Clinical and regulatory advances in the protease inhibitor class ofHIV drugs continued Thursday with Abbott Laboratories'presentation that its ritonavir reduced mortality and diseaseprogression.
It was the first HIV study that addressed clinical endpoints of thedisease rather than surrogate markers, such as viral load and CD4 cellcounts. Separately, Merck & Co. Inc. became the third company tofile for regulatory approval of an HIV protease inhibitor with thesubmission of a new drug application for Crixivan (indinavir).
"It's a tremendous step forward," said Hambrecht & Quist analystAlex Zisson.
"It's fair to say the Abbott mortality data and Merck data on viralload probably mean we finally can say the class of HIV proteaseinhibitors is the biggest leap forward since AZT was shown to work."
Mike King, an analyst at Dillon, Read & Co. Inc., in New York, saidthe reduction in mortality "puts ritonavir in a completely differentlight. This is the best hope AIDS patients have had in a long time, ifnot ever."
Both King and Zisson agreed, too, on a few other points followingThursday's completion of the Third Conference on Retroviruses andOpportunistic Infections, in Washington.
The burden of proof for HIV/AIDS drugs in development has beenraised as far as efficacy, the analysts said, both adding, however, thatsurrogate marker information still will be enough for approval.
The Abbott survival data released Thursday came from arandomized, double-blind, placebo-controlled study with 1,090patients at 67 sites in the U.S., Canada, Europe and Australia. Thepatients all had advanced HIV, with CD4 counts of less than 100.Ritonavir or placebo was given twice daily along with existingnucleoside therapies, if any. Patients were followed up to sevenmonths.
The mortality rate among the 543 patients receiving ritonavir was 4.8percent compared to 8.4 percent among the 547 who receivedplacebo. Thirteen percent of those receiving ritonavir died or haddisease progression (onset of a new AIDS-related illness) comparedto 27 percent in the placebo group.
The entire protease inhibitor class got a boost from the conferencethis week with the possible exception of Hoffmann-La Roche Inc.'sInvirase (saquinavir). While the Nutley, N.J., company's drug wasapproved for marketing in December, it is clearly less potent than theMerck and Abbott drugs, said David Stone, a managing director atCowen & Co.'s Boston office.
Stone said one of the most impressive items coming out of theconference was the quickness with which Merck landed a FDA panelmeeting. The Whitehouse Station, N.J., pharmaceutical giant filed anew drug application (NDA) late Wednesday and a panel meeting isset for March 1, 1996.
Abbott, of Abbott Park, Ill., filed an NDA for ritonavir in Decemberand is scheduled to go before an FDA committee on Feb. 29, 1996.Two other HIV protease inhibitors are in development. AgouronPharmaceuticals Inc., of La Jolla, Calif., just started a Phase II/IIIprogram with Viracept. And Vertex Pharmaceuticals Inc., ofCambridge, Mass., is in a multi-dose, dose-escalating Phase II studywith its drug VX 478. (For more on the protease inhibitors, seeBioWorld Today, Jan. 31, 1996, p. 1.)
Stone said he likes what he's seen of the Vertex compound becauseof the apparent advantage in being able to safely go to very highdoses. He said clinical investigators described the Abbott and Merckdrugs as having comparable efficacy. Abbott gets an edge because ofthe clinical endpoint data, Stone said, but might be limited because itsdrug has an interaction problem resulting in the failure of certainother drugs to clear. That gives Merck an edge in ease of prescribing,Stone said, and the side effects seen "in a meaningful fraction ofpatients" with compounds from Merck and Abbott leave the dooropen for other agents, such as those from Vertex and Agouron.
What does it mean? There will be room for a number of proteaseinhibitors and nucleoside analogues, analysts said.
"It's going to be a pretty fragmented market," Zisson said. "There areso many possible two- or three-drug regimens. The medical andAIDS activist communities probably are going to call for a hugerandomized trial over a long period of time to find out whichcombinations are the best. We'll probably have a lot of $50 millionand $100 million drugs. I'm not sure we'll have a $500 million AIDSdrug."
Abbott's stock (NYSE:ABT) gained 50 cents to close at $43Thursday. Merck (NYSE:MRK) lost 25 cents to close at $69.88.Agouron (NASDAQ:AGPH) was down $1 at $41 and Vertex(NASDAQ:VRTX) was up 75 cents to $27.75.
In other conference news:
Trimeris Inc., of Research Triangle Park, N.C., reported that its leaddrug candidate, pentafuside (T-20), stopped infection of HIV in amouse model of the disease. The drug works to block infection bypreventing the virus from joining with the host cell. n
-- Jim Shrine
(c) 1997 American Health Consultants. All rights reserved.