PRNewswire - Monday November 9, 1998

The double PI trial, known as PROA2001, evaluated patients randomized to treatment with Agenerase in combination with one of three protease inhibitors, or Agenerase in combination with the NRTIs AZT+3TC. According to the study results, 63 percent of patients(A) (10 of 16) taking Agenerase plus either indinavir, saquinavir, or nelfinavir had plasma viral RNA below 400 copies/mL at 48 weeks, and 42 percent of these patients (8 of 19) had viral load below 50 copies/mL(B) at 24 weeks. Median increases from baseline in CD4 cell counts of approximately 100 cells were observed in all three dual PI treatment groups through week 48.

The regimens also appear to be well-tolerated. Through 24 weeks of treatment, 96 percent of adverse events were mild to moderate (grade 1 or 2) in severity. Through 48 weeks of treatment, none of the patients on a double protease inhibitor regimen had a severe adverse event that was considered to be drug-related. The most frequently occurring adverse events, regardless of attributability, were diarrhea, nausea, oral/perioral paresthesia, fatigue, headache and rash. A total of 33 patients received study drug. Ten patients withdrew consent, were lost to follow up, or were withdrawn for protocol violations in the first 24 weeks of the study.

Dr. Gabe Torres, Co-Director Bentley Salick Medical Practice said, "The durability of response to this novel therapeutic regimen is very encouraging with strong antiviral activity being observed over the 48-week treatment period. In addition, reported adverse events were mild to moderate through week 24 of the study. This particular combination involving two potent agents from one class, including amprenavir, is very encouraging."

One reason for the success of Agenerase in combination with the other PIs tested could be the apparently unique resistance profile of this new PI compared with others in the class. Current PIs show varying degrees of cross resistance, meaning that treatment with one PI can result in HIV mutations associated with resistance to other PIs. Resistance mutations seen with Agenerase, both in the laboratory and in patients, are unique, differing from those resulting from treatment with other PIs.

Other data presented at Glasgow also suggest that treatment with Agenerase will not rule out future treatment with other protease inhibitors. Clinical results were presented from study ACTG 373, which assessed whether patients who have been previously treated with Agenerase either as a single agent or in combination with other antiretroviral medications (ACTG 347) can be treated successfully with a subsequent regimen containing the protease inhibitor indinavir. After 60 weeks of combination therapy, available data suggests that 86% of evaluable patients (18 of 21) who had previously received Agenerase monotherapy had plasma viral RNA below 400 copies/mL. Overall, approximately 80% of patients receiving a subsequent indinavir containing- regimen had plasma viral RNA below 400 copies/mL at 60 weeks. 55 patients were enrolled in the study.

Jeffrey Goodgame, M.D., Associate Professor at the University of Central Florida and lead investigator for Phase III clinical trial (Protocol 3001), presented in Glasgow previously described 16 week tolerability and efficacy data in a poster. In addition, the poster also contained 24 week preliminary intent-to-treat (observed data) analysis showing that 80% of patients taking triple therapy with Agenerase+Epivir+Retrovir achieved viral load below the limit of detection of standard assays (<400 copies/mL), and that 67% of this patient group achieved viral load below the limit of detection using an investigational ultrasensitive assay (<50 copies/mL)(B). The median CD4 cell rise from baseline for this patient group was 113 cells at 24 weeks. Assessments of antiviral activity and safety will continue until the last patient completes 48 weeks on study. The most commonly reported adverse events in the Agenerase arm of the study at 16 weeks were mild to moderate and transient. They included nausea, vomiting, fatigue, gaseous symptoms, headache, and circumoral paresthesia.

"These studies are representative of a broad international clinical program undertaken to study Agenerase in combination with a variety of antiretroviral agents, in different patient populations," said Dr. Joshua Boger, Chairman, President, and CEO of Vertex. "We are encouraged by the clinical results which suggest that Agenerase can be useful as a component of many different combination regimens, and that initial therapy with Agenerase may not preclude subsequent treatment with another protease inhibitor."

Agenerase has been studied across a wide range of patients in various combinations, including its use with Ziagen(TM) (abacavir; an NRTI) and efavirenz (a non-nucleoside reverse transcriptase inhibitor) in patients failing their current therapy.

Agenerase is currently in Phase III development and is being investigated for use in treatment-naive and treatment-experienced adults and children. Unlike most other existing PIs, Agenerase has a twice daily dosing regimen, which can be important in improving patient adherence. Glaxo Wellcome has filed for market approval of Agenerase in the United States, Canada, and the European Union.

Peter Young, Vice President Therapeutic Development, HIV and Opportunistic Infections, Glaxo Wellcome said, "The antiviral activity demonstrated by amprenavir and abacavir is extremely encouraging. As with our currently available medicines, Combivir, Epivir and Retrovir, these new agents are also well-tolerated and have a twice a day dosing schedule, which marks the company's commitment to both scientific excellence and improving the quality of life of people with HIV/AIDS."

Agenerase was discovered by scientists at Vertex Pharmaceuticals and developed by Glaxo Wellcome under a license agreement.

Glaxo Wellcome is a research-based company bringing innovative medicines and services to patients throughout the world and to the healthcare providers who serve them. Besides Agenerase, Glaxo Wellcome has a broad portfolio of anti-HIV medicines including the already marketed Combivir, Epivir and Retrovir, as well as Ziagen (a reverse transcriptase inhibitor submitted for approval in the U.S., Canada, and Europe) and a non-nucleoside inhibitor program. In 1997, the company spent 1.2 billion pounds sterling on research and development which included an extensive basic research program for HIV, embracing virology and vaccines.

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX - news) 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.

Agenerase, Combivir, Epivir, Retrovir and Ziagen are trademarks of the Glaxo Wellcome Group of companies. Ziagen was discovered and is being developed by Glaxo Wellcome. The rights to related compounds and technology, including intermediates used in the manufacture of abacavir, resulting from the research by Dr. Robert Vince et al, were licensed to Glaxo Wellcome by the University of Minnesota in 1992.

Epivir (lamivudine) was discovered by Biochem Pharma of Laval, Quebec, Canada, and licensed to Glaxo (now Glaxo Wellcome) in 1990.

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.

NOTE(A): Proportions of patients on Phase II clinical trials described in this release represent an as-treated analysis, which includes patients who remained on study medication.

NOTE(B): Measurements of viral RNA below 50 copies were made using the Roche ultradirect assay, which is investigational and yet to be validated.

SOURCE: Vertex Pharmaceuticals Incorporated
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