RARE Daily

European Commission Approves First Treatment for ASMD

June 29, 2022

The European Commission approved Sanofi’s Xenpozyme (olipudase alfa) as the first and only enzyme replacement therapy for the treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency, also known as Niemann Pick disease, in pediatric and adult patients.

Photo: John Reed, executive vice president of Global Head of Research and Development for Sanofi

The approval for patients with ASMD type A/B or ASMD type B is based on positive data from the ASCEND and ASCEND-Peds clinical trials, in which Xenpozyme showed substantial and clinically relevant improvement in lung function (as measured by diffusing capacity of the lung for carbon monoxide, or DLco) and reduction of spleen and liver volumes, with a well-tolerated safety profile.

The EMA granted Xenpozyme PRIority MEdicines (PRIME) designation. In March 2022, Xenpozyme was approved in Japan under the SAKIGAKE (or “pioneer”) designation, marking the first approval for olipudase alfa anywhere in the world. In the United States, where olipudase alfa received Breakthrough Therapy designation, the U.S. Food and Drug Administration is currently reviewing olipudase alfa’s Biologics License Application, with a target action date for the FDA decision anticipated for October 2022.

ASMD is an extremely rare, progressive genetic disease with significant morbidity and mortality, especially among infants and children, as many pediatric patients will not survive to adulthood. Signs and symptoms of ASMD may include enlarged spleen or liver, difficulty breathing, lung infections, and unusual bruising or bleeding, among other disease manifestations. Current management of the disease includes palliative and supportive care to manage the symptoms.

Xenpozyme is an enzyme replacement therapy designed to replace deficient or defective acid sphingomyelinase (ASM), an enzyme that allows for the breakdown of the lipid sphingomyelin. In individuals with ASMD, the insufficient amount of the ASM enzyme means sphingomyelin is poorly metabolized, potentially leading to lifelong accumulation in and damage to multiple organs.

The ASCEND trial randomized 36 adult patients with ASMD type A/B or type B to receive Xenpozyme or placebo for 52 weeks (primary analysis), to evaluate the efficacy and safety of the drug. The study demonstrated that Xenpozyme improved lung function, assessed as the percent change from baseline to week 52 in predicted diffusing capacity of the lung for carbon monoxide (DLco), and reduced spleen size, evaluated as percent change from baseline in multiples of normal (MN) spleen volume.

Patients treated with Xenpozyme had improvement in DLco from baseline to week 52 of 22 percent compared to 3 percent for the patients in the placebo group. The difference between the two treatment arms (19%) was statistically significant.

Patients treated with Xenpozyme had reduction in spleen size by 39.5 percent at week 52 compared to increase by 0.5 percent for the patients in the placebo group. The difference between the two treatment arms (40 percent) was statistically significant.

All ASCEND patients treated with Xenpozyme showed improvement in one or both primary endpoints (DLco and spleen size reduction).

The incidence of adverse events (AEs) was similar in patients receiving Xenpozyme to that in patients receiving placebo. There were five serious AEs in the Xenpozyme arm and 11 in the placebo arm, none of which was treatment-related. There were no AEs that led to treatment discontinuation or study withdrawal. The most common AEs in the ASCEND trial were headache, nasopharyngitis, upper respiratory tract infection, cough, and arthralgia.

The single-arm ASCEND-Peds trial studied 20 pediatric patients with ASMD type A/B or type B who all received Xenpozyme, with a primary objective of evaluating the safety and tolerability of Xenpozyme for 64 weeks. All patients completed the study and continued in an extension trial. The ASCEND-Peds study also explored efficacy endpoints of progressive lung disease and of spleen and liver enlargement. After one year of treatment (52 weeks), the percent predicted DLco mean increase from baseline was 33 percent 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, the spleen volume mean decrease was 49 percent compared to baseline.

Over the 64-week treatment period, all ASCEND-Peds patients experienced at least one AE, which were mostly mild and moderate. Five treatment-related serious AEs 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 AE. The most common AEs in the ASCEND-Peds trial were pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, upper respiratory tract infection, contusion, abdominal pain, nasal congestion, rash, urticaria, scratch, and epistaxis.

“The ASMD community has waited many years for a treatment for this rare and debilitating genetic disease,” said John Reed, executive vice president of Global Head of Research and Development for Sanofi. “The approval of Xenpozyme by the European Commission represents a transformational shift in what we can offer to patients, demonstrated by the clinically important improvements across major manifestations of ASMD and the sustained effects noted over longer term treatment.”

Author: Rare Daily Staff

Stay Connected

Sign up for updates straight to your inbox.