Regulatory news: Olipudase alfa-rpcp (Xenpozyme™) for treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients—FDA Approval summary

Acid Sphingomyelinase Deficiency (ASMD) is a rare genetic disease that is caused by biallelic pathogenic variants in the SMPD1 gene, leading to a deficiency in the activity of the lysosomal enzyme acid sphingomyelinase (ASM) that catabolizes sphingomyelin (SPM). SPM is a major component of cell membranes and a principal phospholipid of the myelin sheath. Deficiency of ASM leads to the accumulation of SPM and secondary increases in cholesterol and other metabolically related lipids.¹ Organ systems affected include the central nervous system (CNS), liver, spleen, lymph nodes, adrenal cortex, lung airways, and bone marrow. The estimated prevalence of ASMD is 0.4 to 0.6 per 100 000 live births.^{2, 3}

Clinically, ASMD can be broadly categorized into three subtypes. Type A is an early-onset severe disease that is characterized by failure to thrive, hepatosplenomegaly, interstitial lung disease (ILD), and rapidly progressive neurodegenerative disease. Type B is a later onset, less severe disease characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and an atherogenic lipid profile. No CNS manifestations occur in ASMD Type B. ASMD type A/B, an intermediate form between type A and type B, is characterized by presence of some CNS manifestations, hepatosplenomegaly, ILD, dyslipidemia, osteopenia, and thrombocytopenia.⁴ Patients with ASMD were managed primarily with supportive therapies prior to approval of olipudase alfa-rpcp on August 31, 2022.

Olipudase alfa-rpcp, a recombinant human ASM, is an enzyme replacement therapy indicated for the treatment of non-CNS manifestations of ASMD in pediatric and adult patients. Olipudase alfa-rpcp is not expected to cross the blood–brain barrier to treat the CNS manifestations of ASMD. It is administered as an intravenous infusion every two weeks (Q2W), with a recommended starting dose of 0.1 mg/kg in adults and 0.03 mg/kg in pediatric patients. The dose is gradually escalated to a recommended maintenance dose of 3 mg/kg over 14 and 16 weeks in adult and pediatric patients, respectively. The dose-escalation regimens provide a gradual “debulking” of SPM and gradual release of ceramide to decrease the potential inflammatory response and adverse reactions that were observed following single-dose administration of olipudase alfa-rpcp in ASM knockout mice and in the first-in-human clinical trial.⁵

Substantial evidence of effectiveness for olipudase alfa-rpcp in ASMD patients was established with one adequate and well-controlled trial with confirmatory evidence.^{8, 9} The efficacy of olipudase alfa-rpcp was demonstrated by a statistically significant improvement in DLco in 13 adult patients with ASMD type B on treatment compared to 18 patients on placebo. Efficacy in the pediatric population relied upon partial extrapolation of efficacy from the adequate and well-controlled study in adults, as well as supportive evidence of efficacy including reductions in organ volumes and an increase in % predicted DLco in an open-label single arm trial in 8 pediatric subjects with type B or type A/B.¹⁰ Confirmatory evidence included well-established ASMD etiology, olipudase alfa-rpcp targeted mechanism of action, and pharmacodynamic biomarker data showing reductions in plasma ceramide and lysosphingomyelin.¹⁰ While the neurological manifestations differ among ASMD types A, B, and A/B, similar non-CNS manifestations are observed in all these disease phenotypes. Due to the mechanism of action of olipudase alfa-rpcp, similar improvements in lung function and liver volume are expected across phenotypes.

Adverse drug reactions associated with the use of olipudase alfa-rpcp are hypersensitivity reactions including anaphylaxis and IARs, APRs, and elevation of liver transaminases during the dose escalation phase. There is a potential for an adverse impact on pregnancy with dose initiation and escalation of olipudase alfa-rpcp. These risks are mitigated through dose escalation, modification, and discontinuation as described in the Warnings and Precautions section of the labeling.¹¹ With these dose mitigation strategies, the benefits of olipudase alfa-rpcp outweigh the risks for adult and pediatric patients with ASMD who have non-CNS manifestations in the context of this rare disease with significant unmet medical need.

The authors declare no conflicts of interest.

The authors report no financial interests or relationships with the commercial sponsor of the product discussed in this report.