February 17, 2009
In several poster presentations at CROI 2009 in Montreal, Canada, three possible new compounds with anti-HIV activity were highlighted. The three compounds, from a very thin pipeline of possible new HIV drugs, are all in early safety study. Should any of these show effectiveness at suppressing HIV, it will still be a couple of years before they would find their way to market.
A maturation inhibitor called MPC-9055 entered study for its safety and tolerability at various doses in healthy HIV-negative volunteers. Maturation inhibitors work at the last stages in the life cycle of HIV, as newly formed HIV exit immune cells. These drugs prevent the creation of HIV's core called the capsid, which protects its genes. This, in turn, leads to the production of non-infectious HIV that could not infect other cells and theoretically not damage the immune system. vA single-dose of MPC-9055 at 1, 2, 4, 8, 16, 32, and 48 mg/kg were given to 55 non-smokers on a fasting schedule and placebo was given to 20 people. The 8mg and 16mg doses were also evaluated to see how high- or low-fat food impacted the doses. Results showed that no serious adverse events or lab trends were found. However, one-third of those on MPC-9055 did experience at least one side effect. These were generally mild and included headache, nausea, diarrhea and stomach pain. Food increased blood-levels of the drug two-fold. A multiple dose-finding study is being planned for HIV-positive volunteers.
Safety information from both animal and human study were made available for a new NNRTI called RDEA427. The drugs in the NNRTI class are highly cross-resistant to one another, and like the latest addition to this class, Intelence (etravirine), a new NNRTI will have to overcome these resistance issues.
This study examined the reaction of both wild type and NNRTI-resistant viruses when exposed to the compound. Injections of RDEA427 were given to several types of animals and to 4 humans to check on its safety and activity.
The results showed that RDEA427 has sustained activity against many of the most common viruses resistant to NNRTIs, including the most commonly transmitted mutation to treatment-naive individuals, K103M. Against K103M, the compound exhibited anti-HIV affect for more than 100 days, and also showed longer suppression of K103M virus than Intelence and the experimental NNRTI called rilpivirine (TMC278). It appears that RDEA427 has equal activity against both wild type and NNRTI-resistant viruses. However, another virus with a common NNRTI-resistant mutation, Y181C, was not controlled by the new drug, a drawback of Intelence and rilpivirine as well.
No adverse events or significant lab abnormalities were seen in the study. However, a possible drawback to using this compound will likely be due to it requiring an injection for dosing. Though it may only be dosed once a day, a daily injection may still be too much for many to even consider.
Another safety study reported data on an NRTI called OBP-601 a derivative of the FDA-approved NRTI, Zerit (stavudine). A single dose of the drug, called festinavir, was examined for safety and tolerability. Lab results, vital signs and safety were assessed at regular intervals. The study followed 64 HIV-negative men in a placebo-controlled single dose escalation study.
There were no serious adverse events and the drug was well tolerated, although mild symptoms such as fatigue, diarrhea and vomiting did occur among a few people. No abnormal lab results were also seen, and food did not have an effect on the drug's absorption in the body.
The anti-HIV activity of the compound persists longer than other NRTIs in test tube study, including against the common NRTI-resistance mutation, M184V. OBP-601 seems to effectively suppress HIV in both wild type and multidrug resistant forms of the virus. The 100mg dose given once a day provided good suppression of virus for 24 hours and is currently under study to further assess its safety and effectiveness in HIV-positive people.