13th Conference On Retrovirus and Opportunistic Infections

Update On Experimential HIV Drugs

As a member of the Community Liaison Committee of CROI (Conference on Retroviruses and Opportunistic Infections), helping to formulate the program for this year’s meeting, it is satisfying to see the conference a success in bringing the latest HIV research to the top scientists, clinicians and community educators from around the world.

Despite the unfortunate news from the SMART study on treatment interruption strategies (see page 37), this year’s CROI offered more positive results on several new drugs and different drug classes. New data is shedding light on three new classes—the integrase inhibitors, maturation inhibitors and co-receptor antagonists. New ways to inhibit the reverse transcriptase enzyme are also being studied in the laboratory. Seeing more research on the new classes in an important meeting such as CROI is encouraging and shows that HIV drug development is moving full steam ahead, improving the scope and range of options, especially for people who have developed resistance and need new drugs.

TMC-114

TMC-114 (generic name darunavir) will most likely be the next approved HIV protease inhibitor (PI), expected on the market later this year. It is very potent and showing proof of effectiveness against virus with protease resistance. At CROI, a pooled analysis of several important studies was presented that provides further information on the drug’s resistance profile. The analysis showed that the drug was still effective in a third of participants who had up to nine PI resistant mutations. Also identified were 11 mutations associated with a diminished response to TMC-114.

The data also showed susceptibility to Aptivus—the latest approved protease inhibitor, even after developing the five TMC-114-associated mutations, showing that it may be possible to take Aptivus after using TMC-114 first. TMC-114 is available in an expanded access program. (Call Tibotec at 1–866–889–2074 for further information.)

TMC-125

TMC-125 (generic name etravirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) also from Tibotec, but is not as far down the pipeline as TMC-114. A study was presented showing more evidence that this drug will also work against drug resistant virus. Two doses of the drug were studied in this analysis of people resistant to non-nucleoside analogs. The 800 mg twice daily dose showed an average 1.18 log viral load decrease from baseline. The 400 mg twice daily dose showed an average 1.4 log decrease. Both were significantly better than the control arm, which showed only a .19 log decrease. It will be interesting to see the results of larger studies of TMC-125, as a new NNRTI is desperately needed.

Tibotec has been focusing on compounds that work against drug resistant HIV and they are opening an unprecedented randomized study called DUET looking at how the combination of these two drugs will work in experienced patients. The issues around design for such a study are complex and this is the first trial with two experimental drugs from one company. Fuzeon is allowed in the trial, which will provide a unique opportunity for those receiving the two Tibotec drugs plus Fuzeon. At CROI an interaction study showed that the drugs can be taken together without seriously affecting each other. The DUET study is open to enrollment across the country (visit www.acria.org for trial information).

Integrase inhibitors

Probably the most hopeful news from CROI this year was a whole new class of HIV drugs that block integrase, a critical enzyme responsible for HIV replication (see page 44). Two companies presented data from two strikingly similar drugs. However, Merck’s MK-0518 is farthest along in the pipeline.

An interim 16 week analysis showed that 72% of highly treatment experienced patients reached a viral load below 50. Everyone receiving drug in the study achieved viral load reductions greater than 2 logs after two weeks on the drug. MK-0518 has no known interactions with current HIV drugs, so there will be no need for dose adjustments due to the way it is metabolized. Encouragingly, there were few adverse events in this study, but the drug is still early in development. Watch for a larger Phase III study. (Check out www.benchmrk.com/secure for Phase III sites.)

Gilead presented data from their integrase inhibitor, GS-9137, in a 10-day monotherapy study. It showed a dose-related viral load response compared to the placebo arm. The only real difference thus far between the two integrase drugs is that Gilead’s is metabolized by the CYP3A4 enzyme and works better if boosted by 100 mg of Norvir. In fact, the arm using the smallest dose of GS-9137 (50 mg) plus 100 mg Norvir once daily showed the highest average viral load drop of 2.03 logs.

Maturation inhibitor

Another new drug breaking in the news is PA-457, an HIV maturation inhibitor by Panacos. It’s called maturation inhibitor because it blocks a “finishing” stage of HIV replication, when the new virus is re-packaging itself. More studies are showing that this new class is active against HIV. A monotherapy study presented at CROI showed that the higher the dose, the better the viral response.

Still, it appears that in order to be competitive, the drug may need to be studied at higher doses or boosted, as the highest viral load reduction seen in this study was a little over 1 log at the 200 mg once a day. PA-547 stays in the bloodstream a very long time and thus far appears to be well tolerated.

It is also not going to be cross resistant to the older medications since it is from a different drug class. According to a complicated scaling system used in culture assays, the company claims that PA-457 is synergistic with other antiretrovirals. Pfizer is doing other work in screening for a new maturation inhibitor. Stay tuned for yet another HIV drug class.

CCR5 antagonists

The CCR5 antagonist class has suffered some setbacks recently, although two of the three drugs in development are moving forward in clinical trials. At CROI, maraviroc (Pfizer) and vicriviroc (Schering Plough) studies were presented.

There are many complicated issues surrounding the development of these compounds. First of all they may work in only a select group of people, and then the drug may cause HIV to shift to using the other co-receptor that is associated with late-stage HIV. Schering Plough halted a vicriviroc study early in treatment-naive people due to a limp response, but continued their studies in treatment-experienced people.

There were two posters presented on maraviroc at CROI. Both are showing more data on resistance and physiological details of the new agent on the CCR5 receptor.

Keep your fingers crossed for this class as it represents another option for those who are drug resistant to the current drugs.

CXCR4 antagonists

The stage is being set for the development of CXCR4 antagonists, the other co-receptor mentioned above as associated with late-stage HIV. A Japanese research team presented in vitro and animal data showing promising results in this very early stage of development. The study looked at activity, specificity, toxicity and half-life in animals. Results show that this will be an oral drug most likely taken once daily.

AMD-070 by Anormed is the only other CXCR4 in development and will be moving into Phase II studies soon.

Monoclonal antibody

TNX-355 (being developed by Tanox) is the first monoclonal antibody that has gotten this far in HIV clinical trials. It is technically an entry inhibitor, as it blocks the CD4 receptor on the cell, preventing HIV entry.

There was one study characterizing HIV isolates from people using the drug in clinical trials. It showed that the virus tropism (the receptor that the person’s HIV prefers to attach to) did not matter, whether the antibody “stuck” on the CD4 receptor or not. This drug is currently in Phase II trials and is administered by IV infusion every two weeks. (See www.acria.org for current studies.)

Reverse transcriptase

There was news of different compounds being developed that look at different ways to inhibit the reverse transcriptase enzyme, the same drugs that were the first on the market to fight HIV. If these pan out, they will provide alternatives to current drugs targeting reverse transcriptase.

There is a nucleotide analogue pro-drug that would compete with Viread. Also, an alternative to Retrovir or Zerit is moving into Phase I studies this year. And nucleotide-competing compounds would provide an alternative to current reverse transcriptase inhibitors. All are in preclinical research—still in the test tube.

Fusion inhibitors

It is also encouraging to see second generation fusion inhibitors being developed after Roche discontinued T-1249, the cousin of Fuzeon (T-20), a couple of years ago. Two compounds are being considered for next phase development by Trimeris. The good news is that they are focusing on compounds that would require fewer injections, specifically once a week. Thus far the studies have only been in the laboratory, as they are trying to tease out the best compound out of a battery of possibilities. One new candidate is showing 150–250 times more activity than Fuzeon.

More hope

After living 18 years with HIV and surviving the dry years where there were no drugs, I am fortunate to be alive to witness this astounding new research in HIV. Not only have we made significant progress with 25 currently approved drugs, but it is apparent that the industry has been re-invigorated to produce better drugs that may be more potent, safer and hopefully easier to take. e

Matt Sharp is Director of Treatment Education at TPAN.