Olipudase Alfa (Xenpozyme)

Olipudase alfa is a recombinant enzyme-replacement drug for acid sphingomyelinase deficiency (ASMD), the disease also known by its older name, Niemann-Pick disease types A/B and B — a rare lysosomal storage disorder in the same broad family this site's Gaucher and Fabry disease pages cover, caused by a different missing enzyme and a different accumulating fat. Approved first in Japan in March 2022, then the EU and, in August 2022, the FDA, it's the first and only approved treatment for ASMD anywhere — but its label is explicitly limited to the disease's non-neurological effects, since the enzyme can't cross into the brain to help the most severe, neurodegenerative form.

A different sphingolipid, the same disease family as Gaucher and Fabry

Acid sphingomyelinase deficiency (ASMD) — also known by its older name, Niemann-Pick disease types A, A/B and B — is a rare lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes acid sphingomyelinase (ASM). Without functional ASM, sphingomyelin, a lipid component of cell membranes, accumulates inside lysosomes throughout the body — most visibly in the liver, spleen, lungs and bone marrow, causing hepatosplenomegaly, interstitial lung disease and low platelet counts, among other findings. Like the lysosomal storage diseases this site's Gaucher (imiglucerase, velaglucerase alfa and taliglucerase alfa) and Fabry (agalsidase beta, pegunigalsidase alfa) pages describe, ASMD's severity varies enormously depending on how much residual enzyme activity a patient's specific mutations leave. The most severe form, historically called Niemann-Pick disease type A, causes near-total enzyme loss and a rapidly progressive neurodegenerative disease fatal in early childhood; the milder type B form leaves more residual activity and causes visceral, non-neurological disease that can be compatible with a normal lifespan if managed; and a spectrum of intermediate “type A/B” presentations fall in between, sometimes with mild to moderate neurological involvement.

Sanofi's olipudase alfa is a recombinant form of human ASM, continuing the same corporate line as several other enzyme-replacement drugs on this site: Genzyme, which developed olipudase alfa, became a Sanofi subsidiary following Sanofi's 2011 acquisition described on this site's imiglucerase and agalsidase beta pages.

Why “non-CNS manifestations” is in the drug's own approved label

ASCEND: the placebo-controlled adult trial

The pivotal adult trial, ASCEND, was a 52-week, randomized, double-blind, placebo-controlled Phase 2/3 study enrolling 36 adults with chronic ASMD, assigned 1:1 to olipudase alfa or placebo by IV infusion every two weeks, with each patient's dose escalated up to a target of 3 mg/kg over the introductory dosing period. At one year, patients on olipudase alfa had statistically significant improvements relative to placebo in percent-predicted diffusing capacity for carbon monoxide (DLCO, a lung-function measure impaired by ASMD's interstitial lung involvement) and in spleen and liver volume by MRI (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, DOI: 10.1016/j.gim.2022.03.021).¹

All 36 participants continued into an open-label extension, and the patients originally randomized to placebo went on to show the same pattern of improvement once they began actual treatment — a within-patient replication of the placebo-controlled result, not just a single comparison.

ASCEND-Peds: an open-label trial in a population too small, and too young, for a placebo arm

The pediatric evidence took a different design, for reasons similar to sebelipase alfa's infant study described on this site's Sebelipase Alfa page: with the pediatric ASMD population small and its disease course in the most affected children severe enough that withholding treatment for a randomized comparison raised real ethical concerns, ASCEND-Peds was an open-label, dose-escalation trial in 20 children and adolescents (ages 1 to 17) with chronic ASMD, treated with IV olipudase alfa every two weeks up to a 3 mg/kg target dose. At the primary one-year timepoint, mean spleen and liver volumes fell by more than 40% from baseline (p<0.0001), lung diffusion capacity improved by a mean of 32.9% among children able to perform the test, and height-for-age z-scores improved by a mean of 0.56 (p<0.0001) — a meaningful finding in a disease that commonly causes growth delay (Diaz GA, Jones SA, Scarpa M, et al., “One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency,” Genet Med 2021;23(8):1543-1550, DOI: 10.1038/s41436-021-01156-3). Infusion-associated reactions, mostly hives, fever or vomiting during or shortly after dosing, occurred in 11 of the 20 children.²

A first approval that came from Japan, not the US

Unusually among the drugs on this site, olipudase alfa's first global regulatory approval came neither from the FDA nor the EMA, but from Japan's Ministry of Health, Labour and Welfare, which cleared Xenpozyme on 28 March 2022 under the SAKIGAKE (“pioneer”) designation — a Japanese fast-track program for genuinely novel therapies with no approved alternative. The European Commission followed with an EU-wide marketing authorization on 28 June 2022, and the FDA approved Xenpozyme in the US on 31 August 2022 (BLA 761261), specifically for the non-CNS manifestations of ASMD in both adult and pediatric patients — making the US label, from its first approval, already broader in eligible age range than most of the enzyme-replacement drugs on this site were at their own initial approval. Olipudase alfa's US label carries a boxed warning for hypersensitivity reactions, including anaphylaxis, reported in both trial populations described above, and recommends premedication with antihistamines, antipyretics or corticosteroids ahead of infusions.

Current status

Xenpozyme remains approved and marketed by Sanofi, through its Genzyme division, in the US, EU, Japan and other markets, as the first and, as of this review, only disease-specific treatment for ASMD anywhere in the world. Longer-term extension data from both ASCEND and ASCEND-Peds, following patients out to five years or more, have continued to show sustained rather than plateauing improvement in spleen and liver volume, lung function and growth — a reassuring sign for a drug whose pivotal trials, like several others on this site, were necessarily small given how few patients with this specific rare disease exist to enroll.