Update From CROI 2008 on Experimental Drugs
Compared to the recent fast pace of new HIV drug development, the next couple of years look relatively quiet. In just over two years, five new drugs were approved by the FDA, including ones from two new classes. While most people -- including those with extensive treatment experience -- are now able to build potent regimens, there remains a need for new drugs.
The Conference on Retroviruses and Opportunistic Infections (CROI) held recently in Boston, MA is the most important annual HIV science conference in the US. This article reviews some of the presentation on experimental HIV drugs at this year's meeting.
Data were presented from a study called VICTOR-E1, looking at the CCR5 antagonist vicriviroc in people with experience taking HIV drugs. While generally positive the results raise further questions about this drug's future.
The study compared two doses of vicriviroc (20 and 30mg, both once daily) to placebo, each combined with the best available background regimen in people with extensive experience taking HIV drugs. The study was relatively small, with about 40 people in each of the three groups.
After 48 weeks, about half the people taking either dose of vicriviroc had HIV levels below 50 copies/mL, compared to 14% taking placebo. Average decline in viral loads were greater for people on vicriviroc as well: 1.77 and 1.75 logs for the vicriviroc groups vs. 0.7 logs for placebo. Vicriviroc was generally well tolerated with few people stopping due to side effects.
While these results suggest fairly potent anti-HIV activity for vicriviroc, further analysis raises significant questions. People with high HIV levels -- defined as above 100,000 copies/mL -- at the beginning of the study were very unlikely to get to below 50 copies/mL (33% for the 30mg group, 17% for the 20mg group, and 10% for the placebo group). Also, many more people taking vicriviroc than placebo were also taking the protease inhibitor Prezista (darunavir) as part of their background regimen. At the very least his confounds any positive results seen in this study.
There were a couple of other presentations on vicriviroc, including two that looked at resistance and one that found no affect of vicriviroc on HCV. A couple of years ago vicriviroc was locked in a head-to-head race with two other drugs, GSK's aplaviroc and Pfizer's Selzentry (maraviroc), to become the first CCR5 drug approved by the FDA. Aplaviroc's development was halted due to rare, but serious liver toxicity. Selzentry was approved a few months ago. The results presented at CROI are generally positive, but do little to overcome the perception that this once promising drug's uncertain future. The company has chosen the 30mg dose for future development.
Other CCR5 Antagonists
There were a couple of presentations on other experimental CCR5 drugs at CROI. Other than vicriviroc, the drug furthest along in development is INCB9471. Data were presented on a 14-day study of multiple doses of the drug compared to placebo in people with R5-only HIV. Overall 49 people were studied, with 9 given a placebo and the rest one of three doses of INCB9471 (100, 200 and 300mg, once daily). No data were presented on reductions in HIV levels or changes in CD4 count. Instead they presented data on people who had X4 HIV emerge during the study. As seen with studies of other R5 drugs, most of the emergence of X4 on these drugs seems to be from a minority population of dual/mixed HIV that was not detected at the start of the study. This highlights the need for better screening tests for R5.
Another experimental R5 drug, called PF-232798, was tested against HIV that had grown resistant to Selzentry. The researchers grew HIV in a lab that was resistant to Selzentry and tested PF-232798 against it. While the activity of PF-232798 dropped off somewhat compared to against non-resistant HIV, it retained sufficient activity to move the drug forward in clinical development.
All of the currently tested CCR5 drugs work by attaching to the R5 protein in such a way that HIV has a difficult time attaching to it. While this strategy can be effective, HIV can develop resistance to these drugs by changing the way it attaches to R5. At CROI, researchers presented early research on another approach to blocking R5 -- using a drug to force R5 to move out of the cell membrane to inside the cell. This approach, if proven safe and effective should be less susceptible to resistance. Researchers tested a large number of compounds for their ability to internalize CCR5. They found one, called ESN-196, that they think warrants further testing as an R5 blocker.
Several new non-nucleoside reverse transcriptase inhibitors are in pre-clinical development. UK-452,061 is being developed by Pfizer. A poster presentation detailed an experiment where UK-452,061 was tested against HIV taken from people who had developed resistance to approved NNRTIs. In all they looked at 62 samples of NNRTI-resistant HIV, and the compound showed good activity against 61 of them. The tests were done in a laboratory, not in people.
Another experiment reported in a poster compared resistance to the experimental NNRTI, IDX899 to the widely used NNRTI Sustiva (efavirenz). In this study, researchers exposed a laboratory strain of HIV to different concentrations of both drugs to try and force resistant HIV to emerge. This type of experiment is done commonly in early drug development. The researchers reported that resistance to IDX899 emerged more slowly compared to Sustiva and neither drug appears to be highly cross-resistant.
Still another experiment looked at two experimental NNRTIs -- RDEA427 and RDEA640 -- compared to Sustiva against HIV with the most common NNRTI mutations. Both experimental drugs worked better than Sustiva. This is not surprising as the HIV tested would be expected to be highly resistant to Sustiva.
They also tested these two along with another experimental NNRTI, RDEA860, to see how affected they are by human proteins. The extent to which drugs attach to human proteins has a profound affect on how easily therapeutic levels of the drug can be achieved. While each of the drugs was significantly affected by protein binding, they were less so than Sustiva, Intelence (etravirine) or rilpivarine (TMC-278).
Bevirimat is an experimental maturation inhibitor being developed by Panacos. Maturation inhibitors work at the same step in HIV's replication cycle as protease inhibitors, but in a different way. Its development has been slowed by problems with formulating the drug. The drug is currently in Phase IIb.
Two poster presentations looked at the development of resistance to bevirimat. One found that protease inhibitor resistant HIV may be less likely than wild type HIV to have resistance to bevirimat. This is a potentially important finding, because bevirimat is being developed for people with extensive HIV treatment experience, who are likely to have HIV that is resistant to PIs. The other study identified several mutations that reduced bevirimat's activity. As the drug moves closer to possible approval, this information will help researchers, regulators and activists as we evaluate the results from clinical studies.
A poster presented at CROI suggests that GS-9148, an experimental NRTI being developed by Gilead, might cause fewer kidney problems than Viread (tenofovir) and might have very good penetration into lymph nodes.
GS-9148 is a nucleotide reverse transcriptase inhibitor (NtRTI). Other NtRTIs, including Viread, cidofovir and adefovir, have caused kidney damage. This poster showed data looking at GS-9148's affect on kidney cells, from both laboratory and animal studies. Compared to other NtRTIs, little of GS-9148 was taken up into kidney cells. This suggests it is less likely to harm those cells.
Gilead is also looking at how well GS-9148 gets into lymph node cells. Lymph nodes are a major site of HIV replication, and most HIV drugs fail to penetrate well into this important area of the immune system.
The NRTI class of drugs has lagged in development for some years now. As a class they have been hampered by relatively low potency and high toxicity. A new NRTI with low toxicity would be welcome, if it is shown to reduce HIV levels well. More research will be needed to see if the promise of this new NRTI can be achieved.
A poster presented at CROI shows potential for another experimental NRTI, apricitabine. The results were from the AVX-201 study, which Project Inform reported about earlier. AVX-201 compared apricitabine to Epivir (lamivudine, 3TC) in people with HIV that harbors the M184V mutation, which is associated with resistance to Epivir and Emtriva (emtricitabine, FTC).
In the first phase of the study, people on failing Epivir regimens were randomly assigned to either stay on Epivir or switch to apricitabine. After 21 days everyone was switched to a background regimen made up of the best available HIV drugs. Results from this second phase were presented at CROI.
After 24 weeks there was a trend toward better outcomes for people taking apricitabine, but the difference wasn't significant. The authors speculated that the potency of the background regimens and the small number of people in the study made this difference too small to be considered significant. There were more treatment related side effects among people taking apricitabine than Epivir. This is not surprising as everyone in the study had experience taking Epivir.
The development course for apricitabine is unclear. Many people have developed resistance to either Epivir or Emtriva, so a viable option for them is needed. Avexa, the developer of apricitabine, will need to show that its drug is potent and well tolerated in larger trials before we will know if it can be that option.
GlaxoSmithKline and Shianogi presented resistance data on a potential integrase inhibitor, called S/GSK364735. Unfortunately this drug appears to have similar resistance patterns as both Isentress (raltegravir) and Gilead's elvitegravir. However, development of this drug is expected to move forward.
In addition to more traditional approaches to HIV therapy, there's quite a bit of interest in testing anti-inflammatory drugs for activity against HIV. One drug, called Aprepitant which is approved for use against nausea caused by cancer chemotherapy, was tested against a broad range of HIV types. The researchers found potent activity against HIV, with little evidence of damage to cells. The fact that this drug is already approved for people with cancer makes it easier to study in people with HIV, as there is already enough data on its use in humans to believe it is safe. While much more study will be needed to know if this could be an effective approach against HIV, the approach of examining approved drugs against HIV should be examined further.
Compared to the last couple of meetings, there wasn't a lot to be truly excited about for experimental HIV drugs at CROI 2008. While the recent flood of new and important drugs is certain to slow for awhile, potentially important new drugs continue to be studied. While some look at the current anti-HIV armamentarium and think it might be sufficient, this is hardly clear. While many of the recently approved drugs have performed quite well in clinical trials, long-term, real-world use will tell the full story. New and better drugs -- probably many of them -- are still needed. Project Inform continues to work to ensure that these compounds are studied and, when warranted, developed.
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