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.

By Liz Highleyman

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%.

Results

	At 48 weeks, rilpivirine demonstrated non-inferior efficacy compared with efavirenz.
	Taken together, 84.3% of participants taking rilpivirine and 82.3% taking efavirenz achieved undetectable HIV viral load < 50 copies/mL:
	ECHO: 82.9% vs 82.8%, respectively; THRIVE: 85.6% vs 81.7%, respectively.
	Among participants with baseline viral load <100,000 copies/mL, those taking rilpivirine had slightly higher response rates, while those taking efavirenz responded slightly better in the high viral load population; these differences, however, were not statistically significant.
	Overall, 9.0% of rilpivirine recipients experienced virological failure compared with 4.8% of efavirenz recipients:
	ECHO: 11.0% vs 4.4%, respectively; THRIVE: 7.1% vs 5.3%, respectively.
	Mean CD4 cell gains from baseline were 192 cells/mm3 with rilpivirine and 176 cells/mm3 with efavirenz.
	No differences in response were seen according to accompanying backbone NRTI combination.
	On the whole, rilpivirine was better tolerated than efavirenz:
	16% of rilpivirine recipients and 31% of efavirenz recipients experienced moderate-to-severe (grade 2-4) adverse events at least possibly related to study drugs; 3% vs 8%, respectively, discontinued therapy due to adverse events; 17% vs 38% experienced central nervous system symptoms; 15% vs 23% experienced any psychiatric symptoms; 8% vs 26% experienced dizziness; 8% vs 13% experienced abnormal dreams or nightmares; 3% vs 14% experienced skin rash. 11% vs 18% experienced serious (grade 3-4) laboratory abnormalities.
	Rilpivirine had a more favorable lipid profile than efavirenz, with lower rates of serious abnormalities in total cholesterol (0.1% vs 2.5%), LDL "bad" cholesterol (0.7% vs 4.1%), and triglycerides (0.3% vs 2.2%).
	There was only minimal change in serum creatinine (a possible indicator of kidney impairment) in both groups.
	There were no observed differences in QTc interval changes, a heart rhythm abnormality that showed up as a safety signal in earlier studies using higher doses of rilpivirine.
	63% of rilpivirine recipients developed new NNRTI resistance mutations (most often E183K) compared with 54% of efavirenz recipients (mostly K103N). In addition, rilpivirine recipients were twice as likely to develop NRTI resistance mutations (68% vs 32%, respectively).

Based on these findings, investigators concluded, "TMC278 [rilpivirine] was efficacious and well tolerated in a large and diverse group of treatment-naive patients."

They characterized response rates as being "among the highest observed in recent treatment-naive trials."

On July 27, Tibotec Pharmaceuticals announced that it has submitted a New Drug Application (NDA) to FDA, based on the 48-week data from ECHO and THRIVE. Regulatory submissions for rilpivirine in other countries are expected in coming months, the company said.

Tibotec also confirmed that it has entered into a license and collaboration agreement with Gilead Sciences to develop a once-daily fixed-dose pill containing rilpivirine plus Gilead's 300 mg tenofovir/200 mg emtricitabine combination. If approved, this would create a single-tablet regimen to compete with Atripla (tenofovir/emtricitabine/efavirenz).

Community Research Initiative of New England, Boston, MA; Saint-Louis Hospital and University of Paris, Department of Infectious Diseases, Paris, France; Hospital Juan A Fernández and Fundación Huesped, Buenos Aires, Argentina; Hospital Universitari Germans Trias i Pujol and irsiCaixa Foundation, Barcelona, Spain; Dr J Fourie Medical Centre, KwaZulu Natal, South Africa; Instituto de Pesquisa Clínica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil; Beijing You'an Hospital, Beijing, China; Royal Free Hospital, London, UK; University of Alabama at Birmingham, Infectious Diseases, Birmingham, AL; Chiang Mai University, Section of Infectious Disease, Chiang Mai, Thailand; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc, Titusville, NJ.

7/27/10

Reference
C Cohen, J-M Molina, P Cahn, and others. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing TMC278 versus efavirenz in treatment-naive, HIV-1-infected patients. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract THLBB206.

Other Source
Tibotec Pharmaceuticals. Tibotec Pharmaceuticals Submits New Drug Application for Investigational Once-Daily HIV Treatment TMC278 to U.S. Food and Drug Administration. Press release. July 26, 2010.