Crinetics Pharmaceuticals, Inc. · NASDAQ:CRNX
Crinetics Pharmaceuticals — Investor Presentation (September 2021)
49 slides from Crinetics Pharmaceuticals's investor presentation, Sep 15, 2021
Slide 1: Corporate Presentation
CORPORATE PRESENTATION September 2021
Slide 2: Safe Harbor Statement
SAFE HARBOR STATEMENT This presentation contains forward-looking statements. Crinetics cautions you that statements contained in this presentation regarding matters that are not historical facts are forward-looking statements. These statements are based on the company’s current beliefs and expectati
Slide 3: Mission: build the leading endocrine company
Mission: To build the leading endocrine company that consistently pioneers new therapeutics to help patients better control their disease and improve their daily lives CRINETICS PHARMACEUTICALS | 3
Slide 4: Strategy: Drugs Built from Scratch for Purpose
Strategy: Drugs Built from Scratch for Purpose We aim to discover, develop and commercialize drugs for endocrine indications with: High Unmet Medical Needs Well established biology Biomarkers as registrational endpoints 1 Clinical proof of concept achieved (POC) in Phase 1 studies Small registration
Slide 5: Endocrinology Development Strategy: Focus on Hormone Levels
Endocrinology Development Strategy: Focus on Hormone Levels from Preclinical to Approval Phase 2/3 Safety, Preclinical POC Disease Efficacy ∆Hormones, ∆Hormones, PROs, PK, Safety PK, Safety Phase 1 Healthy Phase 2/3 Trials Volunteers (Patients) Phase 1 Healthy Volunteer Safety, POC ∆Hormones, PK, Sa
Slide 6: Pipeline Targets Indications with Unmet Need
Pipeline Targets Indications with Unmet Need Well established biology has the potential to allow for the use of biomarkers as registration endpoints Development Stage Prevalence Registrational PROGRAM Preclin Phase 1 Phase 2 Phase 3 Endpoint Global Range US Total per 100,000 Paltusotine (SST2 agonis
Slide 7: Endocrinology Invented Biomarkers: Pharmacologic POC in Phase 1
Endocrinology Invented Biomarkers! Pharmacologic POC in Phase 1 is Our Goal Acromegaly Predose + 10 mg paltusotine (day 1) Plasma Plasma [paltusotine] ng/mL (day -1) [paltusotine] Suppression of GH Phase 1 SAD Data: Stimulate GH with Stimulate GH with GHRH (50 µg) GHRH (50 µg) Serum [GH] Serum [GH]
Slide 8: Paltusotine: Oral Nonpeptide SST2 Agonist
PALTUSOTINE: AN INVESTIGATIONAL, POTENTIAL FIRST-IN-CLASS, ORAL NONPEPTIDE SST2 AGONIST Acromegaly Carcinoid syndrome Nonfunctional neuroendocrine tumors CRINETICS PHARMACEUTICALS | 8
Slide 9: Acromegaly and NETs Treated with Injected SST2 Peptide Agonists
Acromegaly and NETS are Currently Treated with Injected SST2 Peptide Agonists Acromegaly Neuroendocrine Tumors (NETs) • Caused by benign pituitary • NETs arise from aberrant Liver enteroendocrine cells in GI, tumor that secretes excess growth hormone (GH) SST2 Stomach pancreas or lungs • Excess GH c
Slide 10: ~$3B Market Despite Limitations of Current Therapies
~$3B Market Despite Limitations of Current Therapies Sandostatin Somatuline Somavert MYCAPSSA (octreotide) (lanreotide) (pegvisomant) (oral octreotide) $1.4B $1.4B $277M $1M Monthly intramuscular Monthly deep subcutaneous Daily injections 1 ml; 28 – 31- Twice daily oral capsule 5-mL vial; 1½” 19-gau
Slide 11: Paltusotine Showed High Intrinsic Oral Bioavailability
Paltusotine Showed High Intrinsic Oral Bioavailability Peptide: Octreotide Nonpeptide: paltusotine Survive proteolysis Diffuse through lipid bilayer Paltusotine Aided by gut (CRN00808) permeabilizing Intrinsically agents permeable Oral Bioavailability 70% Observed Half Life 42-50 hr. Intestinal epit
Slide 12: Paltusotine Designed to Avoid Drug-Drug Interactions
Paltusotine was Designed to Avoid Drug-Drug Interactions and Be Easy to Prescribe Mass-balance (14C) study in healthy volunteers 250 Paltusotine has not shown clinically Paltuostine meaningful inhibition or induction of drug Total radioactivity metabolizing enzymes Plasma concentration 200 TRA (ng/m
Slide 13: Phase 2 ACROBAT Edge Study Met Primary Endpoint
Phase 2 ACROBAT Edge Study Met Primary Endpoint Hormone suppression maintained after switching from injected SOC to oral paltusotine 3.0 3.0 p<0.0001 IGF-1 p<0.0001 GH 2.5 2.5 p>0.6 p=0.6285 2.0 2.0 GH (ng/mL) IGF-1 (× ULN) p>0.6 p=0.6285 1.5 1.5 1.0 1.0 0.5 0.5 0.0 0.0 Baseline Paltusotine 4 Wks Ba
Slide 14: Evidence of Dose Response from Phase 2 Program
Evidence of Dose Response from Phase 2 Program Results from Switching to Paltusotine: Change in IGF-1 Magnitude of Paltusotine Activity: Change in IGF-1 from from Baseline to Steady State at Indicated Dose Steady State to 4 Weeks After Withdrawal Post-hoc analysis of data from EDGE primary analysis
Slide 15: Phase 3 Program: Broad First-Line Medical Therapy
Phase 3 Program: Designed to Support Potential for Broad First-Line Medical Therapy Two double-blind, placebo-controlled studies planned to support broad labeling in the U.S. and Europe for use in all acromegaly patients who require pharmacotherapy PATHFNDR-1: Switching from SOC Evaluate safety and
Slide 16: Anticipated Paltusotine Milestones
Anticipated Paltusotine Milestones 1 Initiate PATHFNDR-1: switching from SOC ✓ Initiate PATHFNDR-2: use in untreated patients 2 (anticipated in 2H 2021) Initiation of Phase 2 NETs trial in carcinoid syndrome 3 (end of 2021) Report topline data from PATHFNDR-1 & 2 trials 4 (expected in 2023) CRINETIC
Slide 17: CRN04894: Oral Nonpeptide ACTH Antagonist
CRN04894: AN INVESTIGATIONAL, POTENTIAL FIRST-IN-CLASS, ORAL NONPEPTIDE ACTH ANTAGONIST Congenital adrenal hyperplasia (CAH) Cushing’s disease (CD) Other conditions of ACTH excess CRINETICS PHARMACEUTICALS | 17
Slide 18: The HPA Axis is the Body's Emergency Response System
The Hypothalamic-Pituitary-Adrenal (HPA) Axis is the Body’s Emergency Response System for Stress Adrenal Gland ACTH Stress cholesterol Hypothalamus MC2/MRAP CRF Cortisol Adrenal Cortical Cell Pituitary 21-hydroxylase Adrenal Androgens AVP cortisol (17-OHP, A4) peripheral target tissues (Glucocortico
Slide 19: Hypothesis: Oral Selective ACTH Antagonist Will Have Utility
Hypothesis: An Oral, Selective ACTH Antagonist Will Have Utility in Treating Diseases of ACTH Excess Normal Cushing’s Disease (CD) Hypothalamus Congenital Adrenal Hyperplasia (CAH) Hypothalamus Hypothalamus CRF CRF stress CRF Pituitary Pituitary Pituitary negative feedback AVP X AVP Loss of adenoma
Slide 20: CRN04894: First-in-Class ACTH Antagonist
CRN04894: First-in-Class ACTH Antagonist for ACTH Driven Diseases Pituitary Gland Adrenal Gland Target Cells ACTH Cortisol Pituitary Directed ACTH Adrenal GC Agents to Suppress Receptor Steroidogenesis Receptor ACTH Secretion Antagonist Inhibitors Antagonist • Limited efficacy • Limited Efficacy • E
Slide 21: There Are No ACTH Receptor Blocking Agents Available
There Are No ACTH Receptor Blocking Agents Available to Treat ACTH Driven Diseases All currently approved agents and agents in development act upstream or downstream of ACTH ACTH Cortisol Pituitary Gland Adrenal Gland Target Cells Pituitary Directed Agents to Adrenal Steroidogenesis Inhibitors Gluco
Slide 22: CRN04894 is the Only ACTH Antagonist in Clinical Development
CRN04894 is the Only ACTH Antagonist in Clinical Development CRN04894 was carefully crafted by Crinetics in-house discovery team CRN04894 is a potent (Kb= 0.4 nM) competitive Acute suppression of ACTH-induced antagonist of ACTH signaling corticosterone observed in rats Vehicle CRN04894 (1 mg/kg) CRN
Slide 23: CRN04894 SAD Study Design
CRN04894 SAD Study Design to Establish Pharmacologic Proof-of-Concept Follows Crinetics’ core endocrine strategy of using hormonal biomarkers to drive development Study Goals ACTH Challenge Test • Evaluate safety [ 10-80 mg] Baseline (Day -1) Treated (Day 1) • Evaluate pharmacokinetics: oral absorpt
Slide 24: PK Results: CRN04894 Oral Bioavailability
PK Results: CRN04894 Showed Oral Bioavailability With Dose-Proportional Exposure Half-life ~24 hour and tmax ~1 hour 80 mg (N=12) 40 mg (N=6) 20 mg (N=6) 10 mg (N=6) Data shown are mean±SEM CRINETICS PHARMACEUTICALS | 24
Slide 25: CRN04894 Rapidly Reduced Basal Cortisol Output
CRN04894 Rapidly Reduced Basal Cortisol Output from Adrenal Glands Acute reduction of basal cortisol (56% @ 80 mg) 2 hours after administration of CRN04894 17% Baseline (Day -1) -25% -35% -37% Full suppression of cortisol -56% production a Pbo 10 mg 20 mg 40 mg 80 mg (N=9) (N=6) (N=6) (N=6) (N=12) C
Slide 26: Dose-Dependent Cortisol Suppression After ACTH Challenge (250 mcg)
Dose-Dependent Suppression of Cortisol Observed Following Supra-Pathophysiologic ACTH Challenge (250 mcg) CRN04894 resulted in strong cortisol suppression (41% @ 80 mg) despite anticipated ACTH exposure orders of magnitude higher than disease states ACTH Challenge (250 mcg) Placebo (N=7) 0% 80 mg CR
Slide 27: Cortisol Suppression in Response to Disease-relevant ACTH Challenge
Clinically Meaningful Cortisol Suppression Observed in Response to Disease-relevant ACTH Challenge (1 mcg) CRN04894 maintains normal cortisol levels for these subjects in face of disease-relevant ACTH (1 mcg) challenge CRN04894 ACTH Challenge 80 mg (1 mcg) Elevated 20 Cortisol [Cortisol] (mcg/dL) 15
Slide 28: Conclusions from CRN04894 SAD Results
Conclusions from CRN04894 SAD Results Objectives Generally safe and well tolerated at single doses from 10 to 80 mg • Safety and tolerability Achieved targeted pharmacokinetic profile • Drug-like • Rapidly absorbed after oral administration (tmax ~1 hr) Pharmacokinetics • Dose proportional exposure
Slide 29: Recent and Anticipated CRN04894 Milestones
Recent and Anticipated CRN04894 Milestones 1 Open US IND ✓ ✓ (complete) 2 Initiate Phase 1 FIH healthy volunteer POC study 3 Report Phase 1 SAD data (reported August 2021) ✓ Report Phase 1 MAD data 4 (expected 1Q 2022) CRINETICS PHARMACEUTICALS | 29
Slide 30: CRN04777: Oral Nonpeptide SST5 Agonist
CRN04777: AN INVESTIGATIONAL, POTENTIAL FIRST-IN-CLASS, ORAL NONPEPTIDE SST5 AGONIST Congenital hyperinsulinism (HI) CRINETICS PHARMACEUTICALS | 30
Slide 31: Congenital Hyperinsulinism Results in Recurrent Hypoglycemia
Congenital Hyperinsulinism Results in Life Threatening Recurrent Hypoglycemia Congenital HI patients secrete insulin Congenital HI is a devastating rare disease even when blood sugar is low • Untreated hypoglycemia can result in Low High neurodevelopment disorders and death blood blood • Early ident
Slide 32: Serious Unmet Medical Needs in Congenital HI
Serious Unmet Medical Needs in Congenital HI Intensive 24h-glucose management (monitoring, feeding, glucose tube) Current Standard of Care for Congenital HI Patient & Parent Goals Avoid hypoglycemia and its consequences including neurological damage Focal Diffuse Safely sleep through the night
Slide 33: Congenital HI Patient Care is a High Burden on Healthcare Systems
Congenital HI Patient Care is a High Burden on Healthcare Systems Current Challenges Healthcare utilization by a baby girl with Congenital HI • Variable time to diagnosis • Constant dextrose infusion to maintain normal blood sugar levels Born 2014, Original Congenital HI diagnosis 12/2014, First Dia
Slide 34: CRN04777: First-in-class Oral SST5 Agonist
CRN04777: First-in-class Oral SST5 Agonist with Potential to be Broadly Effective in HI Pancreas Directed to suppress insulin secretion Diazoxide Direct therapies Low High • Ineffective in 50%; black box warning IV glucose Off label use of injectable SST2 agonists Enteral dextrose (GT/NG) blood bloo
Slide 35: SST5 Inhibits Insulin Secretion Downstream of HI Mutations
SST5 Inhibits Insulin Secretion Downstream of all Known HI Causing Mutations CRN04777 Pancreas (SST5 Agonist) KATP channel Depolarization Ca2+ channel X SST5 receptor GLUT2 X Glucose sensing ATP/ADP Ca2+ Glucose Glycolysis Inhibition of insulin secretion X Amino acid metabolism Prevention of X Gluco
Slide 36: Proof of Mechanism in Animal Models and Patient Islets
Proof of Mechanism Achieved in Animal Models and Patient Islets CRN04777 suppressed sulfonylurea (SU)-induced CRNX SST5 agonist suppressed insulin from islets insulin secretion and reversed hypoglycemia in rats isolated from patient with Beckwith-Wiedemann Syndrome SU ‘4777 SU + 30 mg/kg CRN04777 Ve
Slide 37: CRN04777 SAD Study Design
CRN04777 SAD Study Design to Evaluate Pharmacologic Proof-of-Concept Follows Crinetics’ core endocrine strategy of using hormonal biomarkers to drive development Study Goals Pharmacodynamic Assessments • Evaluate safety [0.5-120 mg] 1. Intravenous Glucose Tolerance Test (IVGTT) • Evaluate pharmacoki
Slide 38: PK Results: CRN04777 Oral Bioavailability
PK Results: CRN04777 Showed Oral Bioavailability with Dose- Proportional Exposure Half-life ~40 hours and tmax ~1-2 hours at efficacious doses 120 mg 60 mg 27 mg 9 mg 3 mg 1 mg 0.5 mg LLOQ Data shown are mean±SEM; LLOQ = lower limit of quantitation All doses n=6; except n=12 for 60 mg which was eval
Slide 39: CRN04777 SAD Study: IVGTT Design
CRN04777 SAD Study Designed to Evaluate Pharmacologic Proof-of-Concept Follows Crinetics’ core endocrine strategy of using hormonal biomarkers to drive development Study Goals • Evaluate safety [0.5-120 mg] 1. Intravenous Glucose Tolerance Test (IVGTT) • Evaluate pharmacokinetics: oral absorption, d
Slide 40: CRN04777 Dose-Dependently Suppressed Glucose Stimulated Insulin Secretion
CRN04777 Dose-Dependently Suppressed Glucose Stimulated Insulin Secretion CRN04777 dose-dependently reduced insulin …and reduced insulin secretion reduces glucose uptake by secretion stimulated by bolus IV glucose (IVGTT)… tissues resulting in prolonged elevation of plasma glucose Bolus IV Bolus IV
Slide 41: CRN04777 SAD Study: Sulfonylurea Challenge Design
CRN04777 SAD Study Designed to Evaluate Pharmacologic Proof-of-Concept Follows Crinetics’ core endocrine strategy of using hormonal biomarkers to drive development Study Goals • Evaluate safety [0.5-120 mg] 2. Sulfonylurea (SU) Challenge • Evaluate pharmacokinetics: oral Baseline (Day -2) Treated (D
Slide 42: CRN04777 Reversed Sulfonylurea-Induced Hyperinsulinism
CRN04777 Reversed Sulfonylurea-Induced Hyperinsulinism in a Pharmacologic Model of Congenital HI CRN04777 eliminated the need for IV glucose support by inhibiting insulin secretion Glucose Infusion Rate (GIR) – Increases in Proportion to Insulin Secretion Placebo CRN04777 30 mg CRN04777 60 mg 6 6 6
Slide 43: Conclusions from CRN04777 SAD Results
Conclusions from CRN04777 SAD Results Objectives Safe and well tolerated at single doses from 0.5-120 mg • Safety and tolerability Achieved targeted pharmacokinetic profile • Drug-like • Rapidly absorbed after oral administration (tmax ~1-2 hrs) pharmacokinetics • Favorable half-life of ~40 hours ob
Slide 44: Recent and Anticipated CRN04777 Milestones
✓ Recent and Anticipated CRN04777 Milestones US Rare Pediatric Disease and EU Orphan Drug Designations 1 ✓ (received; CRNX may be eligible for priority review voucher in the US) 2 Initiate Phase 1 FIH healthy volunteer POC study 3 Report Phase 1 SAD data (reported September 2021) ✓ Report Phase 1 MA
Slide 45: Achieved 2021 Goal of Three Programs with Clinical Proof-of-Concept
Achieved 2021 Goal of Three Programs with Clinical Proof-of-Concept 1H21 2H21 1H22 2H22 Initiate Paltusotine Initiate PATHFNDR-2 PATHFNDR-1 and PATHFNDR-2 Ongoing PATHFNDR-1 SST2 Agonist for Acromegaly & NETs POC Achieved Initiate P2 NETs Trial Carcinoid Syndrome Phase 2 Ongoing in Carcinoid Syndrom
Slide 46: Appendices
APPENDICES CRINETICS PHARMACEUTICALS | 46
Slide 47: Key Patent Families Anchor a Robust IP Portfolio
Key Patent Families Anchor a Robust IP Portfolio Patent Family Subject Estimated Patent Status Priority Date Matter Expiration Paltusotine Portfolio Granted in: US, AU, IN Composition of Matter Pending in: foreign jurisdictions representing >96% of pharmaceutical July 2016 July 2037 markets Granted
Slide 48: Board of Directors
Board of Directors Wendell Wierenga, PhD Chairman (Former EVP R&D, Santarus) Scott Struthers, PhD Founder & CEO Matt Fust, MBA Former CFO, Onyx Weston Nichols, PhD Founder & Managing Partner, Lynx1 Capital Stephanie Okey, MS Former SVP, Genzyme Corporation Camille Bedrosian, MD Chief Medical Officer
Slide 49: Scientific Advisory Board
Scientific Advisory Board David Clemmons, MD Professor of Medicine at UNC, Chapel Hill President & CEO, Partners Healthcare Anne Klibanski, MD Former Chief of Neuroendocrine Unit at MGH & Professor of Medicine at Harvard Philip Harris, FRCP, PhD Chief Medical Officer, Isotopen Technologien München C
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