Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.

In 2018, the International Niemann-Pick Disease Alliance (INPDA) and the International Niemann-Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann-Pick disease type C (NPC)-an ultra-rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease-modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high-quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re-evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up-to-date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital-based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

Untreated women with Gaucher disease (GD) are at an increased risk of GD-related complications during pregnancy. Enzyme replacement therapy with imiglucerase is effective at improving hematologic, visceral, and bone manifestations of GD, and the Food & Drug Administration prescribing information supports that imiglucerase is not associated with adverse maternal or fetal outcomes when used during pregnancy. This study population included women with GD enrolled in the International Collaborative Gaucher Group Gaucher Registry (NCT00358943) Pregnancy Sub-Registry who were treated with imiglucerase during at least one pregnancy as of October 2023. We describe frequency of pregnancy outcomes, birth outcomes, and maternal and neonatal complications. Imiglucerase exposure was reported in 110 pregnancies in 68 women with GD type 1; 68% of pregnancies were exposed during all three trimesters. Of 104 fetuses with reported data, 92 were live births (88.5%), eight were spontaneous abortions (7.7%), and four were elective/therapeutic terminations (3.8%); no stillbirths (> 20 weeks gestation) were reported. The majority of infants (80 of 85 [94.1%]) were born at term. Among 108 pregnancies with data, maternal pregnancy, labor and delivery, and post-partum complications were reported for 33 (30.6%), 26 (24.1%), and 24 (22.2%) pregnancies, respectively, with anemia, thrombocytopenia, and vaginal bleeding among the most prevalent complications. Among 74 infants with data, neonatal complications were reported for seven infants (9.5%). Most pregnancies to women with GD treated with imiglucerase resulted in live births and healthy infants, with risk of spontaneous abortions similar to that of the general population (12%-18%).

BACKGROUND: The diagnosis of acid sphingomyelinase deficiency (ASMD, Niemann Pick Type A, A/B, B) is frequently delayed by years, because of its heterogeneous and often unspecific clinical features. The involvement of multiple organs including the musculoskeletal and central nervous systems, poses a challenge for accurate diagnosis. To address this, we developed a suspicion index tool (SIT) for healthcare professionals to enable early and accurate diagnosis of ASMD. METHODS: Our methodological approach encompasses five key steps: (i) literature research on ASMD symptomatology, (ii) retrospective expert chart review of international ASMD centers, (iii) retrospective statistical analysis, (iv) development of an individual risk prediction score via random forest regression, and multinomial modeling, (v) internal validation of the tool via bootstrap resampling. RESULTS: Data were collected from 908 patients (48 cases, 52 controls, and 808 non-cases) from eight expert centers. Visceral symptoms emerged as strong indicators of ASMD, particularly isolated unexplained splenomegaly (100% of cases vs. 71% of controls and 0.4% of non-cases) and hepatomegaly (92% of cases vs. 56% of controls and 0.4% of non-cases). Respiratory symptoms, thrombocytopenia, and hypercholesterolemia were also identified as significant indicators. These variables were selected for inclusion in the final SIT using a best subset selection algorithm. Each variable composition was evaluated via extensive repetitions. Additionally, expert input was sought to assess the significance of selected variables. The SIT demonstrated superior accuracy, sensitivity, specificity, and internal validity, confirming its reliability. CONCLUSIONS: The SIT is currently under development as a web-based platform for facilitating the diagnosis of ASMD and other treatable diseases in at-risk populations.

Background:Arimoclomol has been approved in the US for the treatment of Niemann-Pick disease type C (NPC) in patients aged ≥2 years, in combination with miglustat. This multicenter, open-label substudy of the phase 2/3 NPC-002 trial (NCT02612129) evaluated the safety, pharmacokinetics (PK) and impact on clinical status outcomes of arimoclomol in infants with NPC 6-<24 months of age. Methods:Infants with NPC aged 6-<24 months received arimoclomol in addition to their standard of care management for up to 36 months. The dosing regimen used for patients <24 months differed from the regimen recommended in the FDA label. The primary endpoint was safety and tolerability of arimoclomol; secondary endpoints were changes in clinical status (physical examination and Bayley III developmental scores), biomarkers, and PK. Results:Five patients (three females, two males; aged 14-23 months at screening) were enrolled; four remained in the study >12 months; arimoclomol exposure ranged from 72 to 1109 days. All patients received concomitant miglustat. Across 108 reported adverse events (AEs), most were considered mild or moderate in severity and non-serious. A total of 15 serious AEs were reported for two patients. Two AEs in one patient (elevated alanine/aspartate aminotransferases) were considered probably related to arimoclomol and resolved within 51 days; the patient was withdrawn from the substudy. No clinically significant changes were observed in hematology, kidney ultrasound imaging, or vital signs. Mean arimoclomol exposure over the first 8 h post-dose (1378.3-2988 h∙μg/L) was comparable to levels in NPC patients aged 2-19 years. Changes in Bayley III scores and biomarkers varied between individuals. Conclusion:Arimoclomol was well tolerated in infants initiating treatment before 2 years of age, with no new safety signals. PK profiles support the dosing regimen used. These findings suggest that early initiation of arimoclomol could be considered for the 6-24-month population. Further investigation in larger cohorts is warranted to elucidate the impact of arimoclomol in NPC patients under 2 years of age.

Background:In the 12-month, randomized, double-blind, placebo-controlled Phase 2/3 NPC-002 study (NCT02612129), arimoclomol significantly reduced annual disease progression versus placebo, measured by the 5-domain NPC Clinical Severity Scale (5DNPCCSS). Arimoclomol has been approved in the US for treatment of Niemann-Pick disease type C (NPC) in combination with miglustat. This paper introduces the rescored 4-domain NPCCSS (R4DNPCCSS) as a post-hoc primary endpoint in NPC-002, discusses its validation, and presents the results of the post-hoc primary analysis. Methods:To more accurately assess changes in disease course over a 12-month time period in a heterogeneous group of patients, the Cognition domain was removed from the 5DNPCCSS and the Swallow domain was rescored to reflect linearity in disease progression. Rescoring of the Swallow domain was based on input from clinical NPC and swallow experts from a qualitative interview-based study (N = 12), resulting in the R4DNPCCSS. To supplement prior validation analyses, data supporting the overall validity and reliability of the R4DNPCCSS was gathered through additional analyses of construct and convergent validity. The NPC-002 prespecified primary efficacy endpoint analysis based on the 5DNPCCSS score change from baseline to 12 months was repeated with R4DNPCCSS. Results:Construct validity analysis demonstrated high agreement between the R4DNPCCSS domain scores and the Clinical Global Impression Scale of Severity (CGI-S) and NPC Clinical Database (NPC-cdb) scores. Convergent validity was confirmed by strong correlations between the R4DNPCCSS domains and corresponding items on the Scale for Assessment and Rating of Ataxia (SARA), 9-hole peg test (9-HPT), and Video Fluoroscopic Swallowing Study (VFSS) performance tests. The NPC-002 post-hoc primary analysis showed a mean standard error (SE) change in R4DNPCCSS score of 0.35 (0.40) with arimoclomol (N = 34) versus 2.05 (0.54) with placebo (N = 16), and a treatment effect in favor of arimoclomol over placebo of -1.70 (p = 0.0155). In the miglustat subgroup analysis, mean (SE) change in R4DNPCCSS score was -0.23 (1.02) with arimoclomol (N = 22) versus 1.92 (3.37) with placebo (N = 12), representing a treatment effect of -2.21 (p = 0.0077). Conclusion:The R4DNPCCSS is a valid and reliable measure of disease progression demonstrating consistent outcomes with the prespecified 5DNPCCSS endpoint. Arimoclomol significantly slowed disease progression through 12 months as measured by the R4DNPCCSS versus placebo.

Gaucher disease type 3 (GD3) is a lysosomal storage disease characterized by diverse neurological and systemic manifestations. Symptoms of ataxia, cognitive impairment, and other systemic symptoms profoundly impact daily activities and the quality of life for individuals living with the disease. Development of a conceptual model of disease for persons living with GD3 from birth to adulthood would enable objective monitoring of disease progression and assessment of treatment benefits. A targeted literature review, interviews with clinical experts, and interviews with individuals and their caregivers living in the UK and the US were carried out to understand the patient experience. Interviews were transcribed and de-identified data were analyzed to identify signs, symptoms, and impacts of ataxia, cognitive impairment, and other systemic impairments. A conceptual model was developed by integrating relevant signs, symptoms, and impacts experienced from birth through adulthood. Review of symptoms and impacts of GD3 from three published scientific articles, and interviews with six clinical experts, 12 individuals living with GD3, and 12 caregivers, identified 58 patient experience concepts associated with GD3. Signs and symptoms associated with ataxia appear during the first 3 years of life and persist beyond 5 years of age, while signs and symptoms related to neurocognition appear later in life. Difficulty in shifting gaze and/or tracking objects, ataxia, tremors, memory problems, difficulty in processing new information, fatigue, and bone pain are most salient concepts for GD3. In patients aged ≤ 5 years, motor manifestations and symptoms were far more prevalent than neurocognitive signs and symptoms. Inability to work or perform at school, limited social and family engagements, restricted mobility (walking, driving, public transportation), and declining independence were the most important impacts on individuals with GD3. Heterogeneity exists in GD3 manifestations, especially neuromuscular and neurocognitive signs, symptoms, and impacts, across all age ranges of individuals living with GD3. The conceptual model developed in the study provided a comprehensive understanding of the disease in individuals with GD3.