In the race to develop the newest class of AIDS drugs, proteaseinhibitors, Agouron Pharmaceuticals Inc. is trailing three bigpharmaceutical companies, but not by much.
The La Jolla, Calif., company's president and CEO, Peter Johnson,told BioWorld Today the goal is FDA approval of its proteaseinhibitor, Viracept (nelfinavir mesylate), in mid-1997.
He said Tuesday Agouron, which is developing Viracept incollaboration with Tokyo-based Japan Tobacco Inc., began threePhase II/III trials with an expected enrollment of 1,000 AIDSpatients. Data from the studies will be used to support the new drugapplication (NDA) with the FDA.
In two pivotal trials, one in the U.S. and the other in Europe, Viraceptwill be evaluated in combination with nucleoside analogues, AZTand 3TC, which are marketed by London-based Glaxo Wellcome plc.Biochem Pharma Inc., of Laval, Quebec, developed 3TC incollaboration with Glaxo.
The third Agouron pivotal trial, also in the U.S., will test Viracept'seffectiveness with d4T, which is New York-based Bristol-MyersSquibb Co.'s nucleoside analogue.
A year ago, Johnson said, researchers considered that proteaseinhibitors, which attack HIV near the end of its replication cycle,might replace nucleoside analogues, which are reverse transcriptaseinhibitors and interfere with viral replication at the beginning of theprocess.
"That's a dead idea," Johnson said.
Numerous studies now have shown that protease inhibitors incombination with nucleoside analogues constitute a significantlygreater anti-viral punch than either treatment by itself.
Evidence of a combination therapy's effectiveness has been bolsteredthis week at the Third Conference on Retroviruses and OpportunisticInfections in Washington.
Merck & Co., of Whitehouse Station, N.J., presented trial resultsshowing its protease inhibitor, Crixivan, in combination with AZTand 3TC, reduced HIV to undetectable levels after four months oftreatment.
In another study, Merck said Crixivan together with AZT and ddI,another nucleoside analogue made by Bristol-Myers, lowered medianHIV levels by "approximately 99.9 percent" after five months and thepatients "experienced significant immune system recovery" asmeasured by an increase in CD4 cell counts.
Abbott Laboratories, of Abbott Park, Ill., presented data at theWashington conference showing its protease inhibitor, ritonavir, incombination with AZT and ddC also decreased viral load by anaverage of 99 percent after five months. At the conclusion of sixmonths, patients' CD4 cell counts nearly doubled. The nucleosideanalogue, ddC, is made by Roche Holdings Ltd., of Basel,Switzerland.
Because the FDA put potential AIDS drugs on an expedited reviewprocess, the agency has accepted evidence of effectiveness based onsurrogate markers _ increasing CD4 cell counts and decreasing viralload _ rather than the standard clinical endpoints. The agency,however, also required post-market efficacy studies.
Roche was first to get to market with its protease inhibitor, Invirase(saquinavir), which was approved in early December 1995. Abbottfiled an NDA with the FDA for ritonavir, whose brand name isNorvir, in late December 1995. Merck is expected to file its NDA in"a matter of days," a spokesman said.
Vertex Pharmaceuticals Inc. is the fifth company with an HIVprotease inhibitor, VX-478, under development. Vertex, ofCambridge, Mass., and its partner, Glaxo Wellcome, began clinicaltrials in March 1995.
"It's always an advantage to be first to market," Johnson said. "But[AIDS] is a clinical area that will need multiple agents. We don't seeit as a marketplace dominated by any compound."
While all the protease inhibitors are similar, there are somedifferences in potency, side effects and administration.
Agouron has conducted several Phase II studies showing Viraceptwas safe and produced strong antiviral activity.
In one four-week Phase II study with Viracept alone, patientsexperienced mean maximum reductions in HIV from 96 percent to 98percent based on the dose. And after four weeks, average number ofCD4 cells increased at each Viracept dose.
In another trial testing Viracept in combination with d4T, theprotease inhibitor produced mean reductions of HIV below detection.
In addition to its potency, the only side effect seen with Viracept hasbeen mild diarrhea, Johnson said. Another advantage, he added, is thedrug can be taken with or without food.
Agouron's Phase II results were completed too late for inclusion inthe Washington conference. However, the company's stock(NADAQ:AGPH) has benefited from the excitement surrounding theprotease inhibitors, which represent encouraging news after years offrustration in the battle against AIDS.
Agouron's shares jumped $3.37 Tuesday to close at $45.62, an 8percent increase. Merck (NYSE:MRK) was up $1.25 to $70.12.Abbott (NYSE:ABT) ended the day at $42, a $1.87 increase. Vertex(NASDAQ:VRTX) closed at $27.75, up 50 cents.
In examining the protease inhibitors, analysts have said thosedeveloped by Agouron and Vertex are expected to be safer and moreeffective than the others.
Roche's Invirase is considered the least potent and while Merck'sCrixivan and Abbott's Norvir are stronger, they can cause significantaide effects.
Patients on Merck's drug can experience kidney problems. They takethe drug under fasting conditions and drink water regularly tomaintain hydration.
Abbott's protease inhibitor _ in addition to causing diarrhea, nausea,vomiting, fatigue, tingling around the mouth, taste perversion andliver toxicity _ creates problems when it interacts with other drugs.
The protease inhibitors and nucleoside analogues are not consideredcures, but Johnson observed the data from the Washingtonconference and other studies demonstrate the combination therapiesmay be able to reduce the level of HIV to zero and allow the immunesystem to reconstitute itself. The result may be that HIV infection canbe turned off for long periods of time.
With so many combinations of drugs needed, cost is an issue. WhenInvirase was approved for marketing, Roche estimated the wholesaleprice at $5,800 a year. Add in the annual treatment cost of AZT and3TC, which are estimated at between $4,000 and $6,000 combined,and the price could reach $12,000 a year.
Johnson said Agouron has built into its studies pharmacoeconomicanalyses to demonstrate Viracept's cost benefits, such as reducinghospital stays and eliminating the need for other medications. n
-- Charles Craig
(c) 1997 American Health Consultants. All rights reserved.