In 2 clinical trials, olipudase alfa (Sanofi Pharmaceuticals, Bridgewater, NJ), had efficacy for treatment of acid sphingomyelinase deficiency (ASMD) in adults and children. There are currently no treatments for ASMD, which is also known as Niemann Pick disease Type C. Olipudase alfa is the first and only investigational enzyme replacement therapy in late-stage development for the treatment of ASMD.
The measurement of 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 .5% increase in the placebo arm. The difference between the 2 treatment arms, 40%, was statistically significant (P<.0001).
For the US, the spleen volume was further combined with a participant-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=.7); 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 randomized phase 2/3 trial enrolled 36 adult participants with ASMD in 16 countries. Participants received placebo or olipudase alfa intravenous infusion biweekly at a dose of up to 3 mg/kg administered over 52 weeks.
All participants in both the placebo and olipudase alfa arms experienced at least 1 adverse event (AE), but fewer occurred with olipudase alfa, including severe adverse events (5 severe AEs vs 11). The most common AEs were headache, nasopharyngitis, upper respiratory tract infection, cough, and arthralgia.
In the single arm open-label phase 2 trial 20 children with ASMD who did not have rapidly progressive neurologic disease were treated witholipudase alfa (up to 3 mg/kg intravenously) every 2 weeks for 64 weeks. Over the 64 week treatment period, all participants experienced at least 1 adverse event, which were mostly mild and moderate, with 1 participant experiencing a severe and serious anaphylactic reaction considered related to olipudase alfa. The 5 treatment-related serious adverse events were observed in 3 participants: 2 cases of transient, asymptomatic alanine aminotransferase (ALT) increase in 1 participant, 1 case each of urticaria and rash in 1 participant, and 1 anaphylactic reaction in 1 participant. No participant permanently discontinued treatment due to nonserious adverse events, which most commonly were pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, upper respiratory tract infection, contusion, abdominal pain, nasal congestion, rash, urticaria, scratch, and epistaxis.
Crystal Dixon, MD, Miguel Melo-Bicchi, MD, and Kottil W. Rammohan, MD
Michael V. Robers, MD, Deepak Soneji, MD, PhD, and Lilyana Amezcua, MD, MS
Svetlana Primma Eckert, MD, Bianca Weinstock-Guttman, MD, and Stephen Krieger, MD