Early on a rainy Monday morning, Merck scientists Emilio Emini and John Ryan assembled overheads and flip charts before a bleary-eyed group of 11 community treatment activists. Among them were TAG's Michael Ravitch, Michael Becker, Spencer Cox (also of CRI-A), Derek Link and David Gold (both also of GMHC). Michael Ravitch prepared this report.
Merck's anti-protease drug, L-524 as it had become known, began its clinical development (pharmacology and dose-ranging studies) about one year ago to the very day. At the 600 milligram dose (4 times daily), investigators had encountered mild elevations in bilirubin. No clinical toxicity but significant enough that the FDA (understandably Lilly-livered after the recent FIAU disaster) insisted that Merck proceed with a lower dose: 400 milligrams four times daily.
Meanwhile, investigators continued to follow several patients from the original toxicology studies who had take "524" for more than 6 months -- at the 400 mg dose. In all of these patients, it turned out, p24 antigen had dropped 99.9% within the first 4 weeks to an undetectable level. What was even more exciting for the Merck clinicians poring over the numbers, p24 stayed down for more than 6 months. This was accompanied by significant weight gains and rises in CD4+ T cell counts.
But Merck investigators viewed the CD4 cell changes with circumspection; it was the virological changes they were after. And a near 100% drop in p24 antigen (the easiest and least expensive viral marker to measure) seemed impressive enough to put their manufacturing unit into high gear. The company is said to have spent millions on peptides, prepared to build a new plant in order to scale up production of the drug, and was preparing to submit an NDA (New Drug Application) requesting accelerated approval from the FDA early in 1995.
Three weeks later, however, the results came in from the PCR -RNA assay. Run on blood samples from those very same patients, the results were quite different -- and extremely disappointing. While the initial RNA decline paralleled the p24 fall in terms of its dramatic disappearance, after only 16 weeks RNA levels began to creep up again. At 24 weeks, RNA levels had surged to pre-treatment (baseline) levels. And although the assay was relatively new, Dr. Emini (one of the top virologists in the country) felt confident that as a quantitative measure of viral activity, it was top notch.
Two questions arose at that point: First, what explains the discordance between the p24 and the PCR RNA assays? The current explanation is that the rapid elimination of p24 antigen during the first 4 weeks allowed for the explosion of p24 antibody -- and that profusion of antibody interfered with the ability to detect p24 antigen reliably. This theory is supported by various laboratory experiments.
Second, why did the antiviral activity resume after 4-6 months? The most obvious explanation is resistance; however, the Merck team has not yet been able to sequence any genetic mutation for a 524-resistant virus. The assumption, of course though, is that it is present.
Needless to say, Merck has set aside plans for larger clinical trials. The current plan is to amend the previously drawn protocol (006) so that all patients currently receiving drug will receive 600 mg (four times daily) with the hope that the higher dose might overwhelm the putative development of resistance, without incurring serious hepatic toxicity. Combination trials are also in the works. The first will compare 524 to 524 plus AZT versus, of course, AZT alone. The second will test the triple combination of AZT plus ddI plus 524. Both of these trials will be small: 15 patients per arm.
Clearly Merck is very disappointed. Its corporate strategy, one might say, is the opposite of Roche's. Merck is only interested in marketing an excellent product. It is doubtful Merck would pursue a drug (expensive and difficult to make) which would only have a negligible effect on the disease course and would be mired for years (like AZT or ddC) in controversies about clinical efficacy. The company has already spent over $350 million on AIDS drug development, and seems wary of wading in further without the prospect of a homerun product.
On the other hand, that might be a great mistake. Merck execs are drawing these conclusions on the basis of four patients and a brand-new assay. Theoretically, the drug could be superior (even as monotherapy) to anything available currently -- with less toxicity. And who knows for what specific indications the drug could prove helpful (e.g., perinatal transmission, asymptomatics). Hopefully, Merck will not give up too quickly.