Rare Daily Staff

Sanofi reported that its experimental enzyme replacement therapy demonstrated positive results in two separate clinical trials evaluating olipudase alfa for the treatment of acid sphingomyelinase deficiency in adult and pediatric patients.

Acid sphingomyelinase deficiency (ASMD) is also known 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 deficiency 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 United States, Europe, and Japan.

“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, global head of research and development at Sanofi.

Olipudase alfa is an experimental enzyme replacement therapy designed to replace deficient or defective ASM, allowing for the breakdown of sphingomyelin. Olipudase alfa is currently being investigated to treat ASMD Type A/B and B, which predominantly impact the lungs, liver, spleen, and heart. It is not being studied in Type A, which is a neurological form of the disease resulting death in early childhood due to central nervous system complications. Another type of NPD-NPD Type C—is unrelated to ASMD.

The ASCEND phase 2/3 randomized trial of 36 adult patients with ASMD met its two primary endpoints of improved lung function and spleen size, both of which address separate critical manifestations of the condition: lung disease and enlarged spleen.

Patients who received the drug saw a 22 percent improvement in lung function after 52 weeks compared to a 3 percent improvement in the placebo arm. Spleen volume was reduced by 39.5 percent in patients who received olipudase alfa compared to a 0.5 percent increase in the placebo arm.

For patients in the United States, the spleen volume endpoint was further combined with a patient-reported outcome 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, an anomaly that trial investigator Melissa Wasserstein said warrants further exploration considering the clinical meaningfulness of the study results.

Over the 52-week period, all patients in both the placebo and olipudase alfa arms experienced at least one adverse event, and patients in the treatment arm experienced less events than in the placebo arm.  There were no adverse events that led to treatment discontinuation or study withdrawal. The most common adverse events seen in this trial were headache, nasopharyngitis, upper respiratory tract infection, cough, and arthralgia.

The second trial was a single arm, open label phase 2 trial that enrolled 20 pediatric patients from birth to 18 years of age with ASMD. Children with rapidly progressive neurological disease were excluded. The primary objective of the trial was to evaluate the safety and tolerability of olipudase alfa for 64 weeks.

Over the 64-week treatment period, all patients experienced at least one adverse event, with three patients experiencing serious adverse events including one patient having a severe and serious anaphylactic reaction that was considered related to olipudase alfa. But no patients had to permanently discontinue treatment due to an adverse event.

The pediatric study also explored secondary endpoints of progressive lung disease and enlarged spleen. After one year of treatment , lung function increased by a mean of 33 percent  in nine patients who were able to perform the test at baseline, and spleen volumes decreased by a mean of 49 percent.

Sanofi plans to submit results from these trials to future medical meetings and says they will form the basis of global regulatory submissions expected to begin the second half of 2021.

Olipudase alfa has Breakthrough Therapy designation in the U.S, PRIME designation in the European Union, and SAKIGAKE designation in Japan, all of which are designed to expedite the development and review of drugs intended to treat serious or life-threatening diseases or conditions.

Photo: John Reed, global head of research and development, Sanofi

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