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Thursday March 26, 8:40 pm Eastern Time
Company Press Release
SOURCE: Ligand Pharmaceuticals Incorporated
Ligand Reports Positive Final Results of Pivotal International Phase III
Trial For Ligand's Panretin(TM) Gel Confirms Plan to File NDA by End
of May or Earlier
SAN DIEGO, Calif., March 26 /PRNewswire/ -- Ligand Pharmaceuticals Incorporated (Nasdaq: LGND - news) today
announced the unblinding and analysis of the final results of its international Phase III pivotal trial for Panretin(TM) gel in 134
patients with AIDS-related Kaposi's sarcoma (KS). In the final analysis of the trial data, 37.1 percent of patients (23 of 62)
treated with Panretin gel experienced complete or partial response compared to 6.9 percent of patients (5 of 72) using a
placebo (vehicle gel with no active ingredient), producing a ''p value'' of 0.00003. Based on the results of both the North
American and international Phase III trials, the Company now intends to file a U.S. New Drug Application (NDA) by the end
of May or earlier. The Company believes Panretin gel would be the first NDA submitted to the FDA for a topical product to
be used in the treatment of KS.
''We believe the additional positive information from the final results of this pivotal Phase III trial (conducted by our former
ALRT partner through a contract research organization) provides significant added strength to an already strong first NDA
submission. In order to provide sufficient time to insure the highest quality and incorporate the strongest data results available to
us today, we have decided to take an additional six to eight weeks to file our NDA on Panretin gel for KS. We believe that this
time will not only be time well invested for quality purposes, but may also simplify or shorten the review time by the agency,
helping to minimize time to market,'' said Ligand Chairman, President/CEO David E. Robinson.
The international pivotal Phase III trial was stopped early in August of 1997 at 82 patients because a planned interim analysis
specified in the protocol showed a 42 percent (15 of 36 patients) response to Panretin gel compared with 7 percent (3 of 46
patients) response to placebo. The p value of the interim analysis was 0.00027, and the p value of the final analysis is 0.00003,
making the results statistically similar and strongly positive. These results were consistent with the final results of the North
American pivotal Phase III trial of Panretin gel in KS which were reported in December of 1997 and with the final and interim
data from that trial which will be presented at the 12th International AIDS Conference in Geneva, Switzerland in June of this
year.
''We have treated approximately 450 KS patients to date, and the results of all of our clinical trials with Panretin gel in KS
have been consistent and demonstrate the activity of Panretin gel in AIDS-related Kaposi's sarcoma,'' according to Steven D.
Reich, M.D., Ligand Senior Vice President, Clinical Research.
Study Design
The international Phase III trial was a randomized, double-blind, placebo- controlled, 12-week study of topical Panretin gel in
the treatment of cutaneous AIDS-related KS. The objective of the trial was to compare the efficacy of Panretin gel (containing
0.1% active agent) to placebo vehicle gel when applied topically and to determine the safety and tolerability of the formulation
in this patient group.
Methodology
The protocol for the international Phase III trial called for patients to be treated with either a 0.1% gel formulation of Panretin
or placebo vehicle gel, applied twice daily to cutaneous KS lesions for 12 weeks. Patients were seen for assessment at 2, 4, 8
and 12 weeks after trial entry and responses were defined using AIDS Clinical Trial Group (ACTG) criteria applied to topical
therapy of designated KS index lesions. After 12 weeks, qualifying patients could continue treatment with open-label Panretin
gel on a separate protocol.
Results
The international Phase III trial of Panretin gel in patients with AIDS- related KS included 134 patients in the final analysis. In
the trial, 37.1 percent of patients (23 of 62) treated with Panretin gel experienced complete or partial response compared to
6.9 percent of patients (5 of 72) using a placebo (vehicle gel with no active ingredient), a result that was statistically significant
at a ''p value'' of 0.00003. The trial, conducted at approximately 30 centers in the U.S., UK, France, Germany and Australia,
was initiated in September of 1996. The results of this study also are intended to be used to file a Marketing Authorization
Application in Europe.
''Panretin gel was very well-tolerated and was associated with an 5-fold improvement in response rate when compared to
vehicle gel in the international Phase III trial,'' said Dr. Neil Bodsworth, Taylor Square Private Clinic, Sydney, Australia, who
served as a clinical investigator for the study. Dr. Bodsworth will present the interim and final results of the international Phase
III trial at the12th International AIDS Conference in Geneva, Switzerland in June.
Interim Analysis of Phase III International Trial
In August 1997, the international Phase III trial of Panretin gel in patients with AIDS-related KS was stopped early because of
a planned interim analysis which would permit its early conclusion if a significant number of patients were receiving clear benefit
from Panretin gel treatment. The interim analysis showed a 42 percent (15 of 36) patient response to Panretin gel compared
with a 7 percent (3 of 46) patient response to placebo.
Positive North American Trial Results
Results of the Phase III North American trial, which were released in December 1997, demonstrated that 35.1 percent (47 of
134) of patients treated topically with Panretin gel experienced complete or partial response compared to 17.9 percent (24 of
134) of patients using a placebo (vehicle gel with no active ingredient), a result that was statistically significant at a p value of
0.002. Patients in the Panretin gel group had the option of continuing treatment after the blinded portion of the study was
complete. The response rate (complete and partial response) for patients initially assigned to Panretin gel using all currently
available data from the blinded phase through the open-label phase was 49 percent (66 of 134). The final results of the North
American Phase III study, which included 268 patients at 32 U.S. and three Canadian centers, will be presented at the 12th
International AIDS Conference in June.
Kaposi's Sarcoma
Kaposi's sarcoma was first described in 1872 by the Austro-Hungarian dermatologist, Moritz Kaposi. Until the HIV disease
epidemic identified with AIDS, KS was a rarely diagnosed tumor. However, KS is the most frequent malignant cancer lesion in
patients who are HIV-positive and is often characterized by multifocal, widespread lesions at the onset of illness, and may
involve the skin, oral mucosa, lymph nodes and visceral organs, such as the lung and gastrointestinal tract. The Company
estimates that between 15,000 to 25,000 patients in the U.S. are affected by the disease.
Additional Studies with Panretin(TM) Capsules for KS
Panretin capsules have been studied in two single-agent Phase II trials and are in a Phase I/II trial in combination with interferon
for patients with AIDS-related Kaposi's sarcoma. Interim analyses of the two Phase II trials with Panretin capsules in patients
with AIDS-related KS showed intent-to-treat patient response rates at 16 or more weeks of 38 percent and 37 percent.
Results from one or both of these trials will be presented at upcoming scientific meetings including the National Cancer
Institute's (NCI) AIDS Malignancy Conference in Bethesda, MD in April, the American Society of Clinical Oncology (ASCO)
in May in Los Angeles, and the 12th International AIDS Conference in June.
The two studies were similar in design, with one conducted by the AIDS Malignancy Consortium (AMC) sponsored by NCI
and the other sponsored directly by Ligand. Both were multicenter, open-label studies designed to evaluate the safety and
efficacy of Panretin Oral in patients with AIDS-related KS.
Since 1989, Ligand Pharmaceuticals Incorporated has established a leadership position in gene transcription technology,
particularly intracellular receptor (IR) technology and Signal Transducers and Activators of Transcription (STATs). Ligand has
applied IR and STATs technology to the discovery and development of small molecule drugs to enhance therapeutic and safety
profiles and to address unmet patient needs in cancer, women's and men's health and skin diseases, as well as osteoporosis,
metabolic, cardiovascular and inflammatory disease.
This news release may contain certain forward looking statements by Ligand and actual results could differ materially from
those described as a result of factors including, but not limited to, the following. There can be no assurance Panretin Capsules,
Panretin Gel, or any product in the Ligand pipeline, will be successfully developed, that final data will be consistent with interim
data, that regulatory approvals will be granted in a timely manner, or at all, that patient and physician acceptance of these
products will be achieved, that final results will be supportive of regulatory approvals required to market products. Ligand
undertakes no obligation to update the statements contained in this press release after the date hereof.
SOURCE: Ligand Pharmaceuticals Incorporated
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