Objective To investigate the safety and efficacy of N-acetyl-l-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) patients. Methods In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results 33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. Clinicaltrials.gov identifier NCT03759639.

Mutations in the voltage-gated sodium channel na v 1.1 (SCN1A) are linked to various epileptic phenotypes with different severities, however, the consequences of newly identified SCN1A variants on patient phenotype is uncertain so far. The functional impact of nine SCN1A variants, including five novel variants identified in this study, was studied using whole-cell patch-clamp recordings measurement of mutant na v 1.1 channels expressed in HEK293T mammalian cells. E78X, W384X, E1587K, and R1596C channels failed to produce measurable sodium currents, indicating complete loss of channel function. E788K and M909K variants resulted in partial loss of function by exhibiting reduced current density, depolarizing shifts of the activation and hyperpolarizing shifts of the inactivation curves, and slower recovery from inactivation. Hyperpolarizing shifts of the activation and inactivation curves were observed in D249E channels along with slower recovery from inactivation. Slower recovery from inactivation was observed in E78D and T1934I with reduced current density in T1934I channels. Various functional effects were observed with the lack of sodium current being mainly associated with severe phenotypes and milder symptoms with less damaging channel alteration. In vitro functional analysis is thus fundamental for elucidation of the molecular mechanisms of epilepsy, to guide patients' treatment, and finally indicate misdiagnosis of SCN1A related epilepsies.

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BackgroundNiemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative disorder characterized by symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in observational case studies and animal and cellular models of NPC. Therefore, the effects of the active L-enantiomer, N-acetyl-L-leucine (NALL, Sponsor Code IB1001) were evaluated in paediatric and adult patients with NPC.MethodsWe conducted a 9-center, multinational, open-label, rater-blinded Phase 2 study to assess the safety and efficacy of NALL for the treatment of pediatric (≥ 6 years) and adult patients with NPC (IB1001-201 clinical trial). Eligible patients were assessed during three study phases: a baseline period (with or without a study run-in), a 6-week treatment period (dosage of NALL 4 g/d in patients aged ≥13 years; weight tiered doses for patients aged 6-12 years based on approximately 0.1 g/kg/day), and a 6-week post-treatment washout period. The primary outcome was based on the Clinical Impression of Change in Severity (CI-CS) assessment (assessed on a 7-point Likert scale) performed by blinded, centralized raters who compared videos of patients performing a pre-defined primary anchor test (either the 8-Meter Walk Test (8MWT) or 9-Hole Peg Test of the Dominant Hand (9HPT-D)) at different study periods. Secondary outcomes included the cerebellar function evaluations, namely the Scale for Assessment and Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI), and the Clinical Global Impression Scales (CGI) as well as the EuroQol-5D/VAS.ResultsThirty-three subjects aged 7 to 64 years with a confirmed diagnosis of NPC were enrolled according to the trial protocol between 04 September 2019 and 30 January 2020. Thirty-two patients were included in the modified intention-to-treat analysis. IB1001 met its CI-CS primary endpoint (mean difference 0.86 ((90% CI 0.25,1.75, p=0.029). IB1001 also met secondary endpoints, including improvement during treatment on the SARA scale (mean difference −1.19 (90% CI −1.8, −0.5, p=0.001)), investigator’s CGI-C assessment (mean difference from baseline to the end of treatment 0.6 (90% CI 0.5, 1.0, p<0.001)), clinically worsening over the washout period on the SARA (mean difference 1.45 (90% CI 0.5, 2.0, p=0.002)) and investigator’s CGI-C assessment (washout mean difference −0.5 (90% CI −1.0, 0.0, p=0.006). IB1001 was well-tolerated with no treatment related serious adverse reactions occurring.ConclusionsConsistent with its pharmacological action, IB1001 rapidly improved symptoms, functioning, and quality of life in 6-weeks, the clinical effect of which was lost after the 6-week, post-treatment washout period. High consistency and statistical significance between the primary and secondary endpoints demonstrate a clear, clinically meaningful improvement with IB1001. IB1001 was well-tolerated and no drug-related serious adverse events were reported, demonstrating a favorable risk/benefit profile for the treatment of NPC (Funded by IntraBio; ClinicalTrials.gov number, NCT03759639; EudraCT number 2018-004331-71).

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