Maraviroc (Page 8 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis

Long-term oral carcinogenicity studies of maraviroc were carried out in rasH2 transgenic mice (6 months) and in rats for up to 96 weeks (females) and 104 weeks (males). No drug-related increases in tumor incidence were found in mice at 1,500 mg per kg per day and in male and female rats at 900 mg per kg per day. The highest exposures in rats were approximately 11 times those observed in humans at the therapeutic dose of 300 mg twice daily for the treatment of HIV-1 infection.

Mutagenesis

Maraviroc was not genotoxic in the reverse mutation bacterial test (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes, and mouse bone marrow micronucleus test.

Impairment of Fertility

Maraviroc did not impair mating or fertility of male or female rats and did not affect sperm of treated male rats at approximately 20-fold higher exposures (AUC) than in humans given the recommended 300-mg twice-daily dose.

14 CLINICAL STUDIES

14.1 Clinical Studies in Adult Subjects

The clinical efficacy and safety of maraviroc are derived from analyses of data from 3 trials in adult subjects infected with CCR5-tropic HIV-1: Trials A4001027 and A4001028 in antiretroviral treatment-experienced adult subjects and Trial A4001026 in treatment-naive subjects. These trials were supported by a 48-week trial in antiretroviral treatment-experienced adult subjects infected with dual/mixed-tropic HIV-1, Trial A4001029.

Trials in CCR5-Tropic, Treatment-Experienced Subjects

Trials A4001027 and A4001028 were double-blind, randomized, placebo-controlled, multicenter trials in subjects infected with CCR5-tropic HIV-1. Subjects were required to have an HIV-1 RNA greater than 5,000 copies per mL despite at least 6 months of prior therapy with at least 1 agent from 3 of the 4 antiretroviral drug classes (greater than or equal to 1 NRTI, greater than or equal to 1 NNRTI, greater than or equal to 2 PIs, and/or enfuvirtide) or documented resistance to at least 1 member of each class. All subjects received an optimized background regimen consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subject’s prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the optimized background regimen, subjects were then randomized in a 2:2:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo. Doses were adjusted based on background therapy as described in Dosage and Administration ( 2) , Table 1.

In the pooled analysis for Trials A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 16). Of the 1,043 subjects with a CCR5-tropism result at screening, 7.6% had a dual/mixed-tropism result at the baseline visit 4 to 6 weeks later. This illustrates the background change from CCR5- to dual/mixed-tropism result over time in this treatment-experienced population, prior to a change in antiretroviral regimen or administration of a CCR5 co-receptor antagonist. Table 16. Demographic and Baseline Characteristics of Subjects in Trials A4001027 and A4001028

Maraviroc Twice Daily (n = 426) Placebo (n = 209)
Age (years) Mean (range) 46.3 (21-73) 45.7 (29-72)
Sex:
Male 382 (89.7%) 185 (88.5%)
Female 44 (10.3%) 24 (11.5%)
Race:
White 363 (85.2%) 178 (85.2%)
Black 51 (12.0%) 26 (12.4%)
Other 12 (2.8%) 5 (2.4%)
Region:
U.S. 276 (64.8%) 135 (64.6%)
Non-U.S. 150 (35.2%) 74 (35.4%)
Subjects with previous enfuvirtide use 142 (33.3%) 62 (29.7%)
Subjects with enfuvirtide as part of OBT 182 (42.7%) 91 (43.5%)
Baseline plasma HIV-1 RNA (log 10 copies/mL) Mean (range) 4.85 (2.96-6.88) 4.86 (3.46-7.07)
Subjects with screening viral load ≥100,000 copies/mL 179 (42.0%) 84 (40.2%)
Baseline CD4+ cell count (cells/mm 3) Median (range) 167 (2-820) 171 (1-675)
Subjects with baseline CD4+ cell count ≤200 cells/mm 3) 250 (58.7%) 118 (56.5%)
Subjects with Overall Susceptibility Score (OSS): a 0 1 2 ≥3 57 (13.4%) 136 (31.9%) 104 (24.4%) 125 (29.3%) 35 (16.7%) 44 (21.1%) 59 (28.2%) 66 (31.6%)
Subjects with enfuvirtide resistance substitutions 90 (21.2%) 45 (21.5%)
Median number of resistance-associated: b
PI substitutions NNRTI substitutions NRTI substitutions 10 1 6 10 1 6

a OSS — Sum of active drugs in OBT based on combined information from genotypic and phenotypic testing.

b Resistance substitutions based on IAS guidelines. 1 The Week 48 results for the pooled Trials A4001027 and A4001028 are shown in Table 17.

Table 17. Outcomes of Randomized Treatment at Week 48 in Trials A4001027 and A4001028

Outcome Maraviroc Twice Daily (n = 426) Placebo (n = 209) Mean Difference
Mean change from Baseline to Week 48 inHIV-1 RNA (log 10 copies/mL) -1.84 -0.78 -1.05
<400 copies/mL at Week 48 239 (56%) 47 (22%) 34%
<50 copies/mL at Week 48 194 (46%) 35 (17%) 29%
Discontinuations: Insufficient clinical response Adverse events Other 97 (23%) 19 (4%) 27 (6%) 113 (54%) 11 (5%) 18 (9%) — — —
Subjects with treatment-emergent CDC Category C events 22 (5%) 16 (8%)
Deaths (during trial or within 28 days of last dose ) 9 (2%) a 1 (0.5%)

a One additional subject died while receiving open-label therapy with maraviroc subsequent to discontinuing double-blind placebo due to insufficient response.

After 48 weeks of therapy, the proportions of subjects with HIV-1 RNA less than 400 copies per mL receiving maraviroc compared with placebo were 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to Week 48 were –1.84 log 10 copies per mL for subjects receiving maraviroc + OBT compared with –0.78 log 10 copies per mL for subjects receiving OBT only. The mean increase in CD4+ cell count was higher on maraviroc twice daily + OBT (124 cells per mm 3) than on placebo + OBT (60 cells per mm 3).

Trial in Dual/Mixed-Tropic, Treatment-Experienced Subjects

Trial A4001029 was an exploratory, randomized, double-blind, multicenter trial to determine the safety and efficacy of maraviroc in subjects infected with dual/mixed co-receptor tropic HIV-1. The inclusion/exclusion criteria were similar to those for Trials A4001027 and A4001028 above and the subjects were randomized in a 1:1:1 ratio to maraviroc once daily, maraviroc twice daily, or placebo. No increased risk of infection or HIV-1 disease progression was observed in the subjects who received maraviroc. Use of maraviroc was not associated with a significant decrease in HIV-1 RNA compared with placebo in these subjects and no adverse effect on CD4+ cell count was noted.

Trial in Treatment-Naive Subjects

Trial A4001026 was a randomized, double-blind, multicenter trial in subjects infected with CCR5-tropic HIV-1 classified by the original TROFILE tropism assay. Subjects were required to have plasma HIV-1 RNA greater than or equal to 2,000 copies per mL and could not have: 1) previously received any antiretroviral therapy for greater than 14 days, 2) an active or recent opportunistic infection or a suspected primary HIV-1 infection, or 3) phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz. Subjects were randomized in a 1:1:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with lamivudine/zidovudine. The efficacy and safety of maraviroc are based on the comparison of maraviroc twice daily versus efavirenz. In a pre-planned interim analysis at 16 weeks, maraviroc 300 mg once daily failed to meet the pre-specified criteria for demonstrating non-inferiority and was discontinued. The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups were comparable (Table 18). Subjects were stratified by screening HIV-1 RNA levels and by geographic region. The median CD4+ cell counts and mean HIV-1 RNA at baseline were similar for both treatment groups.

Table 18. Demographic and Baseline Characteristics of Subjects in Trial A4001026

Maraviroc 300 mg Twice Daily + Lamivudine/Zidovudine (n = 360) Efavirenz 600 mg Once Daily + Lamivudine/Zidovudine (n = 361)
Age (years):
Mean 36.7 37.4
Range 20-69 18-77
Female, n% 104 (29) 102 (28)
Race, n%: White Black Asian Other 204 (57) 123 (34) 6 (2) 27 (8)

198 (55) 133 (37) 5 (1) 25 (7)

Median (range) CD4+ cell count (cells/μL) 241 (5-1,422) 254 (8-1,053)
Median (range) HIV-1 RNA (log 10 copies/mL) 4.9 (3-7) 4.9 (3–7)

The treatment outcomes at 96 weeks for Trial A4001026 are shown in Table 19. Treatment outcomes are based on reanalysis of the screening samples using a more sensitive tropism assay, enhanced sensitivity TROFILE HIV tropism assay, which became available after the Week 48 analysis; approximately 15% of the subjects identified as CCR5-tropic in the original analysis had dual/mixed- or CXCR4-tropic virus. Screening with enhanced sensitivity version of the TROFILE tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original TROFILE HIV tropism assay.

Table 19. Trial Outcome (Snapshot) at Week 96 Using Enhanced Sensitivity Assay a

Outcome at Week 96 b Maraviroc 300 mg Twice Daily + Lamivudine/Zidovudine (n = 311) n (%) Efavirenz 600 mg Once Daily + Lamivudine/Zidovudine (n = 303) n (%)
Virologic Responders: (HIV-1 RNA <400 copies/mL) 199 (64) 195 (64)
Virologic Failure:
Non-sustained HIV-1 RNA suppression 39 (13) 22 (7)
HIV-1 RNA never suppressed 9 (3) 1 (<1)
Virologic Responders: (HIV-1 RNA <50 copies/mL) 183 (59) 190 (63)
Virologic Failure:
Non-sustained HIV-1 RNA suppression 43 (14) 25 (8)
HIV-1 RNA never suppressed 21 (7) 3 (1)
Discontinuations due to:
Adverse events 19 (6) 47 (16)
Death 2 (1) 2 (1)
Other c 43 (14) 36 (12)

a The total number of subjects (311, 303) in Table 19 represents the subjects who had a CCR5-tropic virus in the reanalysis of screening samples using the more sensitive tropism assay. This reanalysis reclassified approximately 15% of subjects shown in Table 18 as having dual/mixed- or CXCR4-tropic virus. These numbers are different than those presented in Table 18 because the numbers in Table 18 reflect the subjects with CCR5-tropic virus according to the original tropism assay.
b Week 48 results: Virologic responders (less than 400): 228 of 311 (73%) in maraviroc, 219 of 303 (72%) in efavirenz; Virologic responders (less than 50): 213 of 311 (69%) in maraviroc, 207 of 303 (68%) in efavirenz.
c Other reasons for discontinuation include lost to follow-up, withdrawn, protocol violation, and other.
The median increase from baseline in CD4+ cell counts at Week 96 was 184 cells per mm 3 for the arm receiving maraviroc compared with 155 cells per mm 3 for the efavirenz arm.

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