Peptide education
Enfuvirtide
Fuzeon · T-20
Enfuvirtide is an HIV-1 fusion inhibitor. It blocks a viral protein needed for HIV to enter a cell and was used with other antiretroviral medicines in people whose HIV remained detectable despite treatment.
In TORO 1, adding enfuvirtide to an optimized antiretroviral regimen produced a larger reduction in HIV-1 RNA at 24 weeks. The least-squares mean reductions were 1.696 versus 0.764 on a log10 scale, where a one-unit decrease means a tenfold lower viral load.
Overview
Quick answer
The former US Fuzeon indication was for combination treatment in treatment-experienced patients. FDA later withdrew approval of the Fuzeon application after the product was no longer marketed.
How does enfuvirtide work?
It binds HIV-1 gp41 and interferes with fusion of the virus and the host cell membrane.
Who was Fuzeon used for?
The former label covered people with HIV-1 replication despite prior antiretroviral treatment. It was used with other antiretroviral agents.
What happened to the US Fuzeon application?
The manufacturer ended US marketing and distribution, and FDA withdrew approval of the Fuzeon application at the applicant's request. The FDA notice permitted qualifying stock already in inventory to be dispensed until depleted, expired, or otherwise violative.
How was it given in adults?
The former label described 90 mg injected subcutaneously twice daily, alongside other antiretrovirals. Pediatric dosing in that label was based on weight.
What were the main safety concerns?
Injection-site reactions were common. The label also described systemic hypersensitivity and a higher observed pneumonia rate in controlled trials; a causal connection with pneumonia was uncertain.
Evidence
Evidence snapshot
Fuzeon was indicated with other antiretrovirals for treatment-experienced patients with ongoing HIV-1 replication.
FDA withdrew the named application after the applicant requested withdrawal because the product was no longer marketed.
At 24 weeks, the average HIV-1 RNA reduction was greater when enfuvirtide was added to an optimized background regimen than with the background regimen alone.
The former label reports at least one local injection-site reaction in 98% of participants receiving Fuzeon in the referenced trials.
Claims
Common claims vs evidence
| Claim | Human evidence | Verdict |
|---|---|---|
| Enfuvirtide was used alone to treat HIV-1. | TORO 1 compared enfuvirtide plus an optimized background regimen with the background regimen alone. The former label described combination treatment. | The trial and former indication both used enfuvirtide with other antiretrovirals. |
| The former Fuzeon label describes its current US approval. | The label describes the former product and indication. A later FDA notice withdrew approval of the Fuzeon application at the applicant's request. | The application was withdrawn; the label is historical context. |
| A higher pneumonia rate proves enfuvirtide caused pneumonia. | Controlled trials observed more pneumonia in the enfuvirtide group. A subsequent observational comparison left uncertainty about the relationship to the drug. | The safety signal warrants attention, but causation was not established. |
Bottom line
Main takeaway
Enfuvirtide blocks HIV entry and was used with other HIV medicines in people with prior treatment experience.
FDA withdrew the Fuzeon application after the product was no longer marketed in the United States.
TORO 1 compared an optimized background regimen with and without enfuvirtide over 24 weeks.
Identity
What it is
Enfuvirtide is a synthetic 36-amino-acid peptide that targets the HIV-1 envelope protein gp41. Its historical formulation was given under the skin.
In treatment-experienced people with HIV-1, TORO 1 studied enfuvirtide added to a background regimen chosen using treatment history and resistance information.
Use context
Routes, doses, and cycle patterns
The former Fuzeon label described twice-daily subcutaneous dosing in combination with other antiretrovirals. TORO 1 used a similar adult dose with an optimized background regimen.
Human studies and product labels
Former Fuzeon label, adults
- Purpose
- HIV-1 infection with ongoing replication after prior treatment
- Context
- Historical US prescribing information
- Route
- Subcutaneous
- Amount
- 90 mg
- Frequency
- Twice daily with other antiretroviral agents
- Duration
- The label described ongoing combination treatment
FDA later withdrew approval of the named Fuzeon application.
Former Fuzeon label, pediatric patients
- Purpose
- HIV-1 infection in treatment-experienced pediatric patients
- Context
- Historical US prescribing information
- Route
- Subcutaneous
- Amount
- The label describes 2 mg/kg per dose, up to 90 mg, using a weight-band table
- Frequency
- Twice daily in patients weighing at least 11 kg
The label's weight bands specify 27 to 90 mg per dose rather than an exact calculation for every weight. Safety and effectiveness in children younger than six years were not established.
TORO 1
- Purpose
- Treatment-experienced HIV-1 infection
- Context
- Randomized open-label clinical trial
- Route
- Subcutaneous
- Amount
- 90 mg
- Frequency
- Twice daily with an optimized background regimen
- Duration
- Primary viral-load outcome assessed at 24 weeks
The comparator received an optimized background regimen without enfuvirtide.
Research
Research evidence
TORO 1 found a larger average viral-load reduction when enfuvirtide was added to an optimized regimen for treatment-experienced patients. The trial was open-label and used a last-observation-carried-forward analysis.
| Study / evidence area | Population | Design | Product context | Main outcome | Limitations | Weight |
|---|---|---|---|---|---|---|
| TORO 1 | 501 treatment-experienced people with HIV-1 were randomized; 491 received treatment and had a post-treatment viral-load measurement | Randomized open-label phase 3 trial | Enfuvirtide plus optimized background therapy versus background therapy alone | The least-squares mean HIV-1 RNA change was a reduction of 1.696 versus 0.764 log10 copies/mL at 24 weeks, respectively, in the reported intention-to-treat analysis. | The study was open-label and reflects the antiretroviral options available during the trial. | Strong for the studied combination |
Cautions
Safety and unknowns
- The former label reports injection-site reactions in 98% of Fuzeon recipients in the referenced controlled trials.
- The former label contraindicated Fuzeon in people with known hypersensitivity to enfuvirtide or its ingredients. It called for stopping treatment and seeking immediate medical evaluation for signs of systemic hypersensitivity, and said not to restart after signs and symptoms consistent with such a reaction.
- Controlled trials observed a higher pneumonia rate among enfuvirtide recipients. A later observational study left the relationship to the drug uncertain.
Mechanism
How it is proposed to work
Enfuvirtide binds an HIV-1 envelope protein and blocks the membrane fusion step needed for the virus to enter a cell.
The target is gp41, part of the HIV-1 envelope; interference with gp41 prevents viral entry into CD4 cells.
Details
Technical details
Sources
References
- 1.
DailyMed. Fuzeon prescribing information
Historical US indication, subcutaneous dosing, pharmacology, and safety; Fuzeon's application was subsequently withdrawn.
- 2.
Federal Register. Withdrawal of approval of new drug applications including Fuzeon
FDA withdrew Fuzeon NDA 021481 after the applicant requested withdrawal; the notice includes a provision for existing inventory.
- 3.
PubMed. Enfuvirtide for drug-resistant HIV infection in North and South America
doi:10.1056/NEJMoa035026 PMID:12637625
TORO 1 randomized enfuvirtide plus optimized background therapy against optimized therapy alone.
- 4.
Genentech. Genentech update on Fuzeon in the United States
The manufacturer announced the end of US marketing and commercial distribution.