PREZISTA (Page 8 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg was administered to rats. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).

Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reserve mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.

Impairment of Fertility

No effects on fertility or early embryonic development were observed with darunavir in rats.

14 CLINICAL STUDIES

14.1 Description of Adult Clinical Trials

The evidence of efficacy of PREZISTA/ritonavir is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211) HIV-1-infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data are included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.

14.2 Treatment-Naïve Adult Subjects

TMC114-C211

TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects. Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC).

HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than or equal to 5000 copies/mL. Randomization was stratified by screening plasma viral load (HIV-1 RNA less than 100,000 copies/mL or greater than or equal to 100,000 copies/mL) and screening CD4+ cell count (less than 200 cells/mm3 or greater than or equal to 200 cells/mm3). Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 689 subjects in trial TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the lopinavir/ritonavir arm (see Table 19). Table 19 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg per day arm in trial TMC114-C211.

Table 19: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C211
PREZISTA/ritonavir 800/100 mg once daily + TDF/FTCN=343 lopinavir/ritonavir 800/200 mg per day + TDF/FTCN=346
FTC=emtricitabine; TDF=tenofovir disoproxil fumarate
Demographic characteristics
Median age (years) (range, years) 34 (18–70) 33 (19–68)
Sex
Male 70% 70%
Female 30% 30%
Race
White 40% 45%
Black 23% 21%
Hispanic 23% 22%
Asian 13% 11%
Baseline characteristics
Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.86 4.84
Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 228 (4–750) 218 (2–714)
Percentage of patients with baseline viral load ≥100,000 copies/mL 34% 35%
Percentage of patients with baseline CD4+ cell count <200 cells/mm3 41% 43%

Week 192 outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from trial TMC114-C211 are shown in Table 20.

Table 20: Virologic Outcome of Randomized Treatment of Trial TMC114-C211 at 192 Weeks
PREZISTA/ritonavir 800/100 mg once daily + TDF/FTCN=343 lopinavir/ritonavir 800/200 mg per day + TDF/FTCN=346
N = total number of subjects with data; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate
*
95% CI: 1.9; 16.1
Includes patients who discontinued prior to Week 192 for lack or loss of efficacy and patients who are ≥50 copies in the 192-week window and patients who had a change in their background regimen that was not permitted by the protocol.
Window 186–198 Weeks.
§
Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL
Virologic success HIV-1 RNA <50 copies/mL 70%* 61%
Virologic failure 12% 15%
No virologic data at Week 192 window
Reasons
Discontinued trial due to adverse event or death § 5% 13%
Discontinued trial for other reasons 13% 12%
Missing data during window but on trial <1% 0%

In trial TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258 cells/mm3 in the PREZISTA/ritonavir 800/100 mg once daily arm and 263 cells/mm3 in the lopinavir/ritonavir 800/200 mg per day arm. Of the PREZISTA/ritonavir subjects with a confirmed virologic response of <50 copies/mL at Week 48, 81% remained undetectable at Week 192 versus 68% with lopinavir/ritonavir. In the 192 week analysis, statistical superiority of the PREZISTA/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.

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