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M4 Safety and tolerability of BN82451B in huntington’s disease
  1. Stefan Bohlen1,
  2. Alzbeta Mühlbäck2,
  3. Ralf Marquard2,
  4. Christian Saß3,
  5. Katrin Reetz4,
  6. Johannes Schiefer4,
  7. Carsten Saft5,
  8. Zacharias Kohl6,
  9. Raphael Bonelli7,
  10. Alexander Münchau8,
  11. Stephan Klebe9,
  12. Adolf Weindl10,
  13. Alexander Storch11,
  14. Matthias Löhle11,
  15. Thomas Klopstock12,
  16. Ludger Schöls13,
  17. Klaus Seppi14,
  18. Kai Boelmans15,
  19. Robin Schubert1,
  20. Carine Brisset16,
  21. Ingo Meyer17,
  22. Frank Schaumann18,
  23. Werner Rein19,
  24. Lydie Poitout20,
  25. Isabelle Paty19,
  26. Ralf Reilmann1
  1. 1George Huntington Institute, Münster, Germany
  2. 2Klinik Taufkirchen (Vils), Taufkirchen (Vils), Germany
  3. 3Asklepios Klinikum Harburg, Hamburg, Germany
  4. 4Universitätsklinikum RWTH Aachen, Aachen, Germany
  5. 5Ruhr-Universität Bochum, Bochum, Germany
  6. 6Universitätsklinikum Erlangen, Erlangen, Germany
  7. 7Sigmund Freud University Vienna, Vienna, Austria
  8. 8Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
  9. 9Universitätsklinikum Freiburg, Freiburg, Germany
  10. 10Technische Universität München, Munich, Germany
  11. 11Universität Rostock, Rostock, Germany
  12. 12Ludwig-Maximilians-Universität München, Munich, Germany
  13. 13Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Tübingen, Germany
  14. 14Medizinische Universität Innsbruck, Innsbruck, Austria
  15. 15Universitätsklinikum Würzburg, Würzburg, Germany
  16. 16Aepodia France, Les Ulis, France
  17. 17CRS Clinical Research Services Kiel, Lübeck, Germany
  18. 18CRS Clinical Research Services Mönchengladbach, Mönchengladbach, Germany
  19. 19Independent MD, working for Ipsen Innovation, Les Ulis, France
  20. 20Ipsen Innovation, Les Ulis, France

Abstract

Background BN82451B is a small, orally active molecule with good CNS penetration. Preclinical studies in tgHD R6/2 mice suggested improved motor function and prolonged survival. In addition antidyskinetic activity was observed in other models. The proposed mechanisms of action (MOA) are (1) antiexcytotoxic due to a sodium channel blocking potential, (2) antioxidant, (3) anti-inflammatory due to a cyclooxygenase (COX) inhibitory potential and (4) mitochondrial protective.

Aims The primary objective of this phase 2a study (NCT02231580) is to investigate the safety and tolerability of BN82451B bid versus placebo for 28 days in male HD subjects. Secondary objectives include assessment of pharmacokinetics and of pharmacodynamics via the effects on quantitative motor (Q-Motor) measures. UHDRS subscales are implemented as exploratory measures.

Methods Subjects: We intend to recruit 30 male HD subjects. 24 receive BN82451B and 6 placebo. The study is conducted in an inpatient setting at a single phase I unit in Germany.

Design A sequential design was chosen to enable dose escalation starting with 40 mg bid with a potential maximum dose of 80 mg bid. Three subsequent cohorts of 10 patients each are randomised with different starting doses. Subjects in group one are treated with 40 mg bid for 14 days and may be increased to 60 mg bid the subsequent 14 days. In group 2, subjects may first receive 60 mg bid with possible increase to 80 mg bid. Group 3 subjects may receive 80 mg bid for 28 days. Dose increases in the consecutive groups are subject to approval by a Data Review Committee (DRC). The decision to increase the dose in individual patient will be based on the investigator’s judgement.

Results Results of the study are expected for Q4/2016.

Conclusions Recruitment in this trial is difficult as in-patient periods of nearly one month are logistically challenging. Safety data will be available soon and pharmacodynamics readouts such as Q-motor measures may help to guide decisions on the further path of development of BN82451B.

  • clinical trial
  • Q-Motor
  • phase II

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