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J09 An update on the proof-HD phase 3 trial: pridopidine’s outcome on function in huntington
  1. Ralf Reilmann1,
  2. Andrew Feigin2,
  3. Anne Rosser3,
  4. Sandra Kostyk4,
  5. Michal Geva5,
  6. Noga Gershoni-Emek5,
  7. Diderik Boot5,
  8. Yael Cohen5,
  9. Y Paul Goldberg5,
  10. Michael R Hayden5,6,
  11. the Huntington Study Group investigators and coordinators
  1. 1George Huntington Institute, Muenster, Germany
  2. 2NYU Langone Health, New York, NY USA
  3. 3University of Cardiff, Cardiff, UK
  4. 4Ohio State University College of Medicine, Columbus, OH, USA
  5. 5Prilenia Therapeutics, Israel
  6. 6CMMT, University of British Columbia, Vancouver, Canada


Background Pridopidine is a well-tolerated, oral Sigma-1 receptor (S1R) agonist. Human PET imaging shows pridopidine 45 mg bid, the dose currently evaluated in PROOF-HD, has selective and robust S1R occupancy. In preclinical HD models, S1R activation by pridopidine enhances multiple cellular processes impaired in HD, leading to neuroprotection. In the PRIDE-HD Ph2 trial, pridopidine 45 mg bid showed a beneficial effect vs placebo (Δ0.87, p=0.0032) on Total Functional Capacity (TFC) at Week 52. TFC is a regulatory-accepted, validated scale for clinical progression of HD. Post-hoc analysis shows this effect is driven by early HD patients (TFC7-13) (Δ1.16, p=0.0003). Responder analysis demonstrates that pridopidine reduced the probability of TFC worsening by 80% (p=0.002).

Aim Evaluate the efficacy and safety of pridopidine 45 mg bid on TFC in early HD.

Design PROOF-HD is a 65-week, double-blind, placebo-controlled, global Ph3 trial assessing pridopidine 45 mg bid in early HD patients. Primary endpoint is change from baseline to week 65 in TFC. Secondary endpoints include proportion of patients with no TFC decline and changes to week 65 in Q-Motor, Total Motor Score (TMS) and the composite UHDRS. Plasma neurofilament (NfL) levels are an exploratory endpoint. PROOF-HD completed enrollment of 499 patients ahead of schedule in Oct 2021. As of June 16th, 2022, low dropout (23/499, 4.6%) and treatment discontinuations (19/499, 3.8%) confirm pridopidine’s favorable tolerability and safety profile. In February 2022, an independent safety monitoring committee reported no safety signals of concern, and recommended PROOF-HD continue as planned. Results are expected in early 2023.

  • pridopidine
  • clinical trial
  • functional capacity
  • sigma-1 receptor

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