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Waiting in the Wings: More New Drugs

By Matt Sharp

November/December 2003

2003 was a banner year for HIV drug approval despite the fact that some of the drugs are very similar to what already exists. Improvements in medical treatment come slowly and incrementally, but lately there seems to be a wave of new treatments that in conjunction with new approved therapies may improve quality of life and benefit those with fewer treatment options. The newer drugs are from existing classes that are improvements on their predecessors, some are easier to take, and some are entirely new classes never used before, targeting other points in the HIV lifecycle. Cumulatively, they may end up representing a new treatment era in HIV.

The following are a few of the drugs furthest along in development.


Repeat Performance

Lexiva (or 908/fos-amprenavir as it is currently known) is the fourth in line for approval this year. It is a new "pro-drug" formulation of amprenavir (or Agenerase) an older, mostly unpopular protease inhibitor. Out of all protease inhibitors, amprenavir was only 5% of the market due to the fact that it required eight horse pills twice a day. The new compound has been reformulated to be easier to take; one tablet twice a day, and will metabolize so that more drug gets into the bloodstream.

More data from clinical trials are shedding light as to the effectiveness of this drug. The NEAT study looked at 908 compared to Viracept with a background regimen of Ziagen and Epivir in treatment naive participants. In those with initial viral levels of greater than 100,000, 71% (908) versus 35% (Viracept) saw their viral load drop below 400. The SOLO study also looked at treatment naive participants with 908 boosted by ritonavir (Norvir). (As with other protease inhibitors, this drug may be more effective with a ritonavir boost.) The study compared once-daily boosted 908 to twice daily Viracept with a background regimen of Ziagen and Epivir. Again, those with higher baseline viral loads had a better viral load result.

One trial called CONTEXT looked at people who had failed one or two protease inhibitors and compared boosted 908 once daily or twice daily to Kaletra twice daily with a nucleoside background. No non-nucleoside reverse transcriptase inhibitors (NNRTIs) were allowed in this study. 48 weeks of data showed little difference in viral outcomes between the two arms, however based on a different analysis the study was able to show that 908 was really worse than Kaletra.

908 has not yet shown cross resistance to other protease inhibitors in laboratory studies, however, and according to the efficacy results thus far it most likely will be better as a first line treatment. Common side effects for 908 are gastro-intestinal and there are significant drug interactions with other medications commonly used in HIV. 908 represents the HIV treatment era we find ourselves in today. While every effort has been made to make an easier drug to take it is probably not any better than what is already available.

Another protease inhibitor in final stages of development is tipranavir, which has shown to be a promising drug for those who are resistant to protease inhibitors. Tipranavir requires up to 20 mutations to become resistant. A Phase II study in protease resistant participants showed a sustained virological suppression for up to 48 weeks. There are two large Phase III studies underway looking at tipranavir with a ritonavir boost in highly protease resistant participants. It is dosed as 500 mg twice daily with a 200 mg ritonavir boost. All indications show tipranavir a useful protease inhibitor in those with multiple resistant PI mutations but the Phase III studies will put to rest any doubt that the drug will be effective in this difficult to treat population. The most common side effects seen were diarrhea. Tipranavir will be next in line for approval.

Another new protease inhibitor that was designed exclusively to work in those with PI resistance is called TMC-114. A Phase II dose finding study in 50 multiple-experienced participants showed that despite multiple resistance to protease inhibitors, all three doses selected showed a median drop of 1.35 log in viral load after 14 days. Again TMC-114 was boosted in this study but it may be effective without the ritonavir. GI side effects were seen in about a third of participants, but that may be due to the ritonavir.


Curtain Call

The three approved non-nukes -- Sustiva, Rescriptor, or Viramune -- are highly cross resistant to one another, but high technology is making it possible to develop new NNRTIs which should not be cross resistant to them. Capravirine is a NNRTI that is nearing Phase III studies. After a significant intermission due to vasculitis in dogs seen in early studies at higher doses than would be used in humans, research in capravirine has restarted and larger studies are being planned. Early indications from Phase II studies involving NNRTI resistant participants show that it may be effective in this group of people, but larger studies and more time will determine if this is true. One good thing is that the rash commonly associated with the older NNRTIs was not seen in early studies.

TMC-125 is a novel approach for those resistant to the current family of NNRTIs because it is a unique compound that is flexible and can fit into various binding pockets of HIV. In one short open label study of 16 HIV participants with a wide range of NNRTI mutations, TMC-125 was effective in suppressing HIV. Again, larger studies need to be performed to fully elucidate the effectiveness of this new drug in those who need a new NNRTI.

There are several other companies looking into novel NNRTI compounds. We need new drugs in this class!


Making a Big Entrance

Entry inhibitors have stepped into the spotlight for people who have used all the older anti-HIV drugs. This progress has led the way to more exciting research, and definitely gives those whose viral load levels are climbing and T-cells falling a degree of excitement and hope. Certainly T-20, now known as Fuzeon, the first approved entry inhibitor, was a milestone in creation of this new class of HIV drugs. Its cousin, T-1249, has showed impressive results in a small preliminary study looking at those who had failed Fuzeon. A median log drop of 1.26 was seen after eleven days of therapy. Participants switched out their Fuzeon for T-1249. It was shown that those who had used Fuzeon for a longer period of time didn't do as well. But the longer people were on T-1249 they continued to see viral load drops. Unfortunately, Roche is moving painfully slow with development of this new drug.

Like an arm holding a key to open a door, another clever way HIV uses to attach and infect T-cells is by using cell co-receptors. One of the co-receptors most prevalent in HIV is called CCR5. This co-receptor is associated with the early stage, slower progression of HIV. Another co-receptor called CXCR4 is associated with rapid progression and quick destruction of T-cells. Since CCR5 is more common, several companies are looking at drug candidates to block this co-receptor. In fact, two candidates are already moving into Phase II studies. At least one CXCR4 compound is in very early studies.

UK-427,857 has been tested in HIV negative people and was found to be safe. This kind of study is necessary in new drugs that have not been widely tested to establish safety. A second short term, monotherapy placebo controlled study looked at HIV positive people who were screened for the CCR5 receptor. The study tested several doses of the drug and saw a 1.42 log reduction in viral load after eleven days of 100 mg twice-daily. This was in seven patients. An eighth patient was later found to be dual tropic at baseline (had both CCR5 and CXCR4 cells), and the drug was ineffective for this patient.

The higher dose also had a higher saturation of CCR5, more than 90%, compared to less than 80% for the lower dose.

The drug seems to be safe in this small, short study. Now, larger studies can be designed to compare to existing HIV drugs, and to further evaluate how safe this CCR5 compound is.

SCH-D is another CCR5 attachment inhibitor in the treatment pipeline. Since some complications developed with the sister compound in early studies, this newer drug is now moving in a similar development path as the UK-427 drug mentioned above.

One major hurdle to overcome in co-receptor research is that if a person is treated with a CCR5 antagonist, will their virus "switch" to the more dangerous CXCR4 virus. In early studies this has not been seen, but more work needs to be done to be sure.

There are four different mechanisms that allow virus entry into a human T-cells. Research is now looking at ways to target each of these mechanisms alone and in combination. This discovery in entry inhibition has opened the door to a whole new era in HIV research.

However, as with any drug research there are many obstacles to overcome, and more clinical trials will paint a fuller picture as to whether or not they will play a role in the future of HIV treatment. What is encouraging is that just a short time ago there were very few promising drugs for people with HIV drug resistance. Now, the time is ripe for a whole new generation of drugs. Encore, encore!


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