2020-01-31| Trials & Approvals

First Sanofi Designed Investigational Enzyme Replacement Therapy for ASMD Gets Green Signal in Phase II/III Trial

by Ruchi Jhonsa
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By Ruchi Jhonsa, Ph.D.

Nieman-Pick Disease

ASMD or Niemann-Pick Disease refers to a group of disorders caused by an autosomal recessive mutation in the acid sphingomyelinase gene (ASM) responsible for digesting sphingolipids. The deficiency of this enzyme results in the accumulation of lipids mostly sphingomyelin and cholesterol in different organs such as the brain, spleen, liver, lungs and bone marrow that leads to cell death and organ malfunction. It is estimated to affect nearly 2000 people in the US. Europe and Japan. Currently, there are no approved treatments for NP.

Olipudase Alfa: First Investigational Therapy for NP

In the beginning, Niemann-Pick patients were treated with anti-depressants and anti-epileptic medicines to relieve the symptoms. Effects of drugs like Miglustat and hydroxypropyl-B-cyclodextrin that delay neurological manifestations along with cholesterol-lowering drugs like lovastatin, cholestyramine, and nicotinic acid were also investigated. Unfortunately, to date, there is no consensus on the outcome of different studies using these drugs.

Trials are now underway for the first Sanofi developed investigational enzyme replacement therapy known as Olipudase Alfa, which is designed to replace deficient or defective ASM. The good news is, it is working. Based on the data from the phase 1b study conducted in 2015, the FDA gave Olipudase alfa a breakthrough therapy designation, the European Medicines Agency has awarded it PRIME designation and the Japanese regulatory body granted SAKIGAKE designation to the drug. In phase II/III trial this year, olipudase alfa has shown a positive outcome by successfully meeting the endpoints.

The Clinical Data Supporting Olipudase Alfa

In a randomized phase II/III, ASCEND trial that included 36 adults in 24 centers in 16 countries, olipudase alfa was administered intravenously every two weeks for a year. Two primary efficacy endpoints were tested that included lung function and spleen volume to address prominent clinical manifestation of ASMD i.e. progressive lung disease and an enlarged spleen. The patient cohort that received the drug showed a 22% improvement from baseline in a measure of lung function in comparison to the placebo cohort that only showed a 3% improvement. Moreover, spleen volume reduced by 39.5% over the course of the clinical trial in patients receiving the drug in comparison to a 0.5% increase in the control group. These figures positively support phase I clinical trial results in which Sanofi linked enzyme replacement therapy to a 23% fall in spleen volume and 24% improvement in lung function.

However, in the U.S., Sanofi missed an endpoint that combined spleen volume data with patient-reported outcome of symptoms associated with enlarged spleen called Splenomegaly Related Score or SRS. In patients receiving the drug, SRS was reduced by 8.0 points whereas in the placebo group it reduced by 9.3 points.

Over a period of a one-year trial, all patients in both the placebo group and the drug group experienced one adverse event. However, the number of adverse events was lower for drug-treated patients (242 events) as compared to placebo (267 events).

The trial was also conducted in 20 pediatric patients with a primary objective to evaluate the safety and tolerability of olipudase alfa. Over the 64-week treatment, all patients experienced one adverse event. All the patients experienced mild reaction but one who experienced serious anaphylactic reaction due to the drug. Nevertheless, none of the patients had to discontinue the trial sue to adverse events.

“These are important data in a disease with no approved treatments available currently” said Melissa Wasserstain, MD, Chief, Division of Pediatric Genetic Medicine and an investigator in the ASCEND trial. With a positive turnaround in phase 2/3 trial, Sanofi plans to submit the results to future medical meetings and expects to start the global regulatory submissions in the second half of 2021.


  2. Santos-Lozano et al., 2015 Ann Transl Med.


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