Mereo BioPharma Group plc · NASDAQ:MREO
Mereo BioPharma — Investor Day (November 2020)
96 slides from Mereo BioPharma's investor day presentation, Nov 24, 2020
Slide 1: Virtual R&D Day
Virtual R&D Day November 24 2020 Mereo BioPharma Group plc NASDAQ: MREO, AIM: MPH
Slide 2: Disclaimer
Disclaimer This presentation has been prepared by Mereo BioPharma Group plc (the “Company”) solely for your information and for the purpose of providing background information on the Company, its business and the industry in which it operates or any particular aspect thereof. For the purposes of thi
Slide 3: Mereo Biopharma Virtual R&D Day - Agenda
Mereo Biopharma Virtual R&D Day - Agenda Welcome, introductions and Agenda Denise Scots-Knight, PhD, CEO Mereo Biopharma Etigilimab : TIGIT as a target/MOA and anti-PD-1/PDL-1 combination approach Tim Yap, MBBS, PhD, FCRP, Associate Professor, Dept of Investigational Cancer Therapeutics, Division of
Slide 4: Today's Speakers
Today’s Speakers John Strickler, MD, Tim Yap, MBBS, PhD, FCRP, Mark Dransfield, MD, Associate Professor of Associate Professor, Dept of Professor and Interim Director, Division of Medicine, Member of the Investigational Cancer Therapeutics, Pulmonary, Allergy and Critical Care Duke Cancer Institute
Slide 5: Our Core Purpose, Strategy & Vision Guide Us
Our Core Purpose, Strategy & Vision Guide Us SUMMARY Mission Strategy Our Track Record Fundamentals • #1 priority – the patients Improving lives of • In-licence or acquire • Acquired/in-licensed 6 Our partners we seek to serve patients with oncology programs for oncology and programs with Phase 1b/2
Slide 6: Late Stage Diversified Clinical Pipeline
Late Stage Diversified Clinical Pipeline Core Programs Product Candidate / Indication Phase 1a Phase 1b Phase 2 Phase 3 Next Milestones Etigilimab Phase 1b/2 Solid tumors Alvelestat Alpha-1 antitrypsin deficiency Phase 2 AATD Phase 1b/2 COVID COVID-19 Setrusumab Extension study Osteogenesis imperfec
Slide 7: Etigilimab
—Sw Mereo BioPharma ~~ Etigilimab
Slide 8: TIGIT
TIGIT Dr. Timothy A. Yap MBBS PhD FRCP
Slide 9: We are in the era of immunotherapy
We are in the era of immunotherapy ? Is IO the new Chocolate? Chocolate makes everything better
Slide 10: Most IO-IO Combos Use Anti-PD-1/PD-L1 as Backbone
Most IO-IO Combos Use Anti-PD-1/PD-L1 as Backbone However, most combos are not based on strong supporting biology "Our paradigm of … let's just add something onto existing therapy may not be correct." – FDA OCE Director Richard Pazdur We need new targets driven by strong biology 9 Mereo Biopharma Gr
Slide 11: TIGIT: The New Kid on the Block
TIGIT: The New Kid on the Block TIGIT 10 Mereo Biopharma Group plc Mellman, Nature 2011
Slide 12: TIGIT is a Negative Regulator of T Cell Responses
TIGIT is a Negative Regulator of T Cell Responses T cell Immunoreceptor with Ig and ITIM domains (TIGIT) Negative regulator of T cell response: • Competes with CD226 for PVR, disrupts CD226 activation, and directly inhibits T cells Expressed on CD4, CD8 and NK cells and is elevated upon activation H
Slide 13: Etigilimab is an IgG1 Anti-TIGIT Antibody with Inhibitory and ADCC Characteristics
Etigilimab is an IgG1 Anti-TIGIT Antibody with Inhibitory and ADCC Characteristics Control Ab Effector function competent Effector function silent Mereo Biopharma Group plc 12
Slide 14: Fc Receptor Binding Important for Biomarker Changes & Efficacy in Preclinical Models
Fc Receptor Binding Important for Biomarker Changes & Efficacy in Preclinical Models 313R12: Mereo’s surrogate anti-mouse antibody used for preclinical studies; comparable affinity to etigilimab (anti- human TIGIT) Mereo Biopharma Group plc 13 Argast et. al. AACR 2018
Slide 15: TIGIT Clinical Landscape
–TIGIT Clinical Landscape 14
Slide 16: CITYSCAPE Study Design
CITYSCAPE Study Design AL Stage Iv NSCLE Tiragolumab 600 mg IV q3w + * EGFR/ALK wild-type Atezolizumab 1200 mg IV q3w ever lase * Tumor PD-L1TPS21%by |, R No of clinical 22C3 IHC by local or : Crossover) benefit central assay Placebo 600 mg IV q3w + N=135 Atezolizumab 1200 mg IV q3w Stratification F
Slide 17: Updated Confirmed Overall Response Rate (ORR)
Updated Confirmed Overall Response Rate (ORR) ITT PD-L1 TPS 2 50% PD-L1 TPS 1-49% (n=135) (n=58) (n=77) 90° 90- 66% 90; _ 804 So 704 x e 60+ 37% [oF 2 fo} =. 3g a Tiragolumab+ Placebo + Tiragolumab+ Placebo + Tiragolumab+ Placebo + Atezolizumab Atezolizumab Atezolizumab Atezolizumab Atezolizumab Ate
Slide 18: Updated Investigator-Assessed PFS: ITT
Updated Investigator-Assessed PFS: ITT — 1007 Median (95% Cl) HR (95% Cl) & = Tira+ Atezo 5.55 mo (4.21-10.4) 0.58* ES 807 Placebo +Atezo 3.88 mo (2.73-4.53) _(0.38-0.89) = 7 *stratified HR ” 604 (0) GC £(>=}PRA Ae SS SS = S= 5 7 ia ] f 1 < 40 Ss a o 207 ' 1 00 | ie) 1 1 a 607 ! 0 1 2 3 4 5 6 rf 8 9
Slide 19: Updated Investigator-Assessed PFS: PD-L1 TPS >= 50%
Updated Investigator-Assessed PFS: PD-L1 TPS = 50% — 1004 Median (95% Cl) HR (95% Cl) x = Tira + Atezo NE mo (5.49-NE) 0.30* = 804 Placebo+Atezo 4.11 mo (2.07-4.73) _(0-15-0.61) = 1 *unstratified HR a) 604 (0) Bo foc oe uw < 40} Ss | a wo 207 ' oD ! fe) 1 a of ‘ 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 #1
Slide 20: Updated Investigator-Assessed PFS: PD-L1 TPS 1-49%
Updated Investigator-Assessed PFS: PD-L1 TPS 1-49% Median (95% Cl) HR (95% Cl) Tira+ Atezo 4.04 mo (1.61-5.55) 0.89* 807 Placebo+ Atezo 3.58 mo (1.45-5.49) _(0.53-1.49) 7 *unstratified HR Rh S oO 1 Progression-Free Survival (%) 6 7 8 9 10 11 12 #13 #14 #15 No. at risk Time (months) Events T+A 38 36
Slide 21: Safety and Efficacy of Vibostolimab Plus Pembrolizumab in NSCLC
Safety and Efficacy of Vibostolimab, an Anti–TIGIT Antibody, Plus Pembrolizumab in Patients With Anti–PD-1/PD-L1–Naive NSCLC Mereo Biopharma Group plc 20 J. Niu et. Al, Phase 1, Presented at the ESMO Virtual Congress 2020; September 19-21, 2020
Slide 22: Summary Clinical Data
Summary Clinical Data Tiragolumab Vibostolimab Etigilimab Type of drug Anti-TIGIT Anti-TIGIT Anti-TIGIT human IgG1 humanized IgG1 humanized IgG1 mAb mAb mAb Trial Ph II Ph I dose Ph I dose randomized escalation escalation ORR monotherapy 0% 3% (1/34) 0% (0/18) DCR monotherapy 17% 35% 39% ORR combo w
Slide 23: Potential of PVR and TIGIT as Predictive Biomarkers
Potential of PVR and TIGIT as Predictive Biomarkers • High levels of PVR are associated with poor prognosis in multiple cancers • PVR/TIGIT potential involvement in resistance to IO • Potential important role of biomarkers beyond PD-L1, e.g. TIGIT, PVR, CD226 PVR IHC Mereo Biopharma Group plc 22
Slide 24: Where is the TIGIT Field Heading?
Where is the TIGIT Field Heading? • Etigilimab is a potent and active IgG1 anti-TIGIT antibody • Monotherapy unlikely to represent registration strategy • Combination with PD-1/L1 inhibitors is promising line of sight to FDA approval • Upcoming anti-TIGIT + PD-1/L1 inhibitor trials will define: - Sp
Slide 25: The Innovation Cycle (aka Gartner's Hype Cycle)
The Innovation Cycle (aka Gartner’s Hype Cycle) GRAPHICAL REPRESENTATION OF THE MATURITY, ADOPTION AND SOCIAL APPLICATION OF SPECIFIC TECHNOLOGIES FIVE KEY PHASES OF A TECHNOLOGY'S LIFE CYCLE 1. Technology Trigger 2. Peak of Inflated Expectations (hype) 3. Trough of Disillusionment 4. Slope of Enlig
Slide 26: Gartner's Hype Cycle for Immunotherapy
Gartner’s Hype Cycle for Immunotherapy Nobel Prize Many monotherapy and combo IOs Approved single agent PD-1/L1 inhibitors Ipi/Nivo in advanced melanoma Ipi/Nivo in unapproved Approved CAR T-cell therapy indications TIGIT NK-cell therapies Bispecifics Intratumor IO IDO-1 inhibitors Peak of Innovatio
Slide 27: The Innovation Cycle for Immunotherapy
The Innovation Cycle for Immunotherapy Many monotherapy and combo IOs Biomarker-driven combos? Ph II results Tiragolumab TIGIT discovery Peak of Innovation Inflated Trough of Trigger Expectations Disillusionment Slope of Enlightenment Plateau of Productivity Mereo Biopharma Group plc 26
Slide 28: Take Home Messages
Take Home Messages • Promising antitumor activity observed in NSCLC, but also in patients who have progressed on or after prior anti-PD(L)-1 treatment in other cancers • Optimal trial designs should be guided by shared knowledge from pre-clinical, translational and early clinical data • Further tran
Slide 29: Etigilimab
Etigilimab Dr. John Strickler, MD
Slide 30: Phase 1 Study Design
Phase 1 Study Design Phase 1a Phase 1b Dose Escalation 20mg/kg Q2W Dose Escalation N=3+3 Tumor types for inclusion 10mg/kg Q2W Tumor types for inclusion 20mg/kg Q2W + nivolumab in dose escalation cohort: N=3+3 in dose escalation cohort: N=3+3 • Histologically confirmed • Histologically confirmed adv
Slide 31: Baseline Characteristics
Baseline Characteristics Phase 1a Phase 1b Total M/F 10/13 6/4 16/17 Tumor Type Head and 4 1 5 Neck Uterine 4 0 4 CRC 3 1 4 Gastric 0 3 3 MSS CRC 3 0 3 TNBC 2 2 Pancreatic 2 0 2 Cancer Other 5 5 10 Mereo Biopharma Group plc 30
Slide 32: RECIST Response Data
RECIST Response Data Dose Phase 1a Phase 1b Total Complete Response 0 0 0/33 (0%) Partial Response 0 1 1/33 (3%) Stable Disease 7 1 8/33 (24%) Progressive Disease 13 6 19/33 (58%) Not Evaluable 3 2 5/33 (15%) Clinical Benefit Rate 7 2 9/33 (27%) Mereo Biopharma Group plc 31
Slide 33: Phase 1a Best % Reduction in Target Lesion Size & Duration on Study
Phase 1a Best % Reduction in Target Lesion Size & Duration on Study etigilimab monotherapy Waterfall Plot of Best Percentage Change in SLD from Baseline (ITT Population) Duration on Study Patient Dose Cancer Patient Dose Cancer 004-013 10mg/kg adenocarcinoma of the pancreas 001-025 20mg/kg* Endometr
Slide 34: Phase 1b Best % Reduction in Target Lesion Size & Duration on Study
Phase 1b Best % Reduction in Target Lesion Size & Duration on Study etigilimab + nivolumab Waterfall 120 Plot of Best Percentage Change in SLD from Baseline (ITT Population) Duration on Study Head and Neck Cancer, 20.0 mg/kg + nivolumab Gastric Cancer, 20.0 mg/kg + nivolumab 100 NSCLC, 3.0 mg/kg + n
Slide 35: Phase 1a Safety Data
Phase 1a Safety Data Related AEs ≥ 5% ≥ Grade 3 Related AEs Immune Related Adverse Events Number Number Adverse event, n Adverse event, n (%) Adverse event, n (%) (%) (%) (%) Number (%) Pruritis 4 (17%) Rash 1 (4%) Skin Disorders 8 (35%) Fatigue 3 (13%) Rash Macular 1 (4%) Pruritis 3 (13%) Nausea 3
Slide 36: Phase 1b Safety Data
Phase 1b Safety Data Phase 1b: ≥Grade 3 Related AEs Phase 1b: Immune-Related Adverse Events (n = 10)* (n=10)* Adverse event, n (%) Number (%) Adverse event, n (%) Number (%) Rash 2 (20%) Skin Disorders 5 (50%) Rash maculopapular 1 (10%) Pruritis 2 (13%) ALT increased 1 (10%) Rash 2 (20%) AST increas
Slide 37: Patient 005-010 Rash
Patient 005-010 Rash Example rash • Pt 005-010, 3 mg/kg, Grade 1-3 rash in multiple areas, topical steroids, skin biopsy on day ~150 • Pathology: perivascular lymphocytic inflammatory infiltrate with scattered eosinophils - Typical rash seen with other checkpoint inhibitors - Received biopsy in-hous
Slide 38: Phase 1 Clinical & Biomarker Findings
Phase 1 Clinical & Biomarker Findings • Seven subjects (30%, n=23) had stable disease as their best response in the single-agent Phase 1a cohort - Majority of patients are heavily pretreated and have tumor types typically non-responsive to anti-PD1 agents • One partial response and 1 stable disease
Slide 39: Etigilimab: A Differentiated Development Strategy
Etigilimab: A Differentiated Development Strategy Dr. Ann Kapoun, SVP Translational R&D, PhD Dr. John Lewicki, Chief Scientific Officer, PhD
Slide 40: Mereo's etigilimab Has Key Differentiating Features
Mereo’s etigilimab Has Key Differentiating Features High affinity Phase 1a and Phase 1b Advanced Biomarker dose escalation and capabilities in place IgG1 antibody safety data available • IgG1 backbone activates • Active IND and drug product • Target engagement of etigilimab antibody-dependent cellul
Slide 41: Non-clinical Biomarkers and Evidence of T Cell and NK Cell Activation
Non-clinical Biomarkers and Evidence of T Cell and NK Cell Activation Anti-TIGIT Promotes Activation of CD8+ and CD4+ T Cells and NK Cells in the Anti-TIGIT Increases CD4+ and CD8+ Cell Frequency in CT26.WT Tumors (IHC) Tumor Microenvironment (FLOW) Mereo Biopharma Group plc 40
Slide 42: Etigilimab Decreased the Number of Treg Cells in Circulation
Etigilimab Decreased the Number of Treg Cells in Circulation and Changed FoxP3 DNA Methylation in Phase 1a Patients Sharma et al Huang et al Time Dose Mereo Biopharma Group plc 41
Slide 43: Etigilimab Increased Markers of Cell Proliferation in T and NK Cells
Etigilimab Increased Markers of Cell Proliferation in T and NK Cells of Phase 1a Patients Pt 6 excluded due to confounding CML Time Dose Increases in Ki67+ observed in CD4 T cells as well as NK & Treg Sharma et al Mereo Biopharma Group plc 42
Slide 44: Anti-TIGIT Phase 1a Biomarker Summary
Anti-TIGIT Phase 1a Biomarker Summary Target engagement of etigilimab demonstrated in Phase 1a patients by multiple modalities: flow cytometry, NGS gene expression, and DNA methylation analysis • Activated immune cells measured by increases in Ki67+TIGIT+CD4 as well as NK cells and increased in intr
Slide 45: Factors & Analyses Influencing Design of Phase 1b/2 Trial
Factors & Analyses Influencing Design of Phase 1b/2 Trial • Survey of large cohorts of tumors for TIGIT/PVR/PD-1 expression, including internal IHC expression data • Study includes tumor types with high PVR/TIGIT and co-expression with PD1 • Tumors showing responsiveness to anti-PD-1/L1 including ra
Slide 46: Biomarker Capabilities in Place
Biomarker Capabilities in Place Example TIGIT & PVR Immunohistochemistry • TIGIT biomarker single & multiplex IHC/IF assays developed with image analysis • These assays were used to survey large cohorts of tumor tissues for indication selection • Robust multiplex IHC assays and staining for PVR, TIG
Slide 47: Biomarker Analysis of TIGIT Expression and Correlation with PD1 Expression
Biomarker Analysis of TIGIT Expression and Correlation with PD1 Expression IHC and gene expression analyses of large tumor cohorts were used to: - Rank tumors for high PVR/TIGIT expression and co-expression with PD1 - Interrogate histological subtypes and rare tumors where anti-TIGIT plus anti-PD1 m
Slide 48: PVR Signaling as a Resistance Mechanism in Tumors
PVR Signaling as a Resistance Mechanism in Tumors • Emerging data suggests the following: - High levels of PVR associated with poor prognosis in cancer patients - High PVR expression associated with resistance to anti-PD1 therapy Huang D-W et. al. Onco Targets Ther. 2017; Braun M. et. al. Immunity 2
Slide 49: High PVR Expression Associated with Poor Clinical Outcome
High PVR Expression Associated with Poor Clinical Outcome Survival probability Time TCGA Blue=low PVR Purple=high PVR Mereo Biopharma Group plc 48
Slide 50: High PVR Expression Associated with Reduced Response to Anti-PD1 Immunotherapy
High PVR Expression Associated with Reduced Response to Anti-PD1 Immunotherapy Melanoma Anti-PD1 plus Anti-CTLA4 n=155 pts Lepletier A. et. al. Clin Cancer Res. 2020 Mereo Biopharma Group plc 49
Slide 51: Phase 1b/2 Basket Study
Phase 1b/2 Basket Study • Clinical design influenced by the following observations: - Survey of large cohorts of tumors for TIGIT/PVR/PD-1 expression, including internal IHC expression data - Study includes tumor types with high PVR/TIGIT and co-expression with PD1 - Tumors showing responsiveness to
Slide 52: ACTIVATE Study Design Etigilimab Phase 1b/2 Basket Study
ACTIVATE Study Design Etigilimab Phase 1b/2 Basket Study HNSCC* Primary endpoint • Overall Response Rate Cervical carcinoma* Secondary • Safety and Tolerability Initiation of Phase Gastric/GE carcinoma* • PK/PD 1b/2 study planned • Duration of response for this quarter Exploratory Endometrial carcin
Slide 53: ACTIVATE Study Design Etigilimab Phase 1b/2 Basket Study
ACTIVATE Study Design Etigilimab Phase 1b/2 Basket Study • Received the study may proceed letter from FDA • 12-15 months study duration • Anticipating initial data in 2H2021 • Site initiation ongoing in US and EU; top sites and investigators in place Mereo Biopharma Group plc 52
Slide 54: Q&A
—Sw Mereo BioPharma ~~ Q&A
Slide 55: Alvelestat
—Sw Mereo BioPharma ~~ Alvelestat
Slide 56: Neutrophil Elastase-Driven Diseases: Alpha-1 Antitrypsin and COVID-19
Professor Mark Dransfield Neutrophil Elastase-Driven Diseases: Alpha-1 Antitrypsin and COVID-19
Slide 57: Neutrophil Elastase - A critical protease in health and agent of disease
Neutrophil Elastase- A critical protease in health and agent of disease - Highly aggressive protease, normally constrained in neutrophil cytoplasmic granules (uM) until activation – Physiological role in intracellular killing and degradation of bacteria – Dysregulated response identified as critical
Slide 58: Pathogenesis of Lung Disease – Balance between Inhibitor and NE
Pathogenesis of Lung Disease – a Critical Balance between Physiological Inhibitor (alpha-1 antitrypsin) and NE Steps leading to Proteinase/Anti-Proteinase concept of Anti-elastase pathogenic role of NE in lung damage absent or – Recognition of the genetic deficiency of the physiological overwhelmed
Slide 59: Identification of Exosomes in NE-driven Pathology (COPD)
Identification of Exosomes in NE-driven Pathology (COPD) Key Findings – Exosomes from activated PMNs harbor surface NE – Activated PMN exosomes bind and degrade Extra Cellular Matrix via NE – Activated PMN exosomes are relatively resistant to α1-AT, but are inhibited by small molecule NEi – CD66b/NE
Slide 60: Alpha-1 Antitrypsin Deficiency Lung Disease
Alpha-1 Antitrypsin Deficiency Lung Disease
Slide 61: Alpha-1 Antitrypsin Deficiency Lung Disease: a Disorder of Elastase Inhibitor Deficiency
Alpha-1 Antitrypsin Deficiency Lung Disease: a Disorder of Physiological Elastase Inhibitor Deficiency Genetic condition – Autosomal co-dominant inheritance – MM (normal), MZ, SZ, ZZ and null – Severity of disease related to level of α1AT Homozygotes (ZZs) and nulls have most severe deficiency and d
Slide 62: The Role of NE in Pathogenesis of AATD Lung Disease
The Role of NE in Pathogenesis of AATD Lung Disease Mereo Biopharma Group plc 61
Slide 63: Failure to Control Elastase is Destruction of the Lung Structure
Failure to Control Elastase is Destruction of the Lung Structure Leading to Early-onset Emphysema • Cross-linking amino acids desmosine and isodesmosine are released on exposure to elastase • Elastin fragments detected in body fluids can be used as markers for elastin- degrading diseases along with
Slide 64: Relationship of Elastin Breakdown Markers and Severity of Lung Disease in AATD-LD
Relationship of Elastin Breakdown Markers and Severity of Lung Disease in AATD-LD Supports the Potential Importance of Controlling Elastase – Levels of elastin breakdown highest at site of pathology (lung), but also raised in plasma – Desmosine/isodesmosine correlate with disease severity: – Plasma
Slide 65: Clinical Management: AATD Current Standard of Care
Alpha-1 Antitrypsin Deficiency (AATD) – Current Standard of Care Clinical Management – ‘COPD’ maintenance treatment, personal lifestyle management, e.g., avoidance of smoking and pollution – Testing of family to enable lifestyle choices – Intravenous plasma-derived augmentation therapy, weekly, appr
Slide 66: Neutrophil Extracellular Traps
Neutrophil Extracellular Traps
Slide 67: COVID-19 Immunopathology
COVID-19- Immunopathology For 80% infections with SARS-Cov 2 causes mild or asymptomatic disease For others, the infection is characterized by dyspnea, hypoxemia, with acute respiratory distress syndrome (ARDS), shock, and multi-organ failure: • Direct damaging effects of viral infection, compounded
Slide 68: Evidence for NETosis Driving Pathogenesis in SARS-Cov2
Evidence for NETosis Driving Pathogenesis in SARS-Cov2 Networks of DNA fibers, extruded from activated neutrophils: • Studded with histones, myeloperoxidase and NE • Can be be 10x size of neutrophil NET NET effects align with pathogenic features of COVID-19: Neutrophil • Cytotoxic to endothelial/epi
Slide 69: Pathology of Organs and Vessels from COVID-19 Patients
Pathology of Organs and Vessels from Patients who Succumbed to COVID-19 are Closely Associated with Excessive Neutrophil/NET Activity Neutrophilic Inflammation Immuno-Thrombosis Fibrin and extravasation NETs into the alveolar space Neutrophils+++ Blood vessel wall Extensive neutrophil infiltration i
Slide 70: Critical Role of Neutrophil Elastase in Formation and Inflammatory Activity of NETs
Critical Role of Neutrophil Elastase in Formation and Inflammatory Activity of NETs Elastase is essential and sufficient for NET formation4 • NE knock-out mice and NE inhibitor treated neutrophils fail to make NETs • In models of NET-induced Acute Respiratory Distress Syndrome (ARDS), pecific NE inh
Slide 71: Alvelestat Inhibits both NET Formation and Inflammatory Activity in Mouse Model
Alvelestat Inhibits both NET Formation and Inflammatory Activity of Pre-formed NETs in Mouse Model (Li et al 2018) Inhibition of Activity of Exogenous NETs Inhibition of NET Formation IL-1b IL-6 TNF-a NET-DNA in Bronchiolar lavage after acid- Administration of exogenous NETs in HBE cells (B–D) incre
Slide 72: Neutrophil Elastase in NETosis-driven Disease (COVID-19)
Neutrophil Elastase in NETosis-driven Disease (COVID-19) Adapted from EBioMedicine Volume 59, 102942, Sept 01, 2020 Mereo Biopharma Group plc 71
Slide 73: COVID-19 Phase 1b/2 Investigator-initiated Study COSTA
Testing the Hypothesis in COVID-19 Phase 1b/2 Investigator-initiated Study “COSTA” (Prof. Mike Wells, UAB) Primary Endpoint • Safety and tolerability (Day 60) • Mortality (Day 90) 10 day dosing period N = 15 2:1 active to placebo Secondary Endpoints Alvelestat bid Pharmacodynamic Biomarkers of: • NE
Slide 74: Alvelestat (MPH-966)
—Sw Mereo BioPharma ~~ Alvelestat (MPH-966)
Slide 75: Alvelestat Mechanism of Action
Alvelestat Mechanism of Action Potent, reversible, oral inhibitor of neutrophil elastase (NE) Compared to natural inhibitors i.e., alpha-1 antitrypsin native protein • Comparable association constant • Not susceptible to oxidative inactivation at sites of inflammation • Active against both soluble a
Slide 76: Inhibition of Neutrophil Elastase Activity
Inhibition of Neutrophil Elastase Activity % change from baseline in Neutrophil Elastase activity. 50 25 • MAD study – once daily dosing • 3 cohort study; 9 subjects per cohort 0 • In each cohort, 6 received active, 3 -25 placebo. Placebo from each cohort pooled. -50 • In placebo arm patients had in
Slide 77: Signal Seeking in Neutrophil-driven Diseases (1) Cystic Fibrosis
Signal Seeking in Neutrophil-driven Diseases (1) Cystic Fibrosis Desmosine week 4 Ratio alvelestat:placebo Alvelestat decreases urinary and plasma DESs in CF (n=56); *P<0.05 Trial Summary • Double-blind, placebo controlled • > 16 years MPH966:placebo • Clinical diagnosis of CF • FEV1 > 40% predicted
Slide 78: Signal Seeking in Neutrophil-driven Diseases (2) Bronchiectasis
Signal Seeking in Neutrophil-driven Diseases (2) Bronchiectasis – Anti-inflammatory and Clinical Effect Spirometry at week 4 Lung Function Improvement over P Value Parameter placebo LSM(SEM) Trial Summary FEV1 100 mls (34.0) 0.006 • Double-blind, placebo controlled SVC 130 mls (74.0 0.079 • 18- 80 y
Slide 79: Alpha-1 Antitrypsin Deficiency (AATD) – High Unmet Medical Need
Alpha-1 Antitrypsin Deficiency (AATD) – High Unmet Medical Need A rare, serious genetic Genetic Condition disorder that results in Progressive life-threatening disease; lack of or early onset pulmonary deficiency in key protein creates damage to lungs disease Autosomal co-dominant inheritance; genet
Slide 80: Alpha-1 Antitrypsin Deficiency (AATD) – Disease Impact
Alpha-1 Antitrypsin Deficiency (AATD) – Disease Impact A rare, serious genetic AATD-Lung Disease disorder that results in Natural protease inhibitor early onset pulmonary is either absent or levels are insufficient disease and dysfunctional Unopposed neutrophil elastase → progressive and severe lung
Slide 81: Current Unmet Need in AATD–Lung Disease
Current Unmet Need in AATD–Lung Disease Improved Efficacy • Inhibition of elastase forms resistant to alpha-1 antitrypsin • Effective lung penetration • Effective inhibition elastase at times of increase activity, e.g. acute exacerbations Convenience • Oral therapy benefit for life-long treatment fo
Slide 82: ASTRAEUS Phase 2 Study Design in Alpha-1 Antitrypsin Deficiency
ASTRAEUS Phase 2 Study Design (NCT03636347) in Alpha-1 Antitrypsin Deficiency A 12-week Study Treating Participants Who Have alpha1-antitrypsin-related COPD with Alvelestat (MPH966) or Placebo. (ASTRAEUS) Primary Endpoint • Within-individual % change in N = 165 12 week dosing period plasma desmosine
Slide 83: Desmosine/Isodesmosine Rationale for Primary Endpoint
Desmosine/Isodesmosine Rationale for Primary Endpoint- supported by Secondary Endpoints of Inflammation, Lung Damage, Lung Physiology and Exacerbations Progressive increase over time along with disease progression in patients with AATD-LD (ZZ/null) • Dynamics of change in target population appropria
Slide 84: ATALANTa Investigator-initiated Study
Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency “ATALANTa” (Investigator-initiated – Mark Dransfield, UAB) N = 66 12 week dosing period 1:1 active to placebo Primary Endpoint Alvelestat Placebo bid N=33 • Within-individual % change in plasma desmosine/isodesmosine Randomisati
Slide 85: NETosis in Systemic Inflammatory Diseases Brings Potential of Indication Expansion
NETosis in Systemic Inflammatory Diseases Brings Potential of Mechanistic Indication Expansion Scientific Rationale • NETosis a pathogenic mechanism highly dependent on neutrophil elastase • Drives hyper-inflammatory and thrombotic tendency common to a range of serious inflammatory disorders • Evide
Slide 86: Alvelestat Key Differentiating Features
SUMMARY Alvelestat Key Differentiating Features Profile for long term treatment of AATD lung disease and NETosis-driven diseases Rapid onset of Combination of Highly specific action < 4 hours twice daily dosing neutrophil elastase High neutrophil to > 90% enzyme and high neutrophil inhibition – elas
Slide 87: Setrusumab (BPS-804)
—Sw Mereo BioPharma ~~ Setrusumab (BPS-804)
Slide 88: Osteogenesis Imperfecta (OI)
Osteogenesis Imperfecta (OI) • Rare genetic bone disease, key symptoms include: • frequent bone fractures, skeletal deformities, pain and respiratory insufficiency • 85-90% linked to a mutation in Type I collagen1,2 • Tangible symptomatology leads to early diagnosis: • more than 55,000 patients in U
Slide 89: Summary of Phase 2B Data
Summary of Phase 2B Data Hierarchical primary Secondary end-points Study not powered to end-point based on based on areal bone show a difference in HRPQCT mineral density fracture rates but a • Trabecular vBMD at the measured by DXA trend of reduction in radius improved at high • Dose dependent stat
Slide 90: Upcoming Milestones
—Sw Mereo BioPharma ~~ Upcoming Milestones
Slide 91: Late-Stage Diversified Clinical Pipeline
Late-Stage Diversified Clinical Pipeline Core Programs Product Candidate / Indication Phase 1a Phase 1b Phase 2 Phase 3 Next Milestones Etigilimab Phase 1b/2 Solid tumors Alvelestat Alpha-1 antitrypsin deficiency Phase 2 AATD Phase 1b/2 COVID COVID-19 Setrusumab Extension study Osteogenesis imperfec
Slide 92: Mereo Upcoming Key Milestones & Opportunities
Mereo Upcoming Key Milestones & Opportunities Product Candidate / Indication 2020 2021 2022 Etigilimab Solid tumors Phase 1b/2 study Alvelestat Alpha-1 antitrypsin deficiency Phase 2 PoC study ASTRAEUS and ATALANTA COVID-19 Phase 1b/2 study COSTA Setrusumab Adult 12-m extension study Osteogenesis im
Slide 93: Investment Highlights
Investment Highlights Developing therapeutics for oncology and rare diseases based on novel targets with strong biological rationale Etigilimab is an anti-TIGIT antibody which actively engages FcyR in a Phase 1b/2 oncology basket study Alvelestat is an oral neutrophil elastase inhibitor in Phase 2 s
Slide 94: Q&A
—Sw Mereo BioPharma ~~ Q&A
Slide 95: Thank You
Thank You Mereo BioPharma Group plc N A S D A Q : M R E O, A I M : M P H
Slide 96: Mereo BioPharma Group plc
Mereo BioPharma Group plc One Cavendish Place London, W1G 0QF UK +44 (0)333 0237 300 Mereo Biopharma Group plc