LA JOLLA, Calif., Jan. 23, 1997 -- Agouron Pharmaceuticals, Inc. (Nasdaq-NNM: AGPH) today summarized results from clinical trials of the company's HIV protease inhibitor VIRACEPT(R) (nelfinavir mesylate). Included are results from pivotal phase II/III clinical trials which form the basis of a New Drug Application submitted by Agouron to the U.S. Food and Drug Administration last month and which represent significant new evidence of the safety and efficacy of VIRACEPT.
General Safety and Efficacy
Each of three double-blind clinical trials evaluated two doses of VIRACEPT: 500mg or 750mg VIRACEPT taken three times daily with meals. In one study, 91 HIV-positive patients were randomized to receive either of the two doses of VIRACEPT alone. In a second study, 297 patients were randomized to receive one of the two VIRACEPT doses plus stavudine (d4T), or d4T alone. In a third study, 308 patients were randomized to receive one of the two VIRACEPT doses plus zidovudine (AZT) and lamivudine (3TC), or AZT and 3TC alone. Primary endpoints followed in these trials were changes in two surrogate markers: viral load (the amount of HIV detected in patients' blood) and CD4+ T cells (cells indicating the status of the immune system). Viral load was generally measured by a standard assay with a lower limit of detection of 500 HIV particles per ml.
In all three trials, the treatment arms containing VIRACEPT produced improvements in viral load compared with control arms that were highly statistically significant (p<0.0001). The treatment arms also produced improvements in CD4+ T cell counts that were statistically significant in all three trials. When all patients were evaluated, the 500mg and 750mg doses of VIRACEPT taken in combination with other anti-HIV drugs were equally effective.
VIRACEPT was safe and well tolerated in the pivotal trials. The only side effect of moderate (Grade 2) or greater intensity with a frequency of 10% or greater was diarrhea. Many of the side effects observed with other HIV protease inhibitors were seen only rarely or not at all with VIRACEPT. In the three pivotal trials, 4% of 696 patients discontinued due to adverse events; only 1.6% of patients discontinued due to diarrhea. Despite the large number of concurrent medications used by the 696 patients in the pivotal studies, only one possible significant drug interaction was reported. Very few laboratory abnormalities were seen in patients on the studies.
Triple Drug Therapy
Dr. William Powderly, M.D. of Washington University School of Medicine, St. Louis, will report results tomorrow from the clinical trial of primary relevance to the prospective clinical use of VIRACEPT -- the study of VIRACEPT taken in combination with AZT and 3TC. After six months of treatment in this study, mean reductions in viral load (when measured to a lower limit of 100 particles/ml) were 2.3 and 2.5 log10 (greater than 99%) for the triple combination arms containing the 500mg and 750mg doses of VIRACEPT, and 1.4 log10 for AZT and 3TC alone. Mean increases in CD4+ T cells were 160 and 155 cells for the triple combination arms containing VIRACEPT and 105 cells for AZT and 3TC alone.
At the end of six months, HIV levels fell below 500 particles per ml in 65% and 81%, of patients receiving the 500mg and 750mg three times daily doses of VIRACEPT in triple drug therapy and in 18% of those receiving AZT and 3TC alone. In the triple drug therapy, the 500mg and 750mg doses of VIRACEPT were equally effective in reducing HIV below 500 particles per ml in patients who had baseline viral loads less than 100,000; but the 750mg dose was significantly superior (p=0.01) in producing such reductions in patients with baseline viral loads greater than 100,000.
All VIRACEPT-containing treatment arms in the three clinical studies produced acute reductions in viral load greater than 1.0 log10 (90%). However, reductions were better sustained after four to six months by the three drug combination than by the combination of VIRACEPT plus d4T (mean reduction of 1.0 - 1.1 log10) or by VIRACEPT monotherapy (mean reduction of 0.2 - 0.6 log10).
Resistance and Cross Resistance
Genetic analysis of HIV from 55 patients from earlier pilot clinical studies showed that resistance to VIRACEPT was strongly associated with a specific mutation (D30N) in the HIV protease. HIV which became resistant to VIRACEPT due to the D30N mutation, whether isolated from patients or created by genetic engineering techniques, remained susceptible to other HIV protease inhibitors. In a separate analysis, 14 of 23 (61%) clinical isolates from patients who were reported to have failed therapy with indinavir, ritonavir or saquinavir remained susceptible to nelfinavir.
VIRACEPT Plus Other Protease Inhibitors
Preliminary data indicate that the combination of VIRACEPT and a second HIV protease inhibitor, Roche's Invirase(TM) soft gel (saquinavir), may be a useful therapy. In a pharmacokinetic study, co-administration of Invirase and VIRACEPT resulted in significant increases in plasma levels of saquinavir and no significant change in plasma levels of VIRACEPT. After 12 weeks of treatment with VIRACEPT and saquinavir, the median decrease in viral load of 13 patients was 2.0 log10 (99%) with HIV falling below 500 particles/ml in eight patients. The median increase in CD4+ T cells was 118 cells. The combination of VIRACEPT and saquinavir was generally safe and well tolerated. An expanded trial of the combination VIRACEPT and saquinavir is currently in progress.
Additional pharmacokinetic studies of VIRACEPT taken concurrently with other protease inhibitors showed that VIRACEPT increased trough plasma levels of indinavir and that indinavir and ritonavir significantly increased plasma levels of VIRACEPT. Clinical trials to evaluate the safety and efficacy of VIRACEPT in combination with these HIV protease inhibitors are planned.
VIRACEPT Pediatric Study
Data from a phase I study of children ages 2-13 indicate that VIRACEPT oral powder and tablets yielded similar plasma concentrations. A dose of 20- 25 mg/kg three times daily in children yielded steady-state plasma concentrations similar to adult patients receiving 500mg or 750mg VIRACEPT three times daily as tablets. VIRACEPT was safe and well tolerated in children.
The results from VIRACEPT studies are the subjects of reports by several investigators this week at the 4th Conference on Retroviruses and Opportunistic Infections in Washington, D.C. Presenters include: Dr. Keith Henry, St. Paul Ramsey Medical Center in St. Paul; Dr. Steven Kravcik, Ottawa General Hospital in Ottawa, Ontario; Dr. Paul Krogstad, University of California, Los Angeles; and Dr. Amy Patick and Dr. Brad Kerr, Agouron Pharmaceuticals, Inc. VIRACEPT is being developed by Agouron in collaboration with the pharmaceutical division of Japan Tobacco Inc.
Agouron Pharmaceuticals, Inc. is a pioneer and leader in technologies permitting the rational design of novel, small molecule drugs based upon the molecular structures of proteins which play key roles in human disease. Agouron is currently applying these technologies to the design and development of novel drugs for treatment of cancer, AIDS, and other serious diseases.
