New antiretrovirals: `pipeline at its fullest for years`

A wealth of new information on anti-HIV compounds in development was presented today at the Tenth Conference on Retroviruses and Opportunistic Infections in Boston.

Speaking at last night’s opening press conference, John Mellors of the University of Pittsburgh told reporters that “the pipeline of new antiretrovirals is fuller than it has been for many years. The efforts of research scientists to identify the many steps of the virus lifecycle is beginning to pay off, and the resources that have been put into basic science are beginning to show results.”

The presentations included information on several completely new classes of antiretrovirals, new protease inhibitors and non-nucleoside reverse transcriptase inhibitors active against drug-resistant virus, and a growing number of chemokine antagonists, which block HIV attachment.

Belgian researchers presented a new class of HIV integrase inhibitors, pyranodipyridamines, which are active against virus resistant to both the Merck and Shionogi integrase inhibitors currently in development. V-165, the lead compound, appears to act at a different stage of the integration of retroviral DNA into the host cell from the compounds already reported. The most potent of the agents also showed activity against reverse transcriptase, and was synergistic with nevirapine.

GlaxoSmithline screened 250 compounds and identified three which are active against NNRTI-resistant viruses in the test tube. These are benzophenone non-nucleoside reverse transcriptase inhibitors.

Roche presented a new protease inhibitor, RO033-4649, that is active against virus isolates that show greater than ten-fold resistance to at least four out of five marketed protease inhibitors. No loss of susceptibility to the compound was seen in the majority of 50 `worst case` viruses with multiple primary protease mutations. RO033-4649 is a moderate inhibitor of cytochrome p450 3A4, somewhat stronger than saquinavir. Phase I human studies have begun.

Pharmasset, a Georgia-based company, presented phase II/IIb data on racivir, a nucleoside analogue. Racivir was administered at three doses (200, 400 or 600mg once daily) in combination with d4T and efavirenz. Six individuals were recruited to each dosing group. After day 15, treatment was discontinued and viral load continued to be monitored until day 35. Viral load had declined by an average 2.02 – 2.42 log by day 14, and remained more than 2 log below baseline at day 28 at all doses. Rebound above this level began to be detected by day 35, but viral load still remained more than 1 log below baseline at this point.

Panacos Pharmaceuticals presented information on PA-457, a betulinic acid derivative, which inhibits the budding of mature virus particles by preventing the processing of the p25 protein into p24. It is synergistic with AZT, nevirapine and indinavir, and active against NNRTI-resistant viruses and virus bearing the V82A and I184V mutations associated with protease inhibitor resistance.

Several chemokine inhibitors were also presented. Research is focused on finding antagonists of the CCR5 receptor, which provides an additional means of entry to cells for HIV. When the CCR5 receptor is not available on the surface of a cell bearing the CD4 receptor, it is more difficult for HIV to gain entry.

Ono Pharmaceuticals, a Japanese company, presented details of AK602, a chemokine antagonist that can be administered orally. Unlike previously reported CCR5 antagonists, AK602 does not totally block interactions between the CCR5 receptor on human cells and CC chemokines, which are necessary for inflammatory reactions. Some researchers fear that the total blockage of such interactions could be harmful, pointing to data showing that individuals with the CCR5 delta 32 deletion have an adverse prognosis for hepatitis C infection compared to individuals who do not have this polymorphism.

Other chemokine antagonists and entry or fusion inhibitors reported today included:

• TAK 220 – under development by Japanese company Takeda, TAK-220 shows favourable interactions in vitro with several licensed antiretrovirals, including AZT, 3TC, indinavir and efavirenz. It is also synergistic with T-20.
• UK-427, 857 – under development by Pfizer, UK-427 blocks the binding of HIV’s gp120 to the CCR5 receptor. This compound has just entered phase I/II human studies.
• SC34EK – under development at Kyoto University, Japan, SC34EK is 69 times more potent than T-20 when tested in vitro against HIV isolates with resistance to T-20.
• HIV-gp41 peptides – Mymetics Corporation reported on its efforts to construct peptides that have structural homologies (matches) to interleukin-2. These peptides appear to have greater anti-HIV activity in the test tube than non-homologous gp41 peptides, and anti-HIV activity equivalent to, or greater than, the gp41 inhibitors T-20 and T-1249. They are active across all HIV-1 subtypes, although activity appears lower against subtype D than other subtypes.

Finally, Dan Kuritzkes reported on an anti-CD4 monoclonal antibody under development by Tanox. This antibody recognises a unique epitope in region 2 of the CD4 receptor, and inhibits a post-attachment interaction between gp120 and the CCR5 chemokine receptor.

TNX-355 was studied in a single dose study, in which 30 patients were enrolled and doses in five groups at escalating doses. Participants had a mean CD4 cell count of 341 cells/mm3 and a mean viral load of 4.78 log (approximately 60,000 copies/ml), all were treatment-experienced and 19 were still taking a failing regimen at the time they entered the study.

Peak antiviral effects were seen at the highest doses (10mg/kg and 25mg/kg), and the antiviral affect of the single dose did not reach its full magnitude until day 14 in the 10mg/kg group and 21 days in the 25mg/kg group. The viral nadir corresponded with the peak of CD4 receptor coating by the antibody. Based on this evidence, Dan Kuritzkes suggested it is likely that this compound will be dosed once weekly or less.

No reduction in CD4+ receptor expression was observed, and the infusion was well tolerated. No antibody to TNX-355 was observed.

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