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PRIDE-HD on behalf of the HSG PRIDE-HD Investigators

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PRIDE-HD on behalf of the HSG PRIDE-HD Investigators, HSG 2016

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PRIDE-HD on behalf of the HSG PRIDE-HD Investigators

  1. 1. PRIDE-HD on behalf of the HSG PRIDE-HD Investigators HSG Presentation of Trial Results November 3, 2016
  2. 2. HART on behalf of the HSG HART Investigators HDCRS Presentation of Trial Results October 16, 2010
  3. 3. Pridopidine represents a novel therapeutic class of agents: dopamine stabilizers High Low Normal psychomotor activity Pridopidine High Low Normal psychomotor activity Standard antipsychotic
  4. 4. Phase II Trial in Huntington Disease • Randomized, double-blind, placebo controlled trial • n = 58 • Pridopidine 50 mg/d (n = 28) • Followed for 28 days *Component of Modified Motor Score Components of the Total Motor Scale of the UHDRS, with Modified Motor Score Highlighted Ocular Pursuit Saccade Initiation Saccade Velocity Dysarthria* Tongue Protrusion* Finger Taps* Pronate/Supinate Hands* Luria (Fist-hand-palm test)* Rigidity – arms* Body bradykinesia* Maximal Dystonia Maximal Chorea Gait* Tandem Walking* Retropulsion Pull Test*
  5. 5. Clinical motor improvement by pridopidine – HART and MermaiHD studies results 5 • Phase III study with 437 patients in eight European countries • Significant effects on TMS after 26 weeks; -3.0 points (p = 0.004) • The primary endpoint (mMS) was not met • Phase IIb study with 227 patients in the United States and Canada • Significant effect on TMS after 12 weeks; -2.8 points (p = 0.039) • Primary endpoint (mMS) was not met HART studyMermaiHD study Huntington Study Group HART Investigators. Mov Disord. 2013 Sep;28(10):1407-15. Yebenes JG, et al. Lancet Neurol. 2011 Dec;10(12):1049-57.
  6. 6. Disclaimer –Data presented here is based on topline phase 2 analysis –Further analysis is being undertaken –Additional data will be presented at forthcoming meetings –Teva plans to submit results for publication 6
  7. 7. Initial PRIDE-HD design: Evaluation of safety, tolerability and efficacy of higher doses (≥45mg bid) for symptomatic (motor) effects – Global Ph2, dose-ranging study to build on HART and MermaiHD’s findings – Study Duration: 26 wks; adequate for evaluation of motor effects – 4 doses (45, 67.5, 90, 112.5) and placebo – x2.5 higher that HART and MermaiHD – Population: 400 patients no HD stage restrictions – subjects had minimal TMS ≥ 25 – 52 sites – Endpoints: focused on motor symptoms (TMS, mPPT) 7
  8. 8. PRIDE-HD Chronology of Events: –26-week protocol finalization: May 2013 –Type C meeting: July 2013 –First subject first visit: Jan 2014 –52-week amendment: October 2014 –Enrolment Completion: June 2015 –26-week readout: January 2016 –52-week readout: August 2016 –Press release: September 2016 8
  9. 9. Based on new insights into Pridopidine MoA 9 Pridopidine may have broader effect beyond symptomatic relief Phase 2 protocol modified to explore long-term effect on function and rate of progression (52wks) & safety and tolerability Total Functional Capacity* is an established endpoint to assess function and disease progression in HD: pre-specified and collected at 26 and 52 weeks * Shoulson et al. Neurology 1981
  10. 10. PRIDE-HD recruited all stages of HD 10 • Steepest rate of natural decline • Most sensitive to current clinical measures • HD-CAB and TRACK-HD assessments designed specifically for this period and earlier • Difficulty completing assessments • Floor and ceiling effects limit ability to track change • Very significant brain tissue loss yrs 3 5 5-8 >8
  11. 11. No significant effect on TMS in the Full Analysis Set (FAS) at week 26 11 • All groups showed improvement from baseline • Large placebo effect was observed • Similar effects seen at 52 wks -10 -8 -6 -4 -2 0 2 Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid ChangefromBaseline Adj. means ± SEM Week 26 Improvement 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 75 79 81 81 Wk26 ∆ to placebo 1.42 1.71 0.67 2.1 p value 0.3199 0.2235 0.6282 0.1337
  12. 12. Total Functional Capacity (TFC)
  13. 13. Total Functional Capacity is the most widely accepted tool for assessing functional decline in HD 13 • A well established endpoint for trials aiming to slow clinical progression • Range: 0-13 • Floor and ceiling effects make this more sensitive to change in early HD, than late HD Source: Shoulson et al. Neurology 1981
  14. 14. Annual rates of decline in TFC are higher in earlier stages of disease 14 Source: K. Marder et al. Neurology 2000;54:452 HD1 (11-13) HD2 (7-10) HD3 (3-6) HD4 (1-2)
  15. 15. A ‘significant’ slowing of functional decline as measured by TFC is seen 15 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 59 54 56 58 Wk52 ∆ to placebo 1.16 0.36 0.71 0.27 p value 0.0003 0.2704 0.0239 0.4144 Improvement Adj. means ± SEM -1.6 -1.2 -0.8 -0.4 0 0.4 0.8 Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid ChangefromBaseline Week 52 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 75 79 81 81 Wk52 ∆ to placebo 0.87 0.11 0.19 0.24 p value 0.0032 0.7042 0.5099 0.4061 Improvement Adj. means ± SEM -1.6 -1.2 -0.8 -0.4 0 0.4 0.8 Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid ChangefromBaseline Week 52 Full Analysis Set - pre-specified Early Stage (HD1 and HD2) - post-hocTFC annual decline in placebo as expected
  16. 16. The effect on TFC first observed at 26wks 16 -1.6 -1.2 -0.8 -0.4 0 0.4 0.8 Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid ChangefromBaseline -1.6 -1.2 -0.8 -0.4 0 0.4 0.8 Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid ChangefromBaseline Improvement Improvement Full Analysis Set Early Stage (HD1 and HD2) Adj. means ± SEM Adj. means ± SEM 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 75 79 81 81 Wk26 ∆ to placebo 0.34 0.21 0.33 0.42 p value 0.1474 0.3639 0.1465 0.0676 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 59 54 56 58 Wk26 ∆ to placebo 0.56 0.33 0.61 0.67 p value 0.0359 0.215 0.0199 0.0125
  17. 17. Responder Analysis: significant difference in the proportion of subjects that showed no decline in TFC over 52wks between Pridopidine and placebo arms 17 Responder Analysis Questions Observed Data Analysis 45mg bid N=37 Placebo N=41 1. What proportion of early stage subjects had no deterioration on TFC (score ≥0) at 52 weeks? 30(81%) 20(49%) Nominal P-value (Chi-Square) 0.003 1. What proportion of early stage subjects had an improvement of ≥1 points on TFC at 52 weeks? 10 (27%) 5 (12%) Nominal P-value (Chi-Square) 0.099
  18. 18. -2 -1 0 1 2 Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid ChangefromBaseline Adj. means ± SEM Improvement Timed Up and Go Test (sec): Early HD at 52 wks 18 Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 62 59 54 56 58 Baseline 10 11.7 9.7 9.8 9.8 Wk52 ∆ to placebo -1.61 -1.64 -1.46 -0.96 p value 0.1348 0.1369 0.171 0.3827
  19. 19. Summary: Pridopidine shows potential effect on functional decline as measured by TFC • TFC - an accepted endpoint for functional decline in HD • Effect on TFC was more pronounced in early HD, and also was observed in responder analysis • The placebo arm declined as expected • Effects were observed primarily with 45mg bid and 90mg bid, suggesting a non-linear dose response • Improvement in ambulation may be contributing to TFC effect 19
  20. 20. Safety and Tolerability
  21. 21. PRIDE-HD: Summary of safety and tolerability No new findings – Safety and tolerability profile fully compatible with Phase 3 development ECG • QTcF analysis ongoing Vital Signs • Dose dependent increase of heart rate • No effect on blood pressure Labs • No clinically significant abnormalities observed
  22. 22. Psychiatric AEs: Summary & Conclusions • Psychiatric events reported in all arms • Irritability (most frequently observed psychiatric event) was more prevalent in placebo group (9%) • Depression (relatively small number of events) reported in all arms • Suicidality (relatively small number of events) reported in active arms • Columbia suicidality score change from “Negative” to “Positive” reported in all arms including placebo • Rates consistent with published literature
  23. 23. Summary: Pridopidine shows effect on functional decline measured by TFC, an index of clinical progression • First of 12 trials to show slowing of functional decline as measured by TFC - the gold standard scale for measuring HD clinial progression Effect on TFC was significant at 52wks in the full analysis set and in early stage HD at both 26 and 52wks • Preclinical data generated in the last 3yrs support the effects on functional decline • Large placebo response masked motor effects in the full analysis set • Motor effects were observed in early HD subpopulations • No new safety and tolerability issues • PRIDE-HD supports further development 23
  24. 24. Acknowledgements –Patients and their families –The clinical investigators and sites –The PRIDE-HD Steering Committee: Karl Kieburtz, Bernhard Landwehrmeyer, Ralf Reilmann, Andy McGarry –Teva clinical development team led by Spyros Papapetropoulos: Katie Blatt, Igor Grachev and Juha Savola 24
  25. 25. Investigators Slide 1 or 2 12 Countries, 52 sites: Australia Andrew Churchyard Anita Goh Clement Loy Peter Panegyres Austria Klaus Seppi Raphael Bonelli Canada Blair Leavitt Mark Guttman Tilak Mendis Denmark Anette Torvin Moller Lena Hjermind France Anne Catherine Bachoud-Levi Christophe Verny Clemence Simonin Fabienne Calvas Jean-Philippe Azulay Pierre Krystkowiak Germany Carsten Saft Josef Priller Michael Orth Ralf Reilmann Italy Ferdinando Squitieri Giuseppe De Michele Paola Soliveri Sandro Sorbi
  26. 26. Investigators Slide 2 or 2 Netherlands United States Nasir Ahmad Aziz Andrew Feigin Poland Christopher Ross Daniel Zielonka Claudia Testa Grzegorz Witkowski David Shprecher Jaroslaw Slawek Francis Walker Monika Rudzinska Jody Corey-Bloom Russia Karen Anderson Alexander Gustov Karen Marder Sergey Illarioshkin Kevin Biglan Zuleykha Abdullazarovna Zalyalova Pinky Agarwal United Kingdom Susan Perlman Andrea Nemeth Valarie Suski Anne Rosser Victoria Segro David Craufurd Hugh Rickards Oliver Quarrell Roger Barker Suresh Kumar Komati

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