The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has issued a negative opinion on the request to approve an extended dosing regimen for Elfabrio (pegunigalsidase alfa), a treatment for Fabry disease developed by Chiesi Global Rare Diseases and Protalix BioTherapeutics.
The regulatory setback affects the proposed dosing regimen of 2 mg/kg body weight infused every four weeks (E4W), which would have provided patients with a less frequent treatment option compared to the currently approved regimen of 1 mg/kg body weight infused every two weeks (E2W).
Clinical Data Deemed Insufficient
The CHMP's decision was based on data from the BRIGHT trial (formally PB-102-F50), an open-label, switch-over study designed to assess the safety, efficacy and pharmacokinetics of pegunigalsidase alfa 2 mg/kg administered every four weeks. The submission also included data from the ongoing open-label extension study CLI-06657AA1-03 (formerly PB-102-F51), with the two studies combined providing a median exposure of almost six years.
Additional support came from modeling and exposure-response analyses across prior trials including PB-102-F01/-F02, PB-102-F20, and PB-102-F50. However, regulators determined these data were not sufficient to conclude similar efficacy between the proposed extended dosing regimen and the current standard.
Industry Response
"We are disappointed by the result of this review but want to express our immense appreciation for the collaboration of the patient community, researchers and European Commission throughout this process," said Giacomo Chiesi, Executive Vice President, Chiesi Global Rare Diseases. "We are proud to be a part of this community and will continue to prioritize the potential to advance and evolve safe and effective solutions for Fabry disease with reduced treatment burden."
Dror Bashan, Protalix's President and Chief Executive Officer, emphasized continued commitment despite the regulatory outcome. "We, together with Chiesi, remain committed to reducing the treatment burden for patients with Fabry disease. The results of this review do not change this priority. We are grateful to all of the patients and investigators, and their staff members, who participated in the every 4 weeks clinical trial programs."
Patient Community Perspective
Mary Pavlou, President of Fabry International Network (FIN), acknowledged the disappointment while expressing gratitude for collaborative efforts. "We acknowledge this outcome with disappointment but also with gratitude for the dedication shown by all involved – from patients and advocates to researchers and regulators. The Fabry International Network remains committed to fostering collaboration that drives meaningful progress both in safety and effectiveness and strives for advancements that make a real difference in daily life and long-term outcomes."
Current Treatment Landscape
Elfabrio remains approved for the treatment of adults with confirmed Fabry disease at its current dosing regimen. The therapy was approved by both the FDA and European Medicines Agency in May 2023. Fabry disease is a rare, inherited lysosomal storage disorder caused by mutations in the GLA gene, leading to a deficiency of the enzyme alpha-galactosidase A.
This deficiency results in accumulation of globotriaosylceramide (GL-3) in the body's cells, affecting the heart, kidneys, skin, nervous system, and other organs. The condition can cause fatigue, chronic pain, gastrointestinal issues, decreased ability to sweat, progressive kidney failure, heart complications, and increased risk of stroke.
Safety Profile
Clinical trial data showed that 20 (14%) Elfabrio-treated patients experienced hypersensitivity reactions, with four patients (3%) experiencing anaphylaxis reactions occurring within 5 to 40 minutes of initial infusion. Additionally, 41 (29%) patients experienced one or more infusion-associated reactions. The most common adverse reactions (≥15%) were infusion-associated reactions, nasopharyngitis, headache, diarrhea, fatigue, nausea, back pain, pain in extremity, and sinusitis.
Future Collaboration
Despite the regulatory setback, Chiesi and Protalix indicated they intend to continue working together to support the Fabry disease community. The companies' commitment to reducing treatment burden for patients remains unchanged, though they will need to explore alternative approaches to achieve less frequent dosing options.
