GMHC Treatment Issues; September 1, 1996
Theo Smart

Given the activity of established drugs in the same class, some of the new reverse transcriptase and protease inhibitors seem destined to proceed smoothly through the clinical trials process. It is unclear to what extent such agents truly will increase people's therapeutic options because of problems such as cross-resistance and intolerance. The most significant advances may arise from the work of researchers who are looking for other aspects of HIV's lifecycle that could be as successfully exploited as reverse transcriptase and protease have been.

Binding and Fusion

Eric de Clerq, M.D., of the Rega Institute for Medical Research in Belgium has long been working with compounds that block the way HIV binds to cells. Among these is dextran sulfate, one of the first anti-HIV drugs studied in people. De Clerq's team now has demonstrated that the virus can become resistant to the compound in cell culture studies by changing certain amino acids in the V3 loop of HIV's gp120 envelope protein (conference abstract Th.A.152). Although clinical study of dextran sulfate was discontinued because of its toxicity, the finding is significant because it helps explain where the virus is susceptible to attack by compounds such as dextran sulfate. Less toxic compounds might be developed to exploit this weakness in the virus envelope. One such drug, PRO 2000, was reported to be safe when administered as a ten-minute infusion to HIV-negative volunteers (abstract We.B.3129).

There were a number of poster and oral presentations on T-20, a compound made by Trimeris, Inc. (abstracts Tu.A.263, Mo.A.1080, L.B.A.6015). T-20, which mimics a small portion of the HIV envelope protein, blocks fusion sometime after HIV's envelope protein binds to the CD4 receptor. This binding changes the shape of the HIV surface protein so that the surface of the virus is brought into close proximity to the cell, allowing for fusion. T-20 interferes with this conformational change.

"T-20 is the most potent agent that we've ever looked at in [a mouse model for HIV infection]," according to Paul Black, M.D., Ph.D., of the Food and Drug Administration. In his study, the drug completely blocked HIV infection in a mouse model. Since the drug is a protein derived from part of HIV, there is a fear that its administration could provoke an antibody response that may inactivate it. Another potential problem is that the compound cannot be taken orally since it is broken down by acids and enzymes in the digestive tract. In its current form, the drug would have to be given as an injection two or three times a day. To cut down the number of injections, Trimeris is looking at second-generation drug candidates that persist longer in the blood. They also are considering administering the drug via "mini-osmotic pumps," small implanted devices that secrete a constant level of drug over time. These pumps could be implanted in the arm, supplying drug for weeks or perhaps longer. First, though, Trimeris Pharmaceuticals intends to determine whether the current form of T-20 has activity in people. Dose-ranging studies are planned to begin by the end of the year.

Reverse Transcriptase Inhibitors

The surprising activity of Glaxo-Welcome's new nucleoside analog 1592U89 (see August's Treatment Issues, page 6) has shown that it may be possible to optimize the potency of this class of drugs. Dr. Jan Balzarini, also of the Rega Institute for Medical Research in Belgium, presented data on a modified form of d4T that is 50- to 100-fold more potent in cell culture studies, because it enters cells more readily (abstract Mo.A.1012). Meanwhile, a group at Emory University working with a lipid-associated form of ddI in mice, found that the new agent more effectively reached and persisted in lymphoid tissue than standard ddI (abstract Mo.A.1079).

The National Cancer Institute has moved a new nucleoside analog, F-DDA, into phase I/II dose-ranging studies (abstract Mo.A.1076). The drug's active form is similar to ddI, though the ddI-resistant virus remains susceptible to F-DDA. Like ddI, F-DDA's activity in cell culture is increased by the addition of hydroxyurea and ribavirin. Unlike ddI, the new drug does not need to be formulated with a buffer, and thus should not cause the gastrointestinal side effects that make ddI so hard to tolerate. If the drug is found to be active in the dose-ranging study, it will be developed by U.S. Bioscience, makers of the anti-PCP drug trimetrexate.

Two posters presented the antiviral activity, resistance and safety profile of Hoechst-Bayer's NNRTI (non-nucleoside reverse transcriptase inhibitor) HBY-097 (abstracts Mo.A.1102, Mo.B.1326). In four studies with doses ranging from 375 to 3000 mg per day, the drug reduced viral load by an average of 1.38 to 1.63 logs (95.8 to 97.7%). Four out of ten patients treated with higher doses of HBY-097 developed a rash similar to that seen with nevirapine and delavirdine. The drug is currently in dose-ranging and drug interaction studies (including a study with indinavir, and another with AZT). Pivotal clinical studies are slated to begin next year. For more information call 800/TRIALS-A (800/874-2572).

Preclinical data were reviewed for DMP-266, an NNRTI discovered by Merck and now licensed to DuPont-Merck (abstract Mo.A.1077). This drug has established antiviral activity and is currently in phase II clinical trials (see May's Treatment Issues, page 8). While most NNRTIs are defeated by the evolution of just one resistance-conferring mutation in the HIV reverse transcriptase, it takes two to protect HIV against this drug. Nevertheless, two mutations in the enzyme have been shown to readily occur when NNRTIs are used with AZT alone or in other suboptimal combinations. It remains to be seen how quickly resistance to DMP-266 will occur in the current studies that combine the drug with indinavir or AZT/3TC.

Using NNRTIs in combination with more potent regimens may be the best hope for defeating NNRTI-resistant virus. A second option would be the development of compounds that can attack HIV resistant to nevirapine or delavirdine. Preclinical work has suggested that the virus would need to develop a unique mutation to evade the effects of HBY-097. In human studies, this novel mutation has yet to be seen. A mutation that causes resistance to delavirdine, though, was seen in two out of ten patients treated with HBY-097 at study end (fourteen days), but it is not yet clear how much or whether these mutations will allow the virus to resist the effects of this new drug.

Another promising group of agents has yet to enter clinical trials: Compounds owned by Uniroyal, related to UC10 (see Treatment Issues, September 1995, page 9) have been shown to be active against virus containing all five of the major mutations that confer resistance to the other NNRTIs (abstract Mo.A.1051). Furthermore, the addition of the Uniroyal compounds to 3TC produces, in Dr. de Clerq's words, "a knock-out combination." In his laboratory experiments the virus could not become resistant to both drugs at the same time and still retain the ability to replicate. Though the Uniroyal compounds are not yet in the hands of an entity that develops drugs, Dr. de Clerq claims there is a good chance that they may be licensed to a pharmaceutical company in the near future and moved into clinical testing. He notes that these compounds are stable in human blood, and some have been shown safe and bioavailable in animals.

Integrase Inhibitors

A number of researchers spoke of the HIV integrase enzyme as the next important target of antiretroviral therapy. Integrase is an enzyme that integrates HIV genetic material into the host cell's DNA.

In one presentation, Edward Robinson, Ph.D., of University of California Irvine reported preclinical data on a class of compounds derived from Bolivian plants that inhibit integrase activity. Merck Pharmaceutical's Daria Hazuda, M.D., Ph.D., presented a poster on integrase inhibitors found by screening other natural products (abstract Mo.A.1020). Though the fungus-derived compounds she reported upon are very potent blockers of integrase catalytic activity in drug screening tests, they do not show activity against HIV when cultured with cells. Lack of activity in cell culture is a common problem with many of the integrase inhibitors that have been identified. Either the compounds do not effectively get into the cell, or doses that inhibit HIV are also lethal to the cells the drug is meant to protect.

Dr. Hazuda believes that further structural studies using these compounds, and others Merck has yet to announce, may show them how to modify the structures to create a potential drug candidate. This will take time: Dr. Hazuda commented, "We are several years away from developing clinically useful integrase inhibitors."

The one integrase inhibitor to reach human studies is Aronex's ARR-177, which now sports the name zintevir (abstract Th.B.943). This compound does not inhibit the "active" part of the integrase enzyme. Instead, it keeps integrase from binding to the HIV genetic material in the first place. Dose-ranging studies have recently begun in San Francisco.

Zinc Finger Inhibitors

HIV's zinc fingers are amino acid structures on the surface of one of HIV's core proteins. The zinc fingers capture and help package HIV genetic material into newly budding virions, and also appear to play a role during the earlier stages of cell infection. Two zinc finger inhibitors are currently in clinical studies. One owned by Parke-Davis has completed initial pharmacokinetic studies and will enter phase I/II dose-ranging studies within a month (see Treatment Issues, October, 1995, pages 7-8). ADA, the other compound, is owned by the Dutch company Van de Velde and is now the subject of a European phase II study. According to William Rice, Ph.D., of the National Cancer Institute, the zinc finger mechanism of action for this drug was identified only recently. Both of these compounds, though, may become inactivated by common substances in the body. For example, Parke-Davis's zinc-finger inhibitor breaks down when exposed to glutathione, an antioxidant present in most cells.

Dr. Rice presented data on a new class of zinc finger inhibitors that are as active as the earlier compounds but not sensitive to glutathione or other antioxidants (abstract Th.A.150). Members of this class of chemicals are currently being studied for safety and activity in animal models.

Novel Protease Inhibitors

Dr. Masatoshi Taneka of the National Cancer Institute reported that his agency, in collaboration with the Kyoto Pharmaceutical University and Japan Energy Co., has discovered a protease inhibitor, KNI-241, that is not stopped by HIV that has developed resistance to other available protease inhibitors (abstract Tu.A.260). The same group had taken one protease inhibitor, KNI-272, into clinical trials, but this drug is defeated by the same resistance-conferring mutations that inactivate ritonavir and indinavir, and did not seem to be as potent as the approved drugs. Development of KNI-272 is being discontinued in favor of KNI-241.

Finally, Suvit Thaisrivongs, Ph.D., of Pharmacia & Upjohn presented preclinical data on its third and most powerful protease inhibitor (abstracts Tu.A.261 and Mo.A.1084). Because of its potency, the company believes it will be active despite its tendency to become bound to albumin in the blood, a problem that led to the discontinuation of Pharmacia & Upjohn's two previous lead compounds. The drug is relatively easy to make and is active against HIV resistant to any of the approved protease inhibitors. Phase I dose-escalation studies will begin in Michigan before the end of the year.

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