Slide 1: CRN04894: First in Human Single Ascending Dose (SAD) Preliminary Results
CRN04894: FIRST IN HUMAN SINGLE ASCENDING DOSE (SAD) PRELIMINARY RESULTS August 10, 2021
Slide 2: Safe Harbor Statement
Safe Harbor Statement This presentation contains forward-looking statements. Crinetics cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the company’s current beliefs and expectat
Slide 3: Phase 1 Pharmacologic Proof-of-Concept for CRN04894 in Healthy Volunteers
Phase 1 Pharmacologic Proof-of-Concept for CRN04894 in Healthy Volunteers PK Results • Orally bioavailable, dose proportional pharmacokinetics • Well-tolerated Safety Results • No Serious Adverse Events (SAEs) • All Adverse Events (AEs) considered mild • Dose-dependent reduction of basal cortisol le
Slide 4: Crinetics' Endocrine Development Strategy: Hormone Levels from Preclinical to Approval
Crinetics’ Endocrine Development Strategy: 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, Pharmacologic POC ∆Horm
Slide 5: Harvey Cushing
Harvey Cushing CRINETICS PHARMACEUTICALS | 5
Slide 6: The HPA Axis is the Body's Emergency Response System for Stress
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 7: HPA Axis: Cortisol Levels Rise and Fall in a Diurnal Rhythm
Hypothalamic-Pituitary-Adrenal (HPA) Axis: Cortisol Levels Rise and Fall in a Diurnal Rhythm Time course of plasma cortisol levels over a diurnal cycle Normal Biology Plasma Cortisol, mcg/dL 30 Pituitary gland Cushing’s Disease Patients1 secretes ACTH 20 ACTH 10 Adrenal Healthy Subjects1 0 Cortisol
Slide 8: Hypothesis: An Oral, Selective ACTH Antagonist Will Have Utility in Treating Diseases of ACTH Excess
Hypothesis: An Oral, Selective ACTH Antagonist Will Have Utility in Treating Diseases of ACTH Excess Normal Cushing’s Disease (CD) Congenital Adrenal Hyperplasia (CAH) Hypothalamus Hypothalamus Hypothalamus CRF CRF stress CRF Pituitary Pituitary Pituitary negative feedback AVP X AVP Loss of adenoma
Slide 9: There Are No ACTH Receptor Blocking Agents Available to Treat ACTH Driven Diseases
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 10: 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 11: CRN04894 SAD Study Design to Establish Pharmacologic Proof-of-Concept
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 12: PK Results: CRN04894 Showed Oral Bioavailability With Dose-Proportional Exposure
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 | 12
Slide 13: CRN04894 Rapidly Reduced Basal Cortisol Output from Adrenal Glands
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 14: Dose-Dependent Suppression of Cortisol Following Supra-Pathophysiologic 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 15: Clinically Meaningful Cortisol Suppression in Response to Disease-relevant ACTH Challenge (1 mcg)
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 16: 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 17: CRN04894: First-in-Class ACTH Antagonist for ACTH Driven Diseases
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 18: Pipeline With Two Candidates Beyond Pharmacologic Proof-of-Concept
Pipeline With Two 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 Dia
Slide 19: On Track to Achieve 2021 Goal of Three Programs with Proof-of-Concept Demonstrated in the Clinic
On Track to Achieve 2021 Goal of Three Programs with Proof-of-Concept Demonstrated in the Clinic Q1 Q2 Q3 Q4 Initiate Paltusotine Initiate PATHFNDR-2 PATHFNDR-1 SST2 Agonist for Acromegaly & NETs POC Achieved Initiate Phase 2 NETs Trial in Carcinoid Syndrome Initiate Phase 1 CRN04894 Phase 1 SAD Dat