42-Lowering Agent, in Alzheimer s s Disease: A Phase 2 Trial of up to 24 Months of Treatment. Gordon K. Wilcock*, University of Oxford, UK

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1 Efficacy and Safety of Tarenflurbil (Flurizan ), a Selective Aβ42A 42-Lowering Agent, in Alzheimer s s Disease: A Phase 2 Trial of up to 24 Months of Treatment Gordon K. Wilcock*, University of Oxford, UK Sandra E. Black, Suzanne Hendrix, Kenton Zavitz, Mark Laughlin, Edward Swabb & AD Phase 2 Study Investigators *Disclosure: In the past 3 years, GKW has been a paid consultant for Eisai, Johnson & Johnson, Lundbeck, Marix Drug Development, Myriad Pharmaceuticals, Novartis, Pfizer, and Shire.

2 Tarenflurbil Clinical Rationale Selective Aβ42A 42-Lowering Agent (SALA) in vitro & in vivo Allosteric modulation of γ-secretase,, not inhibition Reduces insoluble amyloid in mouse brain Improves spatial reference learning and memory performance in mice Effective concentrations achievable in humans at clinically safe doses 2 tarenflurbil

3 Phase 2 Study of Tarenflurbil in Subjects with Mild to Moderate AD (MMSE 15-26) Randomized, Double-Blind, -Controlled 31 sites in Canada and the United Kingdom 207 Subjects in 3 treatment groups (1:1:1) BID 12-month study / stable AChEI allowed ADAS-cog; ADCS-ADL;CDR ADL;CDR Sum of Boxes Optional 1-year 1 follow-on on study available in Canada 3 tarenflurbil

4 Pre-specified Statistical Analysis Plan ITT Population Primary Analysis Assumption: No Treatment by Severity Interaction Assumption Not Met (p = 0.03) Planned Analysis of MMSE < and > 20 Mild AD (MMSE > 20) Moderate AD (MMSE < 20) Primary Outcomes: ADAS-cog ADCS-ADL ADL vs. CDR-sb Exploratory Analyses: vs., Drug Concentration Effect (Slope analysis) Primary Outcomes: ADAS-cog ADCS-ADL CDR-sb vs. Exploratory Analyses: vs., Drug Concentration Effect (Slope analysis) 4 tarenflurbil

5 Mean Baseline Characteristics in Mild AD (MMSE 20) (n=46) (n=36) (n=48) % of Total Patients 75% 58% 73% Age % AChEI Use 97% 94% 94% Mean Duration AChEI Use at baseline (months) MMSE ADAS-cog (*80 point) ADCS-ADL CDR-sb tarenflurbil

6 Optional 12-Month Follow-on on Study Treatment groups remained blinded to subject/investigator Eligible Subjects n=106 Enrolled n=86 Moderate Subjects n=24 Mild Subjects n=62 Continue: n=18 Continue: n=23 n=21 Randomization n=9 n=12 6 tarenflurbil

7 Cognition Mild Subjects (MMSE 20 at Baseline) ITT analysis 0 (n=48) Mean Change in ADAS-cog Effect Size (d=52%)( Slope Comparison*: p=0.109 (800 vs. placebo 0-12 p=0.013 (800 vs. 400) 12) 2 (n=36) (n=46) (n=23) 4 (n=18) Change UK and Canada Month Canada only *Mixed Model 7 tarenflurbil

8 Activities of Daily Living Mild Subjects (MMSE 20 at Baseline) ITT analysis 0 Mean Change in ADCS-ADL ADL Effect Size (d=67%)( Slope Comparison*: (800 vs. placebo ) p= Change UK and Canada Month Canada only *Mixed Model 8 tarenflurbil

9 Global Function Mild Subjects (MMSE 20 at Baseline) ITT analysis Mean Change in CDR-sb Effect Size (d=72%)( Slope Comparison*: (800 vs. placebo ) p= Change UK and Canada Month Canada only *Mixed Model 9 tarenflurbil

10 Patients Re-randomized to Drug at 12 months ( Staggered Start ) Patients treated for 24 months decline more slowly than those treated for only 12 months Annual Decline Rate Over 24 Months 24 months treatment at: 12 months placebo randomized to: (n=36) (n=48) ADAS-cog 3.72* 2.20* (n=9) (n=12) ADCS-ADL ADL * CDR-sb * *p<0.01, 24 vs. 12 months treatment 10 tarenflurbil

11 Exploratory Drug Concentration Response: Cognition Subjects who achieved a higher plasma concentration (C( max ) had a better response (p=0.148) ADAS-cog 12 Month Slope Observed C-max (Quintile Average) (μg/ml) 11 tarenflurbil

12 Exploratory Drug Concentration Response: Activities of Daily Living Subjects who achieved a higher plasma concentration (C( max ) had a better response (p=0.027) ADCS-ADL 12 Month Slope Observed C-max (Quintile Average) (μg/ml) 12 tarenflurbil

13 Exploratory Drug Concentration Response: Global Function Subjects who achieved a higher plasma concentration (C( max ) had a better response (p=0.024) CDR sb 12 Month Slope Observed C-max (μg/ml) (Quintile Average) 13 tarenflurbil

14 Exploratory Cognition Mild Subjects (MMSE 20 at Baseline) ITT analysis 0 (n=48) Mean Change in MMSE Effect Size (d=67%)( Slope Comparison*: p<0.001 (800 vs. 400) p=0.001 (800 vs. placebo as randomized as randomized ) Change (n=46) (n=36) UK and Canada (n=23) (n=18) (n=21) Canada only Month *Mixed Model as randomized 14 tarenflurbil

15 Discontinuations Over Time (ITT) Cumulative Discontinuations Over Time Number of Subjects months 6 months 9 months 12 months 0 Overall discontinuations in 12 months ~ 20% 15 tarenflurbil

16 AD2: Most Common AEs Leading to Discontinuation (0-12 months) MedDRA Body System (n=66) 400 mg BID (n=71) 800 mg BID (n=70) Total (n=207) Gastrointestinal 3 (4.5%) 2 (2.8%) 2 (2.9%) 7 (3.4%) Metabolism and Nutrition 1 (1.5%) 2 (2.8%) 2 (2.9%) 5 (2.4%) Psychiatric 3 (4.5%) 0 2 (2.9%) 5 (2.4%) 16 tarenflurbil

17 Discontinuations Due to Disease Progression (0-12 months) (n=66) All patients 6 (9.1%) Mild patients 4 (8.7%) (n=71) 2 (2.8%) 1 (2.8%) (n=70) 1 (1.4%) 0 17 tarenflurbil

18 AD2: Safety Summary Flurizan was well tolerated Discontinuations due to AEs were comparable between and placebo Adverse events (higher frequency than placebo) transient eosinophilia, mild anemia, bp elevation, lower respiratory infection, rash Fewer events than placebo urinary incontinence psychiatric events 18 tarenflurbil

19 Posthoc: : Time to Psychiatric Event by Treatment Group (Mild Patients, (Mild Patients, MMSE MMSE 20) 100% Patients without a Psychiatric Event (%) 90% 80% 70% 60% 50% 40% 30% 20% 10% # of Patients with AE p value Median Time to Event days >333 days p value % Days on Study 19 tarenflurbil

20 Conclusions Subjects with mild AD on showed a reduced rate of decline (slope) At 12 months At 24 months Activities of Daily Living Global Function Cognition (positive trend) d=44% (p=0.033) d=42% (p=0.042) d=20% (p=0.327) d=67% (p=0.015) d=72% (p=0.0005) d=52% (p=0.109) Positive effects increasing over time on all scales Consistent with predicted effects of a disease modifying agent Well tolerated up to 24 months Confirmatory Phase 3 Studies ongoing in Mild Patients 20 tarenflurbil