BETHESDA, Md. _ Merck & Co. Inc. released preliminary datashowing that its protease inhibitor, MK-639, decreased viral particlesin the blood and boosted immune system cells in AIDS patients.

The news came on Thursday as Merck, Hoffman-La Roche Inc. andAbbott Laboratories _ three companies at the head of the proteaseinhibitor pack _ reported on the status of their respective productsand plans for Phase III clinical trials to the National Task Force onAIDS Drug Development (NTFADD).

Companies with protease inhibitors in earlier stages of developmentinclude Agouron Pharmaceuticals Inc., of La Jolla, Calif., BurroughsWellcome Co., of Research Triangle Park, N.C., and The UpjohnCo., of Kalamazoo, Mich.

Merck, of Whitehouse Station, N.J., said that, among 18 patients whoreceived MK-639 for about a year in various uncontrolled Phase IIstudies, viral RNA (as measured by polymerase chain reaction) wasreduced approximately 100-fold. However, patients' viral loadsreturned to baseline levels within three to six months due to thedevelopment of drug resistance.

In the same group of patients, CD4 cell counts _ a critical measureof immune system strength _ rose and remained a median of 50cells/mm3 above baseline levels at the one-year mark. This findingwas all the more dramatic because it occurred among patients whosemedian pre-treatment CD4 cell count was 59 cells/mm3, a levelsignifying advanced disease.

According to Jeffrey Chodakewitz, a Merck official who presentedthe new data to NTFADD, MK-639's ability to rapidly anddramatically boost CD4 cell counts, even among very sick patients,combined with its "favorable" safety profile, makes it a primecandidate for accelerated approval. The dose-dependent decrease inviral burden, though transient, enhances the drug's potential. "Thisrepresents a significant step forward in anti-HIV therapy," saidChodakewitz.

Chodakewitz suggested that the potency and relative safety of MK-639 and other protease inhibitors could shift the risk/benefit ratio forAIDS therapy in favor of early intervention in the disease process.The goal would be to produce a profound, sustained anti-viral effectpossibly by treating patients with a "cocktail" of several differentpotent compounds.

Although Merck portrayed its findings in a positive light, companyofficials conceded that the link between surrogate markers, such asviral load levels and CD4 cell counts, and survival or meaningfulclinical benefit has yet to be irrefutably established. "This drugrepresents an advance only if the link between degree and duration ofviral suppression and clinical benefit is validated," admitted EdwardScolnick, Merck's vice president of science and technology and aNTFADD member.

The FDA's accelerated approval program allows for licensure ofdrugs that demonstrate clear activity against surrogate markers on thecondition that companies commit to run post-marketing (Phase IV)studies that definitively prove clinical benefit.

Some have questioned whether or not the FDA will be willing or ableto withdraw approved drugs from the market if they fail in Phase IVstudies. Such an action could be highly controversial and politicallysensitive. FDA Commissioner and NTFADD member David Kesslerpredicted that the agency would rescind accelerated approval if adrug showed no clinical benefit.

Merck plans to file for accelerated approval of MK-639 in 1996based on data that will be generated by several Phase III studies set tobegin in coming weeks. Three of the proposed studies will look onlyat MK-639's impact on surrogate markers, while one, in Brazil, willlook for an effect on hard endpoints, such as a decrease in the numberof AIDS-defining clinical events. Other Phase III studies are on thedrawing board.

Is Merck Taking `Advantage' Of Accelerated Approval?

A report prepared by the Treatment Action Group (TAG) and theGay Men's Health Crisis (GMHC), patient advocacy groups based inNew York, questioned whether the studies proposed by Merck andother manufacturers will adequately define what benefits a time-limited,treatment-induced reduction in viral load can impart to sick patients.They said that companies are taking advantage of acceleratedapproval regulations to develop and market drugs "without provingwhether or not they work."

"Merck, the world's largest drug company, will submit the world'ssmallest efficacy data base to the FDA in 1996," said TAG activistMichael Ravitch, whose group urged Merck to study both surrogatemarkers and clinical endpoints in trials with larger numbers ofpatients for increased statistical power.

Hoffman-La Roche, a unit of Roche Holdings Ltd., of Switzerland,has said it plans to file for accelerated approval of its proteaseinhibitor, Saquinavir, later this year. The drug, which was tested insmall, early studies in combination with the already-approvednucleoside analogs AZT and ddC, has shown modest virologic andimmunologic effects. It is currently being tested in an 80-week,3,330-patient Phase III study. That study, according to theTAG/GMHC report, could answer important questions about clinicalbenefit.

Abbott, based in Abbott Park, Ill., is developing a protease inhibitorcalled ABT-538 that has demonstrated powerful antiviral effects asmeasured by a new viral load test developed by Emeryville, Calif.-based Chiron Corp., the branched DNA assay. It also boosted CD4cell counts three-fold in a Phase I/II study of 23 patients. Abbottplans three efficacy studies of its drug but details have not beendisclosed.

Officials from Merck, Hoffman-La Roche and Abbott all expressedfrustration at the meeting about the difficulties of manufacturingprotease inhibitors. Merck said that it will have to produce hundredsof thousand of kilograms of MK-639 to treat the 500,000 to 1 millionpatients each year who might need the drug. The synthesis of MK-639 is a complex, 15-step process. Merck is currently working onmanufacturing facilities that could allow widespread distribution ofthe drug, under an "expanded access" program, within one year.Likewise, Abbott officials said their manufacturing yield for ABT-538 is two percent, meaning it takes 100 kilograms of chemicals toproduce enough drug for two patients. n

-- Lisa Piercey Washington Editor

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

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