An industry perspective on biomarker-based drug discovery Advancing Therapeutic Development for Pain and Opioid Use Disorders through Public-Private Partnerships: A Workshop National Academies of Sciences, Washington DC October 12, 2017 Andrew H. Ahn, MD PhD
Disclosures The speaker is a full-time employee of Eli Lilly and Company The views expressed in this discussion are those of the speaker and do not represent the views of Eli Lilly and Company Galcanezumab (LY2951742) is a CGRP neutralizing antibody currently under clinical development by Eli Lilly and Company for the treatment of migraine and cluster headache
Overview A story of biomarker-based development CGRP (calcitonin gene-related peptide) and migraine CGRP antagonists and clinical activity Target engagement and clinical efficacy Key enablers of biomarker-based discovery Biomarker assay development Biomarker association with disease state Biomarkers confirming target engagement
Biomarker Association with Disease Plasma CGRP associates with migraine attacks and human migraine model Plasma concentration (pmol/l) 150 100 50 0 CGRP Control Migraine no Aura Migraine with Aura Substance P Neuropeptide Y Neuropeptide Goadsby et al, Ann Neurol 1990;28:183 with permission CGRP (pm) Hansen et al, Cephalalgia 2010;30:1179 with permission Edvinsson, CNS Drugs 2001;15:745 with permission
Bioassay Development and Validation CGRP Assays using Meso Scale Discovery and Quanterix Platforms 100000 MSD Quanterix 10000 Signal 1000 100 0.1 1 10 100 1000 CGRP (pg/ml) LOD=0.2 pg/ml LOD=0.02pg/ml Key validation properties of a CGRP assay Sensitivity at physiological levels Verified in tissues/collection media Dilutional linearity Specificity by immunodepletion Spike recovery Chai et al American Headache Society 2016
CGRP antagonist: migraine abortive Ocegepant (BIBN4096BS) IV Olesen et al, NEJM 2004 with permission
CGRP antagonist: migraine abortive Telcagepant (MK-0974) Ho et al, Lancet 2008, with permission Ho et al, Neurology 2008, with permission
CGRP antagonist: migraine prevention Ho et al, Cephalalgia 2016 with permission Ho et al, Neurology 2014 with permission
Biomarker of peripheral target engagement CGRP blockade inhibits capsaicin-induced dermal blood flow, Sets nominal CGRP-inhibitory activity required for peripheral activity Sinclair et al, BJCP 2010:69:15 with permission galcanezumab Capsaicin Vermeersch et al, JPET 2015 with permission Eli Lilly and Company, data on file
Dose-Exposure Relationship Monthly doses of galcanezumab 5, 50, 120 and 300 mg SC Galcanezumab Exposure LY2951742 Serum Concentration (nmol/l) 1000 100 10 1 0.1 Visit 5 Week 4 Doses: Visit 7 Week 8 5 mg Q4W 50 mg Q4W 120 mg Q4W 300 mg Q4W Visit 8 Week 10 Note: The middle line in each box plot represents the median; the top and bottom margins of the box represent the 75th and 25th percentiles; the whiskers extend to the 95th and 5th percentiles; data points outside the whiskers represent the points beyond the percentiles. Kielbasa et al Amer Acad Neurol 2016 Visit 9 Week 12 Weeks 4, 8, and 12 collected at 4 weeks postdose (trough level). Week 10 collected at midpoint of the dosing interval, at 2 weeks after the last dose (peak level)
CGRP antibodies: migraine prevention Galcanezumab reduces monthly migraine headache days LS Mean Overall Change from Baseline 0-2 -4 M igraine * * PBO (N=132) LY5mg (N=65) LY50mg (N=68) LY120mg (N=69) LY300mg (N=66) Migraine Headache Days * p-value = 0.018 error bars represent 95% CI Skljarevski et al, Japanese Headache Society 2015
CGRP Bioassay Demonstrates Target Engagement CGRP concentrations rise after 5, 50, 120, and 300 mg SC CGRP Plasma Concentration (nmol/l) 10 1 0.1 0.01 Visit 2 Baseline Placebo 5 mg Q4W 50 mg Q4W 120 mg Q4W 300 mg Q4W Visit 3 Baseline Visit 5 Week 4 Visit 7 Week 8 Visit 8 Week 10 Visit 9 Week 12 Note: The middle line in each box plot represents the median; the top and bottom margins of the box represent the 75th and 25th percentiles; the whiskers extend to the 95th and 5th percentiles; data points outside the whiskers represent the points beyond the percentiles. Using a drug-tolerant assay, baseline (predose) CGRP concentrations were assessed at Visit 2 and Visit 3. Weeks 4, 8, and 12 collected at 4 weeks postdose. Week 10 collected at mid-point of the dosing interval, at 2 weeks after the last dose. (Excludes measures below limit of assay quantification) Kielbasa et al, Amer Acad Neurol 2016
Drug Exposure-Biomarker Relationships Plasma CGRP levels plateau under an excess of galcanezumab CGRP Plasma Concentration (nmol/l) 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 100 200 300 400 500 600 700 800 900 LY2951742 Serum Concentration (nmol/l) Placebo 5 mg Q4W 50 mg Q4W 120 mg Q4W 300 mg Q4W Kielbasa et al, Amer Acad Neurol 2016
Exposure-Efficacy Relationships Galcanezumab exposure vs reduction in migraine headache days Reduction in Headache Days Median Change from Baseline Number of Migraine Headache Days per 28-day Period -2-3 -4-5 -6 Placebo 1.06-13.05 All Doses Visit 9 13.05-37.24 37.24-116.04 LY2951742 Serum Concentration (nmol/l) Quartiles Galcanezumab Exposure 116.04-876.97 Kielbasa et al, Amer Acad Neurol 2016
Study CGAG vs. CGAH Mean Change in Monthly MHD Study CGAG Study CG AH 0 Placebo 0 Placebo Improvement LS Mean Change from Baseline (SE) -1-2 -3-4 -5 GMB 120 mg GMB 240 mg p<.001 (at each month) -6 Baseline Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Improvement LS Mean Change from Baseline (SE) -1-2 -3-4 -5 p<.001 GMB 120 mg GMB 240 mg (at each month) -6 Baseline Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Abbreviations: GMB=galcanezumab; LS=least square; MHD=migraine headache days; SE=standard error Note: not statistically significant between GMB doses at any month. Skljarevski et al, American Headache Society 2017 Stauffer et al, American Headache Society 2017 2017 Eli Lilly and Company
Study CGAI Mean Change in Monthly MHD 0 Placebo Im provem ent LS M ean Change from Baseline (SE) -1-2 -3-4 -5 GM B 120 m g GM B 240 m g **p <.0 1 p <.00 1 (at each m onth) ** -6 Baseline M onth 1 M onth 2 M onth 3 Note: not statistically significant between GMB doses at any month Detke et al, American Headache Society 2017
Questions and Next Steps Specific questions for CGRP biomarkers Tailoring and prediction of individual response Therapeutic hypothesis for other clinical conditions CGRP receptor availability in clinical conditions Key enablers of biomarker-based pain therapies Biomarker assay development/validation Biomarker association with clinical conditions Relationship between biomarker and disease state (ictal/interictal, acute/chronic, clinical subtypes) Biomarkers of target engagement