Just before the holidays, the journal Science Translational Medicine published results from a phase I trial of a new type of anti-HIV drug named VIR-576. The drug inhibits the entry of HIV into target cells by blocking the mechanism the virus uses to anchor itself to the cell. This mechanism involves a harpoon-like extension called the gp41 fusion peptide, which shoots into the cell membrane. VIR-576 gloms onto the end of the gp41 fusion peptide, preventing its penetration (a bit like covering the spear end of a harpoon so it just bounces off the target). Although VIR-576 is not the first entry inhibitor HIV drug, it is the first to target the gp41 fusion peptide. The researchers have dubbed it an "anchoring inhibitor."
The phase I study administered three different doses of VIR-576 to three groups of six untreated HIV-positive people with viral loads over 10,000 copies and CD4 T cell counts above 350. Because VIR-576 is a peptide, administration was via continuous intravenous infusion. The total duration of treatment was 10 days. At the highest dose of 5 grams per day, VIR-576 caused an average viral load reduction of 1.2 logs (over 90%). The drug was well tolerated but two participants (one in each of the two lower dose groups) showed signs of an allergic reaction that resolved once treatment was stopped. No evidence of resistance to VIR-576 was documented.
The findings are potentially encouraging for several reasons:
- They show that HIV’s gp41 fusion peptide is a viable drug target, which was previously uncertain.
- The gp41 fusion peptide does not appear able to tolerate mutations as easily as other drug targets, suggesting resistance will be slower to develop.
- The activity of VIR-576 is not affected by resistance to available anti-HIV drugs.
- Fusion peptides are essential to the replication of most enveloped viruses, suggesting the general approach could be applied to other viral pathogens.
However, there are also caveats that were not clearly articulated in some of the media stories that appeared when the study was published. Most obvious is that the current formulation of VIR-576 cannot practically be used a treatment due to the requirement for continuous intravenous infusion. The high dose and potential cost are additional impediments; the dose of the approved HIV entry inhibitor Fuzeon (T-20) is 0.18 grams/day (with a cost of around $25,000 per year) whereas the most effective dose of VIR-576 was a daunting 5 grams/day. The researchers highlight these concerns in the discussion section of the paper and state: “to overcome these drawbacks in costs and administration, we are currently working on the development of small-molecule inhibitors with an analogous mode of action.” In interviews, investigator Frank Kirchoff has estimated that it will likely be at least a year before any oral analogs of VIR-576 are ready for testing.
Sci Transl Med 22 December 2010: Vol. 2, Issue 63, p. 63re3
Wolf-Georg Forssmann1,2,3, Yu-Han The1, Matthias Stoll1, Knut Adermann1,2,3, Uwe Albrecht4, Kleomenis Barlos5,6, Annette Busmann1,2, Angeles Canales-Mayordomo7, Guillermo Giménez-Gallego7, Jochen Hirsch1,2,3, Jesus Jiménez-Barbero7, Dirk Meyer-Olson1, Jan Münch8, Javier Pérez-Castells9, Ludger Ständker1, Frank Kirchhoff8,* and Reinhold E. Schmidt1
1 Department of Immunology and Rheumatology, Hannover Medical University, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.
2 VIRO Pharmaceuticals GmbH & Co. KG, Feodor-Lynen-Strasse 31, D-30625 Hannover, Germany.
3 Pharis Biotec GmbH, 30625 Hannover, Germany.
4 Mediconomics GmbH, Misburger-Strasse 81b, D-30625 Hannover, Germany.
5 Department of Chemistry, University of Patras, GR-26500 Rion-Patras, Greece.
6 CBL-Patras, 26333 Patras, Greece.
7 Departamento de Biología Físico-Química, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, E-28040 Madrid, Spain.
8 Institute of Molecular Virology, University Hospital of Ulm, Meyerhofstrasse 1, D-89081 Ulm, Germany.
9 Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, E-28664 Madrid, Spain.
To infect host cells, most enveloped viruses must insert a hydrophobic fusion peptide into the host cell membrane. Thus, fusion peptides may be valuable targets for developing drugs that block virus entry. We have shown previously that a natural 20-residue fragment of α1-antitrypsin, designated VIRus-Inhibitory Peptide (VIRIP), that binds to the gp41 fusion peptide of HIV-1 prevents the virus from entering target cells in vitro. Here, we examine the efficacy of 10-day monotherapy with the optimized VIR-576 derivative of VIRIP in treatment-naïve, HIV-1–infected individuals with viral RNA loads of ≥10,000 copies per ml. We report that at the highest dose (5.0 grams per day), intravenous infusion of VIR-576 reduced the mean plasma viral load by 1.23 log10 copies per ml without causing severe adverse effects. Our results are proof of concept that fusion peptide inhibitors suppress viral replication in human patients, and offer prospects for the development of a new class of drugs that prevent virus particles from anchoring to and infecting host cells.