Melissa Wasserstein1, Robin Lachmann2, Carla Hollak3, Laila Arash-Kaps4, Antonio Barbato5, Renata C Gallagher6, Roberto Giugliani7, Norberto Bernardo Guelbert8, Takayuki Ikezoe9, Olivier Lidove10, Paulina Mabe11, Eugen Mengel12, Maurizio Scarpa13, Eubekir Senates14, Michel Tchan15, Jesus Villarrubia16, Yixin Chen17, Sandy Furey17, Beth L Thurberg17, Atef Zaher17, Monica Kumar17. 1. Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY. Electronic address: mwassers@montefiore.org. 2. Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom. 3. Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands. 4. Villa Metabolica, Department of Pediatric and Adolescent Medicine, University Medical Center Mainz, Mainz, Germany; Clinical Science for LSD, SphinCS, Hochheim, Germany. 5. Department of Clinical Medicine and Surgery, "Federico II" University Hospital, Naples, Italy. 6. Institute for Human Genetics, University of California San Francisco, San Francisco, CA. 7. Medical Genetics Service and DR BRASIL Research Group, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil; Department of Genetics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; National Institute on Population Medical Genetics (INAGEMP), Porto Alegre, Brazil. 8. Metabolic Disease Service Clinica Universitaria Reina Fabiola, Cordoba, Argentina. 9. Department of Hematology, Fukushima Medical University, Fukushima, Japan. 10. Service de Médecine Interne, Diaconesses Croix Saint-Simon Hospital, Paris, France. 11. Servicio de Pediatría, Clínica Santa María, Santiago, Chile. 12. Clinical Science for LSD, SphinCS, Hochheim, Germany. 13. Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, Udine, Italy. 14. Department of Gastroenterology, Istanbul Medeniyet University, Istanbul, Turkey. 15. Department of Genetic Medicine, Westmead Hospital, Sydney, Australia. 16. Hematology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain. 17. Clinical Development, Sanofi, Bridgewater, NJ.
Abstract
PURPOSE: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults. METHODS: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics. RESULTS: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P = .0004), spleen volume (39% decrease vs 0.5% increase, P < .0001), and liver volume (28% vs 1.5% decreases, P < .0001). Splenomegaly-related score decreased in both groups (P = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event-related discontinuations. Most adverse events were mild. CONCLUSION: Olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD.
PURPOSE: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults. METHODS: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics. RESULTS: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P = .0004), spleen volume (39% decrease vs 0.5% increase, P < .0001), and liver volume (28% vs 1.5% decreases, P < .0001). Splenomegaly-related score decreased in both groups (P = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event-related discontinuations. Most adverse events were mild. CONCLUSION: Olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD.
Keywords:
Diffusing capacity of the lung for carbon monoxide; Niemann-Pick type A/B; Niemann-Pick type B; Organomegaly; Recombinant human acid sphingo-myelinase