October 22, 2004
FDA originally approved Fuzeon on March 13, 2003 under the regulations at 21 CFR 314, Subpart H, for accelerated approval of new drugs for serious or life-threatening illnesses. Approval of this supplement is based on fulfillment of research commitments made by the sponsor, Hoffmann-La Roche, Inc. of Nutley, NJ, under 21 CFR 314.510. The supplemental application submitted in support of traditional approval of enfuvirtide included 48 week safety and efficacy data from studies T20-301 and T20-302. These studies also provided the basis for the accelerated approval. In addition, safety data from clinical access studies, open label safety studies, the early access program, and pediatric studies were submitted in this supplemental application.
There was clear evidence of efficacy in the two randomized, controlled, 48 week trials in heavily pretreated HIV-infected subjects. In these studies, the primary efficacy endpoint was the maintenance or improvement of treatment effect from week 24 to week 48 as measured by the percentage of subjects with a HIV RNA level less than 50 copies/ml, HIV RNA less than 400 copies/ml, or a one log or more decrease in viral load. A greater proportion of subjects receiving enfuvirtide plus an optimized background (OB) antiretroviral regimen had a treatment response at 48 weeks compared to those receiving an OB regimen alone (p<0.001).
Review of the safety data submitted in this supplement did not identify any new or unexpected toxicities for enfuvirtide. As expected, injection site reactions (ISRs) were the most common adverse event and were reported by almost all subjects receiving enfuvirtide (98%). ISRs were common at the week one study visit (86%) and continued to occur throughout treatment. Most ISRs were associated with pain or discomfort, erythema, induration, and nodules or cysts. Infectious complications were rare (1.7%). ISRs and injection difficulties, such as inconvenience and injection fatigue, had a substantial impact on study participation and were the cause of early discontinuation in 7% of the study population. An increased incidence of pneumonia was observed in the first 24 weeks of the phase 3 studies and again in the second 24 weeks. There was no evidence of increasing risk over time, and no new risk factors or changes in severity of pneumonia were identified. Finally, episodes of systemic hypersensitivity, which were reported in less than 1% of subjects during the first 24 weeks of the phase 3 trials, were rare in the second 24 weeks of these studies and in the other studies included in this supplement. The observed toxicities did not outweigh the clear benefit of enfuvirtide as a treatment option for treatment experienced patients with measurable ongoing viremia.
The following changes were made to the package insert and patient package insert:
The pharmacokinetics of enfuvirtide (AUC, Cmax, Ctrough, and apparent clearance) were changed to reflect the results of additional subjects enrolled in studied T20-310. These results were similar to previous findings and did not change the dosing recommendation for pediatric patients.
This section was updated to provide the 48 week efficacy data from studies T20-301 and T20-302.
The outcome table (Table 3) was revised to provide clear information on the outcome for each subject in these studies.
Limited information on the efficacy of enfuvirtide in subgroup populations was added.
This section was revised to reflect the efficacy and safety results from additional subjects enrolled in study T20-310.
The table summarizing individual signs and symptoms of injection site reactions was revised to decrease the number of footnotes and increase the comprehension of the results.
A brief description of the results of an Injection Site Reaction intervention study was added.
Peripheral neuropathy, anxiety, lymphadenopathy, and suicide ideation were added to the list of other reported AEs. Peripheral neuropathy, anxiety and lymphadenopathy were common, but mild.
Because of the difference in rate of exposure, adverse event results for subjects receiving enfuvirtide were provided as percentages and as rates per 100 patient-years.
Similar revisions were made to the patient package insert to improve readability and patient comprehension.
Accelerated approval recognizes improvement in a surrogate marker which is reasonably likely to predict clinical benefit. The subsequent study under the commitments made under the Accelerated Approval requirements demonstrated durable viral suppression and safety for 48 weeks, upon which the traditional approval is based.
The complete revised label will be available soon on the "Drugs@FDA" Web site.