Two new drug classes given to people with HIV for the first time

The 12th Retrovirus Conference heard the results of the first dosing trials to give people with HIV two completely new classes of drugs – maturation inhibitors and integrase inhibitors. Although both have been given to a few HIV negative volunteers in safety studies before, these were the first trials to give them to people with HIV and observe their effect on HIV in vivo.

PA-457: maturation inhibitor

PA-457, being developed by biotech Panacos pharmaceuticals, is a derivative of the natural product betulinic acid whose anti-HIV activity was first announced at the 10th Retrovirus Conference in 2003. HIV particles produced in the presence of this drug are non-infectious and have distorted capsids (the ‘core’ of HIV containing the RNA genome).

Further investigation found that PA-457 is unique in its mechanism of action. It inhibits neither a viral enzyme like current classes, nor a host factor like CCR5, but a protein produced by HIV-infected cells which would normally become a component of new HIV particles.

During the viral life cycle the protein components making up new viruses are synthesized as one long protein chain. HIV protease then snips these into individual viral components; protease inhibitors block this action.

What PA-457 does is to create a chemical bridge between two protein components so that HIV protease cannot separate them. To use a metaphor, while protease inhibitors blunt HIV’s scissors, PA-457 makes its cloth impossible to cut.

In an initial study, Panacos gave a single dose of PA-457 to 24 men with HIV who were either drug-naive or who had not taken HAART for at least four weeks. Six men each were given 75, 150 or 220 mg of the drug or a placebo.

The 150mg and 250mg doses cut the median via load roughly threefold (by 0.45 and 0.51 logs respectively). This is a respectable amount for a single dose of drug. Presenter David Martin compared this with the drugs tenofovir and d-d4FC (Reverset), which in single dose studies produced median reductions of 0.33 and 0.45 logs respectively.

The 75mg dose produced a reduction statistically equivalent to zero, and a minority of subjects had little response to the larger doses, which may indicate that response to this drug may vary according to host factors.

The most interesting finding was that the viral reduction appeared to be sustained for many days. PA-457 has a half-life of 2-3 days, and a viral load reduction of more than 0.35 logs was maintained for eight to nine days after treatment in the two larger doses.

Martin announced that a 10-day study of PA-457 monotherapy is ongoing and phase II efficacy studies are planned to start towards the end of 2005.

L-870810 – integrase inhibitor

In contrast to PA-457, which is a recent and serendipitous discovery, drugs to inhibits the third HIV enzyme integrase, which splices the HIV genome into the human one, have been hypothesised ever since HIV’s life cycle was first understood; the first conference specifically dedicated to this target took place in January 1995.

Ten years later, Susan Little of the University of California San Diego was finally able to announce the results of the first 10-day study of monotherapy with an integrase inhibitor, Merck’s L-870810, in HIV-infected subjects.

In the trial, 30 HIV positive patients were given placebo (six patients) or 200 or 400mg of L-870810 (seven and 17 patients respectively). Fifteen of the 24 patients given the drug were ARV-experienced.

After 10 days of twice-daily doses, the mean viral load decrease in the 200mg and 400mg doses was 1.73 and 1.77 logs respectively (the latter is a sixty-fold reduction in viral load). There was a wide range of response, from 0.95 to 2.49 logs, but no non-responders. Six out of 16 patients on the higher dose (37.5%) had a viral load below 400 by day 10. After dosing was stopped viral load increased again and was back to baseline by day 24 in most subjects.

This was the last study that will ever be performed on this specific compound. Research on L-870810 has now been stopped after unacceptable liver and kidney cell toxicity was found in dogs. One of the reasons for the slow progress on integrase inhibition is that many candidates have turned out to be toxic and to inhibit other vital cellular functions.

However Little said that there was no evidence of human toxicity in the current study and that studies in rats had shown none. There were four discontinuations in this study, none related to drug toxicity and three solely due to the suspension of the study when the dog toxicity data was released. Research on the related drug candidate L-870812 is proceeding.