Intelence (Page 7 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg/kg were administered to mice and doses of 70, 200 and 600 mg/kg were administered to rats in the initial period of approximately 41 to 52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50 to 66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2-to-0.7-fold (rats).

Mutagenesis

Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

Impairment of Fertility

No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg/day, resulting in systemic drug exposure up to the recommended human dose (400 mg/day).

14 CLINICAL STUDIES

14.1 Treatment-Experienced Adult Subjects

The clinical efficacy of INTELENCE is derived from the analyses of 48-week data from 2 ongoing, randomized, double-blinded, placebo-controlled, Phase 3 trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2) in subjects with 1 or more NNRTI resistance-associated substitutions. These trials are identical in design and the results below are pooled data from the two trials.

TMC125-C206 and TMC125-C216 are Phase 3 studies designed to evaluate the safety and antiretroviral activity of INTELENCE in combination with a background regimen (BR) as compared to placebo in combination with a BR. Eligible subjects were treatment-experienced HIV-1-infected subjects with plasma HIV-1 RNA greater than 5000 copies/mL while on an antiretroviral regimen for at least 8 weeks. In addition, subjects had 1 or more NNRTI resistance-associated substitutions at screening or from prior genotypic analysis, and 3 or more of the following primary PI substitutions at screening: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M. Randomization was stratified by the intended use of ENF in the BR, previous use of darunavir/ritonavir, and screening viral load. Virologic response was defined as HIV-1 RNA less than 50 copies/mL at Week 48.

All study subjects received darunavir/ritonavir as part of their BR, and at least 2 other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF). Of INTELENCE-treated subjects, 25.5% used ENF for the first time (de novo) and 20.0% re-used ENF. Of placebo-treated subjects, 26.5% used de novo ENF and 20.4% re-used ENF.

In the pooled analysis for TMC125-C206 and TMC125-C216, demographics and baseline characteristics were balanced between the INTELENCE arm and the placebo arm (Table 13). Table 13 displays selected demographic and baseline disease characteristics of the subjects in the INTELENCE and placebo arms.

Table 13: Demographic and Baseline Disease Characteristics of Subjects(Pooled Analysis TMC125-C206 and TMC125-C216)–
INTELENCE + BRN=599 Placebo + BRN=604
RASs = Resistance-Associated Substitutions, BR=background regimen, FC = fold change in EC50
*
IAS-USA primary PI substitutions [August/September 2007]: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M
Tibotec NNRTI RASs [June 2008]: A98G, V90I, L100I, K101E/H/P/Q, K103H/N/S/T, V106A/M/I, V108I, E138A/G/K/Q, V179D/E/F/G/I/T, Y181C/I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P255H, F227C/L, M230I/L, P236L, K238N/T, Y318F
The PSS was calculated for the background therapy (as determined on Day 7). Percentages are based on the number of subjects with available phenotype data. For fusion inhibitors (enfuvirtide), subjects were considered resistant if the drug was used in previous therapy up to baseline. INTELENCE is not included in this calculation.
Demographic characteristics
Median age, years (range) 46(18–77) 45(18–72)
Sex
Male 90.0% 88.6%
Female 10.0% 11.4%
Race
White 70.1% 69.8%
Black 13.2% 13.0%
Hispanic 11.3% 12.2%
Asian 1.3% 0.6%
Other 4.1% 4.5%
Baseline disease characteristics
Median baseline plasma HIV-1 RNA (range), log10 copies/mL 4.8(2.7–6.8) 4.8(2.2–6.5)
Percentage of subjects with baseline viral load:
< 30,000 copies/mL 27.5% 28.8%
≥ 30,000 copies/mL and < 100,000 copies/mL 34.4% 35.3%
≥ 100,000 copies/mL 38.1% 35.9%
Median baseline CD4+ cell count (range), cells/mm3 99(1–789) 109(0–912)
Percentage of subjects with baseline CD4+ cell count:
< 50 cells/mm3 35.6% 34.7%
≥ 50 cells/mm3 and < 200 cells/mm3 34.8% 34.5%
≥ 200 cells/mm3 29.6% 30.8%
Median (range) number of primary PI substitutions * 4(0–7) 4(0–8)
Percentage of subjects with previous use of NNRTIs:
0 8.2% 7.9%
1 46.9% 46.7%
> 1 44.9% 45.4%
Percentage of subjects with previous use of the following NNRTIs:
Efavirenz 70.3% 72.5%
Nevirapine 57.1% 58.6%
Delavirdine 13.7% 12.6%
Median (range) number of NNRTI RASs 2(0–8) 2(0–7)
Median fold change of the virus for the following NNRTIs:
Delavirdine 27.3 26.1
Efavirenz 63.9 45.4
Etravirine 1.6 1.5
Nevirapine 74.3 74.0
Percentage of subjects with previous use of a fusion inhibitor 39.6% 42.2%
Percentage of subjects with a Phenotypic Sensitivity Score (PSS) for the background therapy of:
0 17.0% 16.2%
1 36.5% 38.7%
2 26.9% 27.8%
≥ 3 19.7% 17.3%

Efficacy at Week 48 for subjects in the INTELENCE and placebo arms for the pooled TMC125-C206 and TMC125-C216 study populations are shown in Table 14.

Table 14: Treatment Outcomes at Week 48 (Pooled Analysis TMC125-C206 and TMC125-C216)
INTELENCE + BRN=599 Placebo + BRN=604
BR=background regimen
Virologic responders at Week 48Viral Load < 50 HIV-1 RNA copies/mL 359 (60%) 232 (38%)
Virologic failures at Week 48Viral Load ≥ 50 HIV-1 RNA copies/mL 123 (21%) 201 (33%)
Death 11 (2%) 19 (3%)
Discontinuations before Week 48:
due to virologic failures 58 (10%) 110 (18%)
due to adverse events 31 (5%) 14 (2%)
due to other reasons 17 (3%) 28 (5%)

At Week 48, 70.8% of INTELENCE-treated subjects achieved HIV-1 RNA less than 400 copies/mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was -2.23 log10 copies/mL for INTELENCE-treated subjects and -1.46 log10 copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for INTELENCE-treated subjects was 96 cells/mm3 and 68 cells/mm3 for placebo-treated subjects.

Of the study population who either re-used or did not use ENF, 57.4% of INTELENCE-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies/mL. Of the study population using ENF de novo, 67.3% of INTELENCE-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies/mL.

Treatment-emergent CDC category C events occurred in 4% of INTELENCE-treated subjects and 8.4% of placebo-treated subjects.

Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naïve HIV-1-infected subjects with genotypic evidence of NNRTI resistance at screening or from prior genotypic analysis. The virologic response was evaluated in 116 subjects who were randomized to INTELENCE (59 subjects) or an investigator-selected PI (57 subjects), each given with 2 investigator-selected N(t)RTIs. INTELENCE-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to INTELENCE as compared to the control PI-treated subjects.

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