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

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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 The efficacy of the to-be-marketed formulation of olipudase alfa-rpcp was assessed in a single adequate and well-controlled trial consisting of a 52-week, randomized, double-blinded, placebo-controlled primary analysis period and an open-label extension treatment period in 31 adult patients (13 active treatment, 18 placebo) with ASMD type B. The co-primary efficacy endpoints included the diffusion capacity of the lungs for carbon monoxide (DLco) and a combination endpoint consisting of spleen volume and splenomegaly-related score (SRS), a patient-reported outcome (PRO) measurement derived from patients with myelofibrosis. Olipudase alfa-rpcp was started at a low dose and escalated up to a maintenance dose of 3 mg/kg. At Week 52, the least squares (LS) mean percentage (%) change from baseline in % predicated DLco was 24% in olipudase alfa-rpcp-treated patients compared to 3% in placebo-treated patients (p<0.0001). An LS mean reduction of 39% from baseline in spleen volume was observed in the active treatment group compared to an LS mean increase of 0.5% in the placebo group. The SRS component did not show an advantage for subjects treated with olipudase alfa-rpcp over placebo; this may be due to an insensitive PRO and the differences in disease characteristics between the ASMD and myelofibrosis patient populations. At Week 104, patients who initially randomized to placebo and then received olipudase alfa-rpcp demonstrated a 27% LS mean increase in % predicated DLco and a 37% LS mean reduction in spleen volume from baseline. Patients who randomized and continued to receive olipudase alfa-rpcp demonstrated an LS mean increase of 34% in % predicted DLco and an LS mean decrease of 48% in spleen volume from baseline. The efficacy of the to-be-marketed formulation of olipudase alfa-rpcp was evaluated in 8 pediatric patients aged 1–10 years old with ASMD type B or type A/B, in a 64-week open-label single-arm trial, followed by a long-term extension trial. The mean % reduction in spleen and liver volumes from baseline to Week 52 was 46.7% and 37.3% (n = 8 for both), respectively. The mean percentage increase in % predicted DLco from baseline to Week 52 was 50.6% (n = 3). The mean height Z-score increased by 1.3 from baseline to Month 24 (n = 8). Bone age was delayed by a mean of 26.4 months at baseline and improved to within a mean of 12 months of the chronological age at Month 24 (n = 7). The safety of olipudase alfa-rpcp was assessed using data from three clinical trials in 30 adult patients with ASMD type B receiving 0.4–3.7 years and 8 pediatric patients with type B or type A/B receiving 2.5–3.2 years of treatment. Anaphylaxis was reported in two patients <2 years of age. One of the two patients participated in the pediatric trial; the other patient had ASMD type A and received a version of olipudase alfa manufactured from a different process in the expanded access program. Anti-olipudase alfa-rpcp IgE and IgG antibodies were detected in both patients. Protocol-defined infusion-associated reactions (IARs) were reported in approximately 75% of pediatric and 50% of adult patients. The most frequent IARs included headache, pruritus, urticaria, erythema, nausea, and vomiting. Acute phase reaction (APR) was observed in one adult and one pediatric subject. Elevation in alanine aminotransferase, asparate aminotransferase, or both occurring within 24–48 h after infusion was reported in 13% each of adult and pediatric patients during the dose escalation phase. At the time of the next scheduled infusion, these elevated transaminase levels generally returned to levels observed prior to the olipudase alfa-rpcp infusion. Olipudase alfa-rpcp is not expected to cross the human placenta. However, early embryonic exposure to ceramide (an SPM metabolite) or the sphingosine-1-phosphate receptor modulator fingolimod can produce exencephaly in chicks and mice, respectively.6, 7 Because elevated SPM metabolite levels occur during the dose escalation phase of olipudase alfa-rpcp, and there is an elevated risk of serious hypersensitivity reactions and the potential resultant adverse impact on the pregnancy with dose initiation/escalation, treatment initiation or escalation of olipudase alfa-rpcp is not recommended at any time during pregnancy. 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

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