By Mary Welch
Vertex Pharmaceuticals Inc.'s product of structure-based drug design, the HIV protease inhibitor Agenerase (amprenavir), proved strong in preliminary Phase III trial data.
The early results show the drug reduced viral load to below detectable limits in 88 percent of the patients using it in combination with a pair of reverse transcriptase inhibitors, as opposed to 19 percent given the latter therapy alone.
Agenerase is being developed by Cambridge, Mass.-based Vertex with Glaxo Wellcome plc, of London.
The 16-week data are the first results and "constitute the core of the [new drug application] Glaxo will file sometime this fall," said Vicki Sato, Vertex's senior vice president of research and development and chief scientific officer. "We are pleased that the data is 'clean.' It shows that, at twice-a-day dosing, Agenerase is at least as potent, if not more, as the other protease inhibitors currently on the market. In addition, it is unambiguously potent, active and tolerated."
Significant virus suppression was shown in patients who took Agenerase with Epivir (lamivudine), also known as 3TC, and Retrovir (zidovudine; or AZT). Fifty-nine percent of the patients receiving this regime achieved viral load below the limit of detection of an investigational ultrasensitive assay.
Combination therapy has been the standard HIV treatment since protease inhibitors were introduced in late 1995. 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. Reverse transcriptase inhibitors, also called nucleoside analogues, attack HIV early in the replication cycle. Epivir and Retrovir are marketed by Glaxo, along with Combivir, a combination of the two drugs in one tablet.
Agenerase is a second-generation protease inhibitor that last week became available in an early-access program to patients failing current protease inhibitor-containing regimes. Initially developed by Vertex, its progress was furthered when the company formed a $42 million alliance in 1993 with Glaxo plc, which became Glaxo Wellcome when it later merged with Wellcome plc.
Vertex will receive an undisclosed milestone upon filing with the FDA for marketing clearance. Vertex's partner in Asia is Kissei Pharmaceutical Co. Ltd., of Matsumoto, Japan.
Sato said Agenerase has other advantages over other currently available protease inhibitors.
"The twice-a-day dosing is very important," she said. "Agenerase has a 10-hour half-life, while the others have a half-life of a couple of hours. That allows the patient to have a more convenient dosing schedule with no risk of lessening the potency. We now have to think of HIV treatment as being long-term. That means that you have to come up with a dosing regimen that a patient can adhere to. With Agenerase, a patient can have a more normal life."
Many, if not most, HIV patients on combination therapy take drugs at least five times during the day and must adhere to strict dietary schedules. Agenerase's absorption is unaffected by the presence or absence of food or water. The compound may also have the potential to limit the development of resistant strains of HIV because of the twice-a-day dosing regimen.
"There are no heroic requirements for food or liquid with Agenerase," Sato said. "There's less of a hassle. One of the problems is that as people start to feel better, they often don't adhere to the drug schedule as strictly as they should. They take a holiday. Agenerase is more user-friendly, if you will."
The Phase III study was a double-blind, placebo-controlled international multicenter effort. Side effects were mild to moderate and temporary and included nausea, vomiting, fatigue, gaseous symptoms, headache, and circumoral paresthesia. The study will continue for another 32 weeks.
Two other Phase III trials using Agenerase are under way. "We will have a large family of clinical studies that support the use of Agenerase in a variety of stages of HIV, as well as [patient] ages," Sato said.
Vertex's stock (NASDAQ:VRTX) closed Monday at $24.625, up $0.625.
The Phase III results were reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy meeting in San Diego. In other news from ICAAC:
* Agouron Pharmaceuticals Inc., of La Jolla, Calif., reported favorable results from preclinical studies of AG7088, targeting human rhinovirus, the most frequent cause of the common cold. The drug is an inhibitor of the rhinovirus 3C protease enzyme. It was shown to have a broad spectrum of antiviral activity, unlike those which act by an alternate mechanism.
* Alpha-BetaTechnology Inc., of Worcester, Mass., reported data on a rapid fungal diagnostic assay which could result in earlier detection of life-threatening fungal infections and improve management of the disease. Separately, the company presented research showing that attacking the "molecular glue" of fungal cell walls holds promise as a new way of treating infections.
* Aronex Pharmaceuticals Inc., of The Woodlands, Texas, presented favorable Phase II data on Nyotran, its injectable formulation of nystatin, an approved topical antifungal drug, for the treatment of systemic fungal infection. The study evaluated the intravenous formulation in patients with Candida infections. A preliminary analysis of data from the first 75 patients enrolled indicated 67 percent were successfully treated with Nyotran.
* Aviron, of Mountain View, Calif., said new data from the second year of its Phase III efficacy trial of FluMist in children showed the intranasal influenza vaccine provided 100 percent protection against culture-confirmed influenza strains. The A/Sydney strain expected to be prevalent in the coming season was not included in the vaccine. Earlier this month, the FDA said Aviron's submission to market the vaccine was not acceptable, and the agency said it needed more manufacturing data. (See BioWorld Today, Sept. 2, 1998, p. 1.)
* IntraBiotics Pharmaceuticals Inc., of Mountain View, Calif., reported that Protegrin IB-367 reduced the level of oral bacteria by up to 10,000-fold, while the antimicrobial reduced the incidence, severity and duration of oral mucositis. The drug also was shown to have a "post-antibiotic effect," indicating brief exposure of bacteria to the antimicrobial agent has a prolonged antimicrobial effect. The drug is a synthetically derived analog of naturally occurring antimicrobial substances called protegrins, produced by host defense systems to fight infections of Gram-positive and Gram-negative bacteria as well as fungi.
* Lidak Pharmaceuticals Inc., of San Diego, presented results of pivotal Phase III clinical trials with n-docosanol 10 percent cream as a topical treatment for herpes simplex labialis (oral herpes). A new drug application was filed with the FDA last December. (See BioWorld Today, Aug. 18, 1997, p. 1, and Dec. 29, 1997, p. 1.)
* MedImmune Inc., of Gaithersburg, Md., reported clinical data from two programs: MEDI-501, a candidate vaccine for human papillomavirus, and Synagis (palivizumab), a monoclonal antibody for respiratory syncytial virus (RSV). Patients dosed with the former developed dose-related antibody responses, and the vaccine was safe and generally well tolerated. Synagis was tested in patients who had received hematopoietic stem cell transplants. The drug was maintained at blood concentration levels above those believed to provide protection against RSV.
* NeXstar Pharmaceuticals Inc., of Boulder, Colo., said results from a second Phase I study of MiKasome, a liposomal formulation of amikacin, showed favorable safety and pharmacokinetics in patients with HIV. The study will continue through escalating doses. Blood levels of the drug remained high over long periods, with no kidney, auditory or vestibular abnormalities. *