Sanofi reported positive results from two phase 3 trials of olipudase alfa, an investigational recombinant human acid sphingomyelinase, for the treatment of acid sphingomyelinase deficiency (ASMD), also known as Nieman-Pick disease, in adult and pediatric patients. Data demonstrated positive results in the two separate clinical trials, referred to as ASCEND and ASCEND-Peds. 

ASCEND was a randomized Phase 2/3 trial and 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 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. 

For the U.S., 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; therefore, this combination endpoint was not met. 

The most frequent adverse events were headache, nasopharyngitis, upper respiratory tract infection, cough, and arthralgia.

ASCEND-Peds was a single arm, open label Phase 2 trial and enrolled 20 pediatric patients (birth to <18 years) with ASMD in six countries. 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. 

Over the 64-week treatment period, all patients experienced at least one adverse event. These events were mostly mild and moderate, with one patient experiencing a severe and serious anaphylactic reaction that was considered related to olipudase alfa. Five treatment-related serious adverse events were observed in three patients: two cases of transient, asymptomatic alanine aminotransferase (ALT) increase in one patient, one case each of urticaria and rash in one patient, and one anaphylactic reaction in one patient. No patients had to permanently discontinue treatment due to an adverse event. The most common adverse events were pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, upper respiratory tract infection, contusion, abdominal pain, nasal congestion, rash, urticaria, scratch, and epistaxis.

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.

About Olipudase alfa

Olipudase alfa is an enzyme replacement therapy designed to replace deficient or defective ASM, allowing for the breakdown of sphingomyelin. 

The FDA has granted Breakthrough Therapy designation to olipudase alfa. In addition, olipudase alfa has been awarded PRIority MEdicines, also known as PRIME, designation from the EMA and SAKIGAKE designation in Japan.

About ASMD

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 U.S., 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. 

Source: Sanofi

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