Efficacy and safety of cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo in late-onset Pompe disease (LOPD): A phase 3 trial (PROPEL)


Late-onset Pompe Disease

Poster Number: 129


Tahseen Mozaffar MD, Drago Bratkovic MD, Barry Byrne MD, PhD, Pascal Laforet MD, PhD, Ans van der Ploeg , Mark Roberts MSc, MBChB, FRCP, MD, Benedikt Schoser Prof. Dr. med. FEAN, Antonio Toscano , Hai Jiang PhD, Sheela Sitaraman Das, PhD, PMP, Srilakshmi Kuchipudi , Zoheb Kazi , Mitchell Goldman MD, PhD, Jeff Castelli PhD, Priya S. Kishnani MD, MBBS


1. University of California Irvine, 2. PARC Research Clinic, Royal Adelaide Hospital, 3. University of Florida, 4. Raymond-Poincaré Hospital, 5. ErasmusMC University Medical Center, 6. Salford Royal NHS Foundation Trust, 7. Friedrich-Baur-Institut, Neurologische Klinik, Ludwig-Maximilians-Universität München, 8. Università di Messina, 9. Amicus Therapeutics, Inc., 10. Amicus Therapeutics, Inc., 11. Amicus Therapeutics, Inc., 12. Amicus Therapeutics, Inc., 13. Amicus Therapeutics, Inc., 14. Amicus Therapeutics, Inc., 15. Duke University Medical Center

Background: Pompe disease is a rare autosomal recessive disorder characterized by progressive loss of muscle and respiratory function due to acid α-glucosidase (GAA) deficiency. The approved treatment is enzyme-replacement therapy (ERT) with recombinant human GAA (rhGAA) alglucosidase alfa. AT-GAA is an investigational, 2-component therapy comprising cipaglucosidase alfa, a novel rhGAA with enhanced glycosylation for improved uptake and processing, and miglustat, an enzyme stabilizer. Objectives: Comparison of AT-GAA versus alglucosidase alfa/placebo in a double-blind, parallel-group study (NCT03729362) of adults (aged ≥18 years) with LOPD. ERT-experienced and -naive patients were randomized 2:1 to co-administration of intravenous cipaglucosidase (20 mg/kg)/miglustat or alglucosidase alfa (20 mg/kg)/placebo every 2 weeks. The primary and first key secondary endpoints were mean change from baseline to week 52 in 6-minute walk distance (6MWD) and % predicted forced vital capacity (FVC; sitting), respectively. Other key secondary endpoints included lower extremities manual muscle test (MMT), GSGC (gait, stairs, Gower, chair), PROMIS-physical function, and PROMIS-fatigue. Results: 123 patients were randomized in 62 sites across 24 countries; AT-GAA, n=85; alglucosidase alpha, n=38 (intention-to-treat population). Baseline characteristics were similar between arms. At week 52, 6MWD showed clinical improvement with AT-GAA versus approved therapy but did not reach statistical superiority (mean [SE]: +20.8 [4.6] versus +7.2 [6.6] meters; P=0.072). AT-GAA demonstrated a nominally statistically significant and clinically meaningful improvement in FVC for superiority over approved therapy (-0.9 [0.7] versus -4.0 [0.8]; P=0.023). A clinically significant improvement in GSGC and numerical trends in favor of AT-GAA versus approved therapy in lower MMT, PROMIS-physical function, and fatigue were also observed. Biomarkers showed significant improvements with AT-GAA versus approved therapy (creatine kinase: -22.4% versus +15.6%, P<0.05; urine hexose tetrasaccharide: -31.5% versus +11.0%, P<0.001). Additional endpoints including % predicted 6MWD, GSGC component scores, MIP, MEP, total and upper MMT will be presented. The safety profile was similar between arms. Conclusion: In this study population, AT-GAA showed positive trends or clinically meaningful improvements on motor and respiratory functions and biomarkers, compared with approved ERT.