EDURANT (Page 7 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Two-year carcinogenicity studies in mice and rats were conducted with rilpivirine. In rats, there were no drug related neoplasms at exposures 3 times those observed in humans at the recommended daily dose of 25 mg. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested dose in the mouse carcinogenicity study, the systemic exposure to rilpivirine was 21 times that observed in humans at the recommended daily dose of 25 mg.

Rilpivirine was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Impairment of Fertility

In rat fertility and early embryonic development studies with rilpivirine, no effects on fertility were observed at rilpivirine exposures (AUC) greater than 36 times (male) and 40 times (female) the exposure in humans at the recommended daily dose of 25 mg.

14 CLINICAL STUDIES

14.1 Treatment-Naïve Adult Subjects

The evidence of efficacy of EDURANT is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI resistance-associated substitutions (RASs). The Phase 3 trials were identical in design, apart from the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR.

In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the EDURANT arm and the efavirenz arm. Table 12 displays selected demographic and baseline disease characteristics of the subjects in the EDURANT and efavirenz arms.

Table 12: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis)

	Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials
	EDURANT + BRN=686	Efavirenz + BRN=682
BR=background regimen
Demographic Characteristics
Median Age, years (range)	36 (18–78)	36 (19–69)
Sex
Male	76%	76%
Female	24%	24%
Race
White	61%	60%
Black/African American	24%	23%
Asian	11%	14%
Other	2%	2%
Not allowed to ask per local regulations	1%	1%
Baseline Disease Characteristics
Median Baseline Plasma HIV-1 RNA (range), log10 copies/mL	5.0 (2–7)	5.0 (3–7)
Percentage of Patients with Baseline Plasma Viral Load:
≤100,000	54%	48%
>100,000 to ≤500,000	36%	40%
>500,000	10%	12%
Median Baseline CD4+ Cell Count (range), cells/mm3	249 (1–888)	260 (1–1137)
Percentage of Subjects with:
Hepatitis B/C Virus Co-infection	7%	10%
Percentage of Patients with the Following Background Regimens:
tenofovir disoproxil fumarate plus emtricitabine	80%	80%
zidovudine plus lamivudine	15%	15%
abacavir plus lamivudine	5%	5%

Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled analysis are shown in Table 13. The incidence of virologic failure was higher in the EDURANT arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment. Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm³ experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm³.

Table 13: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215 (Pooled Data) at Week 96

	EDURANT + BRN=686	Efavirenz + BRN=682
N=total number of subjects per treatment group; BR=background regimen.
Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90–103), respectively.
* CI=Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96. † Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol. ‡ Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window. § Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.
HIV-1 RNA <50 copies/mL *	76%	77%
HIV-1 RNA ≥50 copies/mL †	16%	10%
No virologic data at Week 96 window Reasons
Discontinued study due to adverse event or death ‡	4%	8%
Discontinued study for other reasons and last available HIV-1 RNA <50 copies/mL (or missing)§	4%	5%
Missing data during window but on study	<1%	<1%
HIV-1 RNA <50 copies/mL by Baseline HIV-1 RNA (copies/mL)
≤100,000	82%	78%
>100,000	70%	75%
HIV-1 RNA ≥50 copies/mL † by Baseline HIV-1 RNA (copies/mL)
≤100,000	9%	8%
>100,000	24%	11%
HIV-1 RNA <50 copies/mL by CD4+ cell count (cells/mm3)
<200	68%	74%
≥200	81%	77%
HIV-1 RNA ≥50 copies/mL † by CD4+ cell count (cells/mm3)
<200	27%	10%
≥200	10%	9%

At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm³ for EDURANT-treated subjects and 219 cells/mm³ for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278-C215 trials.

Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part [EDURANT doses blinded] followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.

Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥5000 copies/mL, previously received ≤2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RASs.

At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/mL receiving EDURANT 25 mg (N=93) compared to subjects receiving efavirenz (N=89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm³ in subjects receiving EDURANT 25 mg and 160 cells/mm³ in subjects receiving efavirenz.

At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA <50 copies/mL compared to 57% (51/89) of subjects in the control group.