Rectiv

Treatment for Anal Fissure and Fistula

Update: Rectiv (nitroglycerin ointment) Now FDA Approved - June 21, 2011

NDA for Cellegesic is Accepted for Review by FDA


NDA Based on Positive Results of Clinical Trial Conducted Under Special Protocol Assessment Agreed to by FDA

SOUTH SAN FRANCISCO, Calif., September 01, 2004 -- Cellegy Pharmaceuticals, Inc. announced today that the Food and Drug Administration (FDA) has accepted for review the Company's New Drug Application (NDA) for Cellegesic (nitroglycerin ointment) for the treatment of pain associated with chronic anal fissures. The FDA has established May 1, 2005 as the outside date for a decision on approvability of the product for commercial sale in the United States. Scheduling of clinical site audits by the FDA is already underway.

K. Michael Forrest, Cellegy's President and CEO, said, "We are excited by this positive, but not unexpected, development. We have demonstrated in three Phase 3 clinical trials that Cellegesic provides a statistically and clinically significant reduction in the often excruciating pain associated with chronic anal fissures. This result was confirmed by the most recent Phase 3 trial, which was conducted under the provisions of a Special Protocol Assessment (SPA) agreed to by the FDA and the Company. The SPA was intended to provide an assurance that if the primary endpoint of the trial is achieved and no unexpected adverse events are observed, the FDA will approve the product for marketing. We believe we achieved the primary endpoint and expect that the product will be approved in accordance with the stipulations of the SPA. Cellegy plans to commercialize Cellegesic with its own sales force in the United States, assuming approval by the FDA."

Cellegy also recently reported that Cellegesic (branded "Rectogesic(R)" outside the United States) has received "approvable" status by Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom. Formal approval by the MHRA is expected shortly. The MHRA has also agreed to act as a Reference Member State for regulatory filings of the product in other European Community Member States, a process that generally takes about six to nine months from the time formal approval is granted in the Reference Member State.

The United Kingdom will be the first market in Europe in which Rectogesic will be approved, adding to availability in Australia, New Zealand and South Korea, where it was recently launched. Cellegy is currently in discussions with commercial partners for the product in Europe and is seeking a partner in Japan.

It is estimated that there are over two million people in the United States and Europe who suffer from anal fissures, a painful condition for which there are no approved drug products and for which the only effective therapy is a surgical procedure that often leaves patients incontinent. Cellegy believes that the utility of nitroglycerin in treating anal fissures is well recognized and that the Company's product will fill a large unmet medical need. Cellegesic is protected in the United States by issued patents that do not expire until 2017.

About Anal Fissures
An anal fissure is a painful tear in the lining of the anal canal and is associated with increased pressure in the anal canal and a decrease in blood supply. Chronic fissures often are treated with a surgical procedure that involves cutting the internal anal sphincter to decrease pressure in the anal canal. While effective, the procedure is painful, costly and may leave up to 35% of patients with fecal incontinence. Cellegesic may help to avoid the risk of surgery by gently relaxing the sphincter muscle. Fecal incontinence has not been reported in association with Cellegesic.

There are currently no FDA-approved drug therapies for this debilitating condition, which according to Verispan audits, afflicts more than 700,000 Americans and results in more than one million physician visits annually. Recent audit data show about 85,000 annual uses of pharmacy-compounded nitroglycerin for the treatment of anal fissures.

Cellegy believes that, if Cellegesic is approved, the extensive compounding of nitroglycerin by community pharmacies will decline as physicians begin to prescribe Cellegesic. Cellegesic will provide a stable formulation that is prepared under Good Manufacturing Practice conditions to FDA and MHRA approved specifications, and will be consistent from batch to batch.

About the Cellegesic Phase 3 Clinical Trial
Subjects who met the enrollment criteria for a chronic anal fissure were randomized to receive either the placebo ointment or nitroglycerin ointment. The daily records of 24-hour average pain intensity from 187 intent-to-treat subjects (89 Cellegesic-treated and 98 placebo-treated) were analyzed for statistical evidence of efficacy during the first 21 days of treatment as the primary efficacy endpoint. The primary endpoint was successfully achieved (p<0.05).

A secondary endpoint and several tertiary endpoints were also analyzed. The secondary endpoint was time to 50% pain reduction. On average, the time to 50% pain reduction produced by Cellegesic was sooner than the reduction produced by the placebo, although the difference was not statistically significant. Tertiary endpoints included reduction of average pain over the eight-week (56 days) treatment period, reduction of pain upon defecation through days 21 and 56, and healing. Average pain reduction and defecation pain reduction were both statistically significant over 56 days (p<0.05). However, the significance achieved in these tertiary endpoints did not remain statistically significant after applying adjustments to the p-values for the analysis of multiple endpoints. These results were numerically superior to placebo and demonstrate an important positive trend. As in earlier trials, there was no significant difference in fissure healing between Cellegesic and the placebo control.

Side effects seen in the trial were consistent with those observed in the previous two Phase 3 studies. As is typical of nitroglycerin-based products, the most common side effect was headache. Five subjects (5.6% of subjects receiving active drug) withdrew from the study due to headache, but only three (3.4%) of these were nitroglycerin induced.

Results of All Three Phase 3 Studies Combined
Three large, well-controlled studies in 704 subjects with a chronic anal fissure provide by far the largest database related to the effect of nitroglycerin on chronic anal fissure pain. Statistical analysis of the combined data from subjects who applied either Cellegesic or placebo approximately every 12 hours from the three Phase 3 studies showed that reduction in 24-hour average pain intensity was statistically significant through the first 21 days and remained statistically significant for the balance of the eight-week treatment period (56 days). Time to 50% improvement in 24-hour average pain intensity was also significantly shortened. Pain intensity during defecation was significantly reduced through 21 and 56 days.

Headache was the most common side effect in the Phase 3 studies; however, its incidence was similar to that described for nitroglycerin products used to treat angina. Relatively few subjects discontinued treatment due to headache. It is probable that few subjects discontinued due to headache because the relief of their anal fissure pain was more important to them than nitroglycerin-related headaches of relatively short duration. Studies in the clinical literature indicate that nitroglycerin-related headaches may abate with continued use of the medication.

About Cellegy
Cellegy Pharmaceuticals is a specialty biopharmaceutical company that develops and commercializes prescription drugs for the treatment of gastrointestinal disorders, sexual dysfunction, women's health care conditions and certain cancers.

In June 2004, the Company submitted a New Drug Application to the FDA for marketing approval of Cellegesic, a nitric oxide donor for the treatment of chronic anal fissure pain. The product recently received "approvable" status in the United Kingdom. The Company is also pursuing the use of Cellegesic for the treatment of hemorrhoids, as well as dyspareunia, a painful condition that prevents or inhibits sexual intercourse in more than 5 million women in the United States. There is currently no approved product for the treatment for dyspareunia.

Cellegy is also developing two transdermal testosterone gel products. The Company has previously announced results of an interim analysis of a Phase 2 study using Tostrelle(R) for the treatment of female sexual dysfunction showing a favorable response rate of 71% versus a placebo response of 13%. Fortigel(TM), for the treatment of male hypogonadism, was the subject of a Not Approvable letter by the FDA in July 2003. Cellegy is currently in discussions with the FDA that it believes may lead to agreement on the remaining clinical work required for approval of the product. Fortigel (branded Tostrex(R) in Europe) is currently undergoing regulatory review in Sweden. Strakan Pharmaceuticals Ltd., a UK based pharmaceutical company, recently licensed marketing rights to Tostrex for the United Kingdom and other European markets.

Other nitric oxide donor products being developed by Cellegy researchers address a number of conditions including prostate cancer, Raynaud's Disease and Restless Legs Syndrome.

Posted: September 2004

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