Hoffmann-La Roche Inc. filed a new drug application(NDA) with the FDA for approval of its AIDS treatment,a protease inhibitor called Invirase, based on early stagesafety studies and data showing the drug's effect onsurrogate markers, such as CD4 cell counts.

Nutley, N.J.-based Hoffmann-La Roche is seeking anaccelerated review and expects the FDA to act on theNDA by the end of this year. Under an acceleratedapproval process, if the drug is cleared, Hoffmann-LaRoche, a subsidiary of Switzerland-based RocheHoldings Ltd., still must conduct Phase IV post-marketing trials to prove the drug's clinical benefit.

Roche is submitting safety data from Phase I/II studies aswell as interim results from two Phase III trials measuringInvirase's effect on CD4 cell counts and viral load. Thestudies were conducted in Europe and North America.

A Roche spokeswoman said the clinical trial findingssubmitted show Invirase, which is designed to blockreplication of HIV, is safe and has anti-viral activity whentested against the markers. However, the data is notconsidered a definitive gauge of efficacy.

The two Phase III studies are continuing. Roche expectsto have results of the drug's ability to slow progression ofthe disease and reduce AIDS-defined events by mid-1996in the North American trials and by early 1997 in theEuropean studies.

Roche is the first to file an NDA for a protease inhibitortargeting HIV among numerous companies developingthe drugs. The protease inhibitors are designed to blockreplication of HIV and are considered less toxic than thecurrently available nucleoside analogs, AZT and ddc,which attack the virus at an earlier stage in the replicationcycle.

In addition, Roche officials said HIV's resistance toInvirase appears to develop at a reduced rate and, whenused with AZT resistance to both drugs, is slowed.

Roche is seeking FDA approval to use Invirase incombination with ddc, a Roche product, and AZT, whichis sold by London-based Glaxo Wellcome plc. Somescientists have speculated a multidrug approach will beneeded to fight AIDS.

Merck & Co., of Whitehouse Station, N.J., and AbbottLaboratories, of Abbott Park, Ill., are considered Roche'snearest competitors in developing a marketable proteaseinhibitor for AIDS. Merck also is seeking acceleratedapproval of its product, Crixivan, and expects to submitan NDA by early 1996. Abbott officials could not bereached for comment.

David Stone, managing director of Cowen & Co. inBoston, said the Roche, Merck and Abbott proteaseinhibitors all have problems.

"Roche will be first on the market, but the disadvantage isthe drug has poor pharmacokinetics," he said. "It has tobe used in combination with AZT."

Stone said the Merck and Abbott compounds are morepotent, but at higher doses they can cause liver problems.In addition, studies show some patients developresistance to Merck's product in three to six months.

A second generation protease inhibitor in an earlier stageof development is being tested by Vertex PharmaceuticalsInc., of Cambridge, Mass., in association with GlaxoWellcome. Stone said it shows better antiviral activity, issafer at higher doses and is easier to manufacturer thanthe compounds of the three leading companies.

Agouron Pharmaceuticals Inc., of La Jolla, Calif., also isdeveloping a protease inhibitor similar to Vertex.Agouron is working with Tokyo-based Japan TobaccoCo.

"The first three drugs will pave the way for the nextgeneration of compounds, such as Vertex's andAgouron's," Stone said. "And because they have a bettersafety profile at higher doses and better antiviral activitythey will get a share of the $2 billion market." n

-- Charles Craig

(c) 1997 American Health Consultants. All rights reserved.