Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for BOTOX(R) and BOTOX(R) Cosmetic

Posted: July 3, 2011 at 3:48 pm

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Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for BOTOX(R)
and BOTOX(R) Cosmetic (onabotulinumtoxinA)

IRVINE, Calif.–(BUSINESS WIRE)–Allergan, Inc. (NYSE:AGN) announced the United States Food and Drug Administration (FDA) has approved a fully in vitro, cell-based assay for use in the stability and potency testing of BOTOX(R) (onabotulinumtoxinA) and BOTOX(R) Cosmetic. The newly approved assay will be implemented immediately for release of product for sale in the United States. Allergan estimates that use of the new assay will reduce the use of animal-based assay testing for BOTOX(R) and BOTOX(R) Cosmetic by up to 95 percent or more over the next three years, as other regulatory agencies around the world approve this new assay. The new assay is the first to be developed and approved for any botulinum neurotoxin currently available worldwide, and is specifically applicable to Allergan’s botulinum toxin type A product.

“We are proud to have achieved this major scientific milestone in the development of a safe and effective alternative test capable of eliminating the need for an animal-based assay for BOTOX(R),” said Scott
Whitcup, M.D., Allergan’s Executive Vice President, Research and Development and Chief Scientific Officer.

“Following the FDA approval, we will work hard to secure approval of the new assay to replace the current animal testing requirements for the release and stability testing of BOTOX(R) and BOTOX(R) Cosmetic in countries in which we market and distribute the product.”

The FDA approval follows more than a decade of Allergan research and development and an approximately $65 million investment directed toward minimizing to the greatest degree possible the need for animal-based assays in the manufacture of BOTOX(R) and BOTOX(R) Cosmetic. The mouse LD(50) potency assay is required by the FDA, the Medicines and Healthcare products Regulatory Agency (MHRA) in Europe and regulatory agencies around the world for testing final product for release to assure its safety and efficacy.

Limitations associated with the current mouse LD(50) assay, which has been the standard for potency and stability testing of BOTOX(R) and BOTOX(R) Cosmetic and other botulinum neurotoxin type A products, include the necessary involvement of animals due to the current structure of the assay, the complexity of the procedures involved, lack of specificity, as well as variability between assays and laboratories.

“The new cell-based potency assay we have developed for BOTOX(R) and BOTOX(R) Cosmetic has many advantages over current methods including the potential for greater precision and consistency in stability and potency testing, making this a significant breakthrough in both the science and manufacturing of neurotoxins,” said Timothy Terrell, DVM, Ph.D, DACVP, Allergan’s Senior Vice President, Drug Safety Evaluation.

Currently all pharmaceutical manufacturers are required by the FDA and by other worldwide health regulatory agencies to protect patients and consumers by assuring product safety and efficacy through
animal testing and other methods. BOTOX(R) is a unique and complex biological product with 21 different approved medical uses, and is derived from natural sources — in this case from the bacterium C. botulinum.

When manufacturing biological products, testing is particularly critical to ensuring the consistent safety and efficacy of each batch of product. BOTOX(R) and BOTOX(R) Cosmetic are the same product, manufactured in exactly the same way, and therefore the potency and stability of each batch must be determined before release, regardless of whether the batch is intended for medical or aesthetic use. BOTOX(R) is Allergan’s only product that has required use of an animal-based assay for stability and potency testing, as mandated
by global regulatory authorities to ensure safe product use in humans.

About the BOTOX(R) Cell-Based Potency Assay (CBPA)
Over the years a number of attempts have been made to find strategies to replace the animal-based LD(50) assay for testing of botulinum neurotoxins but have fallen short for a variety of reasons. Botulinum
neurotoxin is one of the most potent naturally occurring substances and has a complex multi-stage mechanism of action. Purified botulinum neurotoxin type A is the active ingredient in BOTOX(R) and blocks
the release of neurotransmitters from nerves, resulting in a localized and temporary reduction in the overacting muscle or gland. The amount of neurotoxin in BOTOX(R) is extremely small; in fact, less than one
gram per year is required to supply the entire world.

A suitable replacement potency assay to the LD(50) assay must therefore be sensitive enough to measure the complex mode of action of extremely small amount of the neurotoxin used in BOTOX(R) in the cellular level. Established performance criteria against which the new cell-based potency assay needed to be validated included the ability to assess all primary modes of action of the neurotoxin. In addition, the new assay format had to be suitable for use in an intensely quality-controlled environment and at the high capacity needed to support commercial production.

“This significant achievement was made possible by Allergan scientists’ long-standing leadership and deep expertise in neurotoxin research and development, and by our corporate commitment to the ‘3R’ principles of refinement, reduction and eventual replacement of laboratory animals in the final manufacturing stages of
BOTOX(R),” said Dr. Terrell.

The new cell-based potency assay for BOTOX(R) and BOTOX(R) Cosmetic is specific to Allergan’s formulation of botulinum neurotoxin type A. Allergan is discussing how to license the technology to other
parties that share its commitment to implementing non-animal alternatives to animal-based assays in the manufacture of their medical products.

Over the years a number of attempts have been made to find strategies to replace the animal-based LD(50) assay for testing of botulinum neurotoxins but have fallen short for a variety of reasons. Botulinum
neurotoxin is one of the most potent naturally occurring substances and has a complex multi-stage mechanism of action. Purified botulinum neurotoxin type A is the active ingredient in BOTOX(R) and blocks
the release of neurotransmitters from nerves, resulting in a localized and temporary reduction in the overacting muscle or gland. The amount of neurotoxin in BOTOX(R) is extremely small; in fact, less than one
gram per year is required to supply the entire world.

A suitable replacement potency assay to the LD(50) assay must therefore be sensitive enough to measure the complex mode of action of extremely small amount of the neurotoxin used in BOTOX(R) in the cellular level. Established performance criteria against which the new cell-based potency assay needed to be validated included the ability to assess all primary modes of action of the neurotoxin. In addition, the new assay format had to be suitable for use in an intensely quality-controlled environment and at the high capacity needed to support commercial production.

“This significant achievement was made possible by Allergan scientists’ long-standing leadership and deep expertise in neurotoxin research and development, and by our corporate commitment to the ‘3R’ principles of refinement, reduction and eventual replacement of laboratory animals in the final manufacturing stages of BOTOX(R),” said Dr. Terrell.

The new cell-based potency assay for BOTOX(R) and BOTOX(R) Cosmetic is specific to Allergan’s formulation of botulinum neurotoxin type A. Allergan is discussing how to license the technology to other
parties that share its commitment to implementing non-animal alternatives to animal-based assays in the manufacture of their medical products.

About BOTOX(R) (onabotulinumtoxinA)
BOTOX(R) is a prescription-only medical product that contains tiny amounts of highly purified botulinum toxin protein refined from the bacterium, Clostridium botulinum. BOTOX(R) has a unique, protected molecular structure that stabilizes the core toxin in BOTOX(R) from degradation. When injected at FDAapproved and labeled doses into a specific muscle or gland, BOTOX(R) neurotoxin is expected to diffuse locally and produce a safe and effective result by producing a localized and temporary reduction in the overacting muscle or gland, usually lasting up to approximately three months depending on the individual patient.

BOTOX(R) was first approved by the FDA 21 years ago for the treatment of strabismus and blepharospasm, two eye muscle disorders, making it the first botulinum toxin type A product approved in the world. Since its first approval, BOTOX(R) has been recognized by regulatory authorities worldwide as an effective treatment for 21 different indications in approximately 80 countries, benefiting millions of patients worldwide.

In the United States, BOTOX(R) neurotoxin is also approved to treat the abnormal head position and neck pain that happens with cervical dystonia (CD) in adults, symptoms of severe underarm sweating (severe primary axillary hyperhidrosis) when medicines used on the skin (topical) do not work well enough, as well as for the treatment of increased muscle stiffness in elbow, wrist, and finger muscles in adult patients with upper limb spasticity.

In addition to its therapeutic uses, the same formulation of BOTOX(R) with dosing specific to moderate to severe glabellar lines was approved by the FDA in 2002 under the trade name BOTOX(R) Cosmetic (onabotulinumtoxinA). BOTOX(R) Cosmetic is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines (frown lines between the eyebrows) associated with corrugator and/or procerus muscle activity in adult patients up to 65 years of age. Most recently, in 2010, BOTOX(R) was approved by the FDA for the prophylactic treatment of headaches in adults with Chronic Migraine, a distinct and severe neurological disorder characterized by patients who have a history of migraine and suffer from headaches on 15 or more days per month with headaches lasting four hours a day or longer. This latest indication marks the sixth therapeutic indication for the product in the United States since 1989.

In addition to 21 years of clinical experience, the safety and efficacy of BOTOX(R) have been well established in approximately 50 randomized, placebo-controlled clinical trials and in approximately 11,000 patients treated with BOTOX(R) and BOTOX(R) Cosmetic in Allergan’s clinical trials.(1) Worldwide, approximately 26 million vials of BOTOX(R) and BOTOX(R) Cosmetic have been distributed and approximately 29 million treatment sessions have been performed over the past 20 years (1989-2009).(2) With approximately 2,300 articles on BOTOX(R) and BOTOX(R) Cosmetic in scientific and medical journals,(3) BOTOX(R) neurotoxin is one of the most widely researched medicines in the world.

Allergan
800.433.8871
http://www.allergan.com

http://www.botoxmedical.com

http://www.botoxcosmetic.com

Source: Allergan

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