Slide 1: CRN04777: Phase 1 Multiple Ascending Dose (MAD) Preliminary Results
CRN04777: PHASE 1 MULTIPLE ASCENDING DOSE (MAD) PRELIMINARY RESULTS March 30, 2022
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: CRN04777 MAD Results Build on Pharmacologic Proof-of-Concept Data from SAD Study
CRN04777 MAD Results Build on Pharmacologic Proof-of-Concept Data from SAD Study Well-tolerated at doses from 30 mg to 120 mg administered once daily for 10 days • No Serious Adverse Events (SAEs) • All Adverse Events (AEs) considered mild/moderate Further demonstrated pharmacologic POC by showing d
Slide 4: Crinetics’ Endocrine Development Strategy
Crinetics’ Endocrine Development Strategy Preclinical POC Phase 2/3 Safety, ∆ Glucose & Disease Efficacy Hormones, ∆ Glucose & Hormones, PK, Safety PROs, PK, Safety Phase 1 Healthy Phase 2/3 Trials Volunteers (Patients) Phase 1 Healthy Volunteer Safety, Pharmacologic POC ∆ Glucose & Hormones, PK, Sa
Slide 5: Congenital Hyperinsulinism (HI) Results in Life Threatening Recurrent Hypoglycemia
Congenital Hyperinsulinism (HI) Results in Life Threatening Recurrent Hypoglycemia Congenital HI patients secrete insulin even when Congenital HI is a devastating rare blood sugar is low, causing hypoglycemia disease (U.S. prevalence = 1.5-2K) • Untreated hypoglycemia can result in life- Low High th
Slide 6: Unmet Medical Needs in Congenital HI are Very High
Unmet Medical Needs in Congenital HI are Very High Patient & Parent Goals Avoid hypoglycemia and its consequences including From Congenital Hyperinsulinism International’s 2022 Rare Disease Day neurological damage Awareness Campaign Safely sleep through the night Avoid pancreatectomy Elimina
Slide 7: Current Congenital HI Therapies have Limited Efficacy and Additional Shortcomings
Current Congenital HI Therapies have Limited Efficacy and Additional Shortcomings Direct Glucose Support Direct Low High Glucose blood blood In use: Support sugar sugar • Intravenous glucose sometimes requiring central venous administration Pancreas • Enteral dextrose delivered via a Glucagon Insuli
Slide 8: Current Congenital HI Therapies have Limited Efficacy and Additional Shortcomings
Current Congenital HI Therapies have Limited Efficacy and Additional Shortcomings Shortcomings related to safety, efficacy, & route of administration hamper congenital HI treatments Pancreas Directed to Suppress Insulin Secretion In use: Direct therapies Low High Diazoxide • Ineffective in ~50% of p
Slide 9: CRN04777: Oral SST5 Agonist with Potential to Overcome Shortcomings of Competing Therapies
CRN04777: Oral SST5 Agonist with Potential to Overcome Shortcomings of Competing Therapies Low High blood blood sugar sugar Pancreas CRN04777 in We believe CRN04777 is the only Glucagon Insulin Phase 1 investigational oral product (α-cells) (β-cells) candidate in clinical development that is designe
Slide 10: SST5 Inhibits Insulin Secretion Downstream of all Known HI Causing 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 11: CRN04777 MAD Study Designed to Build on SAD Pharmacologic Proof-of-Concept Data
CRN04777 MAD Study Designed to Build on SAD Pharmacologic Proof-of-Concept Data Follows Crinetics’ core endocrine strategy of using hormonal biomarkers to drive development MAD Study Goals Pharmacodynamic Assessments • Evaluate safety and tolerability with repeat dosing 1. Fasting plasma glucose and
Slide 12: CRN04777 was Well Tolerated with No Dose Discontinuations due to Adverse Events
CRN04777 was Well Tolerated with No Dose Discontinuations due to Adverse Events All causality treatment emergent adverse events Most Frequent Placebo (SAD+MAD) ‘4777 (SAD+MAD) • As expected, GI side effects (mild to moderate nausea, TEAEs (N=29) n (%) (N=78) n (%) vomiting, diarrhea) were the most c
Slide 13: MAD PK Results and Exposures were Consistent with Expectations from SAD Data
MAD PK Results and Exposures were Consistent with Expectations from SAD Data at the Same Doses Favorable PK results support once daily dosing Steady State PK Concentration-Time Profile at Steady State (Day 9) • Oral bioavailability • Favorable half-life of ~40 hours • Rapidly absorbed with a tmax of
Slide 14: Dose-Dependent Decrease in Fasting Insulin Led to Increases in Plasma Glucose
Dose-Dependent Decrease in Fasting Insulin Led to Increases in Plasma Glucose CRN04777 drove rapid and sustained changes in insulin and glucose levels in healthy volunteers Fasting Insulin Levels Plasma Glucose Levels 10 120 Plasma Glucose (mg/dL) 8 110 Insulin (mU/L) 6 100 4 90 2 0 80 1(a) 2 3 4 5
Slide 15: CRN04777 MAD Study Designed to Build on SAD Pharmacologic Proof-of-Concept Data
CRN04777 MAD Study Designed to Build on SAD Pharmacologic Proof-of-Concept Data Follows Crinetics’ core endocrine strategy of using hormonal biomarkers to drive development Sulfonylurea (SU) Challenge Sulfonylureas block KATP channels, Baseline (Day -2) inducing insulin secretion, mimicking Pancreas
Slide 16: CRN04777 Reversed SU-Induced Insulin Secretion in a Pharmacologic Model of Congenital HI
CRN04777 Reversed SU-Induced Insulin Secretion in a Pharmacologic Model of Congenital HI Insulin Levels Following Sulfonylurea (SU) Challenge Placebo QD `4777 30 mg QD `4777 60 mg QD `4777 120 mg QD 60 60 60 60 Day -2 (N=9) Day -2 (N=6) Day -2 (N=6) Day -2 (N=6) Day 10 (N=9) Day 10 (N=6) Day 10 (N=6
Slide 17: CRN04777 Reversed SU-Induced Hyperinsulinism in a Pharmacologic Model of Congenital HI
CRN04777 Reversed SU-Induced Hyperinsulinism in a Pharmacologic Model of Congenital HI CRN04777 eliminated the need for IV glucose support by inhibiting excess insulin secretion Glucose Infusion Rate (GIR) – Increases in Proportion to Insulin Secretion `4777 30 mg QD `4777 60 mg QD `4777 120 mg QD 8
Slide 18: Dose-Dependent Reduction in IV Glucose Support Needed to Maintain Normal Blood Glucose Levels
Dose-Dependent Reduction in IV Glucose Support Needed to Maintain Normal Blood Glucose Levels CRN04777 inhibited SU-induced insulin secretion & eliminated the need for IV glucose support Change in Insulin (AUC-55-120min) Change in Glucose Infusion Rate (AUC0-10h) 50% 20% 17% Compared to Baseline Com
Slide 19: SU Challenge / Glucose Clamp Study Designed to Mirror the Congenital HI Patient Experience
SU Challenge / Glucose Clamp Study Designed to Mirror the Congenital HI Patient Experience Crinetics’ goal is to obviate the need for IV dextrose and/or feeding tubes Mirroring Patient Experience • Sulfonylurea recapitulates the effects of the most common genetic mutations in congenital HI patients
Slide 20: Conclusions from CRN04777 Phase 1 Program
Conclusions from CRN04777 Phase 1 Program Objectives: CRN04777 was well tolerated in the Phase 1 program • Evaluate Safety and tolerability Favorable pharmacokinetics results support once-daily dosing • Rapidly absorbed after oral administration (tmax ~1-3 hrs.) • Evaluate Drug-like • Half-life of ~
Slide 21: Next Steps: Advancing Towards Program in Congenital HI Patients
Next Steps: Advancing Towards Program in Congenital HI Patients 1 Discuss program data package with global regulators Initiate program in congenital HI patients 2 (anticipated in 2H22) Continued engagement with international congenital HI 3 patient advocacy groups and Centers of Excellence CRINETICS
Slide 22: Pipeline Targets Multi-Billion $ Total Addressable Market with Internally Discovered Drug Candidates
Pipeline Targets Multi-Billion $ Total Addressable Market with Internally Discovered Drug Candidates NCE patent portfolio expected to provide protection into the 2040s Development Stage (Potential Registrational Endpoints) Prevalence PROGRAM US Global Range Preclin Phase 1 Phase 2 Phase 3 Total per
Slide 23: 2021 Accomplishments and Anticipated 2022 Milestones
2021 Accomplishments and Anticipated 2022 Milestones 2021 Accomplishments 2022 Accomplishments & Anticipated Milestones ✓ Initiated Ph 3 PATHFNDR program of paltusotine in acromegaly ✓ Strategic partnership for paltusotine in Japan ✓ Phase 1 POC data for CRN04894 ✓ CRN04777 MAD data in 1Q22 ✓ Phase