Replies to post #77032 on Biotech Values

[DewDiligence]

AGN MRX: …black box for all botulinum-toxin products

AGN’s Pyott thinks the class black-box warning for botulinum toxins will increase Botox’s market share in the US by making injectors less likely to switch from tried–and-true Botox to the unknown Dysport. He may have a point.

From a medical standpoint, the FDA’s black-box warning for all drugs in this class is much ado about nothing, IMO. These products are extremely safe when administered by experienced injectors.

[DewDiligence]

AGN Gets CR Letter for Botox in Upper-Limb Spasticity

[This is a good outcome for AGN in two ways: i) the FDA did not request any new trials; and ii) the FDA endorsed a broader product label than the one proposed by AGN. Shares were little changed in AH trading yesterday.]

http://finance.yahoo.com/news/Allergan-Receives-Complete-bw-15350369.html

›Tuesday May 26, 2009, 4:30 pm EDT

IRVINE, Calif.--(BUSINESS WIRE)--Allergan, Inc. (NYSE: AGN ) today announced it has received a complete response letter from the U.S. Food and Drug Administration (FDA) regarding the Company’s Supplemental Biologics License Application (sBLA) for BOTOX® (Botulinum Toxin Type A) to treat upper limb spasticity in post-stroke adults. Allergan submitted its sBLA for this indication in the third quarter of 2008.

The FDA has not requested additional pre-approval clinical studies. However, the FDA has identified items that must be completed before the sBLA can be considered for approval, including the following:

1. Risk Evaluation and Mitigation Strategy (REMS) and Safety Update:

On April 29, 2009, the FDA approved DYSPORT™ (abobotulinumtoxinA) for the treatment of cervical dystonia in adults and the temporary improvement in the appearance of moderate to severe glabellar lines in adults younger than 65 years of age and imposed a REMS for that product. Concurrently, the FDA requested that Allergan adopt a substantially similar REMS for BOTOX®. Allergan has submitted its proposed REMS for the FDA’s review. The FDA indicated that it had not yet reviewed Allergan’s submission and that an approved REMS will be necessary prior to approving BOTOX® to treat upper limb spasticity. Also, the FDA requested that in its reply to the complete response letter, Allergan provide a product safety update from clinical and non-clinical studies across indications.

2. Source Data Documentation:

While the FDA’s complete response letter acknowledges that the sBLA supports the efficacy and safety of BOTOX® for the treatment of upper limb spasticity, the FDA has requested that Allergan independently verify underlying patient source documentation at study sites relating to one of the pivotal clinical studies conducted in 1999 and upon completion of the verification, provide an updated analysis. In the sBLA, Allergan submitted data from 16 studies including an integrated analysis of 7 double-blind, placebo-controlled trials. Allergan estimates that the re-verification can be completed and the analysis submitted to the FDA in approximately 60 to 90 days.

3. Product Labeling:

In its complete response letter, the FDA proposed revisions to Allergan’s proposed labeling, including enhanced safety information and other clarifications. Among other revisions, the FDA proposed a revised spasticity indication. In its sBLA, Allergan proposed the use of BOTOX® for the treatment of upper limb spasticity associated with stroke. In its complete response letter, the FDA noted the focal nature of BOTOX® treatments and the similarities of spasticity across conditions and thus proposed revised labeling that would broaden the indication of use to upper limb spasticity regardless of underlying cause. Also, noting the number of pediatric patients such as those with juvenile cerebral palsy who suffer from upper limb spasticity, the FDA requested that Allergan conduct a post-approval study for BOTOX® to treat upper limb spasticity in pediatric patients 2-17 years of age. This request is consistent with Allergan’s proposal in connection with the submission of its proposed REMS and Allergan hopes to discuss with the FDA a protocol that, if successful, would support an approval for the treatment of children suffering from spasticity.

Allergan will diligently respond to the FDA’s proposed label revisions and will develop a pediatric plan to further study BOTOX® in children.

“A significant unmet medical need for those suffering from upper limb spasticity exists in the United States. It is estimated that nearly 500,000 Americans each year develop stroke-related spasticity, the majority of which includes upper limb spasticity1,2. And yet about half of those patients receive no treatment for their spasticity,” said Scott Whitcup, M.D., Executive Vice President, Research & Development, Chief Scientific Officer, Allergan, Inc. “We have already submitted our REMS for BOTOX® as we anticipated this requirement as a condition to an approved spasticity indication. We will work expeditiously to provide the FDA with all other information requested in the complete response letter to support a rapid final review of our application for BOTOX® as a treatment for upper limb spasticity.”‹

[DewDiligence]

There’s a Botox-like botulinum toxin from the private company, Merz,
that investors rarely hear about. The drug is Xeomin (a/k/a/ NT-201)
and it has been sold in Europe since 2007. Merz says it plans to submit
a BLA to the FDA in the “near future.”

http://finance.yahoo.com/news/Merz-Pharmaceuticals-prnews-15462122.html

›Merz Pharmaceuticals Announces Results of Clinical Trials with NT-201 (Botulinum neurotoxin type A free from complexing proteins) at Annual Movement Disorders Society Meeting

Monday June 8, 2009, 7:00 am EDT

--First of 2 data sets to be released--

PARIS, June 8 /PRNewswire/ -- Results from two randomized, active-controlled clinical trials in patients with blepharospasm and cervical dystonia -- one placebo-controlled spasticity trial and one upper limb spasticity trial -- were presented at the Movement Disorder Society (MDS) 13th annual International Congress in Paris, France. The studies were sponsored by Merz Pharmaceuticals, which plans to file a Biologic License Application (BLA) for NT-201 in the USA in the near future.

"The results of these studies reaffirm our beliefs that NT-201 (Xeomin®; botulinum neurotoxin free from complexing proteins), can be used to potentially aid focal dystonia and post-stroke spasticity sufferers," said Eric Pappert, M.D., Vice President of Medical Affairs, Merz Pharmaceuticals, USA. "In addition, NT-201 showed results in treating upper limb spasticity sufferers of various etiologies including stroke, brain injury, spinal cord injury, multiple sclerosis or cerebral palsy, warranting additional studies as a potential treatment option for a wide scope of patients."

NT-201 is a neurotoxin therapy free from complexing proteins due to a combination of high biologic activity with low bacterial protein load. It has been approved for marketing in Europe since 2007 to treat various movement disorders, and more recently approved in Canada for the indications of symptomatic management of blepharospasm, cervical dystonia and post-stroke spasticity of the upper limb. "Studies in Europe have shown non-inferiority of NT-201 to one other botulinum toxin in the treatment of cervical dystonia," said Pappert.

First Study - Title

Overall clinical efficacy and overall tolerability of NT-201 (Xeomin®; botulinum neurotoxin free from complexing proteins) authored by R. Benecke, S. Grafe, I. Sassin, and G. Comes.

Method

Efficacy in focal dystonia was analyzed on the pooled data from 2 pivotal clinical trials in blepharospasm and cervical dystonia (343 NT 201 patients; 340 BTXCo* patients) and 1 post-stroke spasticity trial (73 NT 201 patients and 75 placebo patients). For the safety analyses, 6 clinical trials (blepharospasm, cervical dystonia, and upper limb spasticity) have been included (n=539 NT 201, n=442 BTXCo and n=75 placebo subjects). For the post-launch evaluation spontaneously reported adverse events were analyzed.

Results

In the randomized, active-controlled, double-blind studies in focal dystonia NT 201 and one other Botulinum toxin (BTXCo) have been used with a dose ratio of 1:1. The results demonstrate equivalent efficacy between the NT 201 and BTXCo. Onset, waning, and duration of effect were comparable. These findings have been confirmed by the Physician´s Global Impression of Efficacy: 70.6% of BTXCo patients and 71.8% of the NT 201 patients were rated as "good" or "very good." Additionally, in the placebo-controlled spasticity trial 62% of the caregivers rated the efficacy as good or very good compared to placebo (33%). 26.7% of patients in the NT 201 group, 26.0% in the BTXCo group, and 22.7% in the placebo group reported an adverse event. There were no clinically relevant differences between the two active treatment groups in the focal dystonia trials and between NT 201 and placebo in the post-stroke spasticity trial concerning safety aspects. All adverse reactions were either already known and/or were considered by the physician unlikely to be related to NT 201. More than 67,000 patients have been treated so far and no new safety concerns have been reported.

Second Study - Title

NT201 (Xeomin®; botulinum neurotoxin free from complexing proteins) is efficacious and well-tolerated in upper limb spasticity of various etiologies authored by Barnes, M., Schnitzler, A., Amaral e Silva, A., Aquilar, M., Lehnert-Batar, A., and Minnasch, P.

Method

Responder analysis of at least 1-point improvement from baseline to week 4 on the Disability Assessment Scale [DAS] for the primary therapeutic target after injection of a 20 U/mL dilution or 50 U/mL dilution was evaluated. After injection, observation over a 12-week period was followed by 8 weeks safety follow-up. Botulinum neurotoxin doses were derived from the recommendations from the organization WE MOVE. The individual injection pattern was adapted to patient's needs. A two-sided 95% Newcombe-Wilson confidence interval [CI] for the difference between groups was calculated.

Results

192 patients with upper limb spasticity caused by either stroke (88%), brain injury (5.7%), multiple sclerosis (0.5%) or cerebral palsy (1.6%) were randomized to the 50 U/mL dilution group (95 patients) or to the 20 U/mL dilution group (97 patients). Limb position (60.4%), Dressing (24.0%), Hygiene (9.4%) and Pain (6.3%) were chosen as primary therapeutic target on the DAS. The maximum injected total dose was 495 units NT 201. Four weeks after injection 57.1% of patients had an at least 1-point DAS reduction from the baseline score for their primary therapeutic target. No dilution group was inferior to each other regarding efficacy. 79.9% of patients and 89.0% of investigators reported an improvement in global assessment of efficacy at week 4. There were no relevant differences regarding safety between groups.

About Merz

Merz (KGAa) is known worldwide for its development of original compounds and formulations for medical professionals and consumers in 90 countries. Globally, Merz is a leader in research and development of pharmaceuticals for the treatment of neurological and psychological disorders as well as for aesthetic dermatology, including products for the treatment of wrinkles and aging skin, hair loss and acne. Research is concentrated in fields that have a strong need for therapeutic innovation such as Alzheimer's disease, Parkinson's disease, tinnitus, chronic pain conditions, addictions, and neuromuscular disturbances.

Merz Pharmaceuticals, LLC is the wholly owned, US subsidiary of the Merz Group of Companies. A specialty pharmaceutical company, Merz Pharmaceuticals, LLC was established in 1995 and is responsible for the commercialization of Merz (KGAa) products in the US.‹

[DewDiligence]

FDA approves Botox for spasticity:

http://finance.yahoo.com/news/BOTOX-OnabotulinumtoxinA-bw-3010154108.html?x=0&.v=1

This is a modestly consequential approval for AGN. Although Botox has been used off-label for spasticity for many years, reimbursement has not been easy in this indication.

p.s. This approval came three weeks before the PDUFA date!

[DewDiligence]

FDA Approves Xeomin for Cervical Dystonia and Blepharospasm

[Xeomin is a type-A botulinum toxin from Germany’s Merz Pharma that is similar to JNJ’s PurTox and is better, IMO, than either Botox or Dysport. I previously mentioned Xeomin with respect to its stellar efficacy in post-stroke spasticity (#msg-38515815). Xeomin does not yet have an FDA label for cosmetic indications. (Merz is the company that acquired Bioform Medical, which was one of my picks in the 2010 SI charity portfolio.)]

http://finance.yahoo.com/news/FDA-Approves-Merz-prnews-4127522849.html?x=0&.v=1

›Monday August 2, 2010, 8:11 am EDT

GREENSBORO, N.C., Aug. 2 /PRNewswire/ -- Merz Pharmaceuticals today announced that the United States (U.S.) Food and Drug Administration (FDA) has approved Xeomin® (incobotulinumtoxinA), a botulinum toxin type A for the treatment of adults with cervical dystonia or blepharospasm. According to an epidemiology study conducted in Rochester, Minnesota, the prevalence of focal dystonia, which includes cervical dystonia and blepharospasm, is estimated at 295 per million people in the U.S.

"This is an important regulatory milestone for XEOMIN and is key to establishing our neurology business in the U.S.," said Jack Britts, President and CEO of Merz Pharmaceuticals, LLC. "We at Merz understand, and are committed to, addressing the complexities of treating and living with these neurological disorders."

The FDA approval of XEOMIN is based on the results of two pivotal U.S. clinical trials involving adult patients diagnosed with either cervical dystonia or blepharospasm. Additionally, active comparator studies conducted in Europe evaluating XEOMIN versus Botox® (onabotulinumtoxinA) were included among the data submitted in support of the registration filing in these conditions.

XEOMIN is the only botulinum toxin that does not require refrigeration prior to reconstitution. Merz believes this may simplify product distribution and storage, and help ensure product integrity at the time of injection. XEOMIN will be available in 50-unit and 100-unit vials allowing dosing flexibility for administration.

About Dystonia

Dystonias are neurological movement disorders in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. These movements, which are involuntary and sometimes painful, may affect a single muscle (focal), a group of muscles such as those in the arms, legs, or neck (segmental), or even the entire body (generalized). Symptoms can be mild or severe and dystonias may be markedly disabling.

Although dystonia is thought to be rare, it is possibly undiagnosed or misdiagnosed due to lack of specific clinical criteria. While focal dystonia, such as blepharospasm or cervical dystonia, can affect people at any age, most people first experience symptoms in middle age.

According to an epidemiology study conducted in Rochester, Minnesota, focal dystonia, which includes cervical dystonia, and may be characterized by twisting of the neck, and blepharospasm, or excessive eyelid spasm is estimated to affect 295 per million people in the U.S. Dystonias can be disabling, painful and often interfere with patients' daily activities.

About XEOMIN

In nature, Clostridium botulinum produces the toxin in association with ancillary complexing proteins. Manufacturers utilize this naturally occurring protein complex to produce therapeutic botulinum toxin products. Now Merz introduces XEOMIN (incobotulinumtoxinA) which employs a proprietary manufacturing process that isolates the therapeutic component and eliminates these ancillary complexing proteins. XEOMIN has been formulated to have high biologic activity with a low protein load.

XEOMIN is a botulinum toxin type A that is free from complexing proteins. It is FDA approved for the treatment of adults with cervical dystonia, to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naïve and previously treated patients and blepharospasm in adults previously treated with Botox® (onabotulinumtoxinA). Please see important safety information below.

More than 84,000 patients have been treated with XEOMIN worldwide since 2005. The U.S. is the 20th country to approve XEOMIN for the treatment of cervical dystonia and blepharospasm.

About Merz

Merz Pharmaceuticals, LLC is a part of Merz, Inc., a wholly owned U.S. subsidiary of the Merz Group of Companies and was established in 1995 to develop and commercialize products for the Merz Group. Areas of therapeutic focus include Neurology, Dermatology, and Podiatry along with the #1 non-prescription product for scars, Mederma®, and Mederma® Stretch Marks Therapy. With a 102 year heritage, Merz (KGaA) is known worldwide for its development of original compounds and formulations for medical professionals and consumers in 90 countries. Globally, Merz is a leader in the development of pharmaceuticals for the treatment of neurological and psychological disorders as well as for aesthetic medicine. Global research is concentrated in fields that have a strong need for therapeutic innovation such as Alzheimer's disease, Parkinson's disease, tinnitus, chronic pain conditions, addictions, and neuromuscular disturbances.‹