Pharmacology Update: Enfuvirtide (Fuzeon—Roche Pharmaceuticals)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA recently approved a new class of antiretroviral drug for treatment of patients with resistant HIV infections. Enfuvirtide (T-20), a synthetic 36-amino acid peptide fusion inhibitor, received an accelerated approval by the FDA. In contrast to existing antiretroviral agents that inhibit replication of HIV-1, enfuvirtide inhibits the entry of the virus into cells by inhibiting the fusion of viral and cellular membranes. The drug, which has made news because of its $20,000 per year price tag, will be marketed by Roche Pharmaceuticals as "Fuzeon."
Enfuvirtide is approved for use in combination with other retroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. It is approved for use in adults and children 6 years of age or older.1
The recommended dose in adults is 90 mg given subcutaneously twice daily. The drug can be injected into the upper arm, anterior thigh, or abdomen. Injection should be given at a different site from the preceding site. The dose in pediatric patients (aged 6-16) is 2 mg/kg twice daily up to a maximum of 90 mg per dose. Body weight should be monitored so that the dose could be adjusted.1
Enfuvirtide is available as 90-mg single-use vials.
Enfuvirtide provides a new site of action and is the first approved fusion inhibitor of HIV entry. It provides an option for patients who have used other antiretroviral drugs and shows evidence of continual viral replication. The addition of enfuvirtide to an optimized combination resulted in improved virologic and immunologic response compared to an optimized regimen alone.3-5 HIV-1 isolates resistant to other antiretroviral agents such as nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors have been found to be susceptible to enfuvirtide in vitro.1 Enfuvirtide does not affect drugs metabolized by CYP450 isoenzymes and it does not appear to interact with other antiretroviral agents.
Enfuvirtide requires twice-daily subcutaneous injection. Injection-site reactions were the most common adverse events as 98% of patients experienced at least 1 reaction. Pain/discomfort requiring analgesics occurred in 9% of patients. Other local adverse events included induration, erythema, and nodules and cysts. About 3% of patients discontinued treatment due to local adverse events.3-5 A higher incidence of bacterial pneumonia has been reported in phase III clinical trials compared to the control. Risk factors for pneumonia include low initial CD4 cell counts, high viral load, intravenous drug use, smoking, and prior respiratory disease. Hypersensitivity reactions and immune-mediated adverse events have also been reported. Resistant isolates have been recovered from patients treated with enfuvirtide.1 The long-term effectiveness of enfuvirtide is not known at this time.
Enfuvirtide is the first in a new class of antiretrovirals, the fusion inhibitors, drugs which block gp-41-mediated fusion of HIV-1 to the D4+ host cell.2 The accelerated approval of enfurvirtide was based on 2 24-week phase III studies involving about 1000 patients. TORO-1 (T-20 vs Optimized Regimen Only [OB]) was conducted in North America and Brazil and TORO-2 in Europe and Australia.3-5 Eligible patients had greater than 3 months (TORO-2) or 6 months (TORO-1) prior experience with 3 classes of antiretroviral drugs and HIV-1 RNA of at least 5000 copies/mL. They were randomized to an optimized regimen of 3-5 agents that was based on prior history and baseline genotypic and phenotypic resistance with or without enfuvirtide. Analysis at 24 weeks was based on intent to treat and last observation carried forward. In TORO-1, viral RNA had a reduction of 1.696 log for enfuvirtide compared to a reduction of 0.764 log for OB alone (P < 0.0001). The median baseline viral load was 5.2 logs for each arm.3,4 Mean changes in CD4+ were +76 cells/mm3 and 32 cells/mm3, respectively (P < 0.0001). In TORO-2, viral RNA was reduced by 1.43 log for enfuvirtide compared to 0.65 for OB (P < 0.0001). Both arms had a baseline viral RNA of 5.1 log.5 Overall 52% of enfuvirtide patients had a 1 log or greater reduction in HIV RNA compared to 26% for OB, and 23% of enfuvirtide patients had HIV RNA < 50 copies/mL compared to 9% for OB.1 Patients who discontinued treatment ranged from 11.3% to 17% for enfuvirtide and 5% to10.9% for OB. The drug has also been studied in 35 pediatric patients, aged 6-16 years in 2 open-label trials with viral response similar to adults.1 Enfuvirtide is expected to cost about $20,000 per year.6 The drug will be provided through a progressive distribution plan and will be shipped through a sole distributor.
Enfuvirtide provides an effective option to patients as an add-on to an optimized background regimen in treatment-experienced patients with viral replication despite continuing antiretroviral therapy. Roche indicated that the supply of enfuvirtide would be limited, and it expects to have enough for 12,000 to 15,000 patients in 2003 and up to 32,000 in 2004.6
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente and Asst. Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
1. Fuzeon Product Information. Roche Pharmaceuticals. March 2003.
2. Chen RY, et al. Expert Opin Investig Drugs. 2002; 11(12):1837-1843.
3. Lalezari JP, et al. www.nejm.org. Article will appear in May 29, 2003 edition of N Engl J Med.
4. Henry K, et al. Int Conf AIDS 2002. Jul 7-12;14abstract#LBOr19B.
5. Clotet B, et al. Int Conf AIDS 2002. Jul 7-12;14abstract#LBOr19A.
6. FDC Report. The Green Sheet. 2003;52(12):1-2.