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Approval of Levacetylleucine as a new treatment for Niemann-Pick type C disease

EMA has recommended granting a marketing authorisation in the European Union for Levacetylleucine for the treatment of neurological manifestations in NPC patients 6 years and older and weighing at least 20 kg, based on the positive results of a phase III, randomized, double-blind, placebo-controlled, two-period crossover trial including 60 patients with NPC.

Niemann–Pick disease type C (NPC) is an autosomal recessive, lysosomal storage disorder with a clinical spectrum that ranges from a neonatal, rapidly progressive and fatal disorder to an adult-onset, chronic neurodegenerative disease (1).
Recent trials have demonstrated that the modified amino acid Levacetylleucine (N-acetyl-l-leucine) improves clinical signs and symptoms in NPC patients (2).
Levacetylleucine is transported into cells via monocarboxylate transporters, which are ubiquitously expressed and facilitate its passage across the blood–brain barrier. At the intracellular level, Levacetylleucine is incorporated into enzyme-regulated metabolic pathways, contributing to the restoration of impaired bioenergetics and enhancement of adenosine triphosphate (ATP) production. Given the close functional interplay between mitochondrial and lysosomal pathways, normalization of energy metabolism secondarily ameliorates lysosomal dysfunction, thereby reducing the pathological accumulation of unesterified cholesterol and sphingolipids (2).
The efficacy and safety of Levacetylleucine were investigated in a phase III, randomized, double-blind, placebo-controlled, two-period crossover trial including 60 patients with NPC, aged 5 to 67 years. After 12 weeks of treatment, patients receiving Levacetylleucine demonstrated significant neurological improvement, as reflected by a mean (±SD) change from baseline in the Scale for the Assessment and Rating of Ataxia (SARA) score of −1.97±2.43, compared with −0.60±2.39 in the placebo group. The least-squares mean difference was −1.28 points (95% CI, −1.91 to −0.65; P<0.001) (2).
As secondary endpoints, the aforementioned trial also included the modified Disability Rating Scale (mDRS), the Spinocerebellar Ataxia Functional Index (SCAFI), the Clinical Global Impression of Improvement (CGI-I) scale, the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L), and, for the pediatric population, the visual-analogue scale (EQ-5D-Y), whose results generally aligned with the primary analysis findings; however, they were not adjusted for multiple comparisons (2).
Importantly, efficacy and safety in the pediatric population were established only in patients weighing ≥15 kg (3).
Adverse event incidence was comparable between the Levacetylleucine and placebo groups, and no treatment-related serious adverse events were observed (2). The most frequently reported adverse reactions (≥5% incidence and greater than placebo) included abdominal pain, dysphagia, upper respiratory tract infections, and vomiting (3).
Based on these findings, the U.S. Food and Drug Administration (FDA) approved Levacetylleucine in 2024 for the treatment of neurological manifestations of NPC in adult and pediatric patients weighing at least 15 kg (3). In July 2025, the European Medicines Agency (EMA) recommended marketing authorisation for Levacetylleucine in the European Union for patients aged ≥6 years and weighing ≥20 kg.
Until this recent approval, miglustat, a substrate reduction therapy for glycosphingolipid lysosomal storage disorders, had remained the only treatment authorised in the European Union for NPC.

Key Points:

  • EMA has recommended granting a marketing authorisation in the European Union for Levacetylleucine for the treatment of neurological manifestations in NPC patients aged 6 years and older and weighing at least 20 kg.
  • Treatment with Levacetylleucine, administered over 12 weeks, improved neurologic signs and symptoms, with a difference of -1.28 points in SARA total score from baseline compared to placebo.
  • Levacetylleucine demonstrated a favourable safety profile, with a low incidence of treatment-related adverse events.

References:

  1. Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Marfa MP, et al. Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis. 2018 Dec;13(1):50.
  2. Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, et al. Trial of N-Acetyl-l-Leucine in Niemann–Pick Disease Type C. N Engl J Med. 2024 Feb;390(5):421–31.
  3. Levacetylleucine FDA Prescribing Information [Internet]. [cited 2025 Aug 20]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/219132s000lbl.pdf

Co Author(s):

  • Kailash Bhatia, UCL Queen Square Institute of Neurology, University College London
  • Michelangelo Mancuso, Neurological Institute, University of Pisa

Publish on behalf of the Coordinating Panel on Rare Neurological Disease

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