Fuzeon 90 mg/ml powder and solvent for solution for injection

Pharmacodynamic properties

Pharmacotherapeutic group: Other antivirals
ATC code: J05AX07

Mechanism of Action: Enfuvirtide is a member of the therapeutic class called fusion inhibitors. It is an inhibitor of the structural rearrangement of HIV-1 gp41 and functions by specifically binding to this virus protein extracellularly thereby blocking fusion between the viral cell membrane and the target cell membrane, preventing the viral RNA from entering into the target cell.

Antiviral activity in vitro: The susceptibility to enfuvirtide of 612 HIV recombinants containing the env genes from HIV RNA samples taken at baseline from patients in Phase III studies gave a geometric mean EC 50 of 0.259 μg/ml (geometric mean + 2SD = 1.96 μg/ml) in a recombinant phenotype HIV entry assay. Enfuvirtide also inhibited HIV-1 envelope mediated cell-cell fusion. Combination studies of enfuvirtide with representative members of the various antiretroviral classes exhibited additive to synergistic antiviral activities and an absence of antagonism. The relationship between the in vitro susceptibility of HIV-1 to enfuvirtide and inhibition of HIV-1 replication in humans has not been established.

Antiretroviral drug resistance: Incomplete viral suppression may lead to the development of drug resistance to one or more components of the regimen.

In Vitro resistance to enfuvirtide: HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in vitro which harbour substitutions in amino acids (aa) 36-38 of the gp41 ectodomain. These substitutions were correlated with varying levels of reduced enfuvirtide susceptibility in HIV site-directed mutants.

In Vivo resistance to enfuvirtide: In phase III clinical studies HIV recombinants containing the env genes from HIV RNA samples taken up to week 24 from 187 patients showed> 4 fold reduced susceptibility to enfuvirtide compared with the corresponding pre-treatment samples. Of these, 185 (98.9%) env genes carried specific substitutions in region of aa 36 – 45 of gp41. The substitutions observed in decreasing frequency were at aa positions 38, 43, 36, 40, 42 and 45. Specific single substitutions at these residues in gp41 each resulted in a range of decreases from baseline in recombinant viral susceptibility to enfuvirtide. The geometric mean changes ranged from 15.2 fold for V38M to 41.6 fold for V38A. There were insufficient examples of multiple substitutions to determine any consistent patterns of substitutions or their effect on viral susceptibility to enfuvirtide. The relationship of these substitutions to in vivo effectiveness of enfuvirtide has not been established. Decrease in viral sensitivity was correlated to the degree of pre-treatment resistance to background therapy. (See Table 5)

Cross-resistance: Due to its novel viral target enfuvirtide is equally active in vitro against both wild-type laboratory and clinical isolates and those with resistance to 1, 2 or 3 other classes of antiretrovirals (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors). Conversely, mutations in aa 36-45 of gp41 which give resistance to enfuvirtide would not be expected to give cross resistance to other classes of antiretrovirals.

Clinical Pharmacodynamic data

Studies in Antiretroviral Experienced Patients: The clinical activity of Fuzeon (in combination with other antiretroviral agents) on plasma HIV RNA levels and CD4 counts have been investigated in two randomised, multicentre, controlled studies (TORO 1 and TORO 2) of Fuzeon of 48 weeks duration. 995 patients comprised the intent-to-treat population. Patient demographics include a median baseline HIV-1 RNA of 5.2 log10 copies/ml and 5.1 log10 copies/ml and median baseline CD4 cell count of 88 cells/mm³ and 97 cells/mm³ for Fuzeon + OB and OB, respectively. Patients had prior exposure to a median of 12 antiretrovirals for a median of 7 years. All patients received an optimised background (OB) regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the patient’s prior treatment history, as well as baseline genotypic and phenotypic viral resistance measurements.

The proportion of patients achieving viral load of <400 copies/ml at week 48 was 30.4% among patients on the Fuzeon+OB regimen compared to 12% among patients receiving OB regimen only. The mean CD4 cell count increase was greater in patients on the Fuzeon + OB regimen than in patients on OB regimen only. (see Table 4)

Table 4 – Outcomes of Randomised Treatment at Week 48 (Pooled Studies TORO 1 and TORO 2, ITT):

Outcomes Fuzeon +OB 90 mg bid (N=661) OB (N=334) Treatment Difference 95% Confidence Interval p-value
HIV-1 RNALog Change from baseline (log 10 copies/ml) * -1.48 -0.63 LSM-0.85 -1.073, -0.628 <.0001
CD4+ cell countChange from baseline (cells/mm 3 ) # +91 +45 LSM46.4 25.1, 67.8 <.0001
HIV RNA>1 log below Baseline ** 247 (37.4%) 57 (17.1%) Odds Ratio3.02 2.16, 4.20 <.0001
HIV RNA <400 copies/ml ** 201 (30.4%) 40 (12.0%) Odds Ratio 3.45 2.36, 5.06 <.0001
HIV RNA <50 copies/ml ** 121 (18.3%) 26 (7.8%) Odds Ratio 2.77 1.76, 4.37 <.0001
Discontinued due to adverse reactions/intercurrent illness/labs 9% 11%
Discontinued due to injection site reactions 4% N/A
Discontinued due to other reasons †φ§ 13% 25%

* Based on results from pooled data of TORO 1 and TORO 2 on ITT population, week 48 viral load for subjects who were lost to follow-up, discontinued therapy, or had virological failure replaced by their last observation (LOCF).
# Last value carried forward.
** M-H test: Discontinuations or virological failure considered as failures.
† Percentages based on safety population Fuzeon+background (N=663) and background (N=334). Denominator for non-switch patients: N=112.
φ As per the judgment of the investigator.
§ Includes discontinuations from loss to follow-up, treatment refusal, and other reasons.

Fuzeon+OB therapy was associated with a higher proportion of patients reaching <400 copies/ml (or <50 copies/ml) across all subgroups based on baseline CD4, baseline HIV-1 RNA, number of prior antiretrovirals (ARVs) or number of active ARVs in the OB regimen. However, subjects with baseline CD4>100 cells/mm³, baseline HIV-1 RNA <5.0 log10 copies/ml, ≤ 10 prior ARVs, and/or other active ARVs in their OB regimen were more likely to achieve a HIV-1 RNA of <400 copies/ml (or <50 copies/ml) on either treatment. (see Table 5)

Table 5 – Proportion of Patients achieving <400 copies/ml and <50 copies/ml at Week 48 by subgroup (pooled TORO 1 and TORO 2, ITT):

Subgroups HIV-1 RNA < 400 copies/ml HIV-1 RNA < 50 copies/ml
Fuzeon + OB 90 mg bid (N=661) OB (N=334) Fuzeon + OB 90 mg bid (N=661) OB (N=334)
BL HIV-1 RNA < 5.0 log 10 1 copies/ml 118/269 (43.9%) 26/144 (18.1%) 77/269 (28.6%) 18/144 (12.5%)
BL HIV-1 RNA ≥ 5.0 log 10 1 copies/ml 83/392 (21.2%) 14/190 (7.4%) 44/392 (11.2%) 8/190 (4.2%)
Total prior ARVs ≤ 10 1 100/215 (46.5%) 29/120 (24.2%) 64/215 (29.8%) 19/120 (15.8%)
Total prior ARVs> 10 1 101/446 (22.6%) 11/214 (5.1%) 57/446 (12.8%) 7/214 (3.3%)
0 Active ARVs in background 1,2 9/112 (8.0%) 0/53 (0%) 4/112 (3.5%) 0/53 (0%)
1 Active ARV in background 1,2 56/194 (28.9%) 7/95 (7.4%) 34/194 (17.5%) 3/95 (3.2%)
≥ 2 Active ARVs in background 1,2 130/344 (37.8%) 32/183 (17.5%) 77/334 (22.4%) 22/183 (12.0%)

1 Discontinuations or virological failures considered as failures.
2 Based on GSS score.

Pharmacokinetic properties

The pharmacokinetic properties of enfuvirtide have been evaluated in HIV-1-infected adult and paediatric patients.

Absorption: The absolute bioavailability after subcutaneous administration of enfuvirtide 90 mg in the abdomen was 84.3 ± 15.5%. Mean (± SD) Cmax was 4.59 ± 1.5 μg/ml, AUC was 55.8 ± 12.1 μg*hr/ml The subcutaneous absorption of enfuvirtide is proportional to the administered dose over the 45 to 180 mg dose range. Subcutaneous absorption at the 90 mg dose is comparable when injected into abdomen, thigh or arm. In four separate studies (N = 9 to 12) the mean steady state trough plasma concentration ranged from 2.6 to 3.4 μg/ml.

Distribution: The steady state volume of distribution with intravenous administration of a 90 mg dose of enfuvirtide was 5.5 ± 1.1 l. Enfuvirtide is 92% bound to plasma proteins in HIV infected plasma over a plasma concentration range of 2 to 10 μg/ml. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein. In in vitro studies, enfuvirtide was not displaced from its binding sites by other medicinal products, nor did enfuvirtide displace other medicinal products from their binding sites. In HIV patients, enfuvirtide levels in the cerebrospinal fluid have been reported to be negligible.

Metabolism: As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool. In vitro human microsomal studies and in in vivo studies indicate that enfuvirtide is not an inhibitor of CYP450 enzymes. In in vitro human microsomal and hepatocyte studies, hydrolysis of the amide group of the C-terminus amino acid, phenylalanine results in a deamidated metabolite and the formation of this metabolite is not NADPH dependent. This metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4 to 15% of the enfuvirtide AUC.

Elimination: Clearance of enfuvirtide after intravenous administration 90 mg was 1.4 ± 0.28 l/h and the elimination half-life was 3.2 ± 0.42 h. Following a 90 mg subcutaneous dose of enfuvirtide the half-life of enfuvirtide is 3.8 ± 0.6 h. Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.

Hepatic Insufficiency: The pharmacokinetics of enfuvirtide have not been studied in patients with hepatic impairment.

Renal Insufficiency: Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide is not affected to any clinically relevant extent in patients with mild to moderate renal impairment. In a renal impairment study AUC of enfuvirtide was increased on average by 43-62% in patients with severe or end stage renal disease compared to patients with normal renal function. Haemodialysis did not significantly alter enfuvirtide clearance. Less than 13% of the dose was removed during haemodialysis. No dose adjustment is required for patients with impaired renal function.

Elderly: The pharmacokinetics of enfuvirtide have not been formally studied in elderly patients over 65 years of age.

Gender and Weight: Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males irrespective of weight and is increased with increased body weight irrespective of gender (20% higher in a 100 kg and 20% lower in a 40 kg body weight patient relative to a 70 kg reference patient). However, these changes are not clinically significant and no dose adjustment is required.

Race: Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide was not different in Afro-Americans compared to Caucasians. Other PK studies suggest no difference between Asians and Caucasians after adjusting exposure for body weight.

Paediatric Patients: The pharmacokinetics of enfuvirtide have been studied in 37 paediatric patients. A dose of 2 mg/kg bid (maximum 90 mg bid) provided enfuvirtide plasma concentrations similar to those obtained in adult patients receiving 90 mg bid dosage. In 25 paediatric patients ranging in age from 5 to 16 years and receiving the 2 mg/kg bid dose into the upper arm, anterior thigh or abdomen, the mean steady-state AUC was 54.3 ± 23.5 μg*h/ml, Cmax was 6.14 ± 2.48 μg/ml, and Ctrough was 2.93 ± 1.55 μg/ml.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and late embryonal development. Long-term animal carcinogenicity studies have not been performed.

Studies in guinea pigs indicated a potential for enfuvirtide to produce delayed contact hypersensitivity. In a rat model on the resistance to influenza infection, an impairment of IFN-γ production was observed. The resistance to influenza and streptococcal infection in rats was only weakly compromised.The clinical relevance of these findings is unknown.