A master protocol to investigate a novel therapy acetyl-l-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia

Abstract

Background The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients’ high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-l-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; “GM2”), and ataxia telangiectasia (A-T). Methods/design The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient’s functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient’s neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-l-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase. Discussion The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients’ quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-l-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases. Trial registration The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511).

Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C

“…Blinded to the time point of each video in each pair, the raters made an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from Video 1 to Video 2. Details of CI-CS administration and assessment have been previously published [7].…”

“…In addition to reducing detection and performance bias for the primary endpoint, the blinded CI-CS served as a metric of clinical importance that could not be obtained from the traditional timed assessments. Instead, raters evaluated clinically meaningful changes in patient's neurological manifestations which correlate to their level of functioning and quality of life, such as the accuracy and fluidity of movements, spasticity, ataxia, and dystonia for the 9HPT-D, and changes in gait patterns such as balance and postural stability, variability, asymmetry, ataxia, and support for the 8MWT [7].…”

“…As previously reported, the widespread, unlicensed use of the commercially available racemate (N-acetyl-dl-leucine; Tanga-nil™) and even, patient's access to chemical grade substitutes of NALL, within the NPC is well-known. This severely limited the feasibility of including a placebo-control, given patients and families reluctance to participate in a study where they would be required to washout from this unlicensed medication and receive an inactive treatment for even 50% of the time [7]. To ensure the study remained well-controlled and minimized bias, controls were put in place for the study-including the centralized, blinded review paradigm and use of intra-patient internal control-to enable a complete assessment of the scientific integrity and validity of the results.…”

“…This IB1001 master protocol was designed through a collaboration between National Regulatory Agencies, leading clinical experts, patient organizations, and the industry sponsor to address the unique ethical and practical challenges to conducting clinical trials for these orphan, heterogeneous patient populations. Details of the trial methods, rationale, design, and oversight have been previously published [7].…”

Acetylation turns leucine into a drug by membrane transporter switching

“…Currently, N -acetyl-leucine is being intensively studied by both academia and industry as a promising treatment for several disorders with unmet medical needs including cerebellar ataxia 2 – 4 , cognition and mobility in the elderly 5 , lysosomal storage disorders 6 – 9 , migraine 10 and restless legs syndrome 11 . Three multinational clinical trials are ongoing with the purified L-enantiomer for the treatment of Niemann-Pick disease type C, the GM2 gangliosidoses, and Ataxia-Telangiectasia 12 (clinicaltrials.gov NCT03759639, NCT03759665, NCT03759678).…”