No abstract

Niemann–Pick type C (NP-C) disease is a rare neurodegenerative lysosomal storage disorder. It is highly heterogeneous, and there is limited awareness of a substantial subgroup that has an attenuated adolescent/adult-onset disease. In these patients psychiatric features, often a psychosis, may dominate the initial impression, although often there is an associated ataxia and cognitive impairment. Typically, patients experience a substantial diagnostic delay. In this review we highlight the importance of early recognition and discuss the pathophysiology, neuropsychiatric presentation and recent changes in the investigation and work-up of these patients, and treatment options.

On receiving a link in my local authority's e-newsletter, I entered my details in Public Health England's 'One You' online heart age checker. 1,2 I am a 34 year-old, male, non-smoker, (BMI) 21.5, normal systolic blood pressure (113 mmHg), cholesterol unknown, with no family history or other risk factors for heart disease. I was told my heart age is 34 and given lifestyle advice. However, I was then told my cholesterol 'Is not known-GET TESTED' in large red letters, and that, although I wouldn't be automatically invited by my GP to have my cholesterol checked, I should get into the habit of 'knowing my numbers'. Using the information I provided (without cholesterol), my QRisk2 score could easily be calculated at 0.6%. 3 Even if my cholesterol was raised, statin medication would not be indicated according to current guidelines, but rather lifestyle advice, 4 which was recommended anyway. Despite large meta-analyses, there is no evidence that cardiovascular screening of asymptomatic subjects reduces mortality or morbidity, with little attention paid to the harms of screening in studies to date. 5 There remain significant concerns about the clinical and cost-effectiveness of the politically driven NHS Health Check Programme for 40-74-year-olds. 6 The likelihood of benefit of cholesterol screening in younger groups under 40 years seems even more unlikely. All this when the NHS and primary care are under huge strain trying to provide evidence-based care that is actually needed. Why is this irresponsible advice being given and when will it be changed?

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).