Acid sphingomyelinase deficiency (ASMD) (historically known as Niemann-Pick disease [NPD] types A and B) is a rare, progressive, genetic lysosomal storage disease that results from reduced activity of the enzyme, acid sphingomyelinase (ASM), caused by pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. ASM breaks down a complex lipid called sphingomyelin that accumulates in the liver, spleen, lung, and brain. The deficiency of ASM causes an intralysosomal accumulation of sphingomyelin (as well as cholesterol and other cell membrane lipids) in various tissues. The diagnosis is confirmed when molecular genetic testing identifies both disease-causing alleles in SMPD1 or when residual ASM activity in peripheral blood leukocytes or cultured skin fibroblasts is less than 10 percent of controls. ASMD has an autosomal recessive pattern of inheritance, and the birth prevalence is estimated at 0.4–0.6/100,000. The most common clinical presentation for individuals with any form of ASMD is hepatosplenomegaly.
- NPD-A (infantile neurovisceral AMSD): The most severe form of ASMD characterized by rapidly progressive disease where there is little to no residual ASM activity. Individuals present with hepatosplenomegaly, interstitial lung disease, feeding difficulties, dyslipidemia, loss of early motor skills in the first few months of life, and may develop macular cherry-red spot. This subtype occurs with greater frequency in individuals of Ashkenazi Jewish descent. Death typically occurs before 2 or 3 years of age.
- NPD-A/B (chronic neurovisceral ASMD): The intermediate form of ASMA whose onset is during childhood. Individuals have a less severe, slower progression of neurological symptoms and prolonged survival compared to infantile neurovisceral ASMD. Ataxia, gross motor delays, and learning disabilities are commonly seen. Progressive multisystem disease manifestations are similar to or more severe than those observed in chronic visceral ASMD. Premature death occurs from liver and respiratory disease (age at death ranges from childhood to adulthood).
- NPD-B (chronic visceral ASMD): Later onset (childhood/adulthood) and less severe than NPD-A, with a good prognosis for survival into adulthood. Common clinical features in childhood include delayed growth and puberty, fatigue, and bone and joint pain. Most individuals with NPD-B have no neurologic abnormalities. Other abnormalities include dyslipidemia, osteopenia, and decreased platelet and white blood cell counts. Pulmonary function may worsen over time, and interstitial lung disease and pulmonary infections are common. The natural history is one of progressive hypersplenism and gradual deterioration of pulmonary function. Individuals may have a normal life span or die prematurely from disease complications that include respiratory failure, liver failure, and/or hemorrhage.
Olipudase alfa-rpcp (Xenpozyme) was approved by the US Food and Drug Administration (FDA) on August 31, 2022, for the treatment of non–central nervous system manifestations of ASMD in adult and pediatric individuals. Olipudase alfa-rpcp (Xenpozyme) is an enzyme replacement therapy that reduces sphingomyelin accumulation. It is not expected to cross the blood-brain barrier or modulate the CNS manifestations of ASMD. Prior to the approval of olipudase alfa-rpcp (Xenpozyme), the only option for treatment was supportive care (e.g., physical therapy, occupational therapy, nutritional support, supplemental oxygen, sedatives, transfusion of blood products, cholesterol-reducing agents).
PEER-REVIEWED LITERATURE
SUMMARY
Adult Individuals
The safety and efficacy of olipudase alfa-rpcp (Xenpozyme) was demonstrated in a multicenter, randomized, double-blinded, placebo-controlled, repeat-dose phase II/III trial (Trial 1: Wasserstein 2022: ASCEND trial) in 31 adults with ASMD (clinical diagnosis consistent with ASMD type B and A/B). Individuals received either olipudase alfa-rpcp (Xenpozyme) (dose escalation, then maintenance dose of 3 mg/kg) or placebo as an intravenous infusion once every 2 weeks. The trial was divided into two consecutive periods: a randomized, placebo-controlled, double-blinded primary analysis period (PAP) that lasted to Week 52, followed by an extension treatment period (ETP) for up to 4 years. Individuals randomly assigned to the placebo arm in the PAP crossed over to receive olipudase alfa-rpcp (Xenpozyme) treatment in the ETP to reach the targeted dose of 3 mg/kg, while individuals in the original olipudase alfa-rpcp (Xenpozyme) arm continued treatment. Individuals enrolled in the trial had a diffusion capacity of the lungs for carbon monoxide (DLco) ≤70% of the predicted normal value and a spleen volume ≥6 multiples of normal (MN) measured by magnetic resonance imaging (MRI). Five males and 13 females with a median age of 34 years (range, 18–66) were included in the placebo arm and eight males and five females with a median age of 34 years (range, 20–59) were included in the olipudase alfa-rpcp (Xenpozyme) arm. Key efficacy endpoints included assessment of % predicted DLco, spleen volume, liver volume, and platelet count. At Week 52 during the PAP, an increase of 21% in the mean percent change in % predicted DLco was observed in the olipudase alfa-rpcp (Xenpozyme) arm compared to the placebo arm (P=0.0003), demonstrating a clinically significant improvement in lung function. A reduction in spleen volume of 39% was observed in the olipudase alfa-rpcp (Xenpozyme) arm compared with the placebo arm (P<0.0001). The changes in % predicted DLco and spleen volume were noted at Week 26 of treatment, the first post-dose endpoint assessment. A decrease in mean liver volume and an increase in mean platelet count were noted in the olipudase alfa-rpcp (Xenpozyme) arm compared to the placebo arm at Week 52 (P<0.0001 and P=0.0280, respectively). The most common adverse reactions that occurred were headache and cough.
Seventeen of 18 individuals previously receiving placebo and 13 of 13 individuals previously treated with olipudase alfa-rpcp (Xenpozyme) for 52 weeks (in the PAP) started or continued treatment with olipudase alfa-rpcp (Xenpozyme), respectively, for up to 4 years. At Week 104, individuals initially randomly assigned to placebo had received olipudase alfa-rpcp (Xenpozyme) for 52 weeks and demonstrated the following percent changes in clinical parameters from baseline (before first administration of olipudase alfa-rpcp [Xenpozyme]): 26.8% increase in predicted DLco, 36.5% reduction in spleen volume, 29.5% reduction in liver volume, and 19.5% increase in platelet count. Individuals in the previous olipudase alfa-rpcp (Xenpozyme) group demonstrated improvement from baseline to Week 104 in the following parameters: 34.1% predicted DLco; 48.3% reduction in spleen volume, 31.7% reduction in liver volume, and 24% increase in platelet count.
Pediatric Individuals
The use of olipudase alfa-rpcp (Xenpozyme) for this indication is supported by evidence from an adequate and well-controlled trial (Trial 1) in adults with supportive efficacy, safety, and tolerability data in pediatric patients (Trial 2 and Trial 3). Compared to adults, a higher percentage of pediatric individuals experienced treatment-related serious adverse reactions, anaphylaxis, hypersensitivity reactions, and infusion-associated reactions that occurred within 24 hours of infusion. An 18 month old receiving olipudase alfa-rpcp (Xenpozyme) and a 16 month old with ASMD type A that received a version of olipudase alfa manufactured from a different process developed anaphylaxis. The most common adverse reactions in pediatric individuals were pyrexia, cough, diarrhea, and rhinitis.
64 Weeks Safety, 52 Weeks Efficacy
Olipudase alfa-rpcp (Xenpozyme) was evaluated in a multicenter, open-label, repeated-dose trial (Trial 2: Diaz 2021 ASCEND-Peds). Olipudase alfa-rpcp (Xenpozyme) was administered intravenously once every 2 weeks (by dose escalation, then maintenance dose of 3 mg/kg) for 64 weeks in eight pediatric individuals aged younger than 18 years (seven individuals from 2 to <12 years old, and one individual <2 years old) with a clinical diagnosis consistent with ASMD type B and A/B. Participants had a spleen volume of 5 or greater MN measured by MRI and height Z-score less than or equal to −1. Exploratory efficacy endpoints resulted in improvements in the following: 46.7% reduction in spleen volume, 38.1% reduction in liver volume, 45.9% mean percent change in % predicted DLco, 37.6% increased in mean platelet counts, and an increase in mean change in height Z-score of 0.5 at Week 52 as compared to baseline.
Long-term trial: 2.5 to 3.2 yearsThe eight pediatric individuals 2 to less than 12 years of age from Trial 2 continued treatment in an open-label long-term trial (Trial 3) and were treated with olipudase alfa-rpcp (Xenpozyme) for 2.5 to 3.2 years. Efficacy analyses showed continued improvements in the three individuals evaluated for % predicted DLco, six individuals evaluated for platelet counts, and all eight individuals evaluated for spleen and liver volumes, compared to baseline, during the additional 6 months extension. In addition, the height Z-score increased by 1.3 from baseline when evaluated through 24 months of olipudase alfa-rpcp (Xenpozyme) treatment. Bone age, as assessed by hand x-ray, was delayed by a mean of 26.4 months at baseline in the seven pediatric individuals enrolled in Trial 2 with a bone age measured at Month 24 in Trial 3. The bone age improved to within a mean of 12 months of the chronological age when assessed at Month 24 in these seven individuals.
OFF-LABEL INDICATION
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
