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Study Published in Journal Headache Shows Botox-R- May Reduce the Frequency of Headaches in Patients With a Chronic Form of Migraine

Posted on: Thursday, 7 April 2005, 09:00 CDT

Allergan, Inc. to Move Ahead with Phase III Clinical Trials

An exploratory study published today in the April 2005 issue of the journal Headache, which has been published on-line at the journal's web site http://ahsnet.org/journal/, shows that BOTOX(R) (botulinum toxin type A), when compared to placebo, significantly reduced the frequency of headache attacks in migraine patients suffering from chronic daily headache (CDH) - i.e., headaches and/or migraines that occur on 16 or more days each month.

This Phase II study is one of multiple Phase II clinical trials that Allergan, Inc. (NYSE:AGN) has sponsored to explore the use of its BOTOX(R) product to treat various forms of headache in an effort to identify an appropriate protocol and patient group that will guide its Phase III program. BOTOX(R) was found to be generally well-tolerated across all studies; however, efficacy was not clearly established in several other Phase II trials which used different protocols and studied different patient groups. All Phase II study results are expected to be available in abstract or manuscript format by the end of June 2005. BOTOX(R) is not currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of any headache disorder.

Based on these Phase II findings in CDH, Allergan has reached an agreement with the FDA to move forward with a large Phase III clinical trial program, currently scheduled to begin in late 2005, to investigate the safety and efficacy of BOTOX(R) as a prophylactic therapy in a subset of migraine patients with CDH.

"Patients suffering from CDH are at the most severe end of the migraine/headache spectrum(1)," said Dr. Scott Whitcup, Allergan's Executive Vice President, Research and Development. "The disability associated with this disorder can be substantial and touch every aspect of a patient's quality of life."

"Little research has been dedicated to investigating prophylactic therapy in migraine patients with CDH," said Ninan T. Mathew, M.D., Director, Houston Headache Clinic, Former President of the International Headache Society and American Headache Society, and lead author of the published study. "This is the first clinical trial of its kind to assess this extremely difficult-to-treat patient population."

Results of the Core Phase II Clinical Trial

This was a randomized, double-blind, placebo-controlled, parallel-group exploratory clinical trial designed to investigate the safety and efficacy of BOTOX(R) as a prophylactic treatment for CDH. The study involved 355 patients (84.5% female; mean age 43.5 years) who suffered from headaches on 16 or more days during the 30-day baseline period. All patients in the study experienced at least one migraine or probable migraine during the baseline period and therefore were classified as migraineurs with CDH.

Patients were randomized to receive three treatments with BOTOX(R) or placebo every 90 days for nine months. The total BOTOX(R) dose range was 105 to 260 units per treatment.

The between-group difference on the primary efficacy measure (i.e., change from baseline in the number of headache-free days) did not reach statistical significance (BOTOX(R) 6.7 vs. placebo 5.2, p=0.30). Significant differences compared to placebo were demonstrated on other key efficacy measures, including:

-- Within 30 days following the first treatment, BOTOX(R)-treated patients experienced significantly fewer headaches than placebo-treated patients, an effect that was sustained throughout the nine-month study. The difference was greatest at day 180, when BOTOX(R)-treated patients experienced an average of 7.1 fewer headache attacks per 30 day period, compared to 3.7 fewer attacks among placebo-treated patients (p=0.001).

-- In addition, a significantly higher percentage of BOTOX(R)-treated patients had a decrease from baseline of greater than or equal to 50% in the frequency of headache days.

-- Differences on key efficacy measures in favor of BOTOX(R) were even more evident in a subgroup analysis of study patients who were not taking other prophylactic medications to treat their headaches.(2) In addition, these patients had a significant decrease in the use of acute medication to treat their headache pain compared to placebo-treated patients.

Treatment with BOTOX(R) was generally well-tolerated in the studied population of migraine patients with CDH. 2.3% (4/173) of BOTOX(R)-treated patients discontinued from the study due to reported treatment-related adverse events. The most frequently reported treatment-related adverse events among BOTOX(R)-treated patients were muscular weakness (22%), neck pain (13.3%), headache (6.9%) and blepharoptosis (6.9%). The most frequently reported treatment-related adverse events in the placebo group were headache (6%) and injection-site hemorrhage (4.9%).

"The results from studies in headache and migraine are sometimes difficult to interpret because of confounding factors such as the simultaneous use of other migraine medications, as well as the high placebo response rates that are common to pain trials in general," said David W. Dodick, M.D., Department of Neurology, Mayo Clinic College of Medicine in Arizona, involved in Allergan's BOTOX(R) Phase II program design, and one of the lead investigators for its Phase III program.

About Chronic Daily Headache

Between 12 and 15 million Americans currently suffer from CDH, a highly disabling headache disorder characterized by 16 or more days of headache per month.(3)

In headache specialty clinics, it is estimated that 80% of all CDH patients are migraine patients whose condition has evolved into a chronic form of frequent headache.(4)

There are no therapies approved by regulatory authorities specifically for the prophylactic treatment of migraine patients with CDH. Classes of drugs currently used for this purpose include beta-blockers, calcium channel blockers, serotonin antagonists, antidepressants, nonsteroidal anti-inflammatory drugs, and antiepileptic drugs.

About BOTOX(R)

BOTOX(R) is a medical product that contains tiny amounts of highly purified botulinum toxin protein refined from a bacterium. The product is administered in small therapeutic doses by injection directly into the affected area, and works by blocking the overactive nerve.

BOTOX(R) therapy was granted approval by the FDA in 1989 for the treatment of strabismus (crossed eyes) and blepharospasm (uncontrollable eye blinking) associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above. BOTOX(R) has since received approval in December 2000 for the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia. In 2002, with dosing specific to treat frown lines between the eyebrows, the product was approved by the FDA for the temporary improvement in the appearance of moderate to severe glabellar lines (the vertical "frown lines" between the eyebrows) in adult men and women aged 65 and younger, under the name BOTOX(R) Cosmetic. More recently, in July 2004, BOTOX(R) was granted FDA approval for the treatment of severe primary axillary hyperhidrosis (excessive underarm sweating) that is inadequately managed with topical agents. In the U.S., BOTOX(R) is currently being investigated for the treatment of additional medical conditions, including migraine and headache, post-stroke spasticity, and overactive bladder.

Important Risk Information

BOTOX(R) and BOTOX(R) Cosmetic treatment is contraindicated in the presence of infection at the proposed injection site(s) and in individuals with known hypersensitivity to any ingredient in the formulation. Serious and/or immediate hypersensitivity reactions have been rarely reported. These reactions include anaphylaxis, urticaria, soft tissue edema, and dyspnea. If such a reaction occurs further injection of BOTOX(R) should be discontinued and appropriate medical therapy immediately instituted. BOTOX(R) and BOTOX(R) Cosmetic should only be diluted with 0.9 percent non-preserved sodium chloride. Individuals with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis, or motor neuropathy) or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should only receive BOTOX(R) or BOTOX(R) Cosmetic with caution. Patients with neuromuscular disorders may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of BOTOX(R) or BOTOX(R) Cosmetic. There have been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. The exact relationship of these events to the botulinum toxin injection has not been established.

BOTOX(R) for Blepharospasm in Patients greater than or equal to 12 Years of Age: Reduced blinking from BOTOX(R) injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal perforation. The most frequently reported treatment-related adverse reactions in these patients are ptosis (20.8%), superficial punctate keratitis (6.3%) and eye dryness (6.3%).

BOTOX(R) for Strabismus in Patients greater than or equal to 12 Years of Age: Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past pointing. The most commonly reported adverse effects are ptosis (16%) and vertical deviation (17%).

BOTOX(R) for Cervical Dystonia in Adults: There have been rare cases of dysphagia severe enough to warrant the insertion of a gastric feeding tube. The most frequently reported adverse reactions in patients with cervical dystonia are dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%).

BOTOX(R) for Severe Primary Axillary Hyperhidrosis Inadequately Managed with Topical Agents: Patients should be evaluated for potential causes of secondary hyperhidrosis (e.g., hyperthyroidism) to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of the underlying disease. The most frequently reported adverse events (3 - 10%) are injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, and anxiety.

BOTOX(R) Cosmetic for Temporary Improvement in the Appearance of Frown Lines between the Brows: The most frequently reported adverse events are headache (13.3%), respiratory infection (3.5%), flu syndrome (2%), blepharoptosis (3.2%) and nausea (3%).

Full prescribing information for BOTOX(R) and BOTOX(R) Cosmetic is available at www.botox.com and www.botoxcosmetic.com.

Forward-Looking Statements

This press release contains "forward-looking statements," including, among other statements, the statements by Dr. Whitcup, Dr. Mathew and Dr. Dodick, statements regarding research and development and regulatory outcomes, efficacy, adverse event profiles, and market and product potential. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from Allergan's expectations and projections. Risks and uncertainties include general industry and pharmaceutical market conditions; general domestic and international economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents obtained by competitors; challenges inherent in product marketing such as the unpredictability of market acceptance for new pharmaceutical and biologic products and/or the acceptance of new indications for such products; domestic and foreign health care reforms; the timing and uncertainty of the research and development and regulatory processes; trends toward managed care and health care cost containment; and governmental laws and regulations affecting domestic and foreign operations. Allergan expressly disclaims any intent or obligation to update these forward-looking statements except as required to do so by law. Additional information concerning these and other risk factors can be found in press releases issued by Allergan, as well as Allergan's public periodic filings with the Securities and Exchange Commission, including the discussion under the heading "Certain Factors and Trends Affecting Allergan and its Businesses" in Allergan's 2004 Form 10-K. Copies of Allergan's press releases and additional information about Allergan is available on the World Wide Web at www.allergan.com or you can contact the Allergan Investor Relations Department by calling 1-714-246-4636.

About Allergan, Inc.

Allergan, Inc., with headquarters in Irvine, California, is a technology-driven, global health care company providing specialty pharmaceutical products worldwide. Allergan develops and commercializes products in the eye care, neuromodulator, skin care and other specialty markets that deliver value to its customers, satisfy unmet medical needs, and improve patients' lives. -0- *T (1)International Headache Society, 2004 (2)Dodick DW, Mauskop A, Elkind AH, DeGryse R, Brin MF, Silberstein SD. Botulinum toxin type A for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medication (a randomized double-blind, placebo-controlled study). Headache 2005: in press. (3)Castillo J, Munoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache 1999;39:190-196. (4)Castillo J, Munoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache 1999;39:190-196. *T

Source: Business Wire

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