TAG 2010 Pipeline Report
The ARV Pipeline in 2010 Fortunately, newer compounds expand the 2010 pipeline (see table 2), which does not include new formulations of existing drugs such as the extended-release nevirapine that may be submitted later this year or the once-daily formulation or indication for raltegravir. Of the compounds in phase III development, rilpivirine (formally TMC-278) is likely to be submitted to the FDA this year, and potentially an additional fixed-dose combination (FDC) of rilpivirine/tenofovir/FTC. Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) from Tibotec that showed short-term activity of <1.2 log in the phase 2a monotherapy study.27 This year top-line results from two phase III studies in treatment-naive patients (TMC278-C209 and C215) have already been reported. When used in combination with tenofovir/FTC, rilpivirine is reported to be noninferior compared to efavirenz, based on the primary endpoint of viral suppression, <50 copies/ml at week 48. Results are due to be presented at the Eighteenth International AIDS Conference in Vienna in July 2010. These will determine submission to the FDA, which is anticipated in the summer of 2010.28 Results for rilpivirine from phase II studies at 96 weeks reported lower rates of side effects including reduced rash, lower central nervous system toxicity, less sleep disturbance, and fewer lipid changes compared to efavirenz. However, grade 3 and 4 side effects and laboratory abnormalities were similar, so while these results are encouraging this is a compound that suggests an improved rather than clean tolerability profile. Early concerns about cardiovascular toxicity (from prolonged QTc intervals, although stabilized), were largely overcome by selection of the 25mg dose.29 If there is wide interpatient variability in drug levels, the low dose would need to demonstrate the proportion of patients failing to achieve the minimum effective concentration (MEC). Efficacy compared to Atripla (the combination efavirenz/tenofovir/FTC) are also likely to determine uptake and use. With intent-totreat analysis both efficacy and tolerability contribute to primary analysis and both should be tracked closely when phase III results are presented. The once-daily low-dose (25mg) formulation supports easier development in FDCs, including the Gilead-led formulation with tenofovir/FTC mentioned above.30 If current bioequivalence studies are successful, this could see regulatory submission for FDCs before the end of 2010. Additionally, a slow-delivery formulation requiring an injection every four weeks is currently undergoing pharmacokinetic studies, potentially for both postexposure prophylaxis and treatment indications. The next most promising pipeline compounds are from Gilead, singly or in fixed-dose formulations: an integrase inhibitor (elvitegravir), a pharmacokinetic booster (cobicistat, 12