TPP1 Extension
Research type
Research Study
Full title
A Multicenter, Multinational, Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 190 in Patients with CLN2 Disease
IRAS ID
174419
Contact name
Paul Gissen
Contact email
Sponsor organisation
BioMarin Pharmaceutical Inc.
Eudract number
2014-003480-37
Duration of Study in the UK
5 years, 9 months, 17 days
Research summary
Research Summary:
Neuronal ceroid lipofuscinosis, CLN2 disease is a rare genetic neurodegenerative disease characterized by the deficiency of tripeptidyl peptidase 1 (TPP1) caused by mutations in the CLN2 gene. The absence of TPP1 results in the accumulation of abnormal storage material in many organs. Symptoms include seizures, movement disorder, dementia and visual loss. Death occurs in childhood and there is neither curative nor disease modifying treatment. BMN 190 is a genetically engineered synthetic human TPP1.
The rationale for this extension study is to provide patients who complete the 190-201 study with the option to continue to receive continued BMN 190 treatment.
The 190-202 study is an open label extension protocol to assess long-term safety and
efficacy.
BMN 190 will be administered alternate weeks by infusion through the reservoir into the lateral cerebral ventricle on the Pediatric Intensive Care of Great Ormond Street Hospital up to week 239. All patients who complete 48 weeks of treatment in the 190-201 study may be eligible to be enrolled in the extension study.
The Screening period for Study 190-202 will start simultaneously with the Week 47 visit in Study 190-201.
Baseline values for Study 190-202 will be recorded at the Study Completion visit of Study 190-201 for all patients on active treatment. The first dose of BMN 190 in Study 190-202 (Week1/Study Day 1) will be given following the Week 49 study assessments in Study 190-201.
Patients will complete safety and efficacy assessments including CSF surveillance labs every2 weeks, CLN2 disease scales every 8 weeks, and physical examination, clinical laboratory assessments, and immunogenicity tests every 12 weeks. MRI will be performed every 24 weeks.
In addition, quality of life measures will be completed, and blood and CSF samples for evaluating exploratory biomarkers will be collected every 24 weeks.
Some patients may experience hypersensitivity reactions, thus prophylactic antihistamine and/or antipyretic may be administered prior to each study drug infusion at the investigator’s discretion.
In the event of a suspected anaphylactic reaction, serious hypersensitivity reaction, or severe hypersensitivity reaction (defined as a clinically severe hypersensitivity reaction of Grade 3 or higher), blood samples will be collected within 1 hour of the event to assess C4, serum tryptase, and total IgE; to assess drug-specific IgE, a blood sample will be collected no sooner than 8 hours after the event (or before the next infusion.
Patients may withdraw voluntarily from receiving study drug at any time, yet will be encouraged to continue to undergo study assessments. Patients may also withdraw entirely from complete study participation at any time, upon request.Summary of Results:
In summary, BMN 190 at a dose of 300 mg every 14 days administered by ICV infusion for a mean duration of 260.8 weeks (range 0.1 - 300.1weeks) was generally well tolerated and had an acceptable safety profile in this population of 24 subjects with CLN2 disease. The reported AEs were consistent with the known safety profile of BMN 190, the patient’s underlying disease or concurrent conditions, and side effects of concomitant medications. The 190-201/202 clinical trial safety data indicated no change in the positive risk-benefit profile of BMN 190.
Evidence of efficacy was durable over the course of > 5 years of BMN 190 treatment and was broad-based across all 4 domains (ambulation, language, seizure frequency, and vision). Analyses comparing 190-202 subjects with natural history subjects demonstrated a large efficacy effect size, with a difference in mean ML slope (CI) of 1.75 (1.46, 2.04) points/48 weeks (p < 0.0001) and a hazard ratio (CI) of 0.14; 95% CI, 0.06 to 0.33; p < 0.0001 for the event of an unreversed ML 2-point decline or score of 0.REC name
East of England - Cambridge South Research Ethics Committee
REC reference
15/EE/0078
Date of REC Opinion
10 Mar 2015
REC opinion
Favourable Opinion