October 27, 2001
Dr. Eron did a quick review of the new antiretrovirals in the development pipeline. It was a summary talk about drugs we have been hearing about at the last few meetings.
He organized his summary of the new drugs by class. There was not a lot of new information, but it was a good overview. The list is long, so I will only summarize the highlights of each compound.
Atazanavir (BMS-232632) is the first once-a-day protease inhibitor. It is reasonably active against HIV (as potent as nelfinavir in trials). The main problem with this new drug is the risk of developing hyperbilirubinemia, a risk that is clearly dose-dependent. This problem makes combination with ritonavir a bad idea since toxicity would only worsen. The good news about this drug is its simplicity of use and the lack of effects in lipid metabolism.
Amprenavir pro-drug. The most unfavorable aspect of agenerase (the "parent" drug of amprenavir) is the pill burden. Full-dose agenerase requires eight large capsules (1,200mg) twice per day. Recently, everyone has been using agenerase combined with low-dose ritonavir to boost agenerase levels, increase its potency and lessen the pill burden (when combined with 100mg of ritonavir, the agenerase dose can be reduced to 600mg -- four pills -- twice a day). This formulation lowers pill burden to two pills BID.
Tibotec 114. This new protease inhibitor is very potent against resistant virus. The company is starting phase I/II studies.
Mozenavir (DMP-450) is an experimental protease inhibitor being developed by Triangle Pharmaceuticals.
Tenofovir is a nucleotide with a half-life of about 17 hours, allowing for once-daily regimens. This drug was just approved by the FDA. Gilead finally received a general approval for use in HIV infection, not just in cases of drug failure. Tenofovir is active against virus with nucleoside resistance, although AZT resistance probably decreases its activity.
In the NNRTI class, Dr. Eron discussed TMC 120 and 125, two NNRTIs being developed by Tibotec-Virco. They have good activity in vitro and in short clinical trials. It is unclear at this time whether these drugs are really "second-generation" NNRTIs.
New targets are being explored actively: attachment inhibitors; fusion inhibitors like T-20 and T-1249; and chemokine receptor inhibitors, the most promising being SCH-C, which recently had its phase I studies reactivated (it had cardiac toxicity at higher doses in normal hosts).
Dr. Eron concluded his talk by discussing the new class of integrase inhibitors Merck is getting ready to evaluate in clinical trials.