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ICAAC Update

Three New Drugs in Development, Plus Isentress With Reyataz

January/February 2010

Introduction

News from the 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), held by the American Society for Microbiology in San Francisco in September.

Although these results are still early, they show continued hope for new drugs and new strategies for fighting HIV in the future. For more information, visit www.icaac.org or www.aidsmap.com.

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New Drug in the Works: GSK-744

Pharmaceutical giant GlaxoSmithKline (GSK), in conjunction with Shionogi Pharmaceuticals from Japan, has a new drug in development with a convenient once-a-day dose.

S/GSK1265744 (744 for short) is an HIV integrase inhibitor drug. These medications interfere with HIV's integrase enzyme, which the virus uses to insert its genetic material into the DNA of human cells. There is currently only one integrase inhibitor on the market, the popular Isentress.

According to this Phase 1-2a (early, small study) report, 744 was taken by both HIV-positive and HIV-negative people.

In the 30 HIV-negative individuals, 744 appeared safe enough for further development and to have favorable pharmacokinetics (how long the drug lasts in the blood after dosing).

In 11 HIV-positive individuals, 744 showed strong antiviral effect. In this group, there was a large drop in viral load (median of 2.6 log) after 10 days of taking the drug by itself in tablet form. At day 14, all but one had viral loads below 50 copies.

In addition, 744 did not show cross resistance, in the test tube, to two other drugs in its class, Isentress and the experimental elvitegravir.

The most commonly reported adverse event was headache (in 7% of participants), which occurred twice as often in the placebo (fake pill) group, and may be the effect of not being allowed to drink caffeine during the 10 day study period.

See News Briefs for related news about GSK HIV drug development. GSK has another integrase inhibitor, "572," further along in development (see IAS Update in November/December issue).


Another New Drug in the Works: PRO 140

PRO 140 is a monoclonal antibody CCR5 antagonist, a new class of drugs that inhibits the entry of HIV into human cells. It is given by injection or intravenous (IV) infusion. Selzentry is currently the only available CCR5 antagonist; it is taken orally.

In this early Phase 2a study, a single dose of either 5 mg or 10 mg was given by IV infusion to 20 participants, resulting in a significant drop in viral load (1.83 log). With the higher dose, more than a 1 log drop was maintained for three weeks after the infusion was given. All 20 participants had at least a 1 log drop in viral load, and some had a 2 log decrease.

No toxicity related to PRO 140 occurred. Studies are moving forward with subcutaneous dosing.

As in other studies of CCR5 antagonists, participation was limited to people who had R5-tropic HIV (virus that uses only the CCR5 co-receptor to enter the cell). One study participant was found to have a dual/mixed-tropic virus, one that uses both the CCR5 and CXCR4 co-receptors to infect cells. Drugs that block the CCR5 co-receptor are not expected to work for people with dual/mixed virus. As would be expected, this person had a poor virologic response to the drug. The dual/mixed virus was discovered using a more sensitive tropism test, and this participant's data were excluded from the efficacy analysis.


In Further Development: Vicriviroc

A poster presentation detailed good results with another experimental CCR5 antagonist, but one that is further along in development.

Participants took one 20 or 30 mg tablet of vicriviroc, or a placebo, once daily, along with a Norvir-boosted protease inhibitor-based optimized background therapy. The vast majority of participants (85 of 86) who had completed a one-year study with vicriviroc continued in an extension study of one more year. The majority of them (more than two-thirds) continued to have undetectable viral loads. CD4 T-cell counts continued to rise as well, by an average of 56 cells for the year.

Adverse events experienced by more than 5% of study participants included sinusitis, cough, and insomnia. Mild upper respiratory tract infections also occurred.

As with PRO 140 above, one study participant experienced treatment failure, and was later found to have dual/mixed virus.

The data was presented in poster #H-923 from M.C. McCarthy et al.


Yet Another New Drug in the Works: MPC-4326

MPC-4326 is from a new class of drugs called HIV maturation inhibitors. They work at the final stage of HIV's reproduction in the body, at the point where it "matures" and heads off to infect new cells.

MPC-4326 (generic name bevirimat) was taken by 32 study participants. Six of them had previous HIV treatment.

In this small trial in early development, participants took either 200 or 300 mg of MPC-4326 twice a day, in 50 mg tablets. The drug was taken with food for two weeks. The 300 mg dose was found to be more effective.

Just when you thought you had finally understood HIV drug resistance, along come polymorphisms at gag cleavage sites.

MPC-4326 interferes with an HIV gene called gag. To date, it is known that polymorphisms (structural differences) at cleavage sites 362 and 369-371 on the gag gene of a person's HIV will limit the drug's effectiveness. In this study, that held true.

Gag is involved in HIV cleavage. In order to reproduce, the virus cuts itself up into smaller pieces (think of a cleaver). There are cleavage sites in gag to help make this happen. Polymorphisms at some of the sites can make MPC-4326 less effective.

The new HIV pieces -- which include gag -- go on to evolve from "immature" to "mature," at which point they are able to infect new cells. People with these polymorphisms had a poorer virologic response compared to other participants. The "polymorphic" people had an average of .48 log decrease vs. an average of .86 log decrease for people without the polymorphisms.

The most commonly reported adverse events were headache (31%), diarrhea (19%), and nausea (16%).


Isentress/Reyataz Combo

Dr. Peter J. Ruane of Los Angeles reported good early results in people switching from a standard combination regimen to the two-drug regimen of two popular HIV medications on the market, Isentress and Reyataz. However, the right dose for this combination is still being debated.

In Ruane's private practice, 30 patients who were successful in reaching undetectable viral loads but were having side effects from their current regimens (gastrointestinal problems, elevated lipid levels, lipodystrophy, and other issues) were switched to a simplified two-drug regimen of Isentress with Reyataz.

Except for two drop-outs, the 28 patients remaining on the two-drug combo maintained undetectable viral loads. Time on therapy at the time of the conference ranged from four to 48 weeks, with only six patients reaching the one-year mark.

There was no viral rebound with Isentress/Reyataz, although there were five single blips of less than 100 copies before the viral load returned to undetectable (less than 48 copies).

Ruane used the standard Isentress dose of 400 mg twice a day, but there are two FDA-approved doses of Reyataz. Ruane picked the once-daily Reyataz dose of 400 mg without a Norvir booster.

His study began before Isentress manufacturer Merck and Reyataz manufacturer Bristol-Myers Squibb (BMS) reported the results of an interaction study between these two drugs in February of last year, at the 16th CROI (Zhu L, et al. Abstract 696, Conference on Retroviruses and Opportunistic Infections, 2009). In a study using HIV-negative volunteers, Reyataz blood levels were lower when taken with Isentress. In turn, Reyataz increased blood levels of Isentress. Based on this study, BMS has enrolled a small study testing this combination, using the standard dose of Isentress and 300 mg twice a day of Reyataz. Data from that study should be available later this year. In the meantime, don't try this at home until more results are in.

Got a comment on this article? Write to us at publications@tpan.com.



  
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This article was provided by Positively Aware. It is a part of the publication Positively Aware. Visit Positively Aware's website to find out more about the publication.
 
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