A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results

• DOI: 10.1016/j.gim.2022.03.021
• Publication Date: 2022-04-26T12:27:09Z
• Authors: Melissa Wasserstein; Robin Lachmann; Carla Hollak; Laila Arash-Kaps; Antonio Barbato; Renata C. Gallagher; Roberto Giugliani; Norberto Bernardo...; Takayuki Ikezoe; Olivier Lidove; Paulina Mabe; Eugen Mengel; Maurizio Scarpa; Eubekir Senates; Michel Tchan; Jesus Villarrubia; Yixin Chen; Sandy Furey; Beth L. Thurberg; Atef Zaher; Monica Kumar
• Keywords: Adult; 0301 basic medicine; Carbon Monoxide; Diffusing capacity of the lung for carbon monoxide; Niemann-Pick type A/B; Niemann-Pick type B; Organomegaly; Recombinant human acid sphingo-myelinase; Niemann-Pick Disease, Type A; Recombinant Proteins; 3. Good health; 03 medical and health sciences; Sphingomyelin Phosphodiesterase; Double-Blind Method; Splenomegaly; Humans; Enzyme Replacement Therapy

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.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.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.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.