Clinical Trial Result Information

Protocol number
T20-206

Title of Study
A Controlled Phase II Trial Assessing 3 Doses of T-20 in Combination with Abacavir, Amprenavir, Ritonavir, and Efavirenz in HIV-Infected Adults

Sponsor
Trimeris Inc; Hoffmann-La Roche Inc.

Company division
Pharmaceutical

Product name
Fuzeon

Generic name
enfuvirtide

Therapeutic area
Treatment of HIV-1 infection

Clinical study summary
This was a multicenter, randomized, controlled, dose-ranging study to evaluate the safety, efficacy, and plasma pharmacokinetics ( PK) of T-20 (Fuzeon) in combination with Abacavir (ABC), Amprenavir (APV), Ritonavir (RTV), and Efavirenz (EFV) in Human Immunodeficiency Virus Type-1 ( HIV-1) infected adults.

Study center(s)
15 centers in the United States.

Phase of development
II

Objectives
Primary: To evaluate the safety, assess the antiretroviral (ARV) activity, and determine the plasma PK for 3 doses of Fuzeon in combination with ABC, APV, RTV, and EFV in HIV-1 infected adults. Secondary: To estimate the incidence of phenotypic and genotypic resistance (not reported here) and assess the changes in CD4+ counts over time.

Methodology
At study initiation, subjects were randomized into 4 treatment groups. Three groups received subcutaneous (sc) injections of Fuzeon at a dose of 50 mg, 75 mg, or 100 mg administered twice daily ( bid )with a background oral (po) ARV regimen of ABC (300 mg bid), APV (1200 mg bid), RTV (200 mg bid), and EFV (600 mg qd). A control group received the background ARV regimen alone.

Number of patients (planned/analyzed)
71 enrolled; 71 intent-to-treat (ITT)

Diagnosis and main criteria for inclusion
HIV-1 infected males and females >=18 years of age; screening plasma HIV-1 RNA level >=400 copies/mL; prior exposure to >=1 protease inhibitor (PI) for >=16 weeks without interruption in their most recent protease inhibitor( PI)-containing ARV treatment prior to the screening visit; non-nucleoside reverse transcriptase inhibitor–naïve.

Test product, dose and mode of administration or test procedure
Fuzeon, 50 mg, 75 mg, or 100 mg/sc/bid

Reference therapy, dose and mode of administration or reference procedure
Background ARV regimen comprising ABC, 300 mg/po/bid; APV, 1200 mg/po/bid; RTV, 200 mg/po/bid; and EFV, 600 mg/po/qd.

Criteria for evaluation (efficacy, safety)
Efficacy: Virologic and immunologic activity; phenotypic and genotypic resistance.

PK: Trough plasma concentrations of enfuvirtide at baseline and at intervals up to Week 48. Intensive PK sampling of selected subjects at Week 4 for plasma enfuvirtide, ABC, APV, RTV and EFV.

Statistical methods
Statistical analyses conducted were for descriptive purposes only; no hypothesis testing was performed and therefore no P values are presented. For both efficacy and safety analyses, data from the Fuzeon dose groups were pooled and presented for the Fuzeon total group. The primary population for efficacy analyses was the ITT population (ie, randomized subjects who received >=1 dose of study medication). Also, all efficacy analyses of the proportions <=400 and <=50 copies/mL were performed for a modified ITT (MITT) population, defined as all randomized subjects who received >=1 dose of study medication and had >=1 follow-up plasma HIV-1 RNA assessment while on their randomized regimen. The virologic efficacy endpoints were (1) number and percent of subjects whose plasma HIV-1 RNA level remained <=400 copies/mL at Weeks 16 and 48, (2) number and percent of subjects whose plasma HIV-1 RNA level remained <=50 copies/mL at Weeks 16 and 48, (3) subjects with >=1.0 log₁₀ reduction in plasma HIV-1 RNA from baseline, (4) change from baseline in log₁₀ transformed plasma HIV-1 RNA, and (5) average area under the curve minus baseline (AAUCMB) for log₁₀ plasma HIV-1 RNA. The immunologic efficacy endpoints were CD₄ cell count (change from baseline and AAUCMB). All randomized subjects who received >=1 dose of study medication were included in the safety analysis. All adverse events were summarized by treatment group.

Summary (efficacy, safety, other results)
Efficacy: All treatment groups benefited from ARV therapy in this study. When all efficacy endpoints were taken into account, there was a tendency for higher Fuzeon dose groups to be associated with increasing efficacy. This was observed despite a large number of discontinuations in the combined Fuzeon group (20/52 subjects, 38.5%) and control group (9/19 subjects, 47.4%) for safety or other reasons. The observed rise in median CD₄ cell count difference of 42 cells/mm³ reflects the immunologic benefit achieved in Fuzeon versus control subjects.

PK: Mean minimum concentration (C_min) for enfuvirtide was 1.04, 2.22, and 2.60 µg/mL for the 50mg, 75mg, and 100mg bid Fuzeon dose groups, respectively. The 12-hour AUC values were 23.1, 42.8, and 48.6 µg·h/mL for the Fuzeon 50mg, 75mg, and 100mg bid dose groups, respectively. The Fuzeon 75mg bid dose had a slightly higher than dose-proportional exposure. Trough enfuvirtide concentrations for the Fuzeon 75mg and 100mg bid dose groups were roughly twice that of the Fuzeon 50mg bid dose group. There were no apparent interactions between Fuzeon and ARVs.

Safety: No deaths occurred during the study. Overall, the percentage of subjects who had a serious adverse event, including injection-site reaction (ISR), was higher in the control group (47.4%) than in the Fuzeon total group (34.6%). The most frequent serious adverse events in Fuzeon-treated subjects were hypersensitivity reaction (11.5%) and neutropenia (9.6%); incidences were comparable in the control group for both events (15.8% and 10.5%, respectively). More tolerability failures were observed in the Fuzeon 100mg bid group (31.3%) than in any other group; incidences of tolerability failures were similar across the other treatment groups, including the control group (range, 12.5%–15.8%). The majority of the tolerability failures occurred during the first 4 weeks of treatment.

Excluding ISR, the most common drug-related adverse events in the Fuzeon population were nausea (18.5%), fatigue (11.1%), dizziness (9.3%), and headache (9.3%). The percentage of subjects who had a marked or severe adverse event was higher in the control group (73.7%) than in the Fuzeon total group (44.2%) or any of the individual Fuzeon treatment groups (range, 40% in the Fuzeon 75mg bid group to 50% in the remaining Fuzeon groups). Pneumonia and nausea were the only 2 severe adverse events that occurred in >=2 subjects treated with Fuzeon.

Approximately two thirds (68.5%) of the Fuzeon total population had an ISR. While the incidence of ISR was slightly higher in the Fuzeon 100mg group, there was no apparent dose relationship (Fuzeon 100mg group, 76.5%; Fuzeon 50mg group, 73.7%; Fuzeon 75mg group, 61.9%). These results suggested that the greater number of daily injections required in the Fuzeon 75mg bid and 100mg bid groups (4 injections/day) as compared to the Fuzeon 50mg bid group (2 injections/day) was not clearly associated with a higher incidence of ISRs. The majority (70.3%) of subjects had their first ISR during the first 2 weeks of treatment. Only 1 subject had a severe ISR (abscess of the abdominal wall requiring drainage). Overall, 11 (21.2%) Fuzeon-treated subjects had a dose modification due to injection-related problems; of these, 3 (5.6%) discontinued Fuzeon due to ISR, 3 (5.6%) had a dose reduction to 50mg bid due to ISR, and 5 (9.6%) chose to withdraw from the study citing injection-site fatigue/inconvenience. No subjects in the Fuzeon 100mg bid group discontinued Fuzeon due to an ISR.

The percentage of subjects with a Grade 3 or Grade 4 laboratory toxicity was higher in the Fuzeon total (26.9%) group compared to the control (15.8%) group. However, the higher percentage of Grade 3 or Grade 4 laboratory toxicities in the Fuzeon total group was not due to any 1 laboratory toxicity, and no dose relationship was observed for any laboratory toxicity. Overall, the analyses of clinical adverse events (including ISR, serious adverse events, tolerability failure, severity, and causality) and laboratory toxicities showed no clear dose-dependent trends.

Conclusions
Fuzeon did not appear to exacerbate known toxicities associated with the 4 oral antiviral therapies. Overall, there were no clear dose-dependent trends with respect to clinical adverse events and laboratory toxicity occurrences, including ISRs. The number of injections did not appear to influence the incidence of ISRs.

Fuzeon demonstrated added virologic and immunologic benefit across treatment arms compared with the ARV control group.

Administration of Fuzeon 50mg, 75mg, and 100mg bid was associated with stable, sustained plasma concentrations of enfuvirtide for 48 weeks. Exposure to enfuvirtide increased in a roughly dose-proportional fashion from 50mg to 100mg, with the 75mg bid dose associated with slightly higher-than-proportional exposure.

Publications (references, if available)
1) Lalezari JP, DeJesus E, Northfelt DW, et al. A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naïve HIV-infected adults. Antivir Ther 2003; 8: 279–87

Date of report
9/19/2001