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

Genet Med. 2022 Apr 26; S1098-3600(22)00716-X. doi: 10.1016/j.gim.2022.03.021.

PMID: 35471153

Melissa Wasserstein, Robin Lachmann, Carla Hollak, Laila Arash-Kaps, Antonio Barbato, Renata C Gallagher, Roberto Giugliani, Norberto Bernardo Guelbert, 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

Highlights: In individuals with acid sphingomyelinase deficiency (ASMD), olipudase alfa was well tolerated and associated with meaningful and wide-ranging improvements in disease pathology and clinically relevant endpoints compared to placebo.

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.

Keywords: Diffusing capacity of the lung for carbon monoxide, Niemann-Pick type A/B, Niemann-Pick type B, Organomegaly, Recombinant human acid sphingomyelinase