FUZEON (Page 4 of 6)

12.4 Microbiology

Mechanism of Action

Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.

Antiviral Activity in Cell Culture

The antiviral activity of enfuvirtide was assessed by infecting different CD4+ cell types with laboratory and clinical isolates of HIV-1. The median EC50 value for baseline clinical isolates was 4.10 nM (ranged from 0.089 to 107 nM; 0.4 to 480 ng/mL) by the cMAGI assay (n=130) and was 55.9 nM (1.56 to 1675 nM; 7 to 7526 ng/mL) by a recombinant phenotypic entry assay (n=627). Enfuvirtide was similarly active in cell culture against clades A, AE, C, D, F, and G (median EC50 value was 7.01 nM; range 3.78 to 27.9 nM; 17-126 ng/mL), and R5, X4, and dual tropic viruses. Enfuvirtide has no activity against HIV-2.

Enfuvirtide did not exhibit antagonism in cell culture assays when combined with individual members of various antiretroviral classes, including non-nucleoside reverse transcriptase inhibitors (NNRTIs: efavirenz), nucleos(t)ide reverse transcriptase inhibitors (NRTIs: lamivudine, zidovudine), and protease inhibitors (PIs: indinavir, nelfinavir).

Drug Resistance

HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in cell culture. Genotypic analysis of these resistant isolates showed amino acid substitutions at the enfuvirtide binding HR1 domain positions 36 to 38 of the HIV-1 envelope glycoprotein gp41. Phenotypic analysis of site-directed mutants in positions 36 to 38 in an HIV-1 molecular clone showed a 5-fold to 684-fold decrease in susceptibility to enfuvirtide.

In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from subjects failing a FUZEON containing regimen. Post treatment HIV-1 virus from 277 subjects experiencing protocol defined virological failure at 48 weeks exhibited a median decrease in susceptibility to enfuvirtide of 33.4-fold (range 0.4-6318-fold) relative to their respective baseline virus. Of these, 249 had decreases in susceptibility to enfuvirtide of greater than 4-fold and all but 3 of those 249 encoded substitutions at gp41 HR1 domain amino acids 36 to 45. HR1 substitutions associated with resistance to enfuvirtide include G36D/E/S/V, I37V, V38A/E/G/M, Q39R, Q40H, N42D/Q/T, N43D/H/K/Q/S, L44M, and L45M. Combinations of HR1 resistance-associated substitutions can lead to greater reductions in susceptibility. Substitutions or polymorphisms in other regions of gp41 have been associated with resistance (e.g., HR2 domain N126K, E137K, and S138A substitutions) and these may affect susceptibility to enfuvirtide.

Cross-resistance

HIV-1 clinical isolates resistant to NNRTIs, NRTIs, and PIs were susceptible to enfuvirtide in cell culture.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Carcinogenicity studies have not been conducted with enfuvirtide.

Enfuvirtide was not genotoxic in in vivo and in vitro assays including a bacterial reverse mutation assay, a mammalian cell forward gene mutation assay in AS52 Chinese Hamster ovary cells, and an in vivo mouse micronucleus assay.

Impairment of Fertility

In a fertility and early embryonic development study in rats, no effects of enfuvirtide on male or female fertility were observed at enfuvirtide exposures (based on surface area) up to 1.6 times higher than human exposure at the RHD.

14 CLINICAL STUDIES

14.1 Antiretroviral-experienced Adult Subjects

T20-301 and T20-302 were randomized, controlled, open-label, multicenter trials in HIV-1 infected subjects. Subjects were required to have either (1) viremia despite 3 to 6 months prior therapy with a nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) or (2) viremia and documented resistance or intolerance to at least one member in each of the NRTI, NNRTI, and PI classes.

All subjects received an individualized background regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the subject’s prior treatment history and baseline genotypic and phenotypic viral resistance measurements. Subjects were then randomized at a 2:1 ratio to FUZEON 90 mg twice daily with background regimen or background regimen alone.

After week 8, subjects on either treatment arm who met protocol defined criteria for virological failure were permitted to revise their background regimens; those on background regimen alone were also permitted to add FUZEON.

Demographic characteristics for studies T20-301 and T20-302 are shown in Table 6. Subjects had prior exposure to a median of 12 antiretrovirals for a median of 7 years.

Table 6 T20-301 and T20-302 Pooled Subject Demographics
FUZEON+Background RegimenN=663 Background RegimenN=334
Sex
Male 90% 90%
Female 10% 10%
Race
White 89% 89%
Black 8% 7%
Mean Age (yr)(range) 42(16-67) 43(24-82)
Median Baseline HIV-1 RNA (log10 copies/mL)(range) 5.2(3.5-6.7) 5.1(3.7-7.1)
Median Baseline CD4 Cell Count (cells/mm3)(range) 89(1-994) 97(1-847)

The disposition and efficacy outcomes of T20-301 and T20-302 are shown in Table 7.

Table 7 Outcomes at Week 48 (Pooled Studies T20-301 and T20-302)
*
Includes never responded, rebound, and missing RNA data.
Includes study discontinuation for virological failure and insufficient response as per the judgment of the investigator.
Includes difficulties with injection, such as injection fatigue and inconvenience.
§
Includes lost to follow-up, treatment refusal, and non-compliance.
Outcomes FUZEON+Background Regimen90 mg bidN=663 Background RegimenN=334
Virological Responder(at least 1 log10 below baseline) 304 (46%) 61 (18%)
Virological Non-responder:
  • Switch
0 220 (66%)
  • Completed 48 weeks randomized regimen *
191 (29%) 12 (4%)
Continued Background Regimen(N=112) Switched to FUZEON(N=220)
Discontinued due to insufficient treatment response 37 (5%) 13 (12%) 22 (10%)
Discontinued due to adverse reactions/intercurrent illness/labs 46 (7%) 9 (8%) 13 (6%)
Deaths 15 (2%) 5 (4%) 2 (1%)
Discontinued due to injection:
  • Injection site reactions
27 (4%) NA 10 (5%)
  • Difficulty with injecting FUZEON
18 (3%) NA 2 (1%)
Discontinued due to other reasons § 25 (4%) 14 (13%) 6 (3%)

At 48 weeks, 154 (23%) of subjects in the FUZEON+background regimen and 27 (8%) in the background regimen alone had HIV-1 RNA levels <50 copies/mL, and 225 (34%) of subjects receiving FUZEON+background regimen had HIV-1 RNA levels <400 copies/mL compared to 44 (13%) in the background regimen alone. Subjects achieving HIV-1 RNA levels <50 copies/mL were included in the <400 copies/mL category and both categories were incorporated in the overall virologic responder category of achieving HIV-1 RNA at least 1 log10 below baseline.

The mean log change in HIV-1 RNA from baseline was -1.4 log10 copies/mL in subjects receiving FUZEON+background and -0.5 in those receiving background alone. The mean change in CD4 cell count from baseline to week 48 was +91 cells/mm3 in the FUZEON+background arm and +45 cells/mm3 in the background alone arm.

Subjects in the FUZEON+background arm achieved a better virologic and immunologic outcome than subjects in the background alone arm across all subgroups based on baseline CD4 cell count, baseline HIV-1 RNA, number of prior ARVs or number of active ARVs in the background regimen.

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