Bayer Ag · XETR:BAYN
Bayer — Technical Presentation (August 2022)
54 slides from Bayer's technical presentation, Aug 29, 2022
Slide 1: Asundexian Investor Webinar
Asundexian Further advancing innovative therapeutic options in the treatment of cardiovascular diseases Investor Webinar August 29, 2022 Christian Rommel Manesh R. Patel Ashkan Shoamanesh John Eikelboom Christoph Koenen Ph.D., Head of R&D, M.D., Duke Clinical M.D., McMaster University M.D., McMaster
Slide 2: Agenda
Agenda 1 Welcome Oliver Maier Head of Investor Relations Bayer AG 2 Prepared Remarks Christian Rommel Manesh R. Patel Ashkan Shoamanesh John Eikelboom Christoph Koenen Ph.D., Head of R&D, M.D., Duke Clinical Research M.D., McMaster University in M.D., McMaster University M.D., Head of Clinical Bayer
Slide 3: Cautionary statements regarding forward-looking information
Cautionary statements regarding forward-looking information This presentation may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the ac
Slide 4: Factor XIa inhibition – Striving to go beyond limits
Factor XIa inhibition – Striving to go beyond limits Dr. Christian Rommel Ph.D., Head of R&D, Bayer Pharmaceuticals 4 /// Asundexian Investor Webinar /// 2022
Slide 5: Treatment of Cardiovascular Disease Has Advanced Over Past Decades
The Treatment of Cardiovascular Disease has Advanced Over the Past Decades, and Bayer has Played a Key Role Antithrombotics Adalat in ACS PCI and stents approved for VTEp in 2008 approved for SPAF in 2011 approved for DVT in 2011 approved for PE in 2012 Pritor approved for ACSsp in 2013 Aspirin Gluc
Slide 6: The Evolution of Anticoagulants
The Evolution of Anticoagulants1,2 Low-molecular weight DOACs (oral) heparin (i.v., s.c.) Direct FXa/thrombin Heparin (i.v., s.c.) Indirect inhibitor of clotting factors inhibitors Indirect inhibitor of clotting factors Warfarin (oral) Fondaparinux (i.v., s.c.) VKA Indirect FXa inhibitor Dicoumarol
Slide 7: Considerable Unmet Medical Need in Stroke Management
Despite Availability of (D)OACs There Remains Considerable Unmet Medical Need in Stroke Management Ischemic Stroke Facts Unmet Medical Need for Patients Patients want stroke protection (what they fear most) without bleeding increase1 Patients would additionally be interested in anti-thrombotics that
Slide 8: Normal Physiology: Without an Anticoagulant
Normal Physiology: Without an Anticoagulant Clot to stop bleeding BUT a pathological When no anticoagulant thrombus could also is used, a clot is formed be created. to stop the bleeding— 8 /// Asundexian Investor Webinar /// 2022
Slide 9: With a DOAC
With a DOAC (e.g., apixaban or rivaroxaban) DOAC Vessel wall danage Clot to stop bleeding When a DOAC is used, FXa BUT can also prevent is inhibited, which prevents the beneficial blood clots pathological thrombi— that stop bleeding in damaged vessels. 9 /// Asundexian Investor Webinar /// 2022
Slide 10: With a Factor XI Inhibitor
With a Factor XI Inhibitor (Hypothesis: Uncoupling Hemostasis from Thrombosis) Factor XI inhibitor Clot to stop bleeding When a Factor XI inhibitor is used, thrombin amplification is AND the tissue factor pathway still inhibited, which prevents produces thrombin, which allows pathological thrombi— b
Slide 11: Current Evidence Supporting FXI(a) Inhibition as a Target
Current Evidence Supporting FXI(a) Inhibition as a Target CONDITION OBSERVATION Individuals with FXI deficiency are reported to have a reduced incidence of VTE and stroke Inherited FXI deficiency1 Hemorrhage occasionally reported after trauma or surgery (dental extractions, tonsillectomies, surgery
Slide 12: Asundexian: Oral Factor XI Inhibitor
Asundexian: Oral Factor XI Inhibitor Small molecule FXIa inhibitor C26H21CIF4N6O4 t1/2 14.2-17.4 hours 15% Renal Elimination Well-tolerated in Phase 1 trials Dose-dependent FXIa inhibition Does not interact with clopidogrel to affect bleeding time No difference across age or sex Does not inhibit or
Slide 13: AXIA Assay to Determine Factor XIa Inhibition
Building on Today’s Standard Assay, We Have Developed AXIA to Determine Factor XIa Inhibition aPTT AXIA Contact activation in human plasma FXlla FXlla FXla FXla Ca2+ Ca2+ FlXa FlXa Thrombin Clot concentration-dependent reduction of FXIa activity concentration-dependent by asundexian prolongation of
Slide 14: PACIFIC Program
PACIFIC Program Concerted evaluation across large several Phase 2 programs Atrial fibrillation Non-cardioembolic ischemic stroke Acute myocardial infarction 20mg asundexian 10mg asundexian 10mg asundexian 50mg asundexian 20mg asundexian + single or + dual antiplatelet dual antiplatelet 20mg asundexi
Slide 15: Main Results of the PACIFIC-AF Trial
Dr. Manesh R. Patel, MD Duke Clinical Research Institute, Duke University on behalf of the PACIFIC- AF Investigators Main Results of the PACIFIC-AF Trial 15 /// Asundexian Investor Webinar /// 2022 Disclaimer: Asundexian is currently investigational and has not been approved for use in any country
Slide 16: PACIFIC-AF
PACIFIC-AF1 Prospective, randomized, double-blind, active-comparator, phase 2 study Primary safety endpoint: bleeding (ISTH major and non- Asundexian 50 mg n = 250 major clinically relevant bleeding) 2 weeks Patients with Asundexian 20 mg n = 250 post study drug Quantification of atrial R observatio
Slide 17: Measuring pharmacodynamic effect of asundexian
Measuring pharmacodynamic effect of asundexian Assay used : activated Factor Xia inhibition assay (AXIA)1 ~220 patients/ arm 4 weeks on once daily drug ~ trough (24-28 hours from last dose) and then again 2-4 hours afterwards Quantify degree of Factor XIa inhibition 1. Heitmeier S, Visser M, Terstee
Slide 18: FXIa Activity - Inhibition Data from PACIFIC-AF
FXIa Activity - Inhibition Data from PACIFIC-AF1 Vertical bars indicate the percent reduction in FXIa activity when compared with baseline. FXIa=activated coagulation factor XI. LLOQ=lower level of quantification. 1. Piccini JP, Caso V, Connolly SJ, Fox KAA, Oldgren J, Jones WS, Gorog DA, Durdil V,
Slide 19: Primary Safety Outcome (ISTH bleeding classification)
Primary Safety Outcome (ISTH bleeding classification)1 On-treatment analysis, % of patients • No ISTH major bleeding in any treatment arm • Significantly lower observed rates of ISTH major and clinically relevant non-major bleeding for either dose of asundexian compared with apixaban in patients wit
Slide 20: Exploratory Efficacy Analysis
Exploratory Efficacy Analysis1 Asundexian Asundexian Apixaban Total 20 mg 50 mg N = 251 N = 254 N = 250 N = 755 IR (90% CI) IR (90% CI) IR (90% CI) IR (90% CI) CV death, MI, ischemic stroke, 2 (0.80 %) 4 (1.57 %) 3 (1.20 %) 9 (1.19 %) or systemic embolism CV death 1 (0.40 %) 3 (1.18 %) 3 (1.20 %) 7
Slide 21: Summary of PACIFIC-AF Trial Outcomes
Summary of PACIFIC-AF Trial Outcomes1 Asundexian, a small oral FXIa inhibitor was well tolerated in a Phase 2 trial of 750 patients with atrial fibrillation Significantly lower observed rates of ISTH major and clinically relevant non-major bleeding for either dose of asundexian compared with apixaba
Slide 22: Main Results of the PACIFIC-Stroke Trial
Main Results of the PACIFIC- STROKE Trial Dr. Ashkan Shoamanesh, M.D., FRCPC on behalf of the PACIFIC-Stroke Steering Committee and Investigators 22 /// Asundexian Investor Webinar /// 2022 Disclaimer: Asundexian is currently investigational and has not been approved for use in any country
Slide 23: PACIFIC-Stroke study
PACIFIC-Stroke study Objectives: • To assess the dose-response of 3 different dosages of asundexian compared with placebo on the primary efficacy outcome and, separately, to evaluate the incidence of the primary safety outcomes to determine the dosage that is most efficacious and safe for testing in
Slide 24: PACIFIC-Stroke: Schema
PACIFIC-Stroke: Schema Prospective, randomized, double-blind, placebo-controlled, phase 2, dose-ranging study Asundexian 50 mg QD n = 447 Asundexian 20 mg QD n = 450 2 weeks Patients with Non-Cardioembolic post study drug Ischemic stroke ≤48 hrs R Asundexian 10 mg QD n = 455 observation from symptom
Slide 25: Results of PACIFIC-Stroke
Results of PACIFIC-Stroke ///////////
Slide 26: Study flow
Study flow Randomized 1808 Never received study drug 22 (1%) Treatment Phase Started 1786 Did not complete treatment phase 205 (11%) Discontinued study drug due to AF 85 (5%) Withdrawal of consent 57 (3%) Treatment Phase Lost-to-follow up 19 (1%) Completed Death 44 (2%) 1581 Included in Analysis Eff
Slide 27: Baseline and Qualifying Stroke Characteristics
Baseline and Qualifying Stroke Characteristics Well Balanced Across Treatment Arms All patients (n=1808) Age (yrs), mean ± SD 67 ±10 Female 34% Race - White 83% - Asian 15% Hypertension 77% Diabetes mellitus 28% Previous Stroke or TIA 16% Hours from qualifying stroke to 36 ±10 randomization, mean ±
Slide 28: Primary Efficacy Outcome
Primary Efficacy Outcome Ischemic Stroke or Covert Infarcts at 6 months 23 22.0% 22 21 20.1% 20 19.1% 18.9% 19 18 % of patients 17 16 15 14 13 12 11 10 Asundexian 10 Asundexian 20 Asundexian 50 Placebo No observed dose-response (Emax2 model t statistic: -0.68, p=0.80)
Slide 29: Secondary Efficacy Outcome
Secondary Efficacy Outcome Incident covert brain infarct(s) on MRI at 6 months (75% of events; 69% small subcortical infarcts) Asundexian, Asundexian, Asundexian, Asundexian, 10 Asundexian, 20 Asundexian. 50 Placebo Outcome 10 mg 20 mg 50 mg mg vs. placebo mg vs. placebo mg vs. placebo (N=456) (N=45
Slide 30: Secondary Efficacy Outcomes
Secondary Efficacy Outcomes Total follow-up (median 10.6 months) Asundexian, Asundexian, 10 Asundexian, Asundexian, 20 Asundexian, Asundexian, 50 vs. Placebo Outcome 10 (N=455) vs. placebo 20 (N=450) vs. placebo 50 (N=447) placebo (N=456) No. of patients HR No. of HR No. of HR No. of patients (%) (9
Slide 31: Secondary Exploratory Outcomes
Secondary Exploratory Outcomes Total follow-up (median 10.6 months) Asundexian, Asundexian, 10 Asundexian, Asundexian, 20 Asundexian, Asundexian 50 vs. Placebo Outcome 10 (N=455) vs. placebo 20 (N=450) vs. placebo 50 (N=447) placebo (N=456) No. of patients HR No. of HR No. of HR No. of patients (%)
Slide 32: Outcome: Recurrent stroke and TIA
Outcome: Recurrent stroke and TIA Exploratory post-hoc subgroup analysis A. Patients with large artery stroke (TOAST, N=320) B. Patients with any extra-/intracranial atherosclerosis (vascular imaging, N= 791) 18 15.8% 8.1% 16 8 14 12 6 % of patients % of patients 10 9.0% 8 4 3.1% 6 4 2 2 0 0 Asundex
Slide 33: Bleeding Outcomes
Bleeding Outcomes A. Major or Clinically-Relevant Non-Major Bleeding (ISTH)1 B. All Bleeding HR 1.57, 90% CI 0.91 – 2.71 5 12 10.8% 10.8% 4.3% 4.3% 10.0% 10.0% 3.9% 10 4 8.3% 3.1% 8 % of patients % of patients 3 2.4% 6 2 4 1 2 0 0 ASU 10 ASU 20 ASU 50 ASU pooled Placebo ASU 10 ASU 20 ASU 50 ASU pool
Slide 34: Conclusions
Conclusions • In this phase 2 trial, inhibition of factor XIa with asundexian did not reduce the composite of covert brain infarction or ischemic stroke and no dose response could be shown in patients with acute, non-cardioembolic ischemic stroke. • Driven by lack of effect on covert brain infarctio
Slide 35: Main Results of the PACIFIC-AMI Trial
Main Results of the PACIFIC- AMI Trial Prof. John Eikelboom, M.D., on behalf of the PACIFIC-AMI Steering Committee and Investigators 35 /// Asundexian Investor Webinar /// 2022 Disclaimer: Asundexian is currently investigational and has not been approved for use in any country
Slide 36: Study Design
Study Design Objective: To evaluate safety and explore the efficacy of 3 doses of asundexian vs placebo in patients with acute MI treated with dual antiplatelet therapy Prospective, randomized, double-blind, placebo-controlled, phase 2, dose-ranging study Quantification of Asundexian 50 mg QD n = 40
Slide 37: Analyses
Analyses Factor XIa inhibition (AXIA Assay) • Percent factor XIa activity at trough (~24-28 hrs from last dose) and peak (~2-4 hrs after dose) at 4 weeks compared to baseline • Measures enzymatic factor XIa activity in citrated plasma by assessing cleavage of a specific fluorogenic peptide FXIa subs
Slide 38: Results
rT Duke Clinical Research Institute Results ™ PACIFIC
Slide 39: Disposition Study Flow
Disposition Screened Study Flow 1664 Screening failures 63 Inclusion/exclusion criteria 51 157 sites, 14 countries Withdrawal by subject 7 June 2020 to July 2021 Randomized Other reasons 5 1601 Never took any study drug 8 Treatment Phase Started Did not complete treatment phase 363 1593 Adverse even
Slide 40: Baseline Characteristics
Baseline Characteristics Well Balanced Across Treatment Arms Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo N = 397 N = 401 N = 402 N = 401 Age (yrs), median (25th, 75th) 67 (62, 73) 68 (61, 73) 68 (63, 73) 68 (60, 73) Female, % 23 22 25 22 Race, % White 84 86 86 85 Asian 13 13 12 13 Wei
Slide 41: Factor XIa Inhibition at 4 Weeks
Factor XIa Inhibition at 4 Weeks Vertical bars indicate the % residual FXIa activity compared to baseline 100 Pre-dose = 100% Trough Peak Ratio to baseline of Factor XIa Activity (%) 80 60 >70% >80% >90% 40 35 23 21 20 14 9 7 LLOQ = 3.7% 0 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg n=327 n=3
Slide 42: Bleeding Outcomes
Two patients with ICH, 1 with asundexian 50 mg Bleeding Outcomes and one with placebo. No fatal bleeding. Significant (BARC 2, 3, or 5) Bleeding Asundexian All vs Placebo HR (90% CI): 0.98 (0.71 to 1.35) 12% 10.5% 10% 9.0% 8.1% 8% 7.6% 6% Asundexian 50 vs Placebo HR (90% CI): 4% 1.20 (0.83 to 1.75)
Slide 43: Bleeding Outcomes
Bleeding Outcomes Any Bleeding 25% 21.3% 20.4% 20% 18.9% 17.7% 15% 10% 5% 0% Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
Slide 44: Efficacy Outcome
Efficacy Outcome CV Death, MI, Stroke or Stent Thrombosis 10% Asundexian 20+50 vs Placebo HR (90% CI): 1.05 (0.69 to 1.61) 8% 6.8% 6.0% 6% 5.5% 5.5% Asundexian 50 vs Placebo 4% HR (90% CI): 1.01 (0.61 to 1.66) 2% 0% Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
Slide 45: Adverse Events
Adverse Events Similar Accross Arms Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo (N=395) (N=397) (N=402) (N=399) Any adverse event (AE) 285 (72.2%) 307 (77.3%) 316 (78.6%) 303 (75.9%) Study drug-related AE 64 (16.2%) 67 (16.9%) 86 (21.4%) 66 (16.5%) AE leading to study drug discontinua
Slide 46: Summary and Conclusion
Summary and Conclusion • First randomized placebo controlled trial with a small molecule factor XIa inhibitor (asundexian), on top of dual antiplatelet therapy, in patients following an acute myocardial infarction. • Asundexian 50 mg daily resulted in near complete (>90%) inhibition of factor XIa ac
Slide 47: The future of asundexian
Modulating coagulation: The future of asundexian Dr. Christoph Koenen M.D., Head of Clinical Development & Operations, Bayer Pharmaceuticals 47 /// Asundexian Investor Webinar /// 2022
Slide 48: PACIFIC Results Show Safety Data and Tolerability of asundexian
PACIFIC Results Show Compelling Safety Data and Tolerability of asundexian at near max. FXIa Inhibition and also First Efficacy Signals Study PACIFIC-AF PACIFIC-Stroke PACIFIC-AMI Indication Prevention of stroke in patients with atrial fibrilation Prevention of secondary non-cardioembolic Prevention
Slide 49: PACIFIC Program Results Confirm Preclinical Findings
Results from PACIFIC Program also Fully Confirm Preclinical Findings Separating thrombosis protection from haemostasis via selective modulation of the coagulation system Research models: Human Genetic studies: Evaluated the pharmacology of asundexian (BAY 2433334), Evidence for reduction in stroke r
Slide 50: AF is a Major Risk Factor for Stroke
AF is a Major Risk Factor for Stroke and a Burden for Patients and Healthcare Systems1–3 There remains an unmet 5× Patients with AF have a ~5× higher risk of stroke than individuals without AF1 need for patients with AF Actual or perceived bleeding AF-related strokes are, on average, more risk is a
Slide 51: Patients with Prior Stroke Have a High Risk of Recurrent Stroke
Patients with Prior Stroke Have a High Risk of Recurrent Stroke1 There remains an unmet need for patients Distribution of ischemic stroke subtypes with prior stroke across North American and European studies2 5% Antiplatelet agents are recommended 20% for the secondary prevention of 25% non-cardioem
Slide 52: OCEANIC Phase III Program
OCEANIC Phase III Program* The OCEANIC program consists of two Phase III studies: OCEANIC-AF OCEANIC-STROKE will test asundexian against apixaban in patients will test asundexian against placebo in patients with with atrial fibrillation. a non-cardioembolic ischemic stroke or high-risk TIA treated w
Slide 53: Bayer Remains Committed to Develop Innovations in Cardiovascular Diseases
Bayer Remains Committed to Develop Clinically Meaningful Innovations in Cardiovascular Diseases Stroke DME Dyslipidaemia ACS Our understanding of the relationship between Hypertension HFpEF/rEF CVD, renal disease and diabetes is growing PE AF Diabetes CAD CKD Thrombosis Vascular disease Heart diseas
Slide 54: Questions & Answers
Questions & Answers Stefan Oelrich Christian Rommel Ashkan Shoamanesh John Eikelboom Christoph Koenen Member of the Board of Ph.D., Head of R&D, M.D., McMaster University in M.D., McMaster University M.D., Head of Clinical Management of Bayer AG, Bayer Pharmaceuticals Hamilton, Canada, in Hamilton,