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Shot Down Early On, Merck Scientists Test Higher Doses And Combinations, Hoping for Success

Production Problems Loom

The Merck protease inhibitor, L-524, has recently begun to generate a lot of talk. The data from the first controlled study in 70 patients is incomplete, and therefore no statistically meaningful data has emerged as yet. Anecdotal reports from the company, however, indicate that the drug has an excellent safety profile and an extremely powerful antiviral effect – at least for the first 3-5 months. After that, resistance appears to develop, and within 6-8 months most patients have seen the amount of virus in their blood return to baseline values.

The only adverse effect associated with L-524 according to Dr. John Ryan, chief of Merck’s HIV Clinical Research Program, is hyperbilirubinemia (an increase in bilirubin). This has occurred in a small percentage of patients taking the drug, and usually resolves on its own. One or two patients have developed mild jaundice, which disappeared upon discontinuation of the drug. Dr. Ryan believes this problem does not result from liver cell dysfunction, and therefore will not be clinically significant.

Dr. Emilio Emini, at the helm of HIV Basic Research at Merck, has identified a specific mutation which he associates with viral resistance. In most of the patients, an overtly resistant phenotype is selected for within 3-8 months. The Merck scientists are slightly encouraged, however, by the fact that CD4+ T cell counts seem to remain up, above baseline, even after the viral RNA has come cycling back – possibly up to 1 year afterwards. (What this means is anyone’s guess.)

Merck has launched three small trials in an attempt to overcome this resistance and achieve a more sustained antiviral effect. They have two strategies: pushing the dose and testing multiple combinations. The first study, already begun, tests the combination of AZT+L-524 v. AZT along v. L-524 alone. A second pits the triple combination of AZT+ddI+524 v. AZT+ddI v. 524 alone.

Both of these trials are restricted to people who have never taken AZT. A third study will analyze the pharmacokinetics and efficacy of higher doses and a different dosing schedule (800 mg three times daily) and a higher dose (1000 mg three times daily). Higher doses may slow down – or hasten – the development of resistance. Other questions are being explored in smaller trials. Judy Falloon, at the NIH, is testing a combination of interleukin-2 and L-524 in a small group of patients, to see if the addition of a potent antiviral will increase the benefit of the immunomodulator.

Drug interaction studies are also in the works (like most drug companies, Merck scientists do not seem to be answering these easy questions quickly enough). TAG urged Merck not to waste any time before conducting a study to see if 524 could be effective in preventing perinatal transmission. Just such a drug, briefly powerful and non-toxic, might be the best candidate at this time. We also have encouraged a small study of combination protease inhibitors. Cross-resistance has been reported with several other protease compounds, but not all.

It was encouraging to learn that Merck scientists agree on the importance of designing studies with clinical endpoints – and disappointing to hear them say they haven’t enough drug to conduct the large, simple study TAG is proposing. They plan to begin their “pivotal” clinical studies at the beginning of 1995 and expect to enroll, at most, 2,000 people. They claim they haven’t enough drug for any kind of compassionate use protocol, either. We were disappointed by these last two points.

First of all, we consider it an ethical responsibility for any company involved in AIDS drug development to provide access to experimental therapies for desperately ill patients. Secondly, we are afraid Merck is squandering its only opportunity to prove how well L-524 works. AIDS researchers have consistently made unrealistic assumptions about the benefit of new therapies, and as a result designed trials too small to reveal what may be significant, if subtle, clinical differences.

Dr. Paul Reider, chief of Merck’s feisty Process Development division, explained that L-524 is the most difficult drug Merck has ever made, both in terms of the number of chemical “steps” (17) and the sheer volume of material required (one kilo per person per year). The pilot plant is running twenty-four hours a day, according to Dr. Reider, and producing at full capacity. Expanded manufacturing facilities should be generating additional drug within 18 months (spring of 1996) when the company hopes to file for approval and begin selling 524.

The lack of a compassionate use program for 1995 is extremely disappointing. It must be admitted, though, that the speed with which Merck has scaled up production is remarkable. L-524 first went into humans in February of 1993. Hoffmann-La Roche, by comparison, is at roughly the same point as Merck, but began its clinical trials of saqunivavir (Ro 31-8959) a full two years earlier. Merck has put an extraordinary amount of resources into L-524, and without certain expectation of payoff.

Over the next two months, Dr. Ryan plans to design the pivotal L-524 efficacy studies. How can Merck design a study that will produce the most thorough answers? One possibility for Merck would be to randomize patients to L-524 or placebo and also allow a wide variety of concomitant medications (e.g., AZT, ddI, ddC and d4T). While not every patient would receive L-524, no one would have to forego other therapies of his or her choice. While this approach is a departure from traditional methodologies for clinical trials, AIDS demands innovation.

If the control arm ends up being AZT or placebo, we can be certain that many participants will drop out or cheat. And if the treatment arm is arbitrarily assigned to a specific combination, many people in that group will also cheat. This is inevitable. Perhaps Merck scientists should design a study in which patients can be honest about their concomitant medications. That way, they may possibly learn something about the advantages and disadvantages of different combination regimens. This sort of study could also create a broader indication for Merck when the drug is licensed.

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