Slide 1: KER-012 Update
August 8, 2023 KER-012 Update
Slide 2: Disclaimer
KER-012 Update 2 Disclaimer Statements contained in this presentation regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Words such as "anticipates," "believes," "expects," "intends,
Slide 3: Agenda
KER-012 Update 3 Agenda Topic Discussant(s) Welcome and Introduction Jasbir Seehra PAH Overview and Unmet Medical Needs Mardi Gomberg-Maitland KER-012 Predicted MoA & Differentiation Simon Cooper KER012 Phase 2 PAH (TROPOS) Trial Rationale, Design Mardi Gomberg-Maitland Anticipated Key Milestone Jas
Slide 4: Keros is a clinical-stage biopharmaceutical company
KER-065 therapeutic protein P R E C L I N I C A L KER-012 Update 4 We believe our product candidates have the potential to unlock the full therapeutic benefits of modulating the TGF-β superfamily and provide disease-modifying benefit to patients P H A S E 3P R E C L I N I C A L P H A S E 1 P H A S E
Slide 5: Mardi Gomberg-Maitland, MD, MSC, TROPOS Steering Committee Chair
KER-012 Update 5 Director of the Pulmonary Hypertension Program at The George Washington University Heart and Vascular Institute. Over 150 publications, including, CHEST, Circulation, Circulation Heart Failure, European Respiratory Journal, Journal of American College of Cardiology (JACC), JACC Hear
Slide 6: Pulmonary Arterial Hypertension Overview
Pulmonary Arterial Hypertension Overview KER-012 Update 6
Slide 7: PAH is Characterized by Vascular Remodeling and Dysfunction
KER-012 Update 7 Normal/Healthy PAH/Diseased Vascular Smooth Muscle Pathology: • Pulmonary Smooth Muscle & Endothelial Cell Proliferation • Inflammation • Vasoconstriction mPAP PVR RV Remodeling & Failure Humbert M, et al. Euro Resp J 2019;53 (1801887) 1-14; mPAP=mean pulmonary arterial pressure
Slide 8: Pulmonary Arterial Hypertension is All Encompassing
8 Bluish lips and skin Fatigue & Weakness Angina (chest pain) Fluttering Chest Sensation Dyspnea (shortness of breath) Dizziness & Fainting Dry Coughing Abdominal Bloating Peripheral Edema (Swelling) Decreased Work Productivity Diminished Functional Capacity Poor Quality of Life Anxiety & Depression
Slide 9: Pulmonary Arterial Hypertension at a Glance
KER-012 Update 9 Epidemiology: ~40,000 addressable PAH patients in U.S. (~59-81% Female1) Reported average age at diagnosis: 36-71 years2 Cause & Prognosis: ~50-60% idiopathic origin (U.S./Europe)1 Slightly above 50% survival at 5 years • Current standard of care (SOC) for PAH is the use of drugs th
Slide 10: MOA and Differentiation in PAH
KER-012 MOA and Differentiation in PAH KER-012 Update 10
Slide 11: KER-012 is a modified activin receptor IIB ligand trap
KER-012 Update 11 KER-012 is a modified activin receptor IIB ligand trap ▸Designed to rebalance TGF-β superfamily signaling ▸ Being developed for the treatment of pulmonary and cardiovascular disorders, including PAH ▸ KER-012 is designed to preferentially inhibit select ligands (activin A, activin
Slide 12: KER-012: A Novel, Investigational Activin Receptor Type IIB Ligand Trap
KER-012 is designed to inhibit select TGF-β superfamily ligands to: • Inhibit pro-proliferative activins and GDFs without increasing RBCs • Spare BMP binding to permit anti-proliferative BMP signaling KER-012 Structure TGF-b TGF-b GDF Activin Pro-Proliferative Anti-Proliferative TGF-b Signaling Imba
Slide 13: KER-012 vs. Native ActRIIA In Vitro Binding Studies
Activin/GDF Ligand Binding BMP Ligand Binding ActRIIA-Fc KER-012 (Modified ActRIIB-Fc) ActRIIA-Fc KER-012 (Modified ActRIIB-Fc) Activin A Strong Strong BMP-2 Semi-Weak Weak Activin B Strong Strong BMP-3 Weak Weak Activin C Weak Weak BMP-4 Semi-Weak Weak BMP-5 Strong Semi-Strong GDF-8 Strong Strong B
Slide 14: KER-012 vs. Native ActRIIA In Vitro Binding Studies
Activin/GDF Ligand Binding BMP Ligand Binding ActRIIA-Fc KER-012 (Modified ActRIIB-Fc) ActRIIA-Fc KER-012 (Modified ActRIIB-Fc) Activin A Strong Strong BMP-2 Semi-Weak Weak Activin B Strong Strong BMP-3 Weak Weak Activin C Weak Weak BMP-4 Semi-Weak Weak BMP-5 Strong Semi-Strong GDF-8 Strong Strong B
Slide 15: RKER-012 Preclinical Data Reduced Pulmonary Arterial Pressure and Cardiac Fibrosis
1. K. Babbs, et al. Am J Respir Crit Care Med 2022;205:A5776; 2. Babbs K, et al. Am Heart Association Scientific Sessions 2021; RKER-012 = Research KER-012 fused with Fc region of murine IgG1 0.0 0.2 0.4 0.6 0.8 Fulton Index R V /( L V + S ) -15.7% -28.0% ✱ ✱ ✱ ✱ ns ✱ ✱ ns 0 20 40 60 80 100 Pulmonar
Slide 16: KER-012 Preclinical and Clinical Data Summary in PAH
PAH Domain Preclinical Data Phase 1 Clinical Trial1,2 MOA & Ligand Specificity: • Strong activin/GDF binding observed • Observed to be BMP-sparing vs. ActRIIA-Fc • We believe PD data support potential for maximal target engagement with doses in Phase 2 Fibrosis & Inflammation: Inflammation Fibro
Slide 17: Rationale of TROPOS Trial in PAH
Rationale of TROPOS Trial in PAH KER-012 Update 17 Mardi Gomberg-Maitland, MD, MSc George Washington University School of Medicine and Health Sciences
Slide 18: Targeting the TGF-β Superfamily in PAH: Phase 3 STELLAR Trial
18 • Sotatercept is an investigational activin receptor llA-Fc (native ActRIIa fused to Fc region of IgG1) ligand trap • A third-party Phase 3 clinical trial of sotatercept1 demonstrated the importance of the TGF-β superfamily in patients with PAH • Improved 6-minute walking distance (6MWD) along wi
Slide 19: Sotatercept Dosing in PAH Limited Due to On-Target AEs
19 • Maximum dose in PAH limited to 0.7 mg/kg in the clinical trial due to increased hemoglobin observed in earlier-phase clinical trials1,2 1. Sherman et al 2013 J. Clin Pharmacol 53(11) 1121–1130; 2. Humbert M et al, New Engl J Med 2023; 384:1204-15; 3. Cappellini MD et al. Haematologica 2019; 104
Slide 20: Loss of BMP Signaling Impairs Endothelial Function and Vascular Integrity
KER-012 Update 20 • BMP-sparing ligand trap has the potential to reduce bleeding risk Loss of BMP Signaling Impairs Endothelial Function and Vascular Integrity
Slide 21: TROPOS is a Global Phase 2 Clinical Trial in PAH
KER-012 Update 21 A Randomized, Phase 2, Double-blind, Placebo-controlled Trial to Investigate the Safety and Efficacy of KER-012 in Combination with Background Therapy in Adult Participants with Pulmonary Arterial Hypertension Planning for ~60 sites TROPOS is a Global Phase 2 Clinical Trial in PAH
Slide 22: Key Eligibility Criteria for Participation
22 WHO/NYHA FC II or III symptoms Stable PAH-specific background therapy (ERA/PDE5-I/sGC stimulator/prostacyclin analogue or receptor agonist). Six-minute walk distance (6MWD) ≥ 150 and ≤ 500 meters ▸Note: Right-heart catheterization will be performed during Screening Adult patients ≥ 18 years of ag
Slide 23: Key Exclusion Criteria
23 • Evidence or history of left ventricular dysfunction and/or clinically significant cardiac disease • Has pulmonary function tests (PFTs) with evidence of significant obstructive or parenchymal lung disease • Evidence of thromboembolic disease assessed by ventilation perfusion (V/Q) lung scan or
Slide 24: TROPOS Trial Design
KER-012 Update 24 Approximately 90 patients diagnosed with PAH and on stable PAH background therapy will be randomized and assigned in a 2:2:2:3 ratio to the 1.5 mg/kg, 3.0 mg/kg, and 4.5 mg/kg KER-012 doses and placebo treatment arms. 1.5 mg/kg KER-012 (Q4W) (n=20) 3.0 mg/kg KER-012 (Q4W) (n=20) 4.
Slide 25: TROPOS Primary & Key Secondary Objective & Endpoint
KER-012 Update 25 Primary Objective Primary Endpoint To evaluate the effect of KER-012 on hemodynamics compared to placebo in participants on background PAH therapy Change from baseline in pulmonary vascular resistance (PVR) at Week 24 Key Secondary Objective Key Secondary Endpoint To evaluate the e
Slide 26: TROPOS Secondary Objectives and Endpoints
KER-012 Update 26 Secondary Objective Secondary Endpoint To evaluate the safety and tolerability of KER-012 Incidence of treatment-emergent AEs, treatment related AEs and discontinuation due to AEs; change from baseline in clinical lab values, vital signs and ECG; Incidence of ADA To evaluate the ef
Slide 27: TROPOS Exploratory Objectives and Endpoints
KER-012 Update 27 Exploratory Objectives Exploratory Endpoints To evaluate physical activity Change from baseline in overall activity as measured by actigraphy To evaluate improvement in additional risk stratification measures Proportion of patients who achieve improvement in REVEAL Lite 2 and COMPE
Slide 28: Anticipated Key Milestones
KER-012 Update 28 ▸KER-050 ▸Complete enrollment in transfusion-dependent cohorts in Phase 2 MDS trial H2 2023 ▸Announce additional data from Part 2 of Phase 2 MDS trial H2 2023 ▸Announce dose escalation data from Phase 2 MF trial H2 2023 ▸Initiate Part 2 of Phase 2 MF trial H2 2023 ▸KER-047 ▸Announc
Slide 29: Questions & Answers
Questions & Answers KER-012 Update 29