Eflornithine, marketed as Iwilfin, has received FDA approval for treating adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy, including anti-GD2 immunotherapy. This approval marks a significant advancement as the first therapy specifically intended to reduce the risk of relapse in pediatric patients with high-risk neuroblastoma. However, its availability in Europe remains uncertain due to the absence of an active EMA approval application.
Efficacy Data Supporting Approval
The FDA's approval was based on data from Study 3b (NCT02395666), which was compared to an external control group from Study ANBL0032. The primary analysis involved a 1:3 propensity score matching of 90 patients from Study 3b and 270 patients from ANBL0032, focusing on event-free survival. Patients in Study 3b received eflornithine twice daily, with the dosage adjusted based on body surface area, continuing until disease progression, unacceptable toxicity, or a maximum of 2 years. The control group in ANBL0032 received dinutuximab, granulocyte-macrophage colony-stimulating factor, interleukin-2, and cis-retinoic acid versus cis-retinoic acid alone. The median age at diagnosis for patients in the primary analysis was 3 years (range: 0.1–20.1 years).
The study revealed a hazard ratio for event-free survival of 0.48 (95% CI: 0.27–0.85) for the eflornithine group compared to the control group. The hazard ratio for overall survival was 0.32 (95% CI: 0.15–0.70), indicating a significant reduction in the risk of relapse and death.
Dosage and Administration
The recommended dosage of eflornithine is based on body surface area: 768 mg twice daily for > 1.5 m2, 576 mg twice daily for 0.75 to 1.5 m2, 384 mg twice daily for 0.5 to < 0.75 m2, and 192 mg twice daily for 0.25 to < 0.50 m2. The product labeling provides detailed instructions on dosage modification, including dose reduction, for adverse reactions such as decreased neutrophils and platelets, anemia, increased liver transaminases, hearing loss, nausea, vomiting, and diarrhea.
Safety Profile and Adverse Events
In Study 3, the most common adverse events of any grade among the 85 patients receiving eflornithine were otitis media (32%), diarrhea (15%), cough (15%), sinusitis (13%), and pneumonia (12%). The most common grade 3 adverse events included hearing loss (7%) and skin infection (4.7%). Grade 3 or 4 laboratory abnormalities included decreased neutrophils (8%), increased alanine aminotransferase (7%), and increased aspartate aminotransferase (6%). Serious adverse reactions occurred in 12% of patients, with skin infection being the most frequent. Adverse events led to treatment discontinuation in 11% of patients, most commonly due to hearing loss.
Eflornithine carries warnings and precautions for myelosuppression, hepatotoxicity, hearing loss, and embryofetal toxicity. Patients are advised against breastfeeding while receiving eflornithine.
EMA Approval Status and European Access
As of March 2024, there is no active application for eflornithine's approval with the European Medicines Agency (EMA). This absence suggests that the medicine is unlikely to be available in Europe in the immediate future. Typically, the EMA approval process takes approximately 210 days from application submission to a decision by the Committee for Medicinal Products for Human Use (CHMP). If a positive recommendation is made, final approval takes an additional 2 months. While eflornithine has an orphan medicine designation in the EU, potentially allowing for a quicker review process of 150 days, an official marketing authorization application is still required.
Given the current status, it is difficult to provide a precise timeline for Iwilfin's availability in Europe. Assuming an application is submitted by May 2024, approval could potentially be granted by the end of the year. However, the subsequent availability in individual EU member states will vary, ranging from an average of 102 days in Germany to 1,081 days in Estonia. Consequently, European patients may not have access to eflornithine until mid-2025 at the earliest, with longer waiting times in some countries.
Alternative Access Options
For patients seeking earlier access to eflornithine, options include participation in clinical trials and utilizing the Named Patient Import regulation. Patients can explore ongoing clinical trials through databases such as ClinicalTrials.gov and EUClinicaltrials.eu. The Named Patient Import regulation allows patients to import medications not yet approved locally for personal use, provided they have a prescription from their doctor.
