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With Its First Protease Trial Completed, Roche Races to FDA With Lukewarm Results, While Activists Cry ‘Foul’

“Tarted-Up Anecdotes”

Results from ACTG 229, a randomized, 24-week, 302-patient study comparing AZT+ddC+saquinavir (Ro 31-8959, Roche’s first protease inhibitor) vs. AZT+saquinavir vs. AZT+ddC, were released on May 31. The analysis was written up by Roland Bassett, David Schoenfeld and Ann Collier for the ACTG 229 study team. The results of ACTG 229 should be viewed with caution. There are many issues of concern.

Doses and resistance. The optimal (most active antiretroviral) dose of saquinavir has yet to be determined. Hoffmann-La Roche tested 600 mg/day for pragmatic reasons, rather than because it was the “best” dose. No dose-limiting toxicity has been found. It is unknown whether higher doses will be more active and/or delay (or accelerate) the development of resistance, which appears only to be a matter of time with the protease inhibitors. “Luckily,” there appears to be little cross-resistance with current protease inhibitors, which all have different molecular configurations.

Confounded control arms. ACTG 229 was a poorly designed study, in which regimens were tested at the whim of Roche, rather than for compelling scientific reasons. The study did not have the power to compare the two “control” arms, AZT+saquinavir and AZT+ddC. (This implies it also lacked the power to do the other comparison, AZT+ddC+saquinavir vs. the 2-drug combinations, because each arm was equal in size.)

Thus, the differences between them, while “statistically” significant, can be regarded as tarted-up anecdotes. Even so, they are bizarre: AZT+saquinavir induced a higher CD4 cell rise and a longer time over baseline than AZT+ddC, but AZT+ddC reduced viral PBMC levels and plasma viremia more than AZT+saquinavir. Conversely, AZT+saquinavir reduced p24 antigen levels more than did AZT+ddC.

The study population and the wash-out. Everyone had received over 4 months of previous AZT on the study. In addition, there was a one month AZT “wash-out” before the study began. Thus, everyone had an initial CD4 rise. What does this mean in the “real” world? Should everyone go on pulsed-dose nucleosides?

Magnitude of surrogate marker responses. We have no idea whether higher CD4 cell rises, or deeper viral load drops, over a period of 24 weeks, confer any longer-term clinical benefit. ACTG 229 provides no information about surrogate or clinical events after the 24-week period of the study. In addition, the intrinsic variability of the surrogate measurements (CD4 levels, CD4 NAUC (normalized area under the curve, a more precise method of quantifying effects on CD4 cells), viral PBMC (peripheral blood mononuclear cells) titer, plasma viremia, and p24 antigen assay) does not give a very exact picture of pre- and post-treatment immunologic and virologic activity. How much of the baseline viral load was due to the AZT “wash-out”? What results would be obtained using more exact virological assays, such as bDNA or QC-PCR? What kind of laboratory studies would one want to be nested inside of follow-up studies of protease inhibitors? What is the depth and duration of the antiviral response with saquinavir compared with other protease inhibitors now in development?

The current scuttlebutt has it that Hoffmann-La Roche has already applied for Accelerated Approval for saquinavir based on the CD4 cell count and virological marker changes seen in ACTG 229. But in an attempt to answer some of the many lingering questions concerning the clinical use of saquinavir, TAG has asked the FDA to hold off on regulatory approval for saquinavir. Among the concerns it laid out in its June 16th letter to the agency, TAG notes that (1) Saquinavir has not been studied for safety in a broad enough patient population for a long enough time; (2) Roche’s proposed follow-up studies are flawed; and (3) The use of surrogate markers to evaluate potential efficacy in ACTG 229 is completely untested in this new class of therapeutic agents.

Instead of Accelerated Approval, TAG members have approached the FDA with a plan for a large placebo-controlled comparative trial which would enroll up to 18,000 people and last from 2 to 5 years. The plan would enroll people with CD4 counts

Once More Into the Fray. The Office of AIDS Research (OAR) reforms are under assault yet again. This time, the House Appropriations Committee is considering yanking away newly appointed OAR Director Dr. William E. Paul’s fiscal authority over the NIH’s AIDS program by giving funds for AIDS research to the individual institutes instead of to the OAR. TAG’s new Legislative Affairs Committee, the American Foundation for AIDS Research (AmFAR), AIDS Action Council (AAC), Gay Men’s Health Crisis (GMHC), AIDS Action Baltimore (AAB) and the Pediatric AIDS Foundation (PAF) are working together to lobby key representatives against such a move. Right now, we are preparing to send out a letter supporting a consolidated AIDS research appropriation for the OAR from eminent scientists including Drs. David Ho, David Baltimore, Bernard Fields, Arnold Levine and Barry Bloom to solicit endorsements from other researchers. Oh, yes … and we need lots of help.

“I’d Rather Gamble It Away in A Casino, Than Flush It Down the Toilet.” So said one of the nations foremost AIDS vaccinologists about the money the NIH is about to spend on assessing the efficacy of one or two of the current preventive HIV vaccines. Most scientists have no faith in these products, but NIAID’s Vaccine Working Group recently gave the green light to further testing of the Genentech or Chiron immunogens. Industry and the Division of AIDS seem to be the major proponents of phase III tests of these vaccines. Besides, if they didn’t go ahead, what would they do with the AIDS Vaccine Evaluation Group? They have to have something to do — don’t they?

The New, Improved Division of AIDS (DAIDS). Last year, after Dr. Fauci fired DAIDS Director Dan Hoth in a fit of election-year panic, everyone had hoped a new face at the helm would bring new life to the flagship of the NIH’s AIDS research program. Former Deputy DAIDS Director, Jack Killen, has been appointed to succeed Dr. Hoth. Early last month, Mark Harrington, Peter Staley, Derek Link, Derek Hodel, Lynda Dee, Moises Agosto and Gregg Gonsalves met with Dr. Killen and DAIDS’s staff including Bopper Deyton, Steve Schnittman, Mary Foulkes, Bill Duncan, Bob Bassin, Rona Schmutter and Debbie Katz. The primary focus of the agenda was the state of the Division’s clinical research programs; in particular, the AIDS Clinical Trials Group (ACTG), which is set to be “recompeted” shortly.

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