By Karen Pihl-Carey

Staff Writer

Positive clinical results of two Gilead Sciences Inc. compounds indicate the company may have an effective treatment for acute cryptococcal meningitis (ACM) in AIDS patients, as well as an anti-HIV agent.

Data from a Phase II trial of the anti-HIV drug tenofovir disoproxil fumarate and of a Phase III trial of AmBisome (liposomal amphotericin B) for ACM were presented Monday at the 39^th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.

In the Foster City, Calif.-based company's Phase II trial of tenofovir, the company found the compound was well tolerated and associated with dose-related antiviral activity when added to a antiretroviral regimen in treatment-experienced HIV patients.

John Martin, president and CEO of Gilead, called the data "encouraging."

"We plan to move to Phase III studies using the highest dose, 300 milligrams, once per day," he told BioWorld Today.

The double-blind trial lasted for 48 weeks and enrolled 189 patients who had been on a stable antiretroviral regimen for at least eight weeks. They were randomized to receive tenofovir doses of either 300 mg, 150 mg or 75 mg or placebo on top of their existing treatment. Halfway through the trial, all placebo patients were switched to the 300 mg group.

Researchers noticed anti-HIV activity in all three active treatment arms with the greatest activity associated with the 300 mg dose. That dose reduced circulating virus in the bloodstream by more than 80 percent, said Robert Schooley, a University of Colorado professor who is principal investigator of the study.

The company plans to launch a Phase III program for tenofovir in the fourth quarter, Martin said.

In a research report, Prudential Securities Inc., of New York, said it expects Gilead to file an NDA for tenofovir in late 2000 or early 2001, with approval expected in the second half of 2001.

"Tenofovir could have much larger market potential than Gilead's first-generation HIV drug, Preveon, because it has a good resistance profile and once-daily dosing, as well as a clean side effect profile observed to date," the report stated.

Gilead's stock (NASDAQ:GILD) closed Monday at $69.562, down $7.75. Caroline Copithorne, an analyst with Prudential, explained Wall Street's response by saying the market anticipated good tenofovir results.

"With this second-generation compound, the hope was to get all the benefit without having the toxicities," she told BioWorld Today. "People pretty much knew what to expect because even before the trial was unblinded, when you didn't know who was on placebo or on treatment, you could see that no one got these toxicities. So I think that's one reason why you didn't see a pop in the stock."

In a Phase III trial, Gilead's AmBisome for treatment of ACM showed efficacy at two doses equal to amphotericin B. But patients on AmBisome showed significantly fewer infusion-related reactions, such as chills, fever and respiratory problems.

Deerfield, Ill.-based Fujisawa Healthcare Inc., Gilead's marketing partner for AmBisome, submitted in July a supplemental new drug application for AmBisome for the treatment of ACM in AIDS patients. AmBisome was approved in August 1997 for the treatment of fungal infections in patients with fever of unknown origin, those who have failed treatment with amphotericin B and those with visceral leishmaniasis (a parasitic infection).

"It is a very important product for Gilead," Martin said. "Our sales for AmBisome are over $100 million per year."

Data from another AmBisome study, expected to be presented today at ICAAC, suggest the drug is well tolerated at high doses of 15 mg/kg per day and may provide an effective therapy for aspergillosis and other filamentous fungal infections.

Vertex's Agenerase Shows Benefit In Combo Therapy

Vertex Pharmaceuticals Inc., of Cambridge, Mass., released at ICAAC 48-week results from a pivotal trial of Agenerase plus Epivir plus Retrovir for HIV. Data from the randomized, double-blind Phase III trial seem to support the use of Agenerase in combination therapy, said W. David Hardy, scientific director of research for Pacific Oaks Research in Beverly Hills, Calif. Agenerase is licensed for development to Glaxo Wellcome plc, of London.

The trial demonstrated a significant difference between two treatment arms - those receiving Agenerase or a placebo twice daily in combination with Epivir and Retrovir - in the number of patients who achieved viral loads below the limit of detection of a standard assay. At week 48, 93 percent of patients in the Agenerase arm achieved undetectable viral loads, compared to 42 percent in the placebo arm. But side effects, such as nausea, vomiting, rash and circumoral parasthesia, were more common in the Agenerase arm.

And data of VX-175/GW433908, the prodrug of amprenavir, indicate it is a candidate for further clinical evaluation. Studies presented Monday showed the prodrug to be highly soluble and bioavailable in animals. It was found to be bioequivalent to amprenavir and showed dose proportionality in a recently completed Phase I study. A dose-ranging Phase II study is now under way.

Triangle's Coactinon Potent And Well Tolerated

Triangle Pharmaceuticals Inc., of Durham, N.C., presented interim 24-week data from a Phase II study indicating Coactinon (emivirine), a non-nucleoside reverse transcriptase inhibitor formerly called MKC-442, is potent and well tolerated in HIV-infected patients.

The open-label, randomized study involved 196 patients and was designed to examine the antiviral activity, safety and tolerability of 500 mg and 750 mg dosage regimens in combination with two nucleoside reverse transcriptase inhibitors, d4T (stavudine) and ddI (didanosine). At 24 weeks, more than 70 percent of patients had undetectable levels of the virus, said Franck Rousseau, executive vice president of medical affairs and chief medical officer of Triangle. The drug was well-tolerated, the company said, and the most frequent side effects were nausea, headache, dizziness, vomiting and rash.

Triangle also presented preclinical data Monday on in vitro activity of DAPD, a dioxolane purine nucleoside reverse transcriptase inhibitor, against drug-resistant strains of HIV. The data suggest DAPD can be effective in combination therapies. The company is conducting a Phase I/II dose-escalation study in HIV patients based on this data.

In other news from the conference:

• University of California professor Judith Currier presented findings showing prophylactic treatment for mycobacterium avium complex (MAC) can be safely discontinued in most HIV-infected patients whose CD4+ T-cell levels show sustained increases in response to potent antiretroviral therapy. Investigators of the study, which Currier chairs and is supported by the National Institute of Allergy and Infectious Diseases, found that highly active antiretroviral therapy may prevent the occurrence of MAC.

• London-based SmithKline Beecham plc's vaccine against hepatitis A and B, Twinrix, is under review by the FDA based on a trial showing the drug provides similar results as does Engerix-B and Havrix, but it requires two fewer injections over a six-month period. The study involved 773 participants.

• Merck & Co. Inc., of Whitehouse Station, N.Y., presented data on once-daily combinations of Crixivan with ritonavir, which showed blood levels were boosted even higher than they were with the approved 800 mg every eight hours dosing of Crixivan. The once-daily regimen consisted of an 800 mg dose of Crixivan with either a 100 mg or a 200 mg dose of ritonavir, or a 1,200 mg dose of Crixivan with a 100 mg dose of ritonavir.

• ViroLogic Inc.'s phenotypic drug susceptibility assay, PhenoSense HIV, is superior to treatment history in predicting sustained HIV suppression in antiretroviral therapy-experienced patients who are starting new treatment regimens, according to a presentation by Michael Saag of the University of Alabama. The South San Francisco-based company's test measures the sensitivity or resistance of a patient's HIV to all available anti-HIV drugs. PhenoSense HIV also is the subject of six other studies being presented at ICAAC.

• Progenics Pharmaceuticals Inc., of New York, presented results from a Phase I trial in which PRO 542, an inhibitor of HIV entry, was shown to have antiviral activity. In the study, 15 patients received a single injection at one of four dose levels and statistically significant decreases were found in patients treated in the high dose cohort.

• Trimeris Inc., of Durham, N.C., and Hoffmann-La Roche Inc., of Nutley, N.J., presented 16-week results from a Phase II clinical trial of T-20, a fusion inhibitor. Results showed 33 of 55 heavily pretreated patients who were given T-20 in combination with oral antiretroviral agents responded with a significant reduction of HIV levels. Twenty of the 55 had virus levels less than 400 copies/mL.