Cipaglucosidase Alfa/Miglustat Therapy Improves Efficacy Outcomes in Enzyme Replacement Therapy-Experienced Patients With Late-Onset Pompe Disease

Mazen M. Dimachkie, MD

(Credit: University of Kansas Medical Center)

A new effect size analysis of the phase 3, randomized, double-blind PROPEL study (NCT03729362) showed that enzyme replacement therapy (ERT)-experienced patients with late-onset Pompe disease (LOPD) who switched to Amicus Therapeutics’ 2-component therapy of cipaglucosidase alfa-atga (Pombiliti)/miglustat (Opfold) (cipa/mig) from alglucosidase alfa/placebo (alg/pbo) demonstrated improvements in various efficacy outcomes. Overall, these findings underscored the potential of this FDA-approved treatment as an option for this specific patient population.¹

Presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, findings showed that patients who remained on alg/pbo (n = 30) showed worsening (d ≤ −0.2) or stability (−0.2 < d < 0.2) across the majority of efficacy outcomes. In the analysis, conducted by lead author Mazen M. Dimachkie, MD, tenured professor of neurology and director of Neuromuscular Division at the University of Kansas Medical Center, results revealed that those that switched to cipa/mig (n = 65) displayed improvement (d ≥ 0.2) or stability in efficacy outcomes.

The PROPEL study compared the efficacy and safety of cipa/mig with alg/pbo among adults with LOPD; prior to study entry, 77% of the participants had previously received ERT with alg/pbo (median, 7.4 years). In this analysis, investigators aimed to explore the effect sizes of cipa/mig and alg/pbo for efficacy outcomes among ERT-experienced patients from PROPEL. Researchers calculated standardized within-group effect sizes (Cohen’s d for correlated measurements, baseline to week 52) for outcomes such as motor and lung function, muscle strength, quality of life and biomarkers in ERT-experienced patients by dividing mean change from baseline by standard deviations of the difference.

Further findings showed that patients who remained on alg/pbo had statistically significant within-group worsening for sitting and supine forced vital capacity; slow vital capacity; maximal expiratory pressure; creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, and significant improvement only for Patient-Reported Outcomes Measurement Information System (PROMIS)–Dyspnea score. Notably, those who switched to cipa/mig did not show significant within-group worsening and demonstrated significant improvements for 6-minute walk distance; manual muscle tests; PROMIS–Fatigue score; Physician and Subject Global Impression of Change (5 subdomains); and CK and Hex4.

In September 2023, the FDA approved the combination of cipaglucosidase alfa-atga/miglustat as the first and only 2-component treatment for patients with LOPD.² The therapy, which is also approved in the European Union and United Kingdom, is indicated for adults with the disease who weigh at least 40 kg and who are not improving on their current enzyme replacement therapy. The US approval was based on the phase 3 PROPEL study where the combined therapy achieved a nominally statistically significant and clinically meaningful 3% mean improvement in percentage predicted forced vital capacity for superiority over approved therapy (P = .023).

Following the announcement of the approval, Barry J. Byrne, MD, PhD, associate chair of pediatrics, and director, Powell Gene Therapy Center, University of Florida; and chief medical advisor, Muscular Dystrophy Association, sat down in an interview with NeurologyLive^® to share his reaction to the news. He talked about how the comapny's 2-part therapy approach adds to the treatment landscape for Pompe. Bryne also spoke about the potential benefits of reducing infusion reactions in the disease and explained the role of newborn screening in shaping the future of Pompe Disease care.

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REFERENCES
1. Dimachkie MM, Bratkovic D, Byrne B, et al. Effect Size Analysis Of Cipaglucosidase Alfa Plus Miglustat Versus Alglucosidase Alfa In Enzyme Replacement Therapy-Experienced Adults With Late-Onset Pompe Disease In PROPEL. Presented at: 2024 AANEM; October 15-18; Savannah, Georgia. Abstract 157.
2. Amicus Therapeutics announces FDA approval and launch of new treatment for Pompe disease. News release. September 28, 2023. Accessed October 15, 2024. https://ir.amicusrx.com/news-releases/news-release-details/amicus-therapeutics-announces-fda-approval-and-launch-new