Second generation HIV drug enters clinical trials

With its lead compound, bevirimat (PA-457) already in Phase II trials, the US pharma firm recently announced that a second-generation 'maturation inhibitor' called PA-040 has now entered Phase I trials. Both drugs aim to prevent the virus maturing into infective particles that can subsequently spread around the body. The HIV virus not only reproduces very rapidly, it also mutates very easily. This leads to infected people having many different forms of the virus in their body and some of these mutations can lead to drug resistance. The company believes the drug's novel mechanism of action could enable it to treat drug-resistant forms of the virus and "perhaps make it more difficult for the virus to evolve resistance to beviramat"​. "Having already demonstrated proof of concept of maturation inhibition with bevirimat, we plan to test several second generation compounds, including PA-040, in single dose testing and then select the optimum compound to take into multiple dose human studies,"​ said Panacos CEO Dr Graham Allaway When an HIV particle emerges from a human cell, it is not yet fully mature or infective. A protein called HIV protease cuts up the so-called GAG complex into its constituent proteins. Several HIV drugs work by blocking HIV protease from working. However, mutations in this protein can prevent the drugs from working. Beviramat, by contrast, binds to the GAG complex itself and prevents HIV protease from breaking it up, according to Panacos. This complex remains largely unaffected by mutations, leading Panacos to hope that resistance will be less of a problem for this class of drug. The company also said that: "beviramat is effective against HIV that has become resistant to other drugs." ​ The last stage of GAG cleavage releases two proteins called capsid and SP1. According to Panacos, this final stage determines how fast the whole process takes place and is therefore a more attractive target for drug development. If capsid remains bound to SP1, it cannot join to other capsid proteins and then for a protective barrier around the viral RNA, according to the pharma firm. This, in turn leaves the virus particle "impotent"​ and it is cleared from the bloodstream, said Panacos. As well as this virus maturation step, two other steps in the lifecycle of a virus could be exploited as potential avenues to new classes of HIV drugs: namely viral entry into cells and viral integration. Merck & Co is currently developing Isentress (raltegravir), an integrase inhibitor, which is currently in Phase III trials. Meanwhile, Pfizer has developed a drug that aims to prevent viral entry into cells. Maraviroc binds to the chemokine (C-C motif) receptor 5 (CCR5) co-receptor located on the surface of immune system cells. The drug is currently being reviewed by the US Food and Drug Administration (FDA).