By Mary Welch
Gilead Sciences Inc. and F. Hoffmann-La Roche Ltd. said their oral influenza drug, GS4104, decreased the duration and severity of acute flu in adults in Phase III trials, and the companies plan to file for FDA marketing approval next year.
Roger Mills, director of clinical research for Foster City, Calif.-based Gilead, said patients given GS4104 showed a "marked improvement" in the trials, which took place in January and February and involved 1,348 adults not vaccinated against the flu.
"What we found was that people got better quicker and they felt bad for a shorter period of time," Mills told BioWorld Today. "When you're ill with the flu, you have the related respiratory effects, such as cough, and the systemic effects, such as fever. With GS4104, [patients received] the broad benefit for all those symptoms, and we found that it reduced the number of complications, such as bronchitis."
The first study, conducted at 60 U.S. sites, included 629 patients, 60 percent of whom were influenza-infected. The second, conducted at 80 sites in 11 countries, involved 719 patients. In the first study, patients were required to have febrile respiratory illness of 36 hours duration; in the second, patients displayed at least one respiratory and one constitutional symptom of 36 hours duration or less.
In both trials, adults were randomly assigned to receive GS4104 at doses of either 75 mg or 150 mg or a placebo twice a day for five days. Results showed duration of influenza was reduced by 30 percent when GS4104 was administered within 36 hours of onset of symptoms. If the drug was given within 24 hours, the second study found, the illness' length was lessened by 40 percent. Among those receiving GS4104, the severity of illness, including cough and fever, also declined by 40 percent.
The study confirmed that the drug was well tolerated, but some patients reported transient side effects such as mild nausea and, in a lesser number, vomiting. None of the 1,348 patients dropped out of the study as a result of side effects, however.
Generally, flu patients are advised to use cough syrup, get plenty of rest and take fluids. Such tactics relieve symptoms, but GS4104, a systemic treatment designed to reach all infection sites, targets the virus itself.
Drug Targets Neuraminidase Protease
The drug aims specifically at one of the two major surface structures of the influenza virus, the neuraminidase protease. If this is inhibited — and the site is virtually the same in all common influenza strains — then the virus is not able to infect new cells.
Each year, up to 40 million Americans develop influenza, about 150,000 are hospitalized, and between 10,000 and 40,000 persons die annually from the flu or its complications. The disease costs the U.S. about $10 billion annually in visits to physicians, lost productivity and wages.
Gilead, which brought GS4104 into preclinical trials, paired up with the Basel, Switzerland-based Roche in 1996 when Roche paid $10 million up front and agreed to another $40 million in milestone payments for worldwide commercialization rights to the drug. Gilead will also receive royalties when the drug reaches the market. (See BioWorld Today, Oct. 1, 1996, p. 1.)
Gilead's stock (NASDAQ:GILD) closed Friday at $25.625, down $0.125.
The Phase III results were disclosed at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in San Diego.
In other news from ICAAC:
* Agouron Pharmaceuticals Inc., of La Jolla, Calif., reported preliminary data from several clinical studies, indicating twice-daily dosing of its protease inhibitor Viracept (nelfinavir mesylate) in combination therapy produces anti-HIV effects at 48 weeks, comparable to those resulting from standard three-times-daily dosing of the drug in combination therapy. Results from trials in the U.S. and Europe were reported.
* Cubist Pharmaceuticals Inc., of Cambridge, Mass., disclosed results from five studies of daptomycin, the company's lead anti-infective product. The studies showed daptomycin has potent bactericidal activity, greater than vancomycin, against a variety of Gram positive clinical isolates, including antiobiotic-resistant bacteria in vitro. In vivo, daptomycin was effective treating mice that had a lethal infection caused by vancomycin resistant enterococci. Cubist is developing intravenous daptomycin for Gram positive skin and soft tissue infections, as well as those of the bloodstream and urinary tract. Phase III studies are expected to begin next year.
* SmithKline Beecham plc, of London, said its LYMErix (recombinant OspA), a vaccine for Lyme disease, proved safe and produced high antibody titers when adminstered at the rate of three doses in six months. An FDA advisory committee recently found the vaccine safe and effective for Lyme disease prevention. The results presented at ICAAC were derived from one of a series of studies evaluating accelerated dosing schedules.
* XOMA Corp., of Berkeley, Calif., presented findings on its bactericidal/permeability-increasing protein (BPI) anti-infective product platform. Three of the studies focused on Neuprex, the company's lead product. A Phase II study showed a dose-related improvement in outcome for Neuprex-treated patients suffering from complicated intra-abdominal infections. Also presented were the first orally absorbed anti-fungal peptides derived from BPI by company scientists using rational library screening methods. XOMA further disclosed results from a study showing that a recombinant BPI protein combined with an antibiotic kills the protozoan parasite that causes toxoplasmosis. *