New Targets Bring New Challenges
A new drug to block HIV at a new point in its lifecycle will be a welcome development. But approving a new drug from a new chemical class will also bring great uncertainties. It's not enough to simply be active against HIV, the new drug will also have to leave host functions alone and meet all of the other criteria for a medicine that is tolerable, easy to take, safe, and affordable. That's a lot to ask for a first time at bat. Advanced lead screening techniques and early use of better toxicity assays will hopefully accelerate the pace of developing the next generation of drugs. Still, the first wave of new-target drugs may go through a few false starts before they become useful medicines used in seamless combination with the older, more refined PI and RT inhibitors. Here's hoping one of these can knock the ball out of the park.
Information on new antiretroviral (ARV) drugs entering human trials was somewhat thin at this year's 9th Annual Retrovirus Conference in Seattle, but a few items stand out. Maybe the most encouraging news is that drug development is alive and chugging away on new products. Despite doomsday warnings by pharmaceutical executives about having to pull out of HIV research if political pressure for affordable access to medicine threatens industry profits, there was evidence of commitments to develop new drugs for new HIV targets from Bristol Myers Squibb (BMS), Glaxo-SmithKline (GSK), Schering and Merck.
Researchers from Shionogi & Co., a Japanese pharmaceutical firm, presented a new inhibitor of integrase, an HIV protein that performs an essential step in the viral lifecycle. Integrase is one of the unique-to-HIV targets that have yet to be attacked with an effective drug. The big news in this presentation was the "GSK" logo that appeared in the corner of the slide. This means that HIV pharmaceutical leader Glaxo has joined the hunt for a novel integrase inhibitor... and if anyone has the capacity and know how to get an AIDS drug developed and moved through the pipeline, it's Glaxo. The drug is currently called S-1360. It is a diketo acid compound that has shown in vitro synergy with approved ARV drugs from every class. Merck also has a diketo acid integrase inhibitor that has previously been reported susceptible to site mutations in the enzyme; additional resistance mutations were also reported at this conference. Has the Shionogi compound gotten around this? S-1360 is proceeding with first human trials in a small number of HIV-infected individuals.
History shows that a new drug might enjoy glowing reports at one year's conference then never be heard from again; it's wise to reserve enthusiasm for agents that have at least entered full Phase II clinical development. In an example of the subtle scientific sniping that goes on at these conferences, a Merck researcher stood up after the Shionogi presentation and inquired about plasma protein binding for S-1360. Drug molecules can become gummed-up with proteins in the blood such as albumin. Protein-bound drugs aren't able to cross into the cells where they need to be and are ultimately eliminated from the bloodstream; too much susceptibility to protein binding in the body can eclipse a drug that shines in the test tube. Yes, S-1360 is highly protein bound, the Shionogi scientist admitted. Dare we hope that Merck has a new integrase inhibitor in the works that overcomes these problems?
The outlook for entry inhibitors is also looking better. T-20 from Trimeris/Roche is likely to be the first of this new class of drugs to be approved, although that may be up to a year from now. T-20 works by blocking HIV as it tries to insert itself into new cells. While a few posters filled out the clinical picture of what to expect from T-20, one detail incidentally slipped out in an unrelated talk by a BMS executive about their new entry inhibitor. Apparently the generic name for T-20 has been settled; initially known as pentafuside, T-20 will now be called enfuvirtide. (See "A T-20 Diary" in this issue.)
The new BMS entry inhibitor was another welcome surprise. Currently called BMS-806, the drug was discovered by screening a library of several hundred thousand variations on a chemical theme to detect potent anti-HIV activity. Eventually a few promising leads were narrowed down to number 806 which showed viral inhibition at concentrations that were not toxic to cells. The molecule is said to be highly specific for binding to the gp120 HIV envelope protein and probably interferes with attachment to cellular CD4. A green light so far, but experience with antibodies against the highly changeable gp120 protein tells us that the evolution of resistance may quickly become a problem. And in case you were wondering, BMS-806 is not highly bound by plasma proteins.
The other prominent entry inhibitors discussed at Retrovirus take a different approach to blocking viral attachment. Instead of sticking to the virus, they bind to receptors on a cell's surface that HIV uses to gain entry. Schering's SCH-C is in human trials and moving through a series of doses to find the best balance between activity and toxicity. Work is proceeding carefully because of abnormalities in a cardiac rhythmic parameter called QTc observed after volunteers received a single 600 mg dose. A ten-day study of 25 mg twice daily in 12 HIV-positive persons has been completed and a 50 mg study is underway. At this point it seems that a slight prolongation of the QTc interval predictably occurs with increasing drug exposure, but it is too soon to say if this effect will doom the drug. After 10 days of SCH-C monotherapy at the 25 mg twice-daily dose, mean viral load for the 12 patients had dropped by over 0.5 log.
SCH-C stops HIV from using the R5 receptor to infect new cells. A more virulent strain of HIV employs the X4 receptor, and is not inhibited by SCH-C. One fear is that using the drug could favor the evolution of X4-using mutants and actually accelerate disease progression. So far there is no evidence from test tube or animal studies that this occurs, but experience in human trials is the test that matters.
AMD-3100 is an entry inhibitor that acts on the X4 cellular receptor -- the one that SCH-C doesn't attack. Although anti-HIV activity was noted in early clinical trials of the drug, studies were stopped a year ago after failing to meet targets for reducing viral load. A look back at the data from those trials and a new analysis of the volunteers' viral genotypes suggest that some patients may have turned in a poor performance on AMD-3100 because they harbored a mixed population of X4 and R5 viral strains. The single individual infected solely with the X4 strain experienced respectable viral suppression. One question: If AMD-3100 acts on the viral phenotype that SCH-C does not, could one drug rescue the other in a synergistic fashion? In another AMD-3100 study presented at Retrovirus, increased heart rates combined with a lack of significant activity at the highest doses caused researchers to take pause. A new oral formulation will hopefully address toxicity problems seen with earlier infused versions of the drug. AMD-3100 may not be dead yet but its tiny biotech developer will surely have to partner with one of the big companies if this drug is to move forward.
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Abstracts, posters and video from the 9th Annual Retrovirus Conference are available online at http://www.retroconference.org.
T. Yoshinaga, et al. Persistence of Transmitted Drug Resistance Among Subjects With Primary HIV Infection Not Receiving Antiretroviral Therapy. 9th Retrovirus Conference, Seattle, 2002. Abstract 8.
M. Witvrouw, et al. Novel Mutations in HIV-1 Integrase Associated With Resistance to Diketo Acids. 9th Retrovirus Conference, Seattle, 2002. Abstract 573.
P-F Lin, et al. Identification and Characterization of a Novel Inhibitor of HIV-1 Entry -- II: Mechanism of Action. 9th Retrovirus Conference, Seattle, 2002. Abstract 10.
J. Reynes, et al. SCH-C: Safety and Antiviral Effects of a CCR5 Receptor Antagonist in HIV-1-Infected Subjects. 9th Retrovirus Conference, Seattle, 2002. Abstract 1.
D. Schols, et al. AMD-3100, a CXCR4 Antagonist, Reduced HIV Viral Load and X4 Virus Levels in Humans. 9th Retrovirus Conference, Seattle, 2002. Abstract 2.
C. Hendrix, et al. AMD-3100 CXCR4 Receptor Blocker Fails to Reduce HIV Viral Load by >1 Log Following 10-Day Continuous Infusion. 9th Retrovirus Conference, Seattle, 2002. Abstract 391.
Back to the GMHC Treatment Issues March 2002 contents page.