Slide 1: CRN04777: First in Human Single Ascending Dose (SAD) Preliminary Results
CRN04777: FIRST IN HUMAN SINGLE ASCENDING DOSE (SAD) PRELIMINARY RESULTS September 15, 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: Phase 1 Pharmacologic Proof-of-Concept for CRN04777 in Healthy Volunteers
Phase 1 Pharmacologic Proof-of-Concept for CRN04777 in Healthy Volunteers • Well-tolerated Safety Results • No Serious Adverse Events (SAEs) • All Adverse Events (AEs) considered mild/moderate Pharmacokinetics • Orally bioavailable with dose proportional pharmacokinetics Results • Evidence of clinic
Slide 4: Crinetics' Endocrine Development Strategy: Hormone Levels from Preclinical to Approval
Crinetics’ Endocrine Development Strategy: Hormone Levels from Preclinical to Approval 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, P
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 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
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 neurological damage Safely sleep through the night Avoid pancreatectomy Eliminate feeding tubes Reduce injections and glucose sticks Avoid side effects of diazoxide
Slide 7: CRN04777: First-in-class Oral SST5 Agonist with Potential to be Broadly Effective in HI
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 8: Somatostatin Receptor SST5 Inhibits Insulin Secretion Downstream of all Known HI Causing Mutations
Somatostatin Receptor 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
Slide 9: CRN04777 is the Only Oral SST5 Agonist in Clinical Development
CRN04777 is the Only Oral SST5 Agonist in Clinical Development CRN04777 suppressed sulfonylurea (SU)- CRN04777 is a potent (EC50=0.4 nM) and induced insulin secretion and reversed selective SST5 agonist hypoglycemia in rats hSST1 SU ‘4777 hSST2 hSST3 hSST4 hSST5 SU + 30 mg/kg CRN04777 Vehicle SU + 1
Slide 10: CRN04777 SAD Study Design to Evaluate Pharmacologic Proof-of-Concept
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 11: PK Results: CRN04777 Showed Oral Bioavailability with Dose-Proportional Exposure
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 12: CRN04777 SAD Study Designed to Evaluate Pharmacologic Proof-of-Concept
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 13: 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 14: CRN04777 SAD Study Designed to Evaluate Pharmacologic Proof-of-Concept
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 15: Sulfonylurea Challenge Provided Disease Relevant Proof-of-Concept
Sulfonylurea Challenge Provided Disease Relevant Proof-of-Concept The administration of sulfonylurea is a pharmacologic model of congenital HI Sulfonylureas block KATP channels, inducing insulin secretion, mimicking Pancreas most common and severe monogenic Sulfonylurea Challenge form of congenital
Slide 16: CRN04777 Reversed Sulfonylurea-Induced Hyperinsulinism in a Pharmacologic Model of Congenital HI
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 17: 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 18: Pipeline With Three Candidates Beyond Pharmacologic Proof-of-Concept
Pipeline With Three Candidates Beyond Pharmacologic Proof-of-Concept Development Stage Prevalence Registrational PROGRAM Preclin Phase 1 Phase 2 Phase 3 Endpoint Global Range US Total per 100,000 Paltusotine (SST2 agonist) Pharmacologic POC Acromegaly IGF-1 Levels 26K 2.8 – 13.0 Carcinoid Syndrome D
Slide 19: 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