PMPA -- First Human Results

PMPA, an antiretroviral being developed by Gilead Sciences, Inc., has shown exceptional activity in some animal tests (see AIDS TREATMENT NEWS #248 and #236). Now the first human multi-dose trial(1), reported this month at ICAR (the International Conference on AIDS Research) in Atlanta, found results which could be much more important than they may at first appear.

This trial found a median 1.1 log (13 fold) viral load reduction after one week of the once-daily treatment (plus an additional single dose given one week earlier), in the eight patients who received the highest dose tested. This is more impressive than it looks, for two reasons:

(1) Because of the half-life of HIV in the blood, the maximum possible decline after one week of therapy would be about 1.1 log -- even for a drug that completely stopped new virus production. In this trial, PMPA produced a median decline of 1.1 log, suggesting that the decline was close to the theoretical maximum. This viral load improvement was roughly equivalent to what is seen from protease inhibitors after one week of therapy. (The trial could not be extended, because a trial must follow a protocol which is based on safety concerns -- especially when testing a new drug with very little data from human experience.)

Animal trials with SIV (simian immunodeficiency virus, often used as a model for HIV) have found two to three log viral load reductions with PMPA alone after four weeks of therapy.

(2) Animals with SIV have been treated with PMPA for about two years, and no resistance has been seen (with AZT, resistance is seen in about four months). Also, laboratory attempts to create HIV which is resistant to PMPA have had little success. Only one resistance mutation has been found, and it gives only a three-fold loss of sensitivity -- probably not enough to keep the drug from working.

In other words, IF PMPA proves safe enough to use and otherwise workable, the currently available information suggests that it might be as active as the protease inhibitors, but without the resistance problems of those drugs. PMPA has a long intracellular half life, which should maintain trough levels and allow once-daily dosing.

Since PMPA itself must be given intravenously, further development will test Bis(POC)PMPA, a form of the drug which is taken orally(2). The next human trial, which should start in early summer, is planned to run for one month; this should be long enough to tell whether or not the short-term activity of the drug is comparable to that of protease inhibitors.

Note: PMPA and Bis(POC)PMPA should not be confused with PMEA and bis-POM PMEA, chemically similar drugs from the same company which are farther advanced in human trials, but probably have less anti-HIV activity.

References

(1)Barditch-Crovo P, Deeks S, Kahn J, and others. PMPA: Safety, pharmacokinetics, and antiretroviral activity when administered as a single dose and for seven consecutive days to patients with HIV infection. International Conference on AIDS Research, Atlanta, April 1997.

(2) Bischofberger N, Naesens L, De Clercq E, and others. Bis(POC)PMPA. An orally bioavailable prodrug of the antiretroviral agent PMPA. 4th Conference on Retroviruses and Opportunistic Infections, January 22-26, 1997 [abstract #214].