PRNewswire - Monday September 28, 1998

The study indicates that Agenerase may be more potent when used in combination with Ziagen, a nucleoside reverse transcriptase inhibitor (NRTI), compared to several other NRTIs. Conversely, Ziagen may be more potent when used in combination with Agenerase, a protease inhibitor, compared to the other protease inhibitors tested. These laboratory data suggest that the combination of Agenerase and Ziagen may have greater potency than other protease inhibitor and NRTI combinations due to their synergy.

"The level of synergy found between these two compounds is good news for HIV-positive patients," said John Bilello, Ph.D., director of preclinical R&D at SRA Life Sciences in Rockville, MD. "These data, together with favorable phase I and II findings for each drug alone, support ongoing clinical studies of the combination of Ziagen and Agenerase."

The study was designed to develop comparative data on the anti-HIV activity of protease inhibitors in combination with nucleoside reverse transcriptase inhibitors. Each protease inhibitor-nucleoside combination was analyzed to determine the degree of synergy. Briefly, the synergy volume is simply the measure of the degree of extra antiviral suppressive effect above that which would be seen with two purely additive drugs. The analysis of Agenerase combinations showed that the greatest synergistic activity was obtained with Ziagen (127.4) which was greater than the synergy found with ddl (105.0), AZT (42.6) and d4T (0.38). Ziagen was more synergistic with Agenerase (127.4), than it was with ritonavir (28.9). No antagonistic combinations of Agenerase or Ziagen were observed in the combinations tested.

"The combination of Agenerase and Ziagen gives the largest volume of antiviral effect due to synergy of any of the combinations of NRTIs and protease inhibitors evaluated," said George Drusano, M.D., professor and director, Division of Clinical Pharmacology, Albany Medical College.

In a study of the two drugs recently presented at the 12th World AIDS Conference in Geneva, six of nine patients with HIV who received a combination of Ziagen and Agenerase had less than 5 viral copies per milliliter of plasma (Investigational Roche Ultrasensitive Boosted Assay) after 48 weeks of treatment. Of the other three patients completing 48 weeks, two had less than 50 copies/mL (Investigational Roche Ultrasensitive Assay) and one had less than 500 copies/mL (Chiron Quantiplex HIV RNA technique).

Ziagen and Agenerase are each in phase III clinical development at Glaxo Wellcome as treatments for HIV and AIDS. Glaxo Wellcome submitted a New Drug Application (NDA) for Ziagen to the Food and Drug Administration in June 1998. Ziagen is currently available through an expanded access program to patients who are no longer maintaining viral suppression with their current treatments.

Agenerase is available through an early access program for patients for whom at least one protease inhibitor-containing regimen has failed.

In clinical trials, Ziagen has been generally well-tolerated with the most commonly reported adverse events consisting of headache, nausea, vomiting, malaise and rash. In 3 percent of patients receiving Ziagen, a hypersensitivity reaction has been observed which is characterized by fever with nausea and/or malaise, and, possibly, an accompanying skin rash. Symptoms of this reaction generally resolve following discontinuation of Ziagen. Patients experiencing this reaction must not take Ziagen again as restarting the drug after a hypersensitivity reaction has resulted in cases of a life-threatening and, in one instance fatal, reaction.

Agenerase was used in combination treatment regimens and has also been generally well-tolerated in clinical trials with the most commonly observed adverse events including nausea, vomiting, headache and rash.

Agenerase was discovered by scientists at Vertex Pharmaceuticals and licensed by Glaxo Wellcome. Ziagen was discovered and is being developed by Glaxo Wellcome. The rights to related compounds and technology, including intermediates used in the manufacture of Ziagen, resulting from research by Dr. Robert Vince, et. al, were licensed to Glaxo Wellcome by the University of Minnesota.

Glaxo Wellcome is the pharmaceutical industry leader in HIV research and therapies. In addition to the investigational drugs Ziagen and Agenerase, the company currently manufactures and markets Epivir(R)(lamivudine; 3TC) and Retrovir(R)(zidovudine; AZT), as well as Combivir(R) which combines Epivir and Retrovir into one tablet.

SOURCE: Glaxo Wellcome
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