João Gonçalves, PhD – Faculty of Pharmacy, University of Lisbon, Derralynn Hughes, BM BCh – Professor, Experimental Hematology, Lysosomal Disorders Unit, Royal Free London NHS Foundation Trust and University College London, and Eric Wallace, MD – Professor of Medicine, The University of Alabama at Birmingham discuss the evolving treatment landscape for Fabry disease, a rare, progressive lysosomal disorder characterized by α-galactosidase A deficiency that impacts multipe sytems in the body. In this expert-led discussion, faculty explored how rational drug design is translating into meaningful clinical impact, with a focus on pegunigalsidase alfa and its emerging role in patient care.
Traditional ERTs for Fabry disease have demonstrated clinical benefit, but challenges remain—including infusion burden, immunogenicity, and durability of response. Pegunigalsidase alfa represents a next-generation approach, engineered with a focus on improving pharmacokinetics and stability.
The therapy utilizes PEGylation to extend circulating half-life and enhance enzyme persistence. This design strategy aims to increase tissue exposure and maintain more consistent enzymatic activity between infusions. Panelists emphasized that this is not simply an incremental improvement, but a purposeful redesign intended to address known limitations of earlier therapies. Importantly, the concept of “rational design” reflects a broader shift in rare disease drug development—moving from replacement alone to optimization of how therapies behave in the body.
A central question addressed in the discussion was whether these design improvements translate into meaningful clinical benefit. Clinical trial and real-world data suggest that pegunigalsidase alfa provides sustained reduction in key biomarkers, including plasma lyso-Gb3, which is closely associated with disease burden.
Speakers highlighted the importance of renal outcomes, given that kidney involvement is a major driver of morbidity in Fabry disease. Data presented in the discussion suggest stabilization of renal function over time, particularly in patients treated earlier in the disease course.
Cardiac involvement—another hallmark of Fabry disease—was also discussed. While longer-term data are still emerging, early signals indicate potential benefit in slowing cardiac progression, reinforcing the importance of sustained enzyme activity.
Immunogenicity remains a critical issue in ERT. The development of anti-drug antibodies can impact both efficacy and safety, and has been a longstanding concern with earlier therapies. Panelists noted that pegunigalsidase alfa may offer advantages in this area, with data suggesting a potentially lower or more manageable immunogenicity profile. While continued monitoring is essential, these findings are encouraging and may have implications for long-term treatment durability.
Infusion-related reactions were also discussed, with experts emphasizing the importance of tolerability in chronic therapy. A more stable and predictable pharmacologic profile may contribute to an improved patient experience.
While clinical trial data are essential, the panel emphasized the importance of real-world evidence in understanding how therapies perform in routine practice. Fabry disease is highly heterogeneous, with variability in presentation, progression, and treatment response.
Real-world data provide insight into how pegunigalsidase alfa performs across broader patient populations, including those with advanced disease, comorbidities, or prior treatment exposure. These insights are critical for informing clinical decision-making and optimizing individualized care.
The discussion also highlighted the role of treatment switching—particularly in patients who may not be achieving desired outcomes on existing therapies. Pegunigalsidase alfa may represent an important option in these scenarios.
As with many rare diseases, early diagnosis remains a key challenge in Fabry disease. Delays in diagnosis can lead to irreversible organ damage, limiting the impact of therapy.
The panel reinforced the need for increased awareness among healthcare providers, particularly in recognizing early signs and symptoms. Screening in high-risk populations and family cascade testing were identified as important strategies for improving diagnosis rates.
Early initiation of therapy—before significant organ involvement—offers the greatest opportunity to alter disease trajectory and improve long-term outcomes.
This educational webinar is based on the presentation “Rational Design Meets Real-World Relevance: Pegunigalsidase Alfa in the Treatment of Fabry Disease” at the WORLDSymposium held in San Diego on February 4th, 2026. The program is sponsored by Chiesi Pharma Inc.