Merck KGaA · XETR:MRK
Merck KGaA — Technical Presentation (November 2021)
44 slides from Merck KGaA's technical presentation, Nov 22, 2021
Slide 1: R&D Update Call 2021
R&D UPDATE CALL 2021 NOVEMBER 22, 2021
Slide 2: Disclaimer
Disclaimer Cautionary Note Regarding Forward-Looking Statements and financial indicators This communication may include “forward-looking statements.” Statements that include words such as “anticipate,” “expect,” “should,” “would,” “intend,” “plan,” “project,” “seek,” “believe,” “will,” and other wor
Slide 3: Well positioned to deliver significant long-term growth
Well positioned to deliver significant long-term growth Early- to mid-stage pipeline NRA Xevinapant Cis-ineligible NRA Xevinapant Cis-eligible NRA Focus today Evobrutinib BTKi NRA Recent Launches • Building focused Established Portfolio leadership NRA = non risk adjusted positions • With five focus
Slide 4: Pipeline with uncorrelated risk and significant potential
Pipeline with uncorrelated risk and significant potential Five focus assets with FIC potential FIC POTENTIAL COMPETITION PROMISE Evobrutinib Tackling unmet need for patients in RMS: (BTK inhibitor) Addressing chronic inflammation and progression between relapses, in addition to reducing acute inflam
Slide 5: Focused Leadership Leveraging and extending deep expertise
Focused Leadership Leveraging and extending deep expertise EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN MS leadership SCCHN leadership NCSLC Lung Cancer Depth & breadth (Likely indication) of clinical trial Disease insights/ experience and data Wealth of data Immune receptor & Apoptosis DNA da
Slide 6: Potential FIC BTK inhibitor, designed for BIC efficacy
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Potential FIC BTK inhibitor, designed for BIC efficacy REMIBRUTINIB/ FIC BTK INHIBITOR EVOBRUTINIB TOLEBRUTINIB FENEBRUTINIB ORELABRUTINIB EVOBRUTINIB ARR at 48 weeks 0.111 0.177 No PhII conducted • Pioneering program, developing (PhII) No PhII cond
Slide 7: Protein turnover of BTK requires BID dosing for optimal occupancy
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Protein turnover of BTK requires BID dosing to achieve optimal BTK occupancy for best efficacy 98% of patients receiving 75mg BID Patients achieving >95% BTKO Food effect enables a achieved >95% trough BTKO1 experienced greatest ARR reduction2 lower
Slide 8: Effective BTK inhibition in the CNS when CSF and free plasma concentrations comparable
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Effective BTK inhibition in the CNS is achieved when CSF and free plasma concentrations are comparable • Effective inhibition of microglia requires therapeutically relevant BTK occupancy • Concentrations in CSF and free plasma concentrations are com
Slide 9: Pronounced pharmacological effect shown in mouse brain
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Pronounced pharmacological effect shown in mouse brain BTK inhibition with Evobrutinib reduced leptomeningeal inflammation detected on MRI and by histopathology Evobrutinib Vehicle Evobrutinib Vehicle Reduction in meningeal contrast enhancement Decr
Slide 10: First clinical evidence of impact on brain lesions
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN First clinical evidence of impact on brain lesions associated with chronic inflammation5,6 ECTRIMS 2021 SELs – A BIOMARKER FOR CHRONIC oral presentation TISSUE LOSS IN THE ABSENCE OF ACUTE EVOBRUTINIB REDUCED SEL VOLUME IN A DOSE-DEPENDENT MANNER AT
Slide 11: De-risked profile based on safety analysis in >1000 patients
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN De-risked profile based on safety analysis in >1000 patients INTEGRATED PHII SAFETY ANALYSIS DEMONSTRATES MS All indications1 Placebo Evobrutinib Placebo Evobrutinib • Evobrutinib was well-tolerated in (n=54) (n=208) (n=271) (n=861) all tested indic
Slide 12: Summary: Potential FIC BTK inhibitor designed for BIC efficacy
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Summary Potential FIC BTK inhibitor designed for BIC efficacy • Pioneering development of breakthrough MoA with potential to rewrite SoC in RMS • Aiming to address chronic inflammation and progression between relapse in addition to reducing acute in
Slide 13: Xevinapant blocks IAPs to unleash cancer cell death cascade
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Xevinapant blocks IAPs to unleash cancer cell death cascade and enhance anti-tumor immune response • Apoptosis is a form of programmed cell death that plays a critical role in removing unneeded and abnormal cells • Resistance to apoptosis is one of
Slide 14: Maximizing chances for cure in LA SCCHN
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Maximizing chances for cure in LA SCCHN PhII: Consistent benefit across primary & secondary endpoints first presented at 3-year update, ESMO 2019 presented at ESMO 2020 PRIMARY ENDPOINT LCR SUBSTANTIAL IMPROVEMENT OF PFS AND OS LCR at 2 years PRIMAR
Slide 15: Leveraging market-leading expertise in SCCHN
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Leveraging market-leading expertise in SCCHN LA SCCHN SIMPLIFIED TREATMENT PARADIGM AND EPIDEMIOLOGY Leveraging our Erbitux heritage TrilynX • LA SCCHN is a curative setting that requires a multi-disciplinary approach SoC: SoC: Chemoradiation Chemor
Slide 16: First launch expected in 2025
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN First launch expected in 2025 2020 2021 2022 2023 2024 ≥ 2025 1 PhIII • Cisplatin-Eligible LA SCCHN study TrilynX • Xevinapant + cisplatin/RT (NCT04459715) • 700 patients1 IA 2 Additional • Cisplatin-Ineligible LA SCCHN To be started registrational
Slide 17: Maximizing chances for cure in LA SCCHN
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Maximizing chances for cure in LA SCCHN • Potential FIC IAP inhibitor to unleash cancer cell death and enhancing anti-tumor immune response • Xevinapant has transformational potential in LA SCCHN, a potentially curative setting that has seen only mo
Slide 18: IV ATR inhibitor with FIC Potential
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN IV ATR inhibitor with FIC Potential Lead program in our DDR pipeline • ATR inhibition allows unhindered cell cycle progression, accumulation of DNA damage and tumor cell death • Berzosertib is a potent and selective intravenously administered ATR in
Slide 19: Development focused on lead indication extensive stage SCLC
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Development focused on lead indication extensive stage SCLC TREATMENT LANDSCAPE FOR ES-SCLC • SCLC is ~15% of all lung cancer and the most aggressive with poor Diagnosis treatment outcomes (7% 5Y survival) (US annual incidence 26,000) • Majority of
Slide 20: Compelling PoC in combination with Topotecan in 2L SCLC
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Compelling PoC in combination with Topotecan in 2L SCLC DEVELOPMENT PROGRAM PHII NCI STUDY1 IN 2L SCLC COHORT IN COMBINATION WITH TOPOTECAN (SINGLE ARM) IN REFRACTORY SCLC ONGOING Relapsed SCLC Patients NCT 03896503 PhII (25 evaluable patients) Rand
Slide 21: Maximizing the potential of Berzosertib
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Maximizing the potential of Berzosertib CURRENT DEVELOPMENT FOCUS BERZOSERTIB POTENTIAL BEYOND SCLC Establish Berzosertib as new Ovarian cancer: SoC in 2L SCLC Biomarker studies to identify best target population for upcoming PhII study of Bersozert
Slide 22: What's next: oral ATRi for monotherapy and PARP inhibitor combinations
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN What’s next: oral ATRi for monotherapy and PARP inhibitor combinations ATR CORE DEVELOPMENT HYPOTHESES SYNTHETIC LETHALITY MODEL DATA ATM mut. PDX model TNBC PDX model (BRCAwt) 1 + chemotherapy – iv ATRi Berzosertib 800 Vehicle M1774 20 mg/kg QD 150
Slide 23: Berzosertib is lead program in our DDR pipeline
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Berzosertib is lead program in our DDR pipeline • ATR inhibition has significant therapeutic potential with 3 distinct applications: • Enhancing chemotherapy efficacy • Achieving synthetic lethality (monotherapy in patients with HRD alterations or c
Slide 24: ADCs optimized along several dimensions
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN ADCs optimized along several dimensions LIMITATIONS OF IMPLICATIONS FOR NOVEL TECHNOLOGY & CONVENTIAL ADCs LOW THERAPEUTIC INDEX STRATEGIES Optimization across multiple dimensions required to increase therapeutic index Novel payloads: Resistence aga
Slide 25: M1231 triple innovation approach along 3 dimensions
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN M1231 “triple innovation” approach along 3 dimensions M1231 – TRIPLE INNOVATION ADC WITH FiC POTENTIAL AIMING FOR ENHANCED THERAPEUTIC INDEX • Increased tumor-specificity/selectivity: Loss of membrane polarization on (1) Bispecific ADC based on EGFR
Slide 26: High level of MUC1/EGFR co-expression in multiple solid tumors
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN High level of MUC1/EGFR co-expression in multiple solid tumors Antigen expression per tumor type (mRNA) – M1231 (MUC1/EGFR co-expression) vs other ADC targets1 Expression ratio: low low low medium high high high very high normal tissue/tumor Potenti
Slide 27: Expansion cohorts in NSCLC and ESCC planned to initiate in Q1 2022
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Expansion cohorts in NSCLC and ESCC planned to initiate in Q1 2022 Nov 2021: 5th dose cohort, reaching NEXT STEPS projected effective dose range 2021 2022 2023 • Recruitment of expansion cohorts to initiate in Q1 2022 All-comers (biomarker- PhI Dose
Slide 28: Triple innovation approach with wide applicability across multiple solid tumors
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Triple innovation approach with wide applicability across multiple solid tumors • Merck’s ADCs are optimized across several dimensions (antibody, linker, payload): • PhI: lead-program M1231 – bispecific anti MUC1/EGFR ADCs is in dose escalation • Pr
Slide 29: Oral TLR7/8 inhibitor with FIC potential in lupus
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Oral TLR7/8 inhibitor with FIC potential in lupus • Toll-like receptors (TLRs) are a family of specialized innate immune TLR FAMILY AND THEIR LIGANDS sensors that recognize conserved microbial structures. TLR activation initiates innate and adaptive
Slide 30: For lupus patients, precise intervention remains an unmet need
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN For lupus patients, precise intervention for improved efficacy at low risk of infection remains an unmet need LIMITATIONS OF AVAILABLE LUPUS THERAPIES Enpatoran Target Profile • Established broad-spectrum immunosupressives and corticosteroid are eff
Slide 31: Compelling MoA together with functional and safety data
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Compelling MoA together with functional and safety data support the hypotheses in CLE and SLE RESULTS FROM PHI HV STUDY BIOMARKER RESULTS FROM PHI HV STUDY • Well-tolerated over the dosing interval, no significant or Inhibition of Ex vivo-Stimulated
Slide 32: PhII study in CLE and SLE planned to initiate in early 2022
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN PhII study in CLE and SLE planned to initiate in early 2022 Initiation planned early 2022 PhII combined PoC & dose finding study with basket and adaptive design PoC expected in H1 2023 CLE Cohort1 SLE Cohort Primary Endpoints: CLASI-A Primary Endpoi
Slide 33: Targeted inhibition of important lupus mediator
EVOBRUTINIB XEVINAPANT BERZOSERTIB M1231 ENPATORAN Targeted inhibition of important lupus mediator aiming for improved efficacy with low infection risk • For lupus patients, precise intervention for improved efficacy at low infection risk remains an unmet need in lupus • Enpatoran is an oral small m
Slide 34: Strengthening the pipeline: Significant progress expected in 2022
Strengthening the pipeline Significant progress expected in 2022 Not exhaustive Q4 2021 Q4 2022E (PROJECTED) PHII PHII PHII PHII PHI PHIII PHI PHIII (PRE POC) (POST POC) (PRE POC) (POST POC) M1231 (anti MUC1/ Berzosertib rSCLC Evobrutinib RMS M9140 (ADC) M1231 (anti MUC1/ Berzosertib rSCLC Evobrutin
Slide 35: Strengthening the pipeline: Key upcoming milestones
Strengthening the pipeline Key upcoming milestones 2022E 2023E STUDY INITIATIONS PhIII Xevinapant cis-ineligible LA SCCHN Evobrutinib RMS Tepotinib EGFRm MetAmp (confirmatory) Post-PoC PhII Berzosertib OC1 Bersozertib rSCLC PoC Studies M1231 3L+ NSCLC M1231 3L+ NSCLC M1231 2L+ ESCCC M1231 2L+ ESCCC
Slide 36: Pipeline with uncorrelated risk to drive topline growth from 2025
Pipeline with uncorrelated risk and significant potential to drive topline growth from 2025 PROMISE INDICATION EARLIEST SUBMISSION Tepotinib Overcoming resistance of Osimertinib 2L EGFR+ NSCLC 2023 (MET inhibitor) (third gen. EGFR inhibitor) post Tagrisso Timeline visibility Evobrutinib Addressing c
Slide 37: Conclusions
Conclusions Pipeline centered around five focus assets Building focused leadership positions in areas with deep expertise Strengthening the pipeline: 2022 will see substantial advancement with new study starts across our early- and late-stage pipeline Key upcoming milestones: • Xevinapant initiation
Slide 38: Today's speakers in the Q&A
Today’s speakers in the Q&A Danny Bar-Zohar Joern-Peter Halle Andrew Paterson Andree Blaukat Amy Kao Jan Klatt Victoria Zazulina Head of Head of Research Chief Marketing Head of Research Head of Research Head of Head of Development Officer Oncology Immunology Development Development Neurology & Onco
Slide 39: Investor Relations contacts
CONSTANTIN FEST SVENJA DJAVAHERI SARA HOFMANN Head of Investor Relations Assistant Investor Relations Assistant Investor Relations +49 6151 72-5271 +49 6151 72-3744 +49 6151 72-3321 constantin.fest@merckgroup.com svenja.djavaheri@merckgroup.com sara.hofmann@merckgroup.com ILJA DOERING GUNNAR ROMER A
Slide 40: Appendix
APPENDIX
Slide 41: Healthcare Pipeline
November 22, 2021 Healthcare Pipeline Phase I Phase II Phase III Registration M1231 M6223 berzosertib xevinapant tepotinib Bispecific MUC1xEGFR anti-TIGIT mAb ATR inhibitor IAP inhibitor MET kinase inhibitor ADC Solid tumors3 Small-Cell Lung Cancer4 Locally advanced squamous cell carcinoma Non-small
Slide 42: BTK occupancy of 95% is needed for maximal efficacy
BTK occupancy of 95% is needed for maximal efficacy; evobrutinib 75 mg BID dose is optimized for robust and sustained efficacy1,2 Evobrutinib Phase II RMS Evobrutinib dose 25 mg QD 75 mg QD 75 mg BID ARR at 48 weeks, mean 0.52 0.25 0.11 (95% CI)2,a (0.33–0.78) (0.12–0.44) (0.04–0.25) BTK occupancy (
Slide 43: PK and BTKO modeled for proposed phase III dose
PK and BTKO modeled for proposed phase III dose BTK occupancy median BTK occupancy 90% prediction interval Exposure median Exposure 90% prediction interval % of patients with trough occupancy >95% 75 mg QD fasted 75 mg BID fasted 45 mg BID fed Dosing regimen – food state BTK occupancy (%) 100.0 Mini
Slide 44: Trilynx design
Trilynx design Xevinapant combo with CRT followed by 3 cycles of monotherapy LA SCCHN Xevinapant oral solution + Xevinapant Extended period of cisplatin 3 cycles of 21 days monotherapy tumor sensitization Stage III, IVa or IVb 3 cycles of 21 days HPV-negative + IMRT 70 Gray towards death signals oro