Comparative Effectiveness of N-Acetyl-L-Leucine vs. Standard of Care and Arimoclomol in Niemann-Pick Disease Type C Using Matched-Adjusted Indirect Comparison
Author(s)
Marc Patterson, MD1, Mohit Jain, PhD MBA1, Ian Billington, PhD1, Tatiana Bremova-Ertl, MD2.
1IntraBio PLC, Austin, TX, USA, 2Department of Neurology, University Hospital Bern (Inselspital), Bern, Switzerland.
1IntraBio PLC, Austin, TX, USA, 2Department of Neurology, University Hospital Bern (Inselspital), Bern, Switzerland.
OBJECTIVES: Niemann-Pick disease type C (NPC) is a rare neurodegenerative lysosomal storage disorder with few treatment options. N-Acetyl-L-Leucine (NALL) demonstrated statistically significant reduction in disease progression in the pivotal phase 3 IB1001-301 trial , yet comparative effectiveness data are limited for longer term outcomes. As HTA methods increasingly recommend indirect comparisons, here we explore their application in NPC. Objective is to assess the effectiveness of NALL versus standard-of-care (SoC) and arimoclomol using matched-adjusted indirect comparison (MAIC) methodology. The analysis considered key confounding covariates aligned with clinical experts and literature.
METHODS: Individual-level data from the IB1001-301 extension trial with NALL were reweighted to match baseline characteristics of comparators from published SoC, placebo and active arm from the arimoclomol pivotal study. The primary outcome was change from baseline in the 5-domain NPC Clinical Severity Scale (NPC-CSS) over 12 months, covariates controlled for in matching included baseline severity, stage of diagnosis, sex and ‘miglustat use’. Sensitivity analysis explored additional covariates and outcomes.
RESULTS: Unweighted IB1001-301 individual data showed a mean change from baseline of -0.32 in NPC-CSS with NALL in 12 months, compared to +1.5 (SoC arm), +2.15 (placebo arm), and +0.76 (arimoclomol arm), a change of 1 point is clinically meaningful. In the base-case MAIC weighted analysis, NALL showed a mean change to baseline of -0.38 matched to SoC (Neffective=25.85), -0.30 matched to placebo (Neffective =27.81), and -0.44 matched to arimoclomol (Neffective =31.56). These improvements in the MAIC were confirmed relative to natural history (mean difference -1.88±2.27, p<0.0125), placebo (mean difference -2.45±2.27, p<0.0013), and arimoclomol (mean difference -1.21±2.53, p=0.051). Sensitivity analyses supported the robustness of findings.
CONCLUSIONS: These findings support the potential of NALL to be the only treatment which offers neuroprotection and meaningfully changes of disease progression in NPC in 12 months. For rare diseases, considering confounders carefully and sensitivity analysis is critical.
METHODS: Individual-level data from the IB1001-301 extension trial with NALL were reweighted to match baseline characteristics of comparators from published SoC, placebo and active arm from the arimoclomol pivotal study. The primary outcome was change from baseline in the 5-domain NPC Clinical Severity Scale (NPC-CSS) over 12 months, covariates controlled for in matching included baseline severity, stage of diagnosis, sex and ‘miglustat use’. Sensitivity analysis explored additional covariates and outcomes.
RESULTS: Unweighted IB1001-301 individual data showed a mean change from baseline of -0.32 in NPC-CSS with NALL in 12 months, compared to +1.5 (SoC arm), +2.15 (placebo arm), and +0.76 (arimoclomol arm), a change of 1 point is clinically meaningful. In the base-case MAIC weighted analysis, NALL showed a mean change to baseline of -0.38 matched to SoC (Neffective=25.85), -0.30 matched to placebo (Neffective =27.81), and -0.44 matched to arimoclomol (Neffective =31.56). These improvements in the MAIC were confirmed relative to natural history (mean difference -1.88±2.27, p<0.0125), placebo (mean difference -2.45±2.27, p<0.0013), and arimoclomol (mean difference -1.21±2.53, p=0.051). Sensitivity analyses supported the robustness of findings.
CONCLUSIONS: These findings support the potential of NALL to be the only treatment which offers neuroprotection and meaningfully changes of disease progression in NPC in 12 months. For rare diseases, considering confounders carefully and sensitivity analysis is critical.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
SA20
Topic
Clinical Outcomes, Economic Evaluation, Study Approaches
Topic Subcategory
Meta-Analysis & Indirect Comparisons
Disease
Neurological Disorders, Rare & Orphan Diseases