New NNRTI Rilpivirine (TMC278) Shows Potent Antiviral Activity and Good Tolerability in Phase 3 Trials, FDA Application Submitted

SUMMARY: The investigational NNRTI rilpivirine (TMC278) continued to demonstrated promising safety and efficacy at 48 weeks in a pair of Phase 3 trials with treatment-naive patients, researchers reported in a late-breaker session last week at the XVIII International AIDS Conference in Vienna. Though rilpivirine and efavirenz were equally likely to suppress viral load, rilpivirine caused fewer side effects, especially neurological symptoms. Tibotec announced on Monday that it has submitted a New Drug Application for rilpivirine to the U.S. Food and Drug Administration (FDA), and a single-tablet combination regimen with tenofovir/emtricitabine is in the works.

Rilpivirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that appears to have a long half-life in the body (about 45 hours) and a somewhat different resistance profile than existing drugs in its class.

In prior Phase 2b studies, rilpivirine demonstrated sustained efficacy similar to that of efavirenz (Sustiva), but with generally better tolerability. A low dose of 25 mg once-daily was chose for further testing.

Cal Cohen from the Community Research Initiative of New England presented data from a pooled 48-week primary analysis of combined data from 2 Phase 3 trials, ECHO (TMC278-C209) and THRIVE (TMC278-C215). The studies are scheduled to continue through 96 weeks.

These international trials together enrolled a total of 1368 previously untreated HIV positive adults. About 75% were men, the median age was 36 years, about 60% were white, about 25% were black, and just over 10% were Asian; about 8% had hepatitis B or C coinfection.

At baseline, the median viral load was 100,000 copies/mL and the median CD4 cell count was about 250 cells/mm3. Participants had no known NNRTI resistance-associated mutations (which can exist due to transmission of resistant virus even in people with no prior antiretroviral drug exposure).

In ECHO, 690 participants were randomly assigned to receive 25 mg once-daily rilpivirine or 600 mg once-daily efavirenz (Sustiva), both in combination with tenofovir/emtricitabine (the drugs in Truvada).

In THRIVE, 678 patients were again randomly assigned to the same doses of rilpivirine or efavirenz, but here they could also take tenofovir/emtricitabine (60%), zidovudine/lamivudine (Combivir)(30%), or abacavir/lamivudine (Epzicom)(10%).

The studies' main objective was to demonstrate whether rilpivirine is non-inferior to efavirenz in suppressing HIV viral load using an intent-to-treat "TLOVR" analysis, within a margin of 12%.