Clinical Trial Result Information

Title of Study:
A Phase II Rollover Protocol for HIV-Infected Adults with Prior Fuzeon Treatment

Fast Facts:

Protocol number:	T20-205
Sponsor:	Hoffmann-La Roche Inc.; Trimeris Inc.
Company division:	Pharmaceutical
Product name:	Fuzeon
Generic name:	enfuvirtide
Phase of development:	II
Therapeutic area, approved indication:	Treatment of HIV-1 infection
Date of report:	10/8/2001

Clinical study summary:
This was a multicenter, uncontrolled, open-label, chronic treatment trial of Fuzeon, 50 mg twice daily ( bid), administered by intermittent subcutaneous ( sc) injection for 96 weeks to Human Immunodeficiency Virus Type-1 ( HIV-1) infected adults who participated in previous short-term Phase I studies of Fuzeon. Patients received Fuzeon in combination with >=2 new or recycled antiretrovirals (ARVs) specific to the individual.

Study center(s) :
11 centers in the United States.

Objectives:
Primary: To evaluate safety of Fuzeon administered sc for 96 weeks, as measured by hematology, urinalysis, clinical chemistry, and adverse event monitoring, in HIV-1 infected adults who had previously taken Fuzeon. Secondary: (1) To determine plasma pharmacokinetics (PK) following administration of Fuzeon; (2) To determine antiviral activity of Fuzeon, as measured by changes in plasma HIV-1 RNA levels; (3) To determine immunological effect of Fuzeon, as measured by changes in CD4 cell numbers.

Methodology:
HIV-infected adults who participated in previous short-term Phase I studies of Fuzeon received 50 mg Fuzeon bid, given by intermittent sc injection for 96 weeks. Safety, pharmacokinetic and efficacy evaluations were made at intervals during the 96 week experimental period.

Patients received Fuzeon in combination with >=2 new or recycled ARVs specific to the individual. HIV-1 RNA was measured by the Roche Amplicor assay and/or the Roche UltraSensitive assay.

Number of patients (planned/analyzed):
71 enrolled; 70 intent-to-treat (ITT)

Diagnosis and main criteria for inclusion:
HIV-1 infected males and females; received Fuzeon in previous clinical trials and had no drug-related toxicities resulting in study discontinuation; provided written informed consent; had a Karnofsky Performance Score >=60%; clinical laboratory results within predefined limits; required to start taking >=2 new or recycled ARVs for concomitant administration with Fuzeon on Day 0.

Test product, dose and mode of administration or test procedure:
Fuzeon, 50 mg/sc/bid up to 96 weeks.

Duration of treatment:
Up to 96 weeks

Reference therapy, dose and mode of administration or reference procedure:
Not applicable

Criteria for evaluation (efficacy, safety):
Efficacy: Efficacy was assessed by change from baseline in plasma HIV-1 RNA, maximum change from baseline in plasma HIV-1 RNA, CD₄ cell count, and resistance to Fuzeon and other ARVs.

PK: The following PK parameters were calculated from the plasma enfuvirtide concentration data for Day 28: area under the concentration-time curve (AUC_0-12), maximum concentration (C_max), minimum concentration (C_min), concentration of drug at steady state (C_ss), and time to maximum concentration (T_max).

Safety: Fuzeon safety was assessed by monitoring hematology, urinalysis, clinical chemistry, adverse events, electrocardiograms (EKGs), and vital signs.

Statistical methods:
All efficacy and safety analyses were performed for the ITT population (ie, all patients who were enrolled into the trial and received >=1 dose of study drug). All efficacy analyses were also performed for the efficacy-evaluable population. All statistical tests were 2-sided. A significance level of <=5% was considered statistically significant from 0 for all analytical comparisons. All analyses were performed on the data as collected; missing data were not interpolated.

Adverse events, hematology, urinalysis, clinical chemistry laboratory results, electrocardiograms( EKGs), and vital signs were summarized to assess safety, and where appropriate, were analysed descriptively.

Pharmacokinetic parameters such as AUC_0-12, C_max, C_min, C_ss and T_max were derived from the plasma enfuvirtide concentration data for Day 28.

Change from baseline in log₁₀ plasma HIV-1 RNA and CD4 cell count data (absolute and percent) were summarized and analyzed using a Wilcoxon signed-rank test for plasma HIV-1 RNA and a paired t-test for CD₄ cell count. The maximum change from baseline log₁₀ plasma HIV-1 RNA over all visits (excluding follow-up) was summarized and analyzed using a paired t-test. Time to virologic failure was tabulated and plotted based on Kaplan-Meier estimates.

Summary (efficacy, safety, other results):
Efficacy: A median suppression of approximately 1 log₁₀ in plasma HIV-1 RNA was maintained throughout the study. The mean reduction (-1.63 log₁₀) from baseline at Week 96 of plasma HIV-1 RNA was statistically significantly different from 0 (P < .001). At Week 96, the median population (n = 29) response showed a decrease of 1.52 log₁₀. At Week 96, 84.3% of patients had reached a >1.0 log₁₀ reduction from baseline at any time during the study. The mean maximum change from baseline was -2.16 log₁₀. At baseline, 3 patients (4.3%) in the ITT population were below the limit of quantification( BLQ). By Week 48, 16 patients (22.9%) had achieved plasma HIV-1 RNA that was BLQ, and another 16 patients (22.9%) achieved plasma HIV-1 RNA BLQ between Weeks and 96.

Virologic failure was defined as 2 consecutive plasma HIV-1 RNA results within 0.5 log₁₀ of the baseline value after the Week 8 visit. A total of 28 patients (40.0%) in the ITT population had virologic failure during the study. A Kaplan-Meier estimate of the time to virologic failure showed a survival probability of 0.52 after 96 weeks of treatment with Fuzeon in combination with oral ARV agents.

For the ITT population, the median absolute CD₄ cell count was 90 cells/µL at baseline. A median 77 cells/µL gain was achieved by the Week 48 visit and a 126 cells/µL gain was achieved at Week 96. Mean increase from baseline at Week 96 of absolute CD CD4 cells was statistically significantly different from 0 (P < .001).

PK: AUC (22.6 µg·h/mL), C_max (2.57 µg/mL) C_min (1.13 µg/mL), C_ss (1.88 µg/mL), and T_max (4.0 h) were derived from the Day 28 enfuvirtide plasma concentration data. At all timepoints during the 12-hour evaluation period on Day 28, plasma enfuvirtide concentration was >1.0 µg/mL. At all visits during the 96-week treatment period (except at Week 88, when the mean trough level was 0.9 µg/mL), the mean trough enfuvirtide plasma concentration was >1.0 µg/mL. No decrease in plasma enfuvirtide levels was observed over 96 weeks of treatment.

Safety: Five (7.1%) patients died during the study; none of these fatalities were considered to be related to Fuzeon. Three (4.3%) patients accounted for 4 serious adverse events considered to be drug-related, including Grade 4 gamma glutamyl transpeptidase elevation, recurrent Grade 4 neutropenia (×2), and anemia. Seven (10.0%) patients discontinued Fuzeon due to an adverse event, but only 1 of these discontinuations (recurrent Grade 4 neutropenia) was drug-related. The most commonly reported adverse events were injection-site reactions (ISRs) (80.0%), followed by diarrhea (58.6%); nausea (51.4%); asthenia (47.1%); vomiting (38.6%); fever (37.1%); and headache, infection, and sinusitis (30.0% each). Most (85.3%) of the adverse events reported (including ISRs) were classified as Grade 1 or Grade 2. In general, the safety profile of Fuzeon in this study population was consistent with that for patients receiving a multiple drug regimen for HIV infection: approximately 60% of the patients had diarrhea, 50% had nausea, 27% had hyperlipidemia, and 19% had peripheral neuropathy. With the exception of ISRs, the most common drug-related adverse events were diarrhea (12.9%) and nausea (10.0%).

As expected, ISRs were the most frequent adverse events; most (80.0%) of the patients had >= 1 ISR but there were no discontinuations due to an ISR or ‘injection fatigue/inconvenience’. The most frequently reported ISRs were injection-site mass (60.0%), pain (27.1%), and inflammation (18.6%). To further support the conclusion that ISRs were not treatment-limiting, over 90% of patients were at least 75% compliant for Fuzeon, 46% completed 96 weeks of treatment, and 31% were 100% compliant throughout 96 weeks. Two (2.9%) patients had a Grade 2 or Grade 3 rash considered to be related to Fuzeon. In both cases, rash resolved on continued Fuzeon therapy. This suggests that, even if caused by Fuzeon, rashes could be treated symptomatically.

Overall, there were no clinically meaningful changes in laboratory parameters following 96 weeks of treatment.

Conclusions:
Fuzeon added to background oral ARV therapy was well tolerated for 96 weeks in heavily pretreated HIV-1 infected patients, as evidenced by the facts that only 1 patient discontinued due to a drug-related adverse event, none of the 5 fatal events were drug-related, most adverse events (including ISRs) were classified as Grade 1 or Grade 2, and ISRs were not treatment-limiting.

Patients with advanced HIV-1 infection had antiviral and immunologic benefit through 96 weeks of treatment with Fuzeon and various ARV regimens. The PK profile seen in Phase I studies was confirmed in the current study population receiving concomitant ARV therapy. Fuzeon levels were stable over long-term exposure.

Publications (references, if available):
1) Lalezari JP, Eron JJ, Carlson M, et al. A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy. AIDS 2003; 17: 691–98