San Diego, CA, September 27, 1998 - Clinical investigators today presented Phase III clinical trial data for the HIV protease inhibitor Agenerase` (amprenavir) which suggest that the drug may be potent and generally well-tolerated in combination with Epivir" (lamivudine) also known as 3TC", and Retrovir" (zidovudine; AZT). These data, presented at a late-breaker slide session at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) support the role of Agenerase in front-line combination antiretroviral therapy.
An as-treated analysis of interim 16 week data showed that 88% of patients taking triple therapy with Agenerase+Epivir+Retrovir achieved viral load below the limit of detection of standard assays (<400 copies/mL), compared to 19% of patients taking Epivir+Retrovir alone. An additional analysis showed that 59% of patients receiving this regimen achieved viral load below the limit of detection of an investigational ultrasensitive assay1 (<50 copies). An as-treated analysis evaluates only those patients who remain on study medication through the entire study period.
"In this trial, Agenerase appears to provide a significant amount of virus suppression when given in combination with two reverse transcriptase inhibitors," said Dr. Jeffrey Goodgame, M.D., lead investigator for the study and Associate Professor at the University of Central Florida. "Data generated in smaller studies have supported the potential clinical utility of Agenerase in a number of different regimens, including dual protease inhibitor combinations."
Agenerase (formerly known as 141W94 or VX-478) is a second-generation protease inhibitor that is now being made available in the United States to certain patients through an early access program. Phase III data presented today are intended to support applications to be submitted later in the fall by Vertex's partner Glaxo Wellcome for approval to market Agenerase in the United States and the European Union.
"Though preliminary, we believe these data are consistent with those generated in smaller Phase II studies which have suggested that Agenerase is a potent inhibitor of HIV," said Lynn Smiley, M.D., Vice President of Antiviral Clinical Research at Glaxo Wellcome. "We are pleased and encouraged by these early results as they support the clinical utility of regimens containing Agenerase."
In clinical trials, Agenerase has been administered twice daily and may be useful in simplifying potent combination antiretroviral drug regimens. Most currently marketed protease inhibitors require three times per day dosing. Currently, the standard of care in HIV treatment calls for first line use of combination therapy that generally includes a protease inhibitor. Since being introduced in late 1995, protease inhibitors have been clearly associated with significant reductions in AIDS-related deaths and progression of disease. Protease inhibitors intervene late in the viral life cycle and are the only class of drugs that block virus production in cells already infected with HIV.
Data reported today by Dr. Goodgame are from Protocol 3001, an ongoing double-blind, placebo-controlled, international multicenter study to compare the safety, tolerance, viral load reduction, and CD4 lymphocyte response of Agenerase+Retrovir+Epivir vs. Retrovir+Epivir at 16 weeks. In this study, Agenerase in combination with Epivir and Retrovir showed statistically significant superiority at reducing the amount of virus in blood as compared to the combination of Epivir and Retrovir alone. At 16 weeks, 88% (65 of 74) of patients in the treatment arm containing Agenerase achieved viral loads below the limit of detection of standard assays (<400 copies/mL), compared to 19% in the Epivir+Retrovir arm (as-treated analysis). Researchers also showed that 59% (52 of 88) of patients receiving triple combination therapy with Agenerase achieved viral load below the limit of detection of an investigational ultrasensitive assay (<50 copies) at 16 weeks (intent-to-treat analysis, collected data only). Preliminary data also suggested that Agenerase is not associated with significant increases in cholesterol and triglyceride levels at 16 weeks.
An additional, more conservative intent-to-treat analysis, in which patients who withdrew from the study prematurely were considered treatment failures, indicated that 59% (66 of 112) of patients receiving triple combination therapy with Agenerase achieved viral load below 400 copies at 16 weeks compared to 17 percent (19 of 109) in the dual combination arm.
Intent-to-treat analyses are the basis on which investigational anti-HIV drugs are reviewed by the FDA, and are considered to offer an expectation of a regimen's success in a population. However, as-treated analyses are preferred by many physicians as they provide a more practical expectation of a regimen's success in individual patients who can be kept on a particular therapy over time. Each analysis provides a different useful perspective.
The most commonly reported adverse events in the Agenerase arm of the study were mild to moderate and transient. They included nausea, vomiting, fatigue, gaseous symptoms, headache and circumoral paresthesia. Of the patients assigned to the Agenerase arm who actually started but later discontinued therapy, 13 discontinued therapy due to nausea or other gastrointestinal symptoms, two discontinued due to anemia, and two discontinued due to rash. Of the patients assigned to the double arm who discontinued therapy, one discontinued due to rash, one discontinued due to anemia, and two discontinued due to gastrointestinal symptoms. The study involved 232 patients who had not previously been treated for HIV. After week 16, patients with plasma HIV RNA levels above the 400 copy/mL limit were allowed to switch therapies, which included adding open label Agenerase and changing other therapies in the regimen. Assessments of antiviral activity and safety will continue until the last subject completes 48 weeks on study.
"The considerable body of data now available suggests that Agenerase is well-suited to the current standard of care and the need for simpler regimens," commented Dr. Vicki Sato, Senior Vice President and Chief Scientific Officer of Vertex. "These Phase III data complement results from Phase II clinical trials that have suggested that Agenerase provides potent antiviral activity when given twice daily in two-, three-, and four-drug combinations involving available and investigational antiretroviral therapies."
A progressive early access program is making Agenerase available to patients in three protocols, including two for patients who have already failed a protease-inhibitor containing regimen. Physicians interested in enrolling patients into the program can call 1-800-248-9757 for more information. Patients must have their physicians call if they are interested in being enrolled.
Agenerase was discovered by scientists at Vertex Pharmaceuticals of Cambridge, Massachusetts. Glaxo Wellcome has been responsible for product formulation, design and implementation of clinical trials, as well as regulatory submissions to the U.S. Food and Drug Administration. Glaxo Wellcome will also lead the commercialization efforts for Agenerase with co-promotion from Vertex Pharmaceuticals. Glaxo Wellcome is the pharmaceutical industry leader in HIV research and therapies. The company currently manufactures and markets Epivir and Retrovir, as well as Combivir(r) (lamivudine/zidovudine) which combines Epivir and Retrovir into one tablet.
Vertex Pharmaceuticals Incorporated (Nasdaq:VRTX) is engaged in the discovery, development and commercialization of novel, small molecule pharmaceuticals for the treatment of diseases for which there are currently limited or no effective treatments. The Company is a leader in the use of structure-based drug design, an approach to drug discovery that integrates advanced biology, biophysics and chemistry. The Company is concentrating on the discovery and development of drugs for the treatment of viral diseases, multidrug resistance in cancer, autoimmune and inflammatory diseases, and neurodegenerative diseases.
There can be no assurance that clinical trials will continue, that initial results will be predictive of any future results, that drugs under development by Vertex or its partners will receive marketing approval from the U.S. Food and Drug Administration or other regulatory authorities, or that drugs, if any, which receive such approval will be marketed successfully. Investors are also directed to consider other risks and uncertainties discussed in Vertex documents filed with the Securities and Exchange Commission.
1 Viral load assays used in this study included the Roche Amplicor (less than 400 copies/mL of plasma) and the Roche Ultrasensitive (less than 50 copies/mL of plasma). The Ultrasensitive assay is still investigational and has yet to be validated.