11/30/2018 Using Delayed Start Design and Analysis to Investigate Potential Disease Modifying Effects in Alzheimer’s Disease

Alzheimer’s Disease (AD) Type of dementia causing problems with memory, cognition, and behavior Symptoms typically develop slowly and worsen over time No cure Approved therapies transient benefits on symptoms do not slow progression of disease Current research efforts aimed at modifying disease course

Delayed Start Trial Designs Suggested by Paul Leber (1997) Used in Parkinson’s Disease research (ADAGIO) Endorsed in Feb 2018 regulatory guidance FDA: Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry EMA: Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease

Analysis Approach Include all randomized patients in one model from randomization to end of Delayed Start (DS) period and make three tests: Treatment difference: end of placebo-controlled period (1) Treatment difference: end of delayed start period (2) Non-inferiority comparison of 2 and 50% of 1 (Ha: 2 – 50% of 1 > 0) tested with a one-sided 90% LCL Three tests combine to give weight of evidence

EXPEDITION and EXPEDITION2 Studies Identical phase 3 studies run concurrently Mild to moderate patients Early Start phase was 18 months Analyses of mild AD participants indicated possible benefits

EXPEDITION and EXPEDITION2 Cognition Results 11/30/2018 Month Test 1 (p-val) Test 2 Test 3 (-LCL) 0.002 na 6 0.006 0.52 12 0.009 0.63 24 0.032 0.46 36 0.043 0.55 48 0.047 0.69 Source: prd/ly2062430/h8a_mc_lzao/final/programs_stat/tfl_output/rmdelay2_adas14_pooled.rtf

EXPEDITION and EXPEDITION2 Function Results 11/30/2018 Month Test 1 (p-val) Test 2 Test 3 (LCL) 0.040 na 6 0.045 0.09 12 0.019 0.35 24 0.119 -0.23 36 -0.21 48 0.014 0.94 Source: prd/ly2062430/h8a_mc_lzao/final/programs_stat/tfl_output/rmdelay2_iadl_pooled.rtf

EXPEDITION3 Results Phase 3 study in Mild AD patients Early Start phase 18 months Primary objective was not met

EXPEDITION3 Cognition Results 11/30/2018 Month Test 1 (p-val) Test 2 Test 3 (LCL) 0.109 na 6 0.516 -0.51 9 0.332 -1.33 Source: prd/ly2062430/h8a_mc_lzax/final/output/shared/rmdelay_adas14_9m1_2_ho3.rtf

EXPEDITION3 Function Results 11/30/2018 Month Test 1 (p-val) Test 2 Test 3 (LCL) 0.019 na 6 0.044 0.07 9 0.247 -0.41 Source: prd/ly2062430/h8a_mc_lzax/final/output/shared/rmdelay_iadl_9m1_2_ho3.rtf

Conclusions Delayed Start clinical trial designs can be used to show disease modification Tests 1-3 provide weight of evidence for disease modification Smaller treatment differences prior to delayed start period are problematic to show disease modification

References Leber P. Slowing the progression of Alzheimer disease: methodological issues. Alzheimer Dis Assoc Disord. 1997; 11: S10–21. Bhattaram VA, Siddiqui O, Kapcala LP, Gobburu JV. Endpoints and analyses to discern disease modifying drug effects in early Parkinson’s disease. AAPS J. 2009; 11: 456–464. Liu-Seifert H, Andersen SW, Lipkovich I, Holdridge KC, Siemers E (2015) A Novel Approach to Delayed-Start Analyses for Demonstrating Disease-Modifying Effects in Alzheimer’s Disease. PLoS ONE 10(3): e0119632. doi:10.1371/journal.pone.0119632 Liu-Seifert H, Siemers E, Holdridge K, Andersen S, Lipkovich I, Carlson C, Sethuraman G, Hoog S, Hayduk R, Doody R, Aisen P. (2015) Delayed-start analysis: Mild Alzheimer’s disease patients in solanezumab trials, 3.5 years. Alzheimer’s& Dementia: Translational Research & Clinical Interventions. 2015; 1-11.

Contact Info Scott Andersen Eli Lilly and Company andersen_scott_w@lilly.com