of PFAS make ski jackets water-repellent, help prevent spilled wine from immediately staining carpet or upholstery, and keep fast food wrappers or takeout containers from becoming soggy, greasy messes before you can finish the food.

But their function goes beyond consumer convenience. These chemicals also serve lifesaving roles.

A type of PFAS is the critical ingredient in the foam that airport and military firefighters use and are required by the Federal Aviation Administration to keep in supply to smother the ferociously hot fires created by burning jet fuel. Dozens of municipal fire departments in Maine as well as petroleum companies also keep PFAS foam on hand.

Fluoropolymers that are part of the PFAS family are also commonly used in lifesaving medical devices such as stents and pacemakers as well as some brands of dental floss.


The complex and hardy chemical compounds that make PFAS so useful in consumer products also mean, however, that the chemicals do not easily break down in the environment or the body. Some compounds are believed to linger for decades centuries, even in soils and take years to exit the body after exposure, hence the nickname forever chemicals.

Concerns over the health effects of PFOA began surfacing in the 1980s among workers at a DuPont factory in West Virginia that produced Teflon products. But the company kept quiet about the growing evidence of PFOAs toxicity even after workers began being diagnosed with higher rates of leukemia and kidney cancer, as well as birth defects among the children of female workers.

Then in 1998, a neighboring farmer whose livestock were mysteriously dying sued the company in a landmark environmental lawsuit that showed DuPont knew for years about the health risks of the chemical. The farmer won that lawsuit, and a subsequent class-action case targeted the company for contaminating local drinking water.

Both PFOA and another toxic chemical cousin, PFOS, are no longer allowed to be manufactured in the U.S., Europe or Japan or used in products made here, although the compounds are still reportedly used in some foreign manufacturing.

The primary manufacturers of PFAS in the U.S. 3M, DuPont and its spinoff, Chemours are also facing dozens of lawsuits filed by plaintiffs claiming the chemicals have caused cancer or other health problems.


Chemical companies have since switched to differently structured forms of PFAS (chemically speaking, six-chain compounds versus the eight-chain versions in PFOS and PFOA) that manufacturers say break down faster and avoid the toxicity problems of their predecessors.

The body of evidence reviewed shows they are not carcinogenic, they do not have developmental or reproductive concerns, the toxicity is much approved over the toxicity of PFOA and PFOS that weve spent a lot of time talking about, Renee Lani of FluoroCouncil told members of Maines PFAS task force in September. The dont bioaccumulate and an evidence analysis that was just published last year demonstrates that they are not an endocrine disruptor.

Environmental health groups and medical professionals strongly dispute industry claims that the next-generation, short-chain PFAS compounds are less problematic. And they point to the widespread development and use of new PFAS varieties as evidence of a federal regulatory system that they say is ill-equipped to keep up with industry and failing to protect public health.

This is chemical whack-a-mole in action, said Trasande, who is vice chairman for research in the NYU School of Medicines Pediatric Department. Just because the chemical has a short half-life, that helps if the exposure is a single point in time. But these are ongoing chemicals with consistent, ongoing exposure.

Trasande, who specializes in endocrine-disrupting chemicals in children, said evidence suggests that the newer, shorter-chain PFAS compounds stay in the body long enough to have health impacts. Laboratory animal studies have shown potential liver and kidney toxicity from some of the newer generation of compounds.

And he said there are serious gaps in our knowledge and toxicology in figuring out how PFAS interact with the hundreds of hormones in the body, particularly among children and adolescents.

There is what we know and what we havent studied, Trasande told Maine lawmakers in March during an appearance before the Legislatures Environment and Natural Resources Committee.

Industry representatives have urged Maine lawmakers as well as members of Congress not to group-label all PFAS as potentially hazardous substances. Companies that make PFAS say the newer, most common types of chemicals are safer and less forever than the now-banned versions definitely linked to cancer, kidney disease and other ailments.

My fear is that an overgeneralization is leading to a lot of misinformation, a lot of fear and a lot of confusion over a chemistry that is not even being used anymore, Brady Pitts, an application chemist for PFAS manufacturer Daikin America, told Maine lawmakers at the same March hearing.

And then there is the potential health threat posed by contamination from the legacy, now-banned versions.

Dr. Abby Fleisch, an attending physician in pediatric endocrinology and diabetes at Maine Medical Center, recently received a five-year, $2.2 million federal grant to study whether childhood or pre-birth exposure to PFAS can contribute to development of diabetes or lower bone densities.

Fleisch and her team is still in the earlier stages of that research, but initial findings suggest that children between the ages of 6 and 10 who had higher PFAS levels in the blood also had lower bone density. That is important because adolescence is peak bone-formation time, and low bone mineral density during teenage years may predispose those individuals to osteoporosis later in life, Fleisch said.

The research team also plans to follow up on earlier work examining the same group of women and children that suggested girls exposed to higher PFAS levels in utero could be predisposed to childhood obesity.

Research suggests that PFAS exposure may impact multiple health outcomes, Fleisch said in an interview. However, we dont have all of the answers and I believe it is important to continue exploring these fields.


Theres been a flurry of activity at the state and federal level in recent years, spurred initially by the discovery of PFAS hotspots around military bases.

In Maine, high levels of PFAS have been found at the former Brunswick Naval Air Station, former Loring Air Force Base and around the Maine Air National Guard base at Bangor International Airport. But the chemicals have also turned up on an Arundel dairy farm, at former tanneries, near landfills and other industrial sites in Maine.

Congress and the federal government are exploring a variety of actions, ranging from adopting tighter health standards for contamination to adding PFAS to the list of chemicals eligible for federal cleanup under the Superfund program. There is also an effort to add at least some forms of PFAS to the list of chemicals that companies are required to report emitting or discharging under the federal Toxics Release Inventory.

Maines PFAS task force is expected to recommend a host of legislative or administrative actions. Those potential actions include expanded statewide tests for contamination, required reporting whenever a fire department uses PFAS-laden foam and mandatory screening for PFAS among all public water systems.

The Maine Department of Environmental Protection, meanwhile, is seeking legislative authority to order companies to clean up PFAS-contaminated sites, something it currently lacks because the federal government doesnt list PFAS as a hazardous material.

Maine is among the handful of states including Washington, Massachusetts, New Hampshire and Michigan that are leading the regulatory charge on PFAS. For instance, Maine lawmakers passed the nations first phase-out of PFAS in food packaging earlier this year, although the law only takes effect when safer alternatives are available.

We dont anticipate a lot of progress in Washington regulating PFAS in food packaging so it is really up to the states to step up, said Schade, of the Safer Chemicals, Healthy Families nonprofit.


Schade is also a firm believer in the power of the consumer. And he says recent decisions by retailers to act on PFAS before the federal government is proof of that power.

Through its Mind the Store campaign, Safer Chemicals, Healthy Families, and like-minded organizations nationwide have tested consumer products and food packaging for the presence of PFAS. They then used those results to attempt to pressure manufacturers or retailers to remove PFAS from products.

For instance, a 2018 report from Mind the Store and the group Toxic-Free Future showed likely PFAS ingredients in many store-brand products and packaging from the major grocery store chains Ahold Delhaize, Whole Foods, Albertsons and Kroger.

Immediately after the report, Whole Foods announced plans to stop using takeout food packaging that contains PFAS. And in September of this year, the owner of Hannaford and Stop & Shop supermarket chains, Ahold Delhaize, announced that it plans to begin removing PFAS from packaging for grocery items, baby products and personal care products.

Both the Lowes and Home Depot home improvement chains also recently announced that they would stop selling carpeting and rugs that contain PFAS. And two weeks ago, Staples announced that it would work with suppliers to begin transitioning to safer alternatives to PFAS and other chemicals in products.

Additionally, the maker of the water-repellent fabric Gore-Tex has committed to eliminate PFAS varieties of environmental concern from 85 percent of its consumer products by the end of next year and from the remaining products by 2023.

So this is really a growing sustainability trend among major retailers and businesses, Schade said. At the same time, we have seen leadership from states such as Maine and Washington in recent years.


According to the Agency for Toxic Substances and Disease Registry within the U.S. Centers for Disease Control and Prevention, exposure to PFOA and PFOS from todays consumer products is usually low, especially when compared to exposures to contaminated drinking water.

But PFAS awareness advocates say there are steps that consumers can take to educate and potentially protect themselves from exposure. They include:

Organizations such the Environmental Working Group, Safer Chemicals, Healthy Families and Toxic-Free Future recommend avoiding nonstick cookware altogether. Thats because even newer versions marketed as PFOA-free could contain the shorter-chain chemical cousins that they maintain have not been proved safe.

Many of those organizations recommend using cast-iron or stainless steel. But advice to consumers on such topics as nonstick cookware can be contradictory and confusing.

In a 2016 fact sheet on PFOA, the American Cancer Society stated: Other than the possible risk of flu-like symptoms from breathing in fumes from an overheated Teflon-coated pan, there are no known risks to humans from using Teflon-coated cookware. While PFOA is used in making Teflon, it is not present (or is present in extremely small amounts) in Teflon-coated products.

Finding out whether a product was made with PFAS is difficult. But Schade with the Mind the Store campaign said consumers should ask manufacturers or retailers such questions, in part to educate themselves and in part to send a message to businesses.

Consumers really need to be savvy and aware, but at the same time none of us should need to have a Ph.D. in chemistry, which is why we need governments to act, he said.

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Ohio Senate bills will ‘give more babies a second chance,’ say supporters – The Dialog

COLUMBUS, Ohio The Ohio Senate Nov. 6 passed a bill that would require a child born alive following an abortion receives the same medical care accorded any newborn at the same gestational age.

A second measure OKd the same day would mandate that abortion facilities inform women that chemical abortions can possibly be reversed to save their unborn childs life.

The Born-Alive Infant Protection Act, or S.B. 208, passed with a 24-9 vote, and the Abortion Pill Reversal Act, or S.B. 155, passed with a 23-10 vote.

Called life-affirming by the Catholic Conference of Ohio, the public policy arm of the states Catholic bishops, the two bills will now be taken up by the Ohio House of Representatives. The conference commended the bills sponsors, Republican Sens. Terry Johnson and Peggy Lehner, respectively. Lehner also was a co-sponsor of the Born-Alive bill.

This legislation acknowledges, promotes and preserves the dignity of human life, Johnson said in a statement. Every new born infant deserves our compassion and care, no matter where we stand in the broader abortion debate.

In addition to the medical care provisions, this legislation creates reporting requirements and penalties for the attending physician who fails to report a born-alive baby. While individual cases will remain confidential, the Ohios Department of Health will publish annually the number of babies who survive abortions.

Current federal law recognizes that all infants born at any stage of development, regardless of the circumstances surrounding the birth, are persons. However, supporters of this legislation believe this recognition alone is insufficient to provide protections for infants born alive following an attempted abortion, said a news release from Johnsons office.

The Born-Alive Infant Protection Act is a vital protection of defenseless babies that survive failed abortions, said a statement from Stephanie Ranade Krider, vice president of Ohio Right to Life. This bill would stand ready to protect these helpless infants and require they are given proper medical attention at their most critical moment.

She added, These babies deserve protection under law like infants born under any other circumstance.

Regarding S.B. 155, Lehner said in a statement: Women who decide to take their babies to term should be celebrated and supported. This bill simply gives women more information about the option for a second chance to make an extremely emotional and difficult decision.

The bill would require doctors prescribing abortion-inducing drugs to also provide written information informing the patient of the possibility of reversing the effects of an abortion in the event she changes her mind within the first two days.

According to a news release from Lehners office, the Mifeprex chemical abortion procedure is a two-day regimen used to terminate early pregnancies by blocking the hormone progesterone needed to sustain pregnancy. A second drug, Misoprostol, stimulates uterine contraction to expel the dead baby.

Women who choose a chemical abortion and regret it within the first two days of taking the first drug have a chance to save their baby, as long as they have not taken the second drug, it said.

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Ohio Senate bills will 'give more babies a second chance,' say supporters - The Dialog

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Transient Wave of Hematopoietic Stem Cell Production in Late Fetuses and Young Adults – Technology Networks

Hematopoietic stem cells (HSCs) are responsible for the constant replenishment of all blood cells throughout life. One of the major challenges in regenerative medicine is to produce tailor-made HSCs to replace the defective ones in patients suffering from blood related diseases. This would circumvent the shortage of donor HSCs available for the clinic. To achieve the controlled production of bona fide HSCs in vitro, in a dish, a better understanding is required of where, when and how HSCs are physiologically produced in vivo, in the living body. Researchers from the groups of Catherine Robin(Hubrecht Institute) and Thierry Jaffredo (UPMC, LBD IBPS, Paris) have found a previously unappreciated hematopoietic wave taking place in the bone marrow of late fetuses and young adults and producing HSCs from resident hemogenic endothelial cells of somite origin. This transient hematopoietic wave fills the gap between the completion of embryonic blood production and the beginning of adult bone marrow hematopoietic production in both chicken and mice.

Endothelial origin of hematopoietic stem cells

The constant production of short-lived blood cells, needed for proper oxygenation of tissues and protection against pathogens throughout life, relies on a small cohort of HSCs. The first HSCs derive from specialized endothelial cells, named hemogenic endothelial (HE) cells, via an endothelial to hematopoietic transition (EHT). EHT transiently occurs in the main arteries, such as the aorta, during the embryonic development of vertebrates. The pool of HSCs is then amplified before migrating to the bone marrow where HSCs will reside during adult life. Whether EHT occurs past the embryonic stage and in other organs, such as the bone marrow, was unknown until now.

Hemogenic endothelial cells in the bone marrow

To find out whether EHT occurs past the embryonic stage and in the bone marrow, the researchers used a combination of experimental embryology, genetic, transcriptomic and functional approaches on chicken and mouse models. By tracing bone marrow-forming endothelial cells through fluorescent genetic labelling and live imaging analyses, they found that the entire vascular network of the bone marrow derives from the somites. The somites are segments of the body that will progressively form important tissues of the organism as the embryo develops, including bones, muscles and skin. Unexpectedly, the researchers found that some somite-derived endothelial cells produce HSCs and multipotent progenitors in the late fetus and young adult bone marrow, through the same EHT process that was thus far only seen in the embryo. These cells are molecularly very similar to the cells undergoing EHT or recently emerged HSCs in the embryonic aorta, with a prominent Notch pathway, endothelial-specific genes and transcription factors involved in EHT. The results therefore demonstrate that HSCs are newly generated past embryonic stages, from hemogenic endothelial cells from somitic origin and via EHT, the same mechanism that occurs in the embryo.

A new wave of blood cell production

The yolk sac of the embryo produces two partially overlapping waves of hematopoiesis. The first (primitive) wave gives rise to hematopoietic cells that last only during embryonic development. The second (definitive) wave produces various progenitors that migrate to the fetal liver to produce the immediately needed blood cells. These progenitors are sufficient for the embryo to survive until birth, when the aorta-derived HSC-dependent wave will take over. The transient hematopoietic production discovered in the present study fills the gap between the end of the yolk sac hematopoiesis and the bone marrow HSC-dependent production of blood cells. Indeed, the pool of HSCs that expanded in the fetal liver starts to colonize the bone marrow only just before birth. HSCs are present in very low numbers and time is most likely required before they find their final adult-type niches and start to differentiate and proliferate into more committed progenitors and mature blood cells. The transient hematopoietic wave that the researchers describe in late fetal and young adult stages might also prepare the bone marrow niches for the HSCs coming from the fetal liver.

Stem cell therapies

Defects in HSCs lead to various blood-related disorders and cancers that are partly treated by HSC transplantations. The controlled production of bona fide HSCs from pluripotent precursors remains very difficult to achieve in vitro, in a petri dish, and therefore requires a better understanding of the HSC production as it occurs physiologically in vivo, in the living body. Identifying all steps of hematopoietic production and the molecular events controlling this process is of fundamental interest and should help to devise innovative stem cell therapies for hematopoietic disorders in the future.

Reference:Yvernogeau, L., Gautier, R., Petit, L., Khoury, H., Relaix, F., Ribes, V., Jaffredo, T. (2019). In vivo generation of haematopoietic stem/progenitor cells from bone marrow-derived haemogenic endothelium. Nature Cell Biology.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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An artist and a transplant researcher discuss the heart – Harvard Gazette

Doris A. Taylors so-called replacement ghost heart suggests something otherworldly, but the eerie-looking form is far from an apparition. Its an innovative approach to organ transplantation that has inspired many in the medical community and at least one artist.

The Texas researchers process piggybacks on natures sophisticated design. Together she and a team of researchers strip cells off human and animal cadaver hearts with a soapy solution, leaving ghostly white protein shells that retain the form of the organ. They inject them with a patients blood or bone-marrow stem cells, and the ghost hearts act as scaffolding on which the newly introduced cells can slowly transform into a beating muscle.

What we said was, Wouldnt it be really cool if we could wash the sick cells out and put the healthy cells back in? said Taylor, director of Regenerative Medicine Research and director of the Center for Cell and Organ Biotechnology at the Texas Heart Institute, during a recent talk at the Radcliffe Institute for Advanced Study.

The hope is that one day these regenerated hearts will resolve the most challenging issues transplant patients currently face: the lack of a permanent artificial replacement, concerns about rejection, and the shortage of viable donor hearts.

Taylors efforts are driving what could become a revolution in organ transplants, and they have sparked the creativity of transdisciplinary artist Dario Robleto, whose latest work, on view at the Johnson-Kulukundis Family Gallery in Radcliffes Byerly Hall, recreates in images and sounds the original pulse wave of the heart first captured in visual form by scientists in the 1900s. Robleto and Taylor, longtime friends and Texas residents, explored those connections during Mondays Radcliffe discussion, which was moderated by Jennifer Roberts, Elizabeth Cary Agassiz Professor of the Humanities.

Robletos exhibit, Unknown and Solitary Seas, touches on the overlap between the medical mysteries and workings of the vascular pump, and the metaphor for the heart as the emotional center of the soul. It includes a video installation that features recreated sounds of a beating heart from the 19th century, reconstructed images of how the earliest pulse waves first appeared on the page, and a series of heart waveform sculptures in brass-plated stainless steel.

Roberts said that with his work, Robleto acknowledges the pulse waves promise, their profundity, their scientific value, but he also reclaims some of their ambiguity and asks us to wonder whether we can or should accept that these waveforms have escaped the realms of art, culture, and emotional communication.

Taylor similarly views her work as a blend of the scientific and the human. It transcends complicated, complex science, she says, in that her ghost hearts require a kind of passion, commitment, care, attention, and nurturing similar to whats required by a small child. Its really about building hearts at the emotional, mental, spiritual, and physical level that I think is going to get them to work, she said.

For Robleto, big ideas, like the creation of a new human heart, require multiple perspectives.

The artist called Taylors work one of the most fascinating and definitely one of the most emotional things Ive ever seen. As an object, he added, the ghost heart is stunningly beautiful but it also raises questions about the self, identity, emotion, the notions of form and where memory is truly held, questions he thinks artists can help address. He cited two of the nations earliest heart transplants, after which the patients wives asked their husbands, who had received donor hearts, if they still loved them.

Taylors work, Robleto said, is right at the edge of identity and materiality and so when the day comes when someone says the first ghost heart transplant I think we will have a similar moment where perhaps we will be forced to re-evaluate what we ask from our heart metaphor.

Dario Robletos Unknown and Solitary Seas is on view in Byerly Halls Johnson-Kulukundis Family Gallery through Jan. 18, 2020.

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Exercise found to block chronic inflammation in mice – Harvard Gazette

Scientists at Harvard-affiliated Massachusetts General Hospital (MGH) have identified a previously unknown biological pathway that promotes chronic inflammation and may help explain why sedentary people have an increased risk for heart disease and strokes.

In a study to be published in the November issue ofNature Medicine, MGH scientists and colleagues at several other institutions found that regular exercise blocks this pathway. This discovery could aid the development of new therapies to prevent cardiovascular disease.

Regular exercise protects the cardiovascular system by reducing risk factors such as cholesterol and blood pressure. But we believe there are certain risk factors for cardiovascular disease that are not fully understood, said Matthias Nahrendorf of the Center for Systems Biology at MGH. In particular, Nahrendorf and his team wanted to better understand the role of chronic inflammation, which contributes to the formation of artery-clogging blockages called plaques.

Nahrendorf and colleagues examined how physical activity affects the activity of bone marrow, specifically hematopoietic stem and progenitor cells (HSPCs). HSPCs can turn into any type of blood cell, including white blood cells called leukocytes, which promote inflammation. The body needs leukocytes to defend against infection and remove foreign bodies.

When these [white blood] cells become overzealous, they start inflammation in places where they shouldnt, including the walls of arteries.

Matthias Nahrendorf

But when these cells become overzealous, they start inflammation in places where they shouldnt, including the walls of arteries, said Nahrendorf.

Nahrendorf and his colleagues studied a group of laboratory mice that were housed in cages with treadmills. Some of the mice ran as much as six miles a night on the spinning wheels. Mice in a second group were housed in cages without treadmills. After six weeks, the running mice had significantly reduced HSPC activity and lower levels of inflammatory leukocytes than the mice that simply sat around their cages all day.

Nahrendorf explains that exercising caused the mice to produce less leptin, a hormone made by fat tissue that helps control appetite, but also signaled HSPCs to become more active and increase production of leukocytes. In two large studies, the team detected high levels of leptin and leukocytes in sedentary humans who have cardiovascular disease linked to chronic inflammation.

This study identifies a new molecular connection between exercise and inflammation that takes place in the bone marrow and highlights a previously unappreciated role of leptin in exercise-mediated cardiovascular protection, said Michelle Olive, program officer at the National Heart, Lung, and Blood Institute Division of Cardiovascular Sciences. This work adds a new piece to the puzzle of how sedentary lifestyles affect cardiovascular health and underscores the importance of following physical-activity guidelines.

Reassuringly, the study found that lowering leukocyte levels by exercising didnt make the running mice vulnerable to infection. This study underscores the importance of regular physical activity, but further focus on how exercise dampens inflammation could lead to novel strategies for preventing heart attacks and strokes. We hope this research will give rise to new therapeutics that approach cardiovascular disease from a completely new angle, said Nahrendorf.

The primary authors of theNature Medicinepaper are Nahrendorf, who is also a professor of radiology at Harvard Medical School; Vanessa Frodermann, a former postdoctoral fellow at MGH who is now a senior scientist at Novo Nordisk; David Rohde, a research fellow in the Department of Radiology at MGH; and Filip K. Swirski, an investigator in the Department of Radiology at MGH.

The work was funded bygrantsHL142494 andHL139598from the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

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‘I’ve become best friends with the woman who saved my life’ –

When Nicky Turkoz (aboveleft) was diagnosed with leukaemia, her only hope was an anonymous stem-cell donation. That donor was Annette Hamson (above right) and the two, once strangers, now share an unbreakable bond

I was wrestling the Christmas decorations down from the loft when I got the call. I can remember hearing the landline ring and telling my daughter, Meltem, who was steadying the ladder, to leave it. They can call back if its urgent, I said. My mobile rang and we left that too, but the landline went again. I better get it, Mum, said Meltem. Someone clearly wants to talk to you. She answered it as I was hauling the last of the decorations down. Its the surgery, she said, passing the phone to me.

That morning Id had a blood test. Id been feeling strange for months and had finally made an appointment to see the GP. I told her I was feeling lethargic and depressed, which was very unlike me, but Id put it down to ageing and a spot of empty-nest syndrome, as my youngest daughter Zeynep had just left home to work abroad. Odd things, such as a recurring gum infection, were making me wonder if something else was going on. My GP seemed unconcerned but sent me for blood tests anyway. A few hours later she was telling me to pack an overnight bag and get to hospital. Your results show youre very anaemic, she said. Theyll need to do some more tests. You might be there a while.

She never used the word cancer. Looking back, I think she knew then but was sugar- coating it for me. We left the decorations.

Three hours later, after more prodding and poking, a consultant told me I had acute myeloid leukaemia, a blood cancer. It seems unbelievable now but I can remember thinking, Well, thank goodness theyve found something wrong with me, I knew I wasnt feeling great. I had no idea, of course, what was coming down the track.

It was a Wednesday evening and I was told they would start my chemotherapy on the Friday, but Id need to stay in hospital in the meantime. So while I was being installed on a ward, my poor daughter was handed a leaflet about myeloid leukaemia and drove home to our undecorated tree.

The first round of chemo lasted 10 days, which meant I had to miss Meltems 23rd birthday on 21 December. Zeynep left Gran Canaria, where she had just started working as a holiday rep, and flew home to be with us. It has always been just the three of us, ever since they were tiny. Im a very can-do sort of person and have always just got on with life whatever it has thrown at us. I couldnt bear it when my girls suddenly had to look after me. It all just seemed so unfair. I suppose everyone feels like that though.

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'I've become best friends with the woman who saved my life' -

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Behind the Scenes of a Radical New Cancer Cure – Scientific American

An unexpected early morning phone call from the hospital is never good news. When Joy Johnson answered, her first thought was that Sharon Birzer, her partner of 15 years, was dead. Her fears were amplified by the voice on the other end refusing to confirm or deny it. Just come in and talk to one of the doctors, she remembers the voice saying.

Johnson knew this was a real possibility. A few weeks earlier, she and Birzer sat in the exam room of a lymphoma specialist at Stanford University. Birzers cancer had grown, and fast first during one type of chemotherapy, then through a second. Out of standard options, Birzers local oncologist had referred her for a novel treatment called chimeric antigen receptor T-cell therapy or CAR-T. Birzer and Johnson knew the treatment was risky. They were warned there was a chance of death. There was also a chance of serious complications such as multi-organ failure and neurological impairment. But it was like warning a drowning person that her lifeboat could have problems. Without treatment, the chance of Birzers death was all but certain. She signed the consent form.

Johnson hung up the phone that early morning and sped to the hospital. She met with a doctor and two chaplains in a windowless room in the cancer ward, where happy photos of cancer alumni smiled down from the walls. This is getting worse and worse, Johnson thought. As she remembers it, the doctor went through the timeline of what happened for 10 minutes, explaining how Birzer became sicker and sicker, before Johnson interrupted with the thought splitting her world in two: I need you to tell me whether shes alive or dead.

Birzer wasnt dead. But she was far from okay. The ordeal began with Birzer speaking gibberish. Then came seizures so severe there was concern she wouldnt be able to breathe on her own. When it took a few different medications to stop Birzer from seizing, her doctors sedated her, put a breathing tube down her throat, and connected her to a ventilator. Now, she was unconscious and in the intensive care unit (ICU).

Birzer was one of the early patients to receive CAR-T, a radical new therapy to treat cancer. It involved removing Birzers own blood, filtering for immune cells called T-cells, and genetically engineering those cells to recognize and attack her lymphoma. CAR-T made history in 2017 as the first FDA-approved gene therapy to treat any disease. After three to six months of follow-up, the trials that led to approval showed response rates of 80 percent and above in aggressive leukemias and lymphomas that had resisted chemotherapy. Patients on the brink of death were coming back to life.

This is something I often dream of seeing but rarely do. As a doctor who treats cancer, I think a lot about how to frame new treatments to my patients. I never want to give false hope. But the uncertainty inherent to my field also cautions me against closing the door on optimism prematurely. We take it as a point of pride that no field of medicine evolves as rapidly as cancer the FDA approves dozens of new treatments a year. One of my biggest challenges is staying up to date on every development and teasing apart what should and shouldnt change my practice. I am often a mediator for my patients, tempering theoretical promises with everyday realism. To accept a research finding into medical practice, I prefer slow steps showing me proof of concept, safety, and efficacy.

CAR-T, nearly three decades in the making, systemically cleared these hurdles. Not only did the product work, its approach was also unique among cancer treatments. Unlike our usual advances, this wasnt a matter of prescribing an old drug for a new disease or remixing known medications. CAR-T isnt even a drug. This is a one-time infusion giving a person a better version of her own immune system. When the FDA approved its use, it wasnt a question of whether my hospital would be involved, but how we could stay ahead. We werent alone.

Today, two FDA-approved CAR-T products called Kymriah and Yescarta are available in more than 100 hospitals collectively across the U.S. Hundreds of clinical trials are tinkering with dosages, patient populations, and types of cancer. Some medical centers are manufacturing the cells on-site.

The FDA approved CAR-T with a drug safety program called a Risk Evaluation and Mitigation Strategy (REMS). As I cared for these patients, I quickly realized the FDAs concerns. Of the 10 or so patients Ive treated, more than half developed strange neurologic side effects ranging from headaches to difficulty speaking to seizures to falling unconscious. We scrambled to learn how to manage the side effects in real time.

Johnson and Birzer, who I didnt treat personally but spoke to at length for this essay, understood this better than most. Both had worked in quality control for a blood bank and were medically savvier than the average patient. They accepted a medical system with a learning curve. They were fine with hearing I dont know. Signing up for a trailblazing treatment meant going along for the ride. Twists and bumps were par for the course.

Cancer, by definition, means something has gone very wrong within a cell has malfunctioned and multiplied. The philosophy for fighting cancer has been, for the most part, creating and bringing in treatments from outside the body. Thats how we got to the most common modern approaches: Chemotherapy (administering drugs to kill cancer),radiation(using high energy beams to kill cancer), and surgery (cutting cancer out with a scalpel and other tools). Next came the genetics revolution, with a focus on creating drugs that target a precise genetic mutation separating a cancer cell from a normal one. But cancers are genetically complex, with legions of mutations and the talent to develop new ones. Its rare to have that one magic bullet.

Over the last decade or so, our approach shifted. Instead of fighting cancer from the outside, we are increasingly turning in. The human body is already marvelously equipped to recognize and attack invaders, from the common cold to food poisoning, even if the invaders are ones the body has never seen before. Cancer doesnt belong either. But since cancer cells come from normal ones, theyve developed clever camouflages to trick and evade the immune system. The 2018 Nobel Prize in Physiology or Medicine was jointly awarded to two researchers for their work in immunotherapy, a class of medications devoted to wiping out the camouflages and restoring the immune systems upper hand. As I once watched a fellow oncologist describe it to a patient: Im not treating you. You are treating you.

What if we could go one step further? What if we could genetically engineer a patients own immune cells to spot and fight cancer, as a sort of best hits of genetic therapy and immunotherapy?

Enter CAR-T. The technology uses T-cells, which are like the bouncers of the immune system. T-cells survey the body and make sure everything belongs. CAR-T involves removing a persons T-cells from her blood and using a disarmed virus to deliver new genetic material to the cells. The new genes given to the T-cells help them make two types of proteins. The first giving the technology its name is a CAR, which sits on the T-cells surface and binds to a protein on the tumor cells surface, like a lock and key. The second serves as the T-cells caffeine jolt, rousing it to activate. Once the genetic engineering part is done, the T-cells are prodded to multiply by being placed on a rocking device that feeds them nutrients while filtering their wastes. When the cells reach a high enough number a typical dose ranges from hundreds of thousands to hundreds of millions they are formidable enough to go back into the patient. Once inside, the cancer provokes the new cells to replicate even more. After one week, a typical expansion means multiplying by about another 1,000-fold.

Practically, it looks like this: A person comes in for an appointment. She has a catheter placed in a vein, perhaps in her arm or her chest, that connects to a large, whirring machine which pulls in her blood and separates it into its components. The medical team set the T-cells aside to freeze while the rest of the blood circulates back into the patient in a closed loop. Then, the hospital ships the cells frozen to the relevant pharmaceutical companys headquarters or transports them to a lab on-site, where thawing and manufacturing takes from a few days to a few weeks. When the cells are ready, the patient undergoes about three days of chemotherapy to kill both cancer and normal cells, making room for the millions of new cells and eradicating normal immune players that could jeopardize their existence. She then gets a day or two to rest. When the new cells are infused back into her blood, we call that Day 0.

I remember the first time I watched a patient get his Day 0 infusion. It felt anti-climactic. The entire process took about 15 minutes. The CAR-T cells are invisible to the naked eye, housed in a small plastic bag containing clear liquid.

Thats it? my patient asked when the nurse said it was over. The infusion part is easy. The hard part is everything that comes next.

Once the cells are in, they cant turn off. That this may cause collateral damage was evident from the start. In 2009 working in parallel with other researchers at Memorial Sloan Kettering Cancer Center in New York and the National Cancer Institute in Maryland oncologists at the University of Pennsylvania opened a clinical trial for CAR-T in human leukemia patients. (Carl June, who led the CAR-T development, did not respond to Undarks interview request.) Of the first three patients who got CAR-T infusions, two achieved complete remission but nearly died in the process. The first was a retired corrections officer named Bill Ludwig, who developed extremely high fevers and went into multi-organ failure requiring time in the ICU. At the time, the medical teams had no idea why it was happening or how to stop it. But time passed. Ludwig got better. Then came the truly incredible part: His cancer was gone.

With only philanthropic support, the trial ran out of funding. Of the eligible patients they intended to treat, the Penn doctors only treated three. So they published the results of one patient in the New England Journal of Medicine and presented the outcomes of all three patients, including Ludwig, at a cancer conference anyway. From there, the money poured in. Based on the results, the Swiss pharmaceutical company Novartis licensed the rights of the therapy.

The next year, six-year-old Emily Whitehead was on the brink of death when she became the first child to receive CAR-T. She also became extremely ill in the ICU, and her cancer was also eventually cured. Her media savvy parents helped bring her story public, making her the poster child for CAR-T. In 2014, the FDA granted CAR-T a breakthrough therapy designation to expedite the development of extremely promising therapies. By 2017, a larger trial gave the treatment to 75 children and young adults with a type of leukemia B-cell acute lymphoblastic leukemia that failed to respond to chemotherapy. Eighty-one percent had no sign of cancer after three months.

In August 2017, the FDA approved a CAR-T treatment as the first gene therapy in the U.S. The decision was unanimous. The Oncologic Drugs Advisory Committee, a branch of the FDA that reviews new cancer products, voted 10 to zero in favor of Kymriah. Committee members called the responses remarkable and potentially paradigm changing. When the announcement broke, a crowd formed in the medical education center of Penn Medicine, made up of ecstatic faculty and staff. There were banners and T-shirts. A remarkable thing happened was the tagline, above a cartoon image of a heroic T-cell. Two months later, in October 2017, the FDA approved a second CAR-T formulation called Yescarta from Kite Pharma, a subsidiary of Gilead Sciences, to treat an aggressive blood cancer in adults called diffuse large B-cell lymphoma, the trial of which had shown a 54 percent complete response rate, meaning all signs of cancer had disappeared. In May 2018, Kymriah was approved to treat adults with non-Hodgkin lymphoma.

That year, the American Society of Clinical Oncology named CAR-T the Advance of the Year, beating out immunotherapy, which had won two years in a row. When I attended the last American Society of Hematology meeting in December 2018, CAR-T stole the show. Trying to get into CAR-T talks felt like trying to get a photo with a celebrity. Running five minutes late to one session meant facing closed doors. Others were standing room only. With every slide, it became difficult to see over a sea of smartphones snapping photos. At one session I found a seat next to the oncologist from my hospital who treated Birzer. Look, she nudged me. Do you see all these non-member badges? I turned. Members were doctors like us who treated blood cancers. I couldnt imagine who else would want to be here. Who are they? I asked. Investors, she said. It felt obvious the moment she said it.

For patients, the dreaded c word is cancer. For oncologists, its cure. When patients ask, Ive noticed how we gently steer the conversation toward safer lingo. We talk about keeping the cancer in check. Cure is a dangerous word, used only when so much time has passed from her cancer diagnosis we can be reasonably certain its gone. But that line is arbitrary. We celebrate therapies that add weeks or months because the diseases are pugnacious, the biology diverse, and the threat of relapse looming. Oncologists are a tempered group, or so Ive learned, finding inspiration in slow, incremental change.

This was completely different. These were patients who would have otherwise died, and the trials were boasting that 54 to 81 percent were cancer-free upon initial follow-up. PET scans showed tumors that had speckled an entire body melt away. Bone marrow biopsies were clear, with even the most sensitive testing unable to detect disease.

The dreaded word was being tossed around could this be the cure weve always wanted?

When a new drug gets FDA approval, it makes its way into clinical practice, swiftly and often with little fanfare. Under the drug safety program REMS, hospitals offering CAR-T were obligated to undergo special training to monitor and manage side effects. As hospitals worked to create CAR-T programs, oncologists like me made the all too familiar transition from first-time user to expert.

It was May 2018 when I rotated through my hospitals unit and cared for my first patients on CAR-T. As I covered 24-hour shifts, I quickly learned that whether I would sleep that night depended on how many CAR-T patients I was covering. With each treatment, it felt like we were pouring gasoline on the fire of patients immune systems. Some developed high fevers and their blood pressures plummeted, mimicking a serious infection. But there was no infection to be found. When resuscitating with fluids couldnt maintain my patients blood pressures, I sent them to the ICU where they required intensive support to supply blood to their critical organs.

We now have a name for this effect cytokine release syndrome that occurs in more than half of patients who receive CAR-T, starting with Ludwig and Whitehead. The syndrome is the collateral damage of an immune system on the highest possible alert. This was first seen with other types of immunotherapy, but CAR-T took its severity to a new level. Usually starting the week after CAR-T, cytokine release syndrome can range from simple fevers to multi-organ failure affecting the liver, kidneys, heart, and more. The activated T-cells make and recruit other immune players called cytokines to join in the fight. Cytokines then recruit more immune cells. Unlike in the early trials at Penn, we now have two medicines to dampen the effect. Steroids calm the immune system in general, while a medication called tocilizumab, used to treat autoimmune disorders such as rheumatoid arthritis, blocks cytokines specifically.

Fortuity was behind the idea of tocilizumab: When Emily Whitehead, the first child to receive CAR-T, developed cytokine release syndrome, her medical team noted that her blood contained high levels of a cytokine called interleukin 6. Carl June thought of his own daughter, who had juvenile rheumatoid arthritis and was on a new FDA-approved medication that suppressed the same cytokine. The team tried the drug, tocilizumab, in Whitehead. It worked.

Still, we were cautious in our early treatments. The symptoms of cytokine release syndrome mimic the symptoms of severe infection. If this were infection, medicines that dampen a patients immune system would be the opposite of what youd want to give. There was another concern: Would these medications dampen the anti-cancer activity too? We didnt know. Whenever a CAR-T patient spiked a fever, I struggled with the question is it cytokine release syndrome, or is it infection? I often played it safe and covered all bases, starting antibiotics and steroids at the same time. It was counterintuitive, like pressing both heat and ice on a strain, or treating a patient simultaneously with fluids and diuretics.

The second side effect was even scarier: Patients stopped talking. Some, like Sharon Birzer spoke gibberish or had violent seizures.Some couldnt interact at all, unable to follow simple commands like squeeze my fingers. How? Why? At hospitals across the nation, perfectly cognitively intact people who had signed up to treat their cancer were unable to ask what was happening.

Our nurses learned to ask a standardized list of questions to catch the effect, which we called neurotoxicity: Where are we? Who is the president? What is 100 minus 10? When the patients scored too low on these quizzes, they called me to the bedside.

In turn, I relied heavily on alaminated booklet, made by other doctors who were using CAR-T, which we tacked to a bulletin board in our doctors workroom. It contained a short chart noting how to score severity and what to do next. I flipped through the brightly color-coded pages telling me when to order a head CT-scan to look for brain swelling and when to place scalp electrodes looking for seizures. Meanwhile, we formed new channels of communication. As I routinely called a handful of CAR-T specialists at my hospital in the middle of the night, national consortiums formed where specialists around the country shared their experiences. As we tweaked the instructions, we scribbled updates to the booklet in pen.

I wanted to know whether my experience was representative. I came across an abstract and conference talk that explored what happened to 277 patients who received CAR-T in the real world, so I emailed the lead author, Loretta Nastoupil, director of the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston. Fortuitously, she was planning a trip to my university to give a talk that month. We met at a caf and I asked what her research found. Compared to the earlier trials, the patients were much sicker, she said. Of the 277 patients, more than 40 percent wouldnt have been eligible for the very trials that got CAR-T approved. Was her team calling other centers for advice? They were calling us, she said.

Patients included in clinical trials are carefully selected. They tend not to have other major medical problems, as we want them to survive whatever rigorous new therapy we put them through. Nastoupil admits some of it is arbitrary. Many criteria in the CAR-T trials were based on criteria that had been used in chemotherapy trials. These become standard languages that apply to all studies, she said, listing benchmarks like a patients age, kidney function, and platelet count. But we have no idea whether criteria for chemotherapy would apply to cellular therapy.

Now, with a blanket FDA approval comes clinical judgment. Patients want a chance. Oncologists want to give their patients a chance. Young, old, prior cancer, heart disease, or liver disease without strict trial criteria, anyone is fair game.

When I was making rounds at my hospital, I never wandered too far from these patients rooms, medically prepared for them to crash at any moment. At the same time, early side effects made me optimistic. A bizarre truism in cancer is that side effects may bode well. They could mean the treatment is working. Cancer is usually a waiting game, requiring months to learn an answer. Patients and doctors alike seek clues, but the only real way to know is waiting: Will the next PET scan show anything? What are the biopsy results?

CAR-T was fundamentally different from other cancer treatments in that it worked fast. Birzers first clue came just a few hours after her infusion. She developed pain in her lower back. She described it as feeling like she had menstrual cramps. A heavy burden of lymphoma lay in her uterus. Could the pain mean that the CAR-T cells had migrated to the right spot and started to work? Her medical team didnt know, but the lead doctors instinct was that it was a good sign.

Two days later, her temperature shot up to 102. Her blood pressure dropped. The medical team diagnosed cytokine release syndrome, as though right on schedule, and gave her tocilizumab.

Every day, the nurses would ask her questions and have her write simple sentences on a slip of paper to monitor for neurotoxicity. By the fifth day, her answers changed. She started saying things that were crazy, Johnson explained.

One of Birzer's sentences was guinea pigs eat greens like hay and pizza. Birzer and Johnson owned two guinea pigs, so their diet would be something Birzer normally knew well. So Johnson tried to reason with her: They dont eat pizza. And Birzer replied, They do eat pizza, but only gluten-free.

Johnson remembers being struck by the certainty in her partners delirium. Not only was Birzer confused, she was confident she was not. She was doubling down on everything, Johnson described. She was absolutely sure she was right.

Johnson vividly remembers the evening before the frightening early-morning phone call that brought her rushing back to the hospital. Birzer had said there was no point in Johnson staying overnight; she would only watch her be in pain. So Johnson went home. After she did, the doctor came by multiple times to evaluate Birzer. She was deteriorating and fast. Her speech became more and more garbled. Soon she couldnt name simple objects and didnt know where she was. At 3 a.m., the doctor ordered a head CT to make sure Birzer wasnt bleeding into her brain.

Fortunately, she wasnt. But by 7 a.m. Birzer stopped speaking altogether. Then she seized. Birzers nurse was about to step out of the room when she noticed Birzers arms and legs shaking. Her eyes stared vacantly and she wet the bed. The nurse called a code blue, and a team of more doctors and nurses ran over. Birzer was loaded with high-dose anti-seizure medications through her IV. But she continued to seize. As nurses infused more medications into her IV, a doctor placed a breathing tube down her throat.

Birzers saga poses the big question: Why does CAR-T cause seizures and other neurologic problems? No one seemed to know. My search of the published scientific literature was thin, but one name kept cropping up. So I called her. Juliane Gust, a pediatric neurologist and scientist at Seattle Childrens Hospital, told me her investigations of how CAR-T affects the brain were motivated by her own experiences. When the early CAR-T trials opened at her hospital in 2014, she and her colleagues began getting calls from oncologists about brain toxicities they knew nothing about. Where are the papers? she remembered thinking. There was nothing.

Typically, the brain is protected by a collection of cells aptly named the blood-brain-barrier. But with severe CAR-T neurotoxicity, research suggests, this defense breaks down. Gust explained that spinal taps on these patients show high levels of cytokines floating in the fluid surrounding the spine and brain. Some CAR-T cells circulate in the fluid too, she said, but these numbers do not correlate with sicker patients. CAR-T cells are even seen in the spinal fluid of patients without any symptoms.

What does this mean? Gust interprets it as a patients symptoms having more to do with cytokines than the CAR-T cells. Cytokine release syndrome is the number one risk factor for developing neurotoxicity over the next few days, she said. The mainstay for neurotoxicity is starting steroids as soon as possible. In the beginning we didnt manage as aggressively. We were worried about impairing the function of the CAR-T, she added. Now we give steroids right away.

But the steroids dont always work. Several doses of steroids didnt prevent Birzer from seizing. The morning after Johnsons alarming phone call, after the meeting at the hospital when she learned what had happened, a chaplain walked her from the conference room to the ICU. The first day, Johnson sat by her partners bedside while Birzer remained unconscious. By the next evening, she woke up enough to breathe on her own. The doctors removed her breathing tube, and Birzer looked around. She had no idea who she was or where she was.

Birzer was like a newborn baby, confused and sometimes frightened by her surroundings. She frequently looked like she was about to say something, but she couldnt find the words despite the nurses and Johnsons encouragement. One day she spoke a few words. Eventually she learned her name. A few days later she recognized Johnson. Her life was coming back to her, though she was still suspicious of her reality. She accused the nurses of tricking her, for instance, when they told her Donald Trump was president.

She took cues from the adults around her on whether her actions were appropriate. The best example of this was her I love you phase. One day, she said it to Johnson in the hospital. A few nurses overheard it and commented on how sweet it was. Birzer was pleased with the reaction. So she turned to the nurse: I love you! And the person emptying the trash: I love you! Months later, she was having lunch with a friend who asked, Do you remember when you told me you loved me? Birzer said, Well, I stand by that one.

When she got home, she needed a walker to help with her shakiness on her feet. When recounting her everyday interactions, she would swap in the wrong people, substituting a friend for someone else. She saw bugs that didnt exist. She couldnt hold a spoon or a cup steady. Johnson would try to slow her down, but Birzer was adamant she could eat and drink without help. Then peas would fly in my face, Johnson said.

Patients who experience neurotoxicity fall into one of three categories. The majority are impaired but then return to normal without long-term damage. A devastating handful, less than 1 percent, develop severe brain swelling and die. The rest fall into a minority that have lingering problems even months out. These are usually struggles to think up the right word, trouble concentrating, and weakness, often requiring long courses of rehabilitation and extra help at home.

As Birzer told me about her months of rehab, I thought how she did seem to fall somewhere in the middle among the patients Ive treated. On one end of the spectrum was the rancher who remained profoundly weak a year after his infusion. Before CAR-T, he walked across his ranch without issue; six months later, he needed a walker. Even with it, he fell on a near weekly basis. On the other end was the retired teacher who couldnt speak for a week she would look around her ICU room and move her mouth as though trying her hardest and then woke up as though nothing happened. She left the hospital and instantly resumed her life, which included a recent trip across the country. In hindsight, I remember how we worried more about giving the therapy to the teacher than the rancher, as she seemed frailer. Outcomes like theirs leave me with a familiar humility I keep learning in new ways as a doctor: We often cant predict how a patient will do. Our instincts can be just plain wrong.

I asked Gust if we have data to predict who will land in which group. While we can point to some risk factors higher burdens of cancer, baseline cognitive problems before therapy the individual patient tells you nothing, she confirmed.

So we wait.

Doctors like me who specialize in cancer regularly field heart-wrenching questions from patients. They have read about CAR-T in the news, and now they want to know: What about me? What about my cancer?

So, who gets CAR-T? That leads to the tougher question who doesnt? That depends on the type of cancer and whether their insurance can pay.

CAR-T is approved to treat certain leukemias and lymphomas that come from the blood and bone marrow. Since the initial approval, researchers have also set up new CAR-T trials for all sorts of solid tumors from lung cancer to kidney cancer to sarcoma. But progress has been slow. While some promising findings are coming from the lab and in small numbers of patients on early phase trials, nothing is yet approved in humans. The remarkable responses occurring in blood cancers just werent happening in solid tumors.

Cancer is one word, but its not one disease. Its easier to prove why something works when it works than show why it doesnt work when it doesnt work, said Saar Gill, a hematologist and scientist at the University of Pennsylvania who co-founded a company called Carisma Therapeutics using CAR-T technology against solid tumors. That was his short answer, at least. The longer answer to why CAR-T hasnt worked in solid cancers involves what Gill believes are two main barriers. First, its a trafficking problem. Leukemia cells tend to be easier targets; they bob through the bloodstream like buoys in an ocean. Solid tumors are more like trash islands. The cancer cells stick together and grow an assortment of supporting structures to hold the mound together. The first problem for CAR-T is that the T-cells may not be able to penetrate the islands. Then, even if the T-cells make it in, theyre faced with a hostile environment and will likely die before they can work.

At Carisma, Gill and his colleagues look to get around these obstacles though a different immune cell called the macrophage. T-cells are not the only players of the immune system, after all. Macrophages are gluttonous cells that recognize invaders and engulf them for destruction. But studies have shown they cluster in solid tumors in a way T-cells dont. Gill hopes genetically engineered macrophages can be the stowaways that sneak into solid tumor and attack from the inside out.

Another big challenge, even for leukemias and lymphomas, is resistance, where the cancers learn to survive the CAR-T infusion. While many patients in the trials achieved remission after a month, we now have two years worth of data and the outlook isnt as rosy. For lymphoma, that number is closer to 40 percent. Patients celebrating cures initially are relapsing later. Why?

The CAR-T cells we use target a specific protein on cancer cells. But if the cancer no longer expresses that protein, that can be a big problem, and were finding thats exactly whats happening. Through blood testing, we see that many patients who relapse lose the target.

Researchers are trying to regain the upper hand by designing CAR-Ts to target more than one receptor. Its an old idea in a new frame: An arms race between our medicines and the illnesses that can evolve to evade them. Too much medical precision in these cases is actually not what we want, as it makes it easier for cancer to pinpoint whats after it and develop an escape route. So, the reasoning goes, target multiple pieces at once. Confuse the cancer.

Then theres the other dreaded c word: Cost. Novartis Kymriah runs up to $475,000 while Kite Pharmas Yescarta is $373,000. That covers manufacturing and infusion. Not included is the minimum one-week hospital stay or any complications.

They are daunting numbers. Some limitations on health care we accept maybe the patients are too sick; maybe they have the wrong disease. The wrong cost is not one we as a society look kindly upon. And drug companies shy away from that kind of attention.

Cost origins in medicine are notoriously murky. Novartis, confident in its technology, made an offer to offset the scrutiny in CAR-T. If the treatment didnt work after one month, the company said it wouldnt send a bill.

Not everyone agrees that cost is an issue. Gill, for example, believes the concern is over-hyped. Its not a major issue, he told me over the phone. Look, of course [with] health care in this country, if you dont have insurance, then youre screwed. That is no different when it comes to CAR-T as it is for anything else, he said. The cost conversation must also put CAR-T in context. Gill went on to list what these patients would be doing otherwise months of chemotherapy, bone marrow transplants, hospital stays for cancer-associated complications and the associated loss of income as patients and caregivers miss work. These could add up to far more than a one-time CAR-T infusion. A bone marrow transplant, for example, can cost from $100,000 to more than $300,000. The cancer-fighting drug blinatumomab, also used to treat relapsed leukemia, costs $178,000 a year. Any discussion of cost is completely irresponsible without weighing the other side of the equation, Gill said.

How the system will get on board is another question. Logistics will be an issue, Gill conceded. The first national Medicare policy for covering CAR-T was announced in August 2019, two years after the first product was approved. The Centers for Medicare and Medicaid Services has offered to reimburse a set rate for CAR T-cell infusion, and while this figure was recently raised, it remains less than the total cost. Despite the expansion of medical uses, at some centers referrals for CAR-T are dropping as hospitals worry its a net loss. And while most commercial insurers are covering CAR-T therapies, companies less accustomed to handling complex therapies can postpone approval. Ironically, the patients considering CAR-T are the ones for whom the window for treatment is narrowest. A delay of even a few weeks can mean the difference between a cure and hospice.

This, of course, poses a big problem. A breakthrough technology is only as good as its access. A major selling point of CAR-T besides the efficacy is its ease. Its a one-and-done treatment. Engineered T-cells are intended to live indefinitely, constantly on the alert if cancer tries to come back. Compare that to chemotherapy or immunotherapy, which is months of infusions or a pill taken indefinitely. CAR-T is more akin to surgery: Cut it out, pay the entire cost upfront, and youre done.

Birzer was lucky in this respect. I asked her and Johnson if cost had factored into their decision to try CAR-T. They looked at each other. It wasnt an issue, said Johnson. They remembered getting a statement in the mail for a large sum when they got home. But Birzer had good insurance. She didnt pay a cent.=

One year after Birzers infusion, I met her and Johnson at a coffee shop near their home in San Francisco. They had saved a table. Johnson had a newspaper open. Birzer already had her coffee, and I noticed her hand trembling as she brought it to her mouth. She described how she still struggles to find exactly the right words. She sometimes flings peas. But shes mostly back to normal, living her everyday life. She has even returned to her passion, performing stand-up comedy, though she admitted that at least for general audiences: My jokes about cancer didnt kill.

People handed a devastating diagnosis dont spend most of their time dying. They are living, but with a heightened awareness for a timeline the rest of us take for granted. They sip coffee, enjoy their hobbies, and read the news while also getting their affairs in order and staying on the lookout, constantly, for the next treatment that could save them.

Hoping for a miracle while preparing to die are mutually compatible ideas. Many of my patients have become accustomed to living somewhere in that limbo. It is humbling to witness. They hold out hope for a plan A, however unlikely it may be, while also adjusting to the reality of a plan B. They live their lives; and they live in uncertainty.

I see patients in various stages of this limbo. In clinic, I met a man with multiple myeloma six months after a CAR-T trial that supposedly cured him. He came in with a big smile but then quietly began praying when it was time to view PET results. He asked how the other patients on the trial were doing, and I shared the stats. While percentages dont say anything about an individual experience, theyre also all patients have to go on. When someone on the same treatment dies, its shattering for everyone. Was one person the exception, or a harbinger anothers fate? Who is the outlier?

I look at these patients and think a sober truth: Before CAR-T, all would likely die within six months. Now, imagine taking 40 percent and curing them. Sure, a naysayer might point out, its only 40 percent. Whats the hype if most still succumb to their cancer? But there was nothing close to that before CAR-T. I agree with how Gill described it: I think CAR-T cells are like chemotherapy in the 1950s. Theyre not better than chemotherapy theyre just different. For an adversary as tough as cancer, well take any tool we can get.

There remain many questions. Can we use CAR-T earlier in a cancers course? Lessen the side effects? Overcome resistance? Streamline manufacturing and reimbursement? Will it work in other cancers? Patients will sign up to answer.

For now, Birzer seems to be in the lucky 40 percent. Her one-year PET scan showed no cancer. I thought of our last coffee meeting, where I had asked if she ever worried she wouldnt return to normal. She didnt even pause. If youre not dead, she said, youre winning.

This article was originally published on Undark. Read the original article.

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Behind the Scenes of a Radical New Cancer Cure - Scientific American

Recommendation and review posted by Bethany Smith

Genentech’s Gazyva (obinutuzumab), in Combination With Standard of Care, More Than Doubles the Percentage of Lupus Nephritis Patients Achieving…

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced data from the Phase II NOBILITY study, investigating the safety and efficacy of Gazyva (obinutuzumab) for adults with proliferative lupus nephritis. The study met the primary endpoint with Gazyva, in combination with standard of care (mycophenolate mofetil or mycophenolic acid and corticosteroids), demonstrating superiority compared to placebo plus standard of care. Patients treated with Gazyva showed increasing rates of complete renal response (CRR) from week 52 to week 76, with 40% of patients in the Gazyva group achieving CRR, compared to 18% of patients in the placebo group at week 76 (p=0.007). Gazyva additionally met key secondary efficacy endpoints showing improved overall renal response (complete or partial renal responses) and serologic markers of disease activity as compared to placebo. No new safety signals were observed with Gazyva in the study at the time of this analysis. Through week 76, serious adverse events (24% vs. 29% in placebo group) and serious infections (6% vs.18% in placebo group) were not increased with Gazyva. These data will be presented at the 2019 American College of Rheumatology (ACR) Annual Meeting in Atlanta, Georgia, on November 10, 2019 (Abstract 939).

We are very encouraged by the positive results from the NOBILITY study, which suggest that Gazyva may provide a clinically meaningful benefit for adults with proliferative lupus nephritis; a condition for which there is a strong need for more effective and targeted treatment options, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. These results support the continued development of Gazyva for people with lupus nephritis and underscore our longstanding commitment to pursue new treatment options that may benefit the lupus community.

Lupus nephritis is a severe and potentially life-threatening manifestation of systemic lupus erythematosus resulting from inflammation of the kidneys, with proliferative lupus nephritis being the most severe form and associated with high-risk of end-stage renal disease and death. In September 2019, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to Gazyva for adults with lupus nephritis based on the Phase II NOBILITY study data. Genentech will initiate a Phase III study for Gazyva in lupus nephritis in 2020.

Phase II data from the NOBILITY study was also presented as a late-breaking oral presentation at the American Society of Nephrologys (ASN) Kidney Week 2019 in Washington, DC, on November 8, 2019 (Abstract FR-OR136).

An audio webcast for analysts and investors on the Phase II NOBILITY study data will be held on Tuesday, November 12, 2019 from 4:30-5:30 p.m. CET / 10:30-11:30 a.m. ET. Further details are available here.

Lupus nephritis overwhelmingly impacts women, particularly young women of color. About 90% of those diagnosed with lupus are women, and African American, Hispanic, Native American and Asian American women are two to three times more likely than Caucasian women to get lupus. Genentech is committed to addressing barriers to clinical trial participation and advancing inclusive research to create new standards for clinical studies. Genentech is taking action to recruit a broader, more diverse population of participants into clinical trials, including diseases such as lupus nephritis, to ensure clinical trial participants more closely reflect those impacted by the disease for which a medicine is being studied. To learn more about Genentechs efforts in this area, please visit

About the NOBILITY Study

The Phase II, randomized, double-blind, placebo-controlled, multi-center study, NOBILITY (NCT02550652), compared the safety and efficacy of Gazyva, combined with mycophenolate mofetil (MMF) or mycophenolic acid (MPA) and corticosteroids, to placebo, combined with MMF or MPA and corticosteroids, in adult patients with ISN/RPS 2003 class III or IV proliferative lupus nephritis. The study enrolled 125 people who were randomized to receive Gazyva or placebo infusions on days 1, 15, 168, and 182. The primary endpoint was the proportion of participants who achieved a protocol-defined complete renal response (CRR) at 52 weeks. Key secondary endpoints included overall renal responses (complete or partial renal response) and serologic markers of disease activity, as compared to placebo. Patients were followed in a blinded fashion through week 104, and patients with persistent B-cell depletion are being followed for safety and continued B-cell measurements.

About Lupus Nephritis

Lupus nephritis is a severe and potentially life-threatening disorder of the kidneys. Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus (SLE), an autoimmune disease where a person's own immune system attacks healthy cells and organs, including, in the case of lupus nephritis, the kidneys. This causes kidney inflammation and may lead to blood and/or protein in the urine, high blood pressure, poor kidney function, or kidney failure. An estimated 1.5 million Americans are affected by lupus, with approximately 70% of cases representing SLE. Up to 60% of people with SLE will develop lupus nephritis, and up to 25% of people with the condition develop end-stage renal disease. Lupus overwhelmingly impacts women, particularly young women of color. About 90% of those diagnosed with lupus are women, and African American, Hispanic, Native American and Asian American women are two to three times more likely than Caucasian women to get lupus. Currently, there is no cure for lupus or lupus nephritis.

About Gazyva

Gazyva is an engineered monoclonal antibody designed to attach to CD20, a protein found only on certain types of B-cells. It is thought to work by attacking targeted cells both directly and together with the body's immune system. Gazyva is part of a collaboration between Genentech and Biogen. Combination studies investigating Gazyva with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

Gazyva Indications

Gazyva (obinutuzumab) is a prescription medicine used:

Important Safety Information

The most important safety information patients should know about Gazyva

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that can become serious or life-threatening, including:

Who should not receive Gazyva:

Patients should NOT receive Gazyva if they have had an allergic reaction (e.g., anaphylaxis or serum sickness) to Gazyva. Patients must tell their healthcare provider if they have had an allergic reaction to obinutuzumab or any other ingredients in Gazyva in the past.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that may become severe or life threatening, including:

The most common side effects of Gazyva in CLL were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

The safety of Gazyva was evaluated based on 392 patients with relapsed or refractory NHL, including FL (81%), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) (a disease for which Gazyva is not indicated), who did not respond to or progressed within six months of treatment with rituximab product or a rituximab product-containing regimen. In patients with follicular lymphoma, the profile of side effects that were seen were consistent with the overall population who had NHL. The most common side effects of Gazyva were infusion reactions, low white blood cell counts, nausea, fatigue, cough, diarrhea, constipation, fever, low platelet counts, vomiting, upper respiratory tract infection, decreased appetite, joint or muscle pain, sinusitis, low red blood cell counts, general weakness and urinary tract infection.

A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of Gazyva as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86%) or marginal zone lymphoma (14%). The most common side effects of Gazyva were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

Patients should tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or Report side effects to Genentech at (888) 835-2555.

Please visit for the Gazyva full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit

Original post:
Genentech's Gazyva (obinutuzumab), in Combination With Standard of Care, More Than Doubles the Percentage of Lupus Nephritis Patients Achieving...

Recommendation and review posted by Bethany Smith

Golf equipment truths: Iron faces are nearly as fast as a drivers. Here’s why – Golf Digest

We are lucky to have two of the most knowledgable golf gearheads in our office. And they are sharing their golf equipment knowledge with you. Golf Digest's equipment editors, Mike Stachura and E. Michael Johnson, have covered the golf equipment business for decades, and there are few who know the equipment industry better. We've asked them to answer your questions in a weekly equipment round-up. Tweet them any equipment questions you have, and they might answer your questions next week. (Click here or here to ask them a question.)

Drivers are hit at most 14 times a round while irons are hit 40+ times a round. Plus the average golfer hits less than 20 percent of their greens in regulation. So why not a bigger effort to create more forgiving, longer irons? @TedWilliams2017

Ahh, the Splendid Splinter, back from cryonics, good to hear from you. Perhaps the fact that youve been in the deep freeze for a couple decades might explain your mistaken understanding of the current golf club technology landscape. The good news is the technology in irons is vastly improved over the past 15 years, sort of like how baseball bats are better now that theyre not made of wood anymore. Of course, the primary reason for better iron designs is that much of the same technologies that have made drivers so awesome have found their ways into irons. Super thin faces? Check. Variable face thicknesses? Check. Multiple materials and dramatic weight savings that allow for a lower center of gravity and higher flight? Check and double check. Those technologies came to drivers first, because, well, as has been said, chicks dig the long ball. But secondly, its a lot easier to work within the structure of a hollow, 460-cubic-centimeter, pie-plate-faced driver than it is in the oddly asymmetrical shape of an iron. But that hasnt stopped progress in irons.

We just finished at looking at more than 70 irons for the 2020 Hot List, and wed guess that at least 95 percent of them have faster faces than they did as little as two years ago. Today, there are a whole bunch of irons with springlike effect very near or in some cases exceeding that of drivers. (OK, technically, no face can violate the springlike effect rules. But some irons are getting pretty spicy hot these days.) Heres another key point, not only are irons hotter today, its easier to make them fly higher, too. In one of our recent tests, we found that not only did new 7-irons go farther than 6-irons from a decade ago, they flew as higher or higher than many of those old 7-irons, too. Even comparing 7-irons from just a handful of years ago, we saw sometimes as much as a 20-yard distance advantage and on average a three-yard gain in carry distance on mis-hits and two yards higher flight. In short, today's irons are longer with better stopping power. And we havent even begun to address the advancements in hybrids or even utility irons that make your old long irons not even worth saving, cryonically or any other way you might choose.

Someone explain to me why lofts have been evolving and getting stronger. Or as Brandel Chamblee calls it, "loft creep." Im guessing guys can dial these clubs in and hit all sorts of trajectories high/low/mid even with the stronger lofts and the distance gained is coveted. @WeekendHack_YT

Dear Hack: Some of this is about physics and some of this is about business. First, the latter: If you want to sell clubs these days, particularly irons, you have to have technology that generates ball speed that shows up on a launch monitor. More ball speed means more distance. Of course, the easiest and fastest way to generate ball speed is not some super thin, heat-treated magic steel alloy. Its by making your 7-iron stronger lofted than someone elses. Weve even heard some manufacturers have taken to retool their demo clubs to a stronger loft than their standard just so they can better compete with other companies lower lofts. Messy, of course, when the 7-iron you got fit for in the shop is longer than the 7-iron that you actually buy, but thats why you should ask an extra question or two about the lofts of the irons youre testing. Not all 7-irons are, well, 7-irons.

Still, there also is some serious physics happening here. As club technologies have allowed for the center of gravity to get lower (leading in some cases to higher launch), an iron can then be designed with a stronger loft that takes advantage of that higher launch. Faster ball speed with the same or higher launch means more distance and a better landing trajectory. Thats why when you start seriously testing potential new irons, dont just look at distance. Use the modern technology of a launch monitor to assess those landing angles. Ideally, you want your shots to have a landing angle of more than 45 degrees for best performance coming into a green. The one problem with these stronger lofts in your middle irons: Bad distance gaps in your short irons. If the set youre eyeballing features a pitching wedge with less than 45 degrees of loft, our recommendation is to add another wedge every 4-5 degrees. The more full swings you can make at the short end of the set, the more scoring youll be doing with the scoring clubs.

If Im measured at a D3 swingweight for a driver, should I apply that same weight to all clubs I buy? @NBMH1

Although it certainly would seem logical that you would want all of your clubs to effectively feel the same as you swing them, fact is, from doing dozens of Whats In My Bags with tour pros for Golf Digest, weve seen it both ways. Some players like to keep all their swingweights the same (although sand and lob wedges tend to have a heavier swingweight), while some have numerous different swingweights with their clubs. Tony Finau, for instance, is D-6+ in his driver and D-4 in his fairway wood, although they rarely vary widely. So although consistency is generally a good thing, its not an absolute. If it feels good to you when youre swinging it, theres probably not much need to mess around with it.

RELATED: Golf equipment truths: Do drivers lose their pop?

Have the changes in wedge grooves in the last six years made a significant difference? @cfkuon

Actually, the new regulations on grooves went into effect in 2010, so it has been almost 10 years that wedge designers have been working within the new framework. Its interesting that back then the rule was viewed as spin Armageddon. Phil Mickelson and Padraig Harrington started using original Ping Eye2 lob wedges because its grooves were grandfathered in and Stewart Cink even went so far as to practice with duct tape on the face of his wedges, feeling that would be the equivalent of the new, less-aggressive grooves. But club designers are smart people and as many of them will tell you, while they dont like to have design within a box, a new rule always provides an opportunity to best figure out how to design within it. Thats what has happened here. Today golfers still apply plenty of spin to the ball and can hit pretty much all the shots they need to. Designers have explored areas such as edge radius and surface roughness, making designs with more grooves closer together and ones that even employ a half-groove on the bottom of the face to squeeze out as many revolutions per minute of spin they can. A significant difference? That might actually be an understatement.

RELATED: Golf equipment truths: Is your golf shaft robbing you of yards?


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Golf equipment truths: Iron faces are nearly as fast as a drivers. Here's why - Golf Digest

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Genetic testing leads woman to take steps to avoid breast cancer: Im one of the lucky ones – WITI FOX 6 Milwaukee

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MILWAUKEE -- The earlier you catch breast cancer, the better your odds are of beating it. That is the idea behind the FOX6 initiative, Buddy Check 6.

Birthdays are a time to celebrate -- especially the big ones like turning 30 years old -- which is what Antonina Sendik was doing last month.

"I'm one of the lucky ones," Sendik said.

In fact, you might say Sendik is just starting her life.

"It's been a very emotional six months," Sendik said.

Sendik's father has had two brain tumors and was recently diagnosed with a disease called Cowden's Syndrome. It is a red flag that Sendik and her five siblings may have inherited the gene mutation that can cause a host of health problems. Doctors recommended genetic testing. They found Sendik had an 86 percent chance of developing breast cancer.

"I had no symptoms. I felt fine besides what was on the inside," Sendik said. "We started talking then about -- I'm probably going to have a double mastectomy."

Sendik learned that reality just a few months ago.

"You never think this is going to happen to you or this can't happen to me," Sendik said. "I would have loved to have blown it off. Learning that risk, I had no choice.

Sendik's doctor felt the same.

"With the genetic mutation, we knew that the risk was there," Dr. Caitlin Patten said.

"She said my job is to keep you safe -- and that's what I'm going to do," Sendik said.

With that, Sendik decided to go through with the surgery. It was a success. Post-surgery, the breast tissue that was removed was tested.

"So there were cancer cells. But it hadn't broken outside the duct -- it hadn't spread anywhere," Sendik said.

Sendik was relieved.

"She got it, it's gone, it's out of me," Sendik said.

Sendik does not need radiation or chemotherapy because the cancer is gone. She just needs to maintain a healthy lifestyle -- and keep regular appointments with her doctor.

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Genetic testing leads woman to take steps to avoid breast cancer: Im one of the lucky ones - WITI FOX 6 Milwaukee

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Healthcast: The importance of genetic testing – KLBK | KAMC |

LUBBOCK, Texas Family trees show where youve been.

But the family tree that genetic counselor Julie Beasley shows her patients at Joe Arrington Cancer Center shows what their future could look like.

Genetics is important for everybody no matter your gender, your race, your age, explained Beasley. Genetic testing and family history can play a vital role in healthcare for any role in any race.

She talks to people who have cancer or family history of cancer and helps them figure out if something is hereditary or can expose them to cancer in their family.

Its important to know your family history to get an idea of whats in your family but not just what they were diagnosed with but how old were they or was it a rare type of cancer, Beasley explained.

This testing can help patients get diagnosed earlier or could prevent it all together.

Interpreters are also available for people who dont speak English so they can also understand what is going on.

I think its very important because sometimes theyre scared to come in because of the diagnosis but if they dont completely understand whats going on then they may not be willing to come back, said Delia Rubio, intake coordinator at Covenant Health. This way theyre informed and they know.

Beasley hopes patients will see the importance of genetic testing and how it can benefit people in the future.

If patients know its there we can help them with managing it so they dont worry as much and they can put that behind them, said Beasley.

Healthcast: The importance of genetic testing - KLBK | KAMC |

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DNA screening of 4,200 Alabamians warns them, helps science –

An Alabama genetic research institute said today it has screened the DNA of 4,200 Alabama men and women for cancer risk and found it in about 150 people or 3 percent.

More than half of that 150 have no strong family history of cancer, researchers at the HudsonAlpha Institute of Biotechnology in Huntsville said today at the institutes annual Tie the Ribbons lunch supporting breast and ovarian cancer research.

The free and low-cost screening program called Information is Power is now entering its fifth year. The test was developed by genetic testing company Kailos Genetics and screens for the well-known BRCA1 and BRCA2 genes plus several others linked to breast, ovarian, colon and other cancers.

Researcher Sara Cooper said the lack of family history in positive test subjects is why this initiative is so important. Testing can fill the gaps in family history with facts, she said.

The screening is available free for men and women between the ages of 28 and 30 living in Madison, Jackson, Limestone, Marshall and Morgan County. Its available for $129 any other person 19 or older wishing to take it.

Cooper said genetic testing can also reveal risk of other medical issues beyond cancer, including cardiovascular disease. It can also help identify medications individuals might want to avoid given their genetic profile and dosage levels that are best for individual patients.

This work is part of a budding initiative at the institute, Cooper said, and it will launch in Alabama within the next year.

It took decades to identify the genes Americans are now tested for as risks, Cooper said. Even when we know what those genes are, we have to develop the technology to efficiently test people and find the changes in their DNA, she said.

There is still work to be done, she said. There are genes researchers havent found that contribute to cancer risk. There are new DNA changes discovered in genes already associated with cancer. These changes have uncertain significance, and HudsonAlpha is developing research techniques to determine whether those changes are meaningful.

The research were doing today lays the foundation for tomorrows success, Cooper said.

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DNA screening of 4,200 Alabamians warns them, helps science -

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The University of Vermont Initiates Genomic DNA Testing in Partnership With Genomics Leader Invitae (NYSE:NVTA) as Cigna Joins Invitae’s Covered Lives…

The University of Vermont Health Network has begun a pilot project to offer Genomic DNA Testing to patients as part of their clinical care. The pilot program is the beginning of an effort to increase the integration of genetic disease risks into routine medical care, which holds promise for providing Vermonters with valuable information to guide their health decisions.

"Our overall health and longevity are determined about 30 percent by genetics," said Debra Leonard, MD, PhD, Chair, Pathology and Laboratory Medicine. "But until now, most of our clinical health care decisions have been made without understanding the differences in each individual's DNA that could help guide those decisions."

Patients who choose to get the Genomic DNA Test can learn about differences in their DNA that make certain diseases more likely, such as cancer and heart disease. Knowing these genetically-determined disease risks may help patients and health care providers adjust their care to keep people as healthy as possible. While genetic testing to identify the cause of a patient's symptoms to reach a diagnosis is now common in health care, proactive genomic testing to identify health risks across a population is just beginning to be considered, and most projects are being done only in the research setting.

The UVM Health Network is partnering with Invitae and LunaPBC on the pilot project. Invitae will provide information for 147 genes that are well-established indicators of increased risk for certain diseases for which clinical treatment guidelines are established. The test also screens for carrier status for other diseases. Follow-up testing for family members will be provided when appropriate.

"Nearly 1 in 6 healthy individuals exhibits a genetic variant for which instituting or altering medical management is warranted," said Robert Nussbaum, MD, Chief Medical Officer of Invitae. "Genetic screening like the Genomic DNA Test in a population health setting can help identify these risk factors so clinicians can better align disease management and prevention strategies for each patient."

The UVM Health Network is offering the Genomic DNA Test as part of clinical care, but health and genomic data can also help researchers learn more about health and disease. Patients who get the test can consent to securely share their data with researchers through LunaDNA, partner LunaPBC's sharing platform. LunaDNA provides patients with the opportunity to share their genomic and electronic health record information to advance health and disease management research. In the future, patients will also be able to share lifestyle, environment, and nutrition data.Shared data is de-identified and aggregatedduring studiesto protect the privacy of each patient while being used to answer important medical research questions.

"Vermonters who choose to share their genomic data for research will play a leading role in the advancement of precision medicine," said Dawn Barry, LunaPBC President and Co-founder. "This effort puts patients first to create a virtuous cycle for research that doesn't sacrifice patients' control or privacy.We are proud to bring our values as a public benefit corporation and community-owned platform to this partnership."

Dr. Leonard spoke about the project, the UVM Health Network's partnership with LunaPBC and Invitae, and the role of genomics in population health on Monday at the Santa Fe Foundation's Clinical Lab 2.0 Workshop in Chicago, a national conference at which pathologists and healthcare leaders from across the country share ways that pathology can be integral to improving population health.

"Vermont and other states are moving away from 'fee-for-service' health care and toward a system that emphasizes prevention, keeping people healthy and treating illness at its earliest stages," Dr. Leonard said. "Integrating genetic risks into clinical care will help patients and providers in their decision-making."

The pilot project began on Friday, November 1, when the first patient agreed to have the test. During the pilot stage of the project over the next year, the Genomic DNA Test will be offered to approximately 1,000 patients over the next year who: are at least 18 years old; receive their primary care from a participating UVM Health Network Family Medicine provider; are not currently pregnant or the partner of someone who is currently pregnant; and are part of the OneCare Vermont Accountable Care Organization (ACO), a care coordination and quality improvement organization.

Patients do not have to pay for the test or for discussions with the UVM Health Network's Genomic Medicine Resource Center's genetic counselors before and after testing. The test uses a small amount of blood, and focuses on the parts of a patient's DNA that most affect health and health care. Results will go into each patient's medical record, protected like all medical information, and available to the patient and all of their health care providers.

"Much work has gone into getting ready to start this project and it has taken an entire team," Dr. Leonard said. "Providers from Family Medicine, Cardiology, the Familial Cancer Program, Medical Genetics and Pathology, patient and family advisors, ethics and regulatory compliance leaders, Planning, Finance and OneCare Vermont have all worked together to get us across the start line for this initiative."

Patients should be aware that the UVM Health Network will never call them on the phone to ask them to get this test. Testing is arranged through a patient's primary health care provider and only if the patient agrees to have the test.

THE FUTUREIt's understanding technology that gets us an edge to find the "next Apple," or the "next Amazon."

This is what CML Pro does. We are members of Thomson First Call -- our research sits side by side with Goldman Sachs, Morgan Stanley and the rest, but we are the anti-institution and break the information asymmetry.

The precious few thematic top picks, research dossiers, and one-on-one CEO interviews, are available for a limited time.Join Us: Discover the undiscovered companies that will power technology's future.

Thanks for reading, friends. The author is long shares of Invitae at the time of this writing.


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The University of Vermont Initiates Genomic DNA Testing in Partnership With Genomics Leader Invitae (NYSE:NVTA) as Cigna Joins Invitae's Covered Lives...

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The Companies Offering DNA Testing To Find The Best Cannabis For You – Benzinga

"Genetics" is a word that is often tossed around in the cannabis industry. Even before the boom in legal cannabis, plant enthusiastsknew the value that gene science could add to the recreational and medical experience.

For the most part, efforts in genetic research surrounding cannabis have been focused on the plantinstead of the user.

Cannabis sativas genetic material has been thoroughly studied and dissected, but the quest to understand how our own genes interact with the plant is still in its early stages. Enough knowledge about human-cannabis interaction has been gathered, however, for companies to leave the realm of academic research and enter the commercial space.

Today, if you have $200 and a mailing address, you can obtain a personalized DNA test that will analyze your unique genetic characteristics and explain what type of cannabis best fits your genetic profile.

After a simple cheek swab, these companies can obtain your entire DNA sequence. Their analysis lets them find out the 1% of DNA that makes you special, and then contrast this data to peer-reviews studies on medical cannabisto recommend a method of consumption; aCBD-to-THC ratio; or a selected terpene profile.

What were doing is, were looking at the genetics in a persons body to determine how the body is going to process and respond to cannabis and the compounds that are in cannabis products, said Dr. Charles Sailey, genetic research partner at MelixGX, a company offering genetic testing.

The company's testing system is basedon certain variants that people have in their DNA that cause each individualto respond differently, such as the gene that encodes an enzyme that processes THC or CBD or a gene that encodes the receptors where cannabinoids and terpenes bind.

After looking at all these variants, MelixGXcomes up with an algorithm that predicts the way a person will respond to a particular cannabis product.

Both companies interviewed we spoke raised the issue of a slewof competitors offering the same service.

A clear rift exists between companies doing the genetic tests themselves and expanding research with in-house scientific teams, and those that lack academic expereience and offer a diluted version of the tests without proper scientific support, the execs said.

Consumers looking to take these tests for themselves are advised to look into the company they hire to ensure the best quality is achieved.

Endocanna Health was one of the first companies in the cannabis space to offer this service.

CEO Len May was focusing his studies on plant genetics when he realized that people have different experiences when they consume the same exact cultivar.

That led him to start the company with the goal of finding out which genes and snips single-nucleotide polymorphisms affect the endocannabinoid system, directly or indirectly, he told Benzinga.

The CEO walked us through the way Endocanna makes recommendations after obtaining a users DNA code.

Every single thing that we say has a reference associated to it. Now, the references are given a different weight. If theres a completed human trial, that gets a grade of a 4. If a study is done on an animal, then it gets a 3. If its done in-vitro, then it gets a 2. And if its an observational study, then it gets a 1. These are all peer-reviewed.

If a study is too specific, Endocanna's scientific team will not accept it.

After having created this database, which is updated as new studies come out,the company came up withthe symptomatic conditions, or traits, that relate back to the use of cannabis and where genetics make a difference. These traits includeanxiety, depression, cognitive function, increased chance of pain, sleep and psychosis.

These are all things that people would use cannabis for, so theres three different variables," May said:

If all these three are positive, Endocanna will make a suggestion to the user, the CEO said.

Dont miss out on the top cannabis stories of the day. Click here to sign up for our daily insider newsletter.

Most people in the cannabis space are aware of the fact that, given the U.S. federal ban on cannabisand the drugs classification as a Schedule 1 narcotic, scientific research licenses are difficult to come by.

This situation widely limits the amount of research done on the plant.Thats why we couldnt help but wonder if the scientific community has obtained enough data for companies like Endocanna and MelixGXto make precise recommendations to patients and customers.

Benzinga raised this question withRob Dhoble, an expert in cannabis science and Managing Director of Havas ECS, a consulting firm focused on cannabis communications that is part of the Havas Group.

The companies face a policy dilemma, he said.

Since these companies work under the principle of cannabis as a medicine, and the DEA is still considersmarijuana to have no medical value federally, their products cannot be approved medical devices, and therefore the algorithms they use are in contradiction withfederal law, Dhoble said.

Endoncanna's May said there will never be enough scientific research to be 100% sure of anything.

The technology behind his company and others is ready to make peoples lives better, the CEO said.

Theres over 15,000 articles alone in pubmed on cannabis, he said.

We dont make any claims, we dont make recommendations, we make suggestions. But people have to be cautious, because the cannabis industry is ever-changing. So, do we need more research? Definitely. We encourage everybody to do research, because that research gets fed into our system, and we will get better.

MelixGX's Sailey saidhis company is solely focusing on anxiety, pain and insomnia at thistime, since these are the three areas in which they were able to secure a reasonable amount of data from over 4,000 publications.

Dr. Susan Trap is a Ph.D. researcher who has done extensive research on terpenes and their therapeutic applications.

In general, these pharmacogenetic tests are useful for the novice user to generalize which strains indica, sativaor hybridbest suit their specific cannabis profile, she told Benzinga.

But in her opinion, thesetests still require much more data sampling in order to increase their accuracy, and Trap said thesewill only come with time.

Dr. Jordan Tishler, a Harvard physician and President of the Association of Cannabis Specialists, said the genetic testing companies are headed in the right direction, but said there are several caveats to the way they operate today.

Tishler is skeptical of any kind of suggestion made outside of a medical context since there may be other illnesses, characteristics, medications or situations that are not apparent simply from the genetic material and need to be factored into any medical recommendation.

No field of medicine would base action solely on one test result, he said.

Genetic testing should be used only at the recommendation or order of a treating clinician, and results should be sent to that clinician for interpretation, communication to the patient,and action as needed.

Dr. Levan Darjania has over 18 years of research experience in the biotech and pharma space and is the chief scientific officer at Vertical Wellness.

"This is just a fresh start that requires way more definitive and specific preclinical and clinical studies and validations before it can be recommended as a 'solution'to patients and users."

Picture byArek SochafromPixabayandNikita Golubevfrom Flaticon.

2019 Benzinga does not provide investment advice. All rights reserved.

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Health Department announces services for the week of Nov 11 – Canton Daily Ledger

The Fulton County Health Department has scheduled the following health clinics and services.

CANTON The Fulton County Health Department has scheduled the following health clinics and services. Please call the number listed with each service for an appointment or more information.

All offices of the Fulton County Health Department will be closed Monday, Nov. 11, 2019 in observance of Veterans Day.

Maternal child health: Health screenings, WIC nutrition education and supplemental food coupons for women, infants and children. To make an appointment or for more information call 647-1134 (ext. 254). For Astoria clinic appointments call 329-2922.

Canton - WIC Nutrition Education - Tuesday, Nov. 12 - 8-4 - Appt needed

Astoria - Clinic, WIC Nutrition Educ. - Wednesday, Nov. 13 - 9-3 - Appt needed

Canton - Clinic - Thursday, Nov. 14 - 8-4 - Appt needed

Adult Health Immunizations: Various vaccines are available. There is a fee for immunization administration. Medicaid cards are accepted. To make an appointment or for more information call 647-1134 (ext. 254).

Canton - Immunizations - Tuesday, Nov 5 - 4-7 - Appt needed

Canton - Immunizations - Wednesday, Nov 6 - 8-4 - Appt needed

Other times available by special arrangement at Canton, Cuba and Astoria.

Blood Lead Screening: Blood lead screenings are available for children ages one to six years. A fee is based on income. To make an appointment or for more information call 647-1134 (ext. 254). For Astoria appointments call 329-2922.

Family Planning: Confidential family planning services are available by appointment at the Canton office for families and males of child-bearing age. Services provided include physical exams, pap smears, sexually transmitted disease testing, contraceptive methods, pregnancy testing, education and counseling. Services are available to individuals of all income levels. Fees are based on a sliding fee scale with services provided at no charge to many clients. Medicaid and many insurances are accepted. After hours appointments are available. To make an appointment or for more information call the 647-1134 (ext. 244). *Program funding includes a grant from the US DHHS Title X.

Pregnancy testing: Confidential urine pregnancy testing is available at the Canton and Astoria offices. This service is available to females of all income levels. A nominal fee is charged. No appointment is needed. A first morning urine specimen should be collected for optimal testing and brought to the health department. Services are provided on a walk-in basis on the following days each week:

Canton: Every Wednesday & Thursday, 8-3:30 (for more information call 647-1134 ext. 244)

Astoria: Every Wednesday, 9-2:30 (for more information call 329-2922)

Womens Health: A womens clinic for pap tests, clinical breast examinations and vaginal examinations is available by appointment. There is a nominal fee for this service. Medicaid cards are accepted. Financial assistance is available for a mammogram. Cardiovascular screenings may be available to age and income eligible women. To make an appointment or for more information call 647-1134 (ext. 244).

Mammograms: Age and income eligible women may receive mammograms at no charge. Speakers are available to provide information to clubs and organizations. For more information or to apply for financial assistance, call 647-1134 (ext. 254).

Mens Health: Prostate specific antigen (PSA) blood tests are available for men for a fee. To make an appointment or for more information call 647-1134 (ext. 224).

Sexually Transmitted Disease (STD) Clinic: Confidential STD and HIV testing services are available by appointment to males and females at the Canton office. Services include physical exams to identify STDs, a variety of STD testing, HIV testing, education, counseling, medications and condoms. There is a nominal fee for services. Services are available to individuals of all income levels. Medicaid cards are accepted. To make an appointment or for more information call 746-1134 (ext. 224).

HIV Testing and Counseling: Confidential HIV testing and counseling services are available by appointment through the sexually transmitted disease (STD) clinic at the Canton office. To make an appointment or for more information call 647-1134 (ext. 224).

Tuberculosis (TB) Testing: TB skin tests are available at no charge by appointment. To make an appointment or for more information call 647-1134 (ext. 254).

Blood Pressure Screenings: The Fulton County Health Department provides blood pressure screenings at no charge on a walk-in basis during the following times:

Astoria - Screening - Wednesday, Nov. 13 - 9-12 - Walk in

Health Watch Wellness Program: The Health Watch Program provides low cost lab services. Through this program adults can obtain venous blood draws for a variety of blood tests. Blood tests offered without a doctors order Comprehensive Metabolic Panel (CMP), Complete Blood Count (CBC), Lipid Panel, Prostate Specific Antigen (PSA) test, Hepatitis C test, and Thyroid Stimulating Hormone (TSH). A wide variety of blood tests are also available with a doctors order. There is a charge at the time of service. To make an appointment or for more information call 647-1134 (ext. 254).

Dental Services: The Dental Center offers a variety of basic dental services to children and adults. An appointment is needed. Medicaid and Kid Care cards are accepted. To make an appointment or for more information call 647-1134 (ext. 292).

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