MKC-442

Cary Moxham, of Triangle Pharmaceuticals, reported preliminary efficacy and safety data of repeated multiple doses of MKC-442. "Structurally MKC-442 resembles a nucleoside analogue but it functions as a NNRTI." They reported oral bioavailability in monkeys and rats to be 68%; in the rat, 100&337; of the amount in plasma penetrates the brain. The Cytochrome P450 liver enzyme system that metabolizes protease inhibitors also metabolizes MKC-442. Therefore, interaction studies will be conducted by Triangle to discover dosing relationships between MKC-442 and other drugs.

Thirty-five HIV-infected asymptomatic volunteers with above 100 CD4 and above 10,000 HIV RNA were randomized in a double-blinded fashion to 1 of 5 dose regimens of MKC-442, and were given repeated oral doses for up to 2 months.

These are the median changes in HIV RNA (viral load) from baseline for each dose studied during first 4 weeks of monotherapy:

Triangle is exploring dose escalation. Resistance to MKC-442 in vivo will be examined by genotype of HIV RT from all patients in study. Investigators characterized the medication as well-tolerated: headache (n=6) and loose stools (n=3) were the most frequent side effect; one patient (100 mg bid) experienced rash and was the only one to discontinue therapy. Minor elevations were reported in liver transaminase levels (GGT) in 1/3 patients and were characterized as being inconsequential.

Commentary: You may be questioning the potential efficacy of MKC-442 because the initial viral load reductions are rebounding. It is standard with other NNRTIs--nevirapine, delavirdine, DMP-266--for viral load to take an initial drop and then rebound relatively quickly when used as monotherapy or when used in a regimen that does not "adequately" lower viral load. The therapeutic benefits of nevirapine were realized in protocol 1046 (see study data on this web site: "Nevirapine: recommended for accelerated approval", and "Nevirapine Update" which includes follow-up data from Vancouver) where it was discovered that a triple-drug combination of nevirapine/AZT/ddI was able to sustain profound reductions in viral load. The theory is that once you lower viral load to "undetectable" levels (it may be crucial to lower viral load to below 50 copies) viral replication and therefore mutation (resistance) is suppressed to the point where viral load remains suppressed for a prolonged period. Studies of nevirapine as monotherapy or in combination with one nucleoside indicated relatively quick rebounds in viral load following initial reductions. Dr. Julio Montaner studied nevirapine in combination with indinavir and 3TC in individuals with below 50 CD4 who were 3TC resistant. These results were also positive (the data is reported in our report of the Retrovirus Conference in our newsletter posted on this web site or a printed edition can be mailed to you by contacting our office (212-219-0106). DuPont Merck reported data for their NNRTI called DMP-266 when used in combination with only indinavir. These results were also positive and again are available in the newsletter or in a report posted to website directly.