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A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results.
Genet Med. 2022 07; 24(7):1425-1436.GM

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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Wasserstein M
Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY. Electronic address: mwassers@montefiore.org.
Lachmann R
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
Hollak C
Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Arash-Kaps L
Villa Metabolica, Department of Pediatric and Adolescent Medicine, University Medical Center Mainz, Mainz, Germany; Clinical Science for LSD, SphinCS, Hochheim, Germany.
Barbato A
Department of Clinical Medicine and Surgery, "Federico II" University Hospital, Naples, Italy.
Gallagher RC
Institute for Human Genetics, University of California San Francisco, San Francisco, CA.
Giugliani R
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.
Guelbert NB
Metabolic Disease Service Clinica Universitaria Reina Fabiola, Cordoba, Argentina.
Ikezoe T
Department of Hematology, Fukushima Medical University, Fukushima, Japan.
Lidove O
Service de Médecine Interne, Diaconesses Croix Saint-Simon Hospital, Paris, France.
Mabe P
Servicio de Pediatría, Clínica Santa María, Santiago, Chile.
Mengel E
Clinical Science for LSD, SphinCS, Hochheim, Germany.
Scarpa M
Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, Udine, Italy.
Senates E
Department of Gastroenterology, Istanbul Medeniyet University, Istanbul, Turkey.
Tchan M
Department of Genetic Medicine, Westmead Hospital, Sydney, Australia.
Villarrubia J
Hematology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
Chen Y
Clinical Development, Sanofi, Bridgewater, NJ.
Furey S
Clinical Development, Sanofi, Bridgewater, NJ.
Thurberg BL
Clinical Development, Sanofi, Bridgewater, NJ.
Zaher A
Clinical Development, Sanofi, Bridgewater, NJ.
Kumar M
Clinical Development, Sanofi, Bridgewater, NJ.

MeSH

AdultCarbon MonoxideDouble-Blind MethodEnzyme Replacement TherapyHumansNiemann-Pick Disease, Type ARecombinant ProteinsSphingomyelin PhosphodiesteraseSplenomegaly

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

35471153

Citation

Wasserstein, Melissa, et al. "A Randomized, Placebo-controlled Clinical Trial Evaluating Olipudase Alfa Enzyme Replacement Therapy for Chronic Acid Sphingomyelinase Deficiency (ASMD) in Adults: One-year Results." Genetics in Medicine : Official Journal of the American College of Medical Genetics, vol. 24, no. 7, 2022, pp. 1425-1436.
Wasserstein M, Lachmann R, Hollak C, et al. A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results. Genet Med. 2022;24(7):1425-1436.
Wasserstein, M., Lachmann, R., Hollak, C., Arash-Kaps, L., Barbato, A., Gallagher, R. C., Giugliani, R., Guelbert, N. B., Ikezoe, T., Lidove, O., Mabe, P., Mengel, E., Scarpa, M., Senates, E., Tchan, M., Villarrubia, J., Chen, Y., Furey, S., Thurberg, B. L., ... Kumar, M. (2022). A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results. Genetics in Medicine : Official Journal of the American College of Medical Genetics, 24(7), 1425-1436. https://doi.org/10.1016/j.gim.2022.03.021
Wasserstein M, et al. A Randomized, Placebo-controlled Clinical Trial Evaluating Olipudase Alfa Enzyme Replacement Therapy for Chronic Acid Sphingomyelinase Deficiency (ASMD) in Adults: One-year Results. Genet Med. 2022;24(7):1425-1436. PubMed PMID: 35471153.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results. AU - Wasserstein,Melissa, AU - Lachmann,Robin, AU - Hollak,Carla, AU - Arash-Kaps,Laila, AU - Barbato,Antonio, AU - Gallagher,Renata C, AU - Giugliani,Roberto, AU - Guelbert,Norberto Bernardo, AU - Ikezoe,Takayuki, AU - Lidove,Olivier, AU - Mabe,Paulina, AU - Mengel,Eugen, AU - Scarpa,Maurizio, AU - Senates,Eubekir, AU - Tchan,Michel, AU - Villarrubia,Jesus, AU - Chen,Yixin, AU - Furey,Sandy, AU - Thurberg,Beth L, AU - Zaher,Atef, AU - Kumar,Monica, Y1 - 2022/04/26/ PY - 2022/01/10/received PY - 2022/03/23/revised PY - 2022/03/28/accepted PY - 2022/4/27/pubmed PY - 2022/7/14/medline PY - 2022/4/26/entrez KW - Diffusing capacity of the lung for carbon monoxide KW - Niemann-Pick type A/B KW - Niemann-Pick type B KW - Organomegaly KW - Recombinant human acid sphingo-myelinase SP - 1425 EP - 1436 JF - Genetics in medicine : official journal of the American College of Medical Genetics JO - Genet Med VL - 24 IS - 7 N2 - 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. SN - 1530-0366 UR - https://www.unboundmedicine.com/medline/citation/35471153/A_randomized_placebo_controlled_clinical_trial_evaluating_olipudase_alfa_enzyme_replacement_therapy_for_chronic_acid_sphingomyelinase_deficiency__ASMD__in_adults:_One_year_results_ DB - PRIME DP - Unbound Medicine ER -