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Olipudase alfa, an investigational recombinant human acid sphingomyelinase, demonstrated positive results in two separate clinical trials evaluating olipudase alfa for the treatment of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients. Olipudase alfa is the first and only investigational enzyme replacement therapy in late-stage development for the treatment of ASMD. No treatments are currently approved for ASMD.
“These significant results for olipudase alfa mark a major scientific advancement for ASMD and an important step toward providing a potential therapy for adult and pediatric patients who currently have no approved treatment options for this devastating disease,” said John Reed, M.D, Ph.D, global head of research and development at Sanofi. “We look forward to engaging with regulatory authorities to bring this potential new treatment to patients.”
The randomized phase 2/3 trial enrolled 36 adult patients with ASMD across 24 centers in 16 countries. Patients received either placebo or olipudase alfa intravenous infusion every two weeks at a dose of up to 3mg/kg administered every two weeks over 52 weeks.
The trial contained two independent primary efficacy endpoints to address separate critical manifestations of ASMD, progressive lung disease and enlarged spleen, which are prominent clinical features in patients with ASMD. The study protocol defines the trial outcome as positive if one of the independent primary endpoints was met.
The first independent primary endpoint measuring improvement in lung function, using the percent predicted diffusing capacity of carbon monoxide (DLco), was met; therefore, ASCEND is declared positive. The relative improvement from baseline to week 52 was 22% for the olipudase alfa arm compared with 3% for the placebo arm. The difference between the two treatment arms (19%) was statistically significant (p=0.0004).
The other independent primary endpoint measuring the effect of olipudase alfa on spleen size, assessed as percent change from baseline in multiples of normal (MN) of spleen volume, was met per the study protocol. In the olipudase alfa arm, spleen volume was reduced by 39.5%, compared with a 0.5% increase in the placebo arm. The difference between the two treatment arms (40%) was statistically significant (p<0.0001).
For the US, the spleen volume endpoint was further combined with a patient-reported outcome (PRO) measurement of symptoms associated with enlarged spleen called Splenomegaly Related Score (SRS). Compared to baseline, the SRS was reduced by 8.0 points in the olipudase alfa arm and 9.3 points in the placebo arm (p=0.70); therefore, this combination endpoint was not met.
“These are important data in a disease with no approved treatments available currently,” said Melissa Wasserstein, MD, Chief, Division of Pediatric Genetic Medicine, Children's Hospital at Montefiore; Professor of Pediatrics and Genetics, Albert Einstein College of Medicine; and an investigator in the ASCEND trial. “Treatment with olipudase alfa showed clinically meaningful improvement in pulmonary function and reduction in spleen size, critical manifestations of this progressive disease. Both of these findings are consistent across the clinical studies with olipudase alfa. The absence of an effect on SRS in this trial requires exploration, in light of the significant reduction in spleen size.”
The single arm, open label phase 2 trial enrolled 20 pediatric patients (birth to <18 years) with ASMD in six countries. Children with rapidly progressive neurological disease were excluded. The primary objective of the trial was to evaluate the safety and tolerability of olipudase alfa at a dose of up to 3mg/kg administered intravenously every two weeks for 64 weeks.
The study also explored secondary endpoints of progressive lung disease and enlarged spleen. After one year of treatment (52 weeks), the percent predicted DLco increased by a mean of 33% in nine patients who were able to perform the test at baseline (children over the age of five were assessed if they were able to perform the test). Additionally, at 52 weeks, the spleen volumes decreased by 49% as assessed by mean MN (individual patient decreases ranged from 23% to 61%).
Results from these trials will be submitted to future medical meetings and will form the basis of global regulatory submissions expected to begin the second half of 2021.
Traditionally referred to as Niemann-Pick Disease (NPD) Type A and Type B, ASMD is a rare, progressive and potentially life-threatening lysosomal storage disorder that results from a deficient activity of the enzyme acid sphingomyelinase (ASM), which is found in special compartments within cells called lysosomes and is required to breakdown lipids called sphingomyelin. If ASM is absent or not functioning as it should, sphingomyelin cannot be metabolized properly and accumulates within cells, eventually causing cell death and the malfunction of major organ systems. The deficiency of the lysosomal enzyme ASM is due to mutations in the sphingomyelin phosphodiesterase 1 gene (SMPD1). The estimated prevalence of ASMD is approximately 2,000 patients in the US, Europe and Japan.
ASMD represents a spectrum of disease caused by the same enzymatic deficiency, with two types that may represent opposite ends of a continuum sometimes referred to as NPD Type A and Type B. NPD Type A is a rapidly progressive neurological form of the disease resulting in death in early childhood due to central nervous system complications. NPD Type B is a serious and potentially life-threatening disease that predominantly, but not only, impacts the lungs, liver, spleen and heart. NPD Type A/B represents an intermediate form that includes varying degrees of neurologic involvement. Another type of NPD is NPD Type C, which is unrelated to ASMD.
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