What Clinicians Should Know About Extended Dosing of Pegunigalsidase Alfa

Fabry disease is a rare, X-linked lysosomal storage disorder caused by deficient α-galactosidase A activity, leading to progressive accumulation of globotriaosylceramide across multiple organ systems. Clinically, patients may present with a spectrum of manifestations, including neuropathic pain, renal dysfunction, cardiomyopathy, and cerebrovascular complications. Although enzyme replacement therapy (ERT) has significantly improved disease management, the need for lifelong, frequent infusions continues to impose a substantial burden on patients, caregivers, and healthcare systems.

Recently, the European Commission approved an alternative dosing regimen for pegunigalsidase alfa (Elfabrio®; Chiese Global Rare Diseases), allowing administration at 2 mg/kg every four weeks in adults with Fabry disease who are stable on ERT. This regulatory decision was supported by findings from the open-label BRIGHT study, as well as interim data from ongoing extension analyses evaluating long-term safety, efficacy, and pharmacokinetics. Notably, the extended dosing schedule aims to maintain therapeutic exposure while potentially reducing infusion frequency and improving treatment flexibility in real-world care.

In light of this development, NeurologyLive® spoke with Rachele Berria, MD, PhD, of Chiesi Global Rare Diseases, to discuss the clinical rationale supporting the every-4-week regimen, its potential impact on treatment burden and adherence, and how this dosing flexibility may shape long-term management strategies for patients living with Fabry disease.

NeurologyLive: Can you briefly outline the clinical data, including findings from the BRIGHT study, that supported the European Commission’s approval of the every-four-week dosing regimen for pegunigalsidase alfa?

Rachele Berria, MD, PhD: This approval is a result of one of the most extensive clinical development programs ever conducted in Fabry disease, one that was designed from the outset to reflect the full spectrum of patients living with this condition. The European Commission’s decision was informed by results from the open-label BRIGHT study, which evaluated the safety, efficacy, and pharmacokinetics of pegunigalsidase alfa administered at 2 mg/kg every four weeks (E4W) over 52 weeks in adults with Fabry disease who were stable on enzyme replacement therapy. The submission was also supported by interim data from an ongoing open-label extension study evaluating the long-term safety and efficacy of the E4W dosing regimen.

From a clinical management perspective, how might extending the dosing interval from every two weeks to every four weeks affect treatment burden and adherence for adults living with Fabry disease?

Fabry disease requires lifelong therapy, and for many patients, that means regular infusions that become a recurring part of their routine. For patients stable on enzyme replacement therapy, extending the infusion interval from every 2 weeks to every 4 weeks may reduce the treatment burden associated with this condition. Fewer infusions can make it easier for patients and caregivers to integrate treatment into their daily lives, which may support long-term adherence and continuity of care.

What pharmacokinetic or mechanistic considerations supported the feasibility of maintaining therapeutic activity with the less frequent dosing schedule?

The feasibility of the every-4-weeks dosing regimen was supported by pharmacokinetic and pharmacodynamic analyses, including comparisons using a population PK/PD model integrating data from multiple clinical studies. These analyses showed that 2 mg/kg every 4 weeks resulted in similar pharmacokinetics to 1 mg/kg every 2 weeks.

This was further supported by matched subgroup analyses using integrated clinical trial data, as well as results from the BRIGHT study and the ongoing open-label extension study.

How does this dosing flexibility position Elfabrio within the broader treatment landscape for Fabry disease, particularly compared with other enzyme replacement therapies or emerging approaches?

Enzyme replacement therapy remains an important treatment option in Fabry disease. Pegunigalsidase alfa is an approved enzyme replacement therapy for Fabry disease, with an established clinical development program evaluating its safety, efficacy, and pharmacokinetics.

The CHMP positive opinion for the every-4-weeks dosing regimen is specific to the European Union and is based on data submitted as part of the Type II Variation, including clinical studies, long-term extension data, observational outcomes, and pharmacokinetic/pharmacodynamic modeling analyses.

Any dosing regimen for pegunigalsidase alfa must be used in accordance with the approved Summary of Product Characteristics, and regulatory authorities in other regions make independent decisions regarding approval.

Looking ahead, what additional data or real-world experience will be important to monitor as clinicians begin to adopt the every-four-week regimen in practice?

As clinicians begin to gain experience with the every-4-week regimen, continued data generation will be important. Long-term safety and efficacy data from ongoing extension studies will provide additional insights, and real-world clinical experience will also help inform how this dosing option is used in practice.

Monitoring patient outcomes, treatment persistence, and overall disease management will help clinicians better understand which patients are most likely to benefit from this dosing flexibility.

Transcript edited for clarity.