pride-hd on behalf of the hsg pride-hd investigators

PRIDE-HDon behalf of the HSG PRIDE-

HD InvestigatorsHSG Presentation of Trial

ResultsNovember 3, 2016

HART

on behalf of the HSG HART Investigators

HDCRS Presentation of Trial Results

October 16, 2010

Pridopidine represents a novel therapeutic class of agents: dopamine stabilizers

High

Low

Normal

psychomotor activityPridopidine

High

Low

Normal

psychomotor activityStandard antipsychotic

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*

Clinical motor improvement by pridopidine – HART and MermaiHD studies results

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• 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.

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

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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)

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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

Based on new insights into Pridopidine MoA

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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

PRIDE-HD recruited all stages of HD

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• 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

No significant effect on TMS in the Full Analysis Set (FAS) at week 26

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• All groups showed improvement from baseline

• Large placebo effect was observed

• Similar effects seen at 52 wks

Total Functional Capacity (TFC)

Total Functional Capacity is the most widely accepted tool for assessing functional decline in HD

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• 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

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)

A ‘significant’ slowing of functional decline as measured by TFC is seen

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45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bidN 59 54 56 58Wk52 ∆ to placebo 1.16 0.36 0.71 0.27p value 0.0003 0.2704 0.0239 0.4144

Impr

ovem

ent

Adj. means ± SEM

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid

-1.6

-1.2

-0.8

-0.4

0

0.4

0.8

Chan

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om B

asel

ine

Week 52

45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bidN 75 79 81 81Wk52 ∆ to placebo 0.87 0.11 0.19 0.24p value 0.0032 0.7042 0.5099 0.4061

Impr

ovem

ent

Adj. means ± SEM

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid

-1.6

-1.2

-0.8

-0.4

0

0.4

0.8

Chan

ge fr

om B

asel

ine

Week 52

Full Analysis Set - pre-specified Early Stage (HD1 and HD2) - post-hocTFC annual decline in placebo as expected

The effect on TFC first observed at 26wks

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Responder Analysis: significant difference in the proportion of subjects that showed no decline in TFC over 52wks between Pridopidine and placebo arms

Responder Analysis Questions Observed Data Analysis45mg bidN=37

PlaceboN=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) 0.0031. 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

Timed Up and Go Test (sec): Early HD at 52 wks

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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

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Safety and Tolerability

PRIDE-HD: Summary of safety and tolerability

No new findings – Safety and tolerability profile fully compatible with Phase 3 developmentECG• QTcF analysis ongoing

Vital Signs• Dose dependent increase of heart rate• No effect on blood pressure

Labs• No clinically significant abnormalities observed

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

: 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 progressionEffect 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 development23

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

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Investigators Slide 1 or 2

12 Countries, 52 sites:Australia

Andrew ChurchyardAnita GohClement LoyPeter Panegyres

AustriaKlaus SeppiRaphael Bonelli

CanadaBlair LeavittMark GuttmanTilak Mendis

DenmarkAnette Torvin MollerLena Hjermind

FranceAnne Catherine Bachoud-LeviChristophe VernyClemence SimoninFabienne CalvasJean-Philippe AzulayPierre Krystkowiak

GermanyCarsten SaftJosef PrillerMichael OrthRalf Reilmann

ItalyFerdinando SquitieriGiuseppe De MichelePaola SoliveriSandro Sorbi

Investigators Slide 2 or 2

Netherlands United StatesNasir Ahmad Aziz Andrew Feigin

Poland Christopher RossDaniel Zielonka Claudia TestaGrzegorz Witkowski David ShprecherJaroslaw Slawek Francis WalkerMonika Rudzinska Jody Corey-Bloom

Russia Karen AndersonAlexander Gustov Karen MarderSergey Illarioshkin Kevin BiglanZuleykha Abdullazarovna Zalyalova Pinky Agarwal

United Kingdom Susan PerlmanAndrea Nemeth Valarie SuskiAnne Rosser Victoria SegroDavid CraufurdHugh RickardsOliver QuarrellRoger BarkerSuresh Kumar Komati