Slide 1: CRN04894: Phase 1 Multiple Ascending Dose (MAD) Preliminary Results
CRN04894: Phase 1 Multiple ascending dose (MAD) Preliminary Results May 25, 2022 Exhibit 99.1
Slide 2: Forward-looking statements
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 expectations. Such forward-look
Slide 3: CRN04894 MAD Results Support Moving to Patient Studies in Both CAH and Cushing's
CRN04894 MAD Results Support Moving to Patient Studies in Both CAH and Cushing’s MAD: Multiple-ascending dose SAD: Single-ascending dose; MTD: Maximum tolerated dose; POC: Proof-of-concept; PK: Pharmacokinetic; CAH: Congenital adrenal hyperplasia Favorable pharmacokinetics support goal of once daily
Slide 4: Crinetics' Endocrine Development Strategy: Hormone Levels from Preclinical to Approval
Crinetics’ Endocrine Development Strategy: Hormone Levels from Preclinical to Approval POC: Proof-of-concept; PK: Pharmacokinetic; PRO: Patient reported outcome Preclinical POC ∆Hormones, PK, Safety Phase 1 Healthy Volunteer Safety, Pharmacologic POC ∆Hormones, PK, Safety Phase 2,3 Safety, Disease E
Slide 5: The HPA Axis: The ACTH Receptor Is Key for Adrenal Activation
The Hypothalamic-Pituitary-Adrenal (HPA) Axis: The ACTH Receptor Is Key for Adrenal Activation Adrenal Gland cholesterol Cortisol Adrenal Cortical Cell ACTH Receptor (MC2/MRAP) cortisol Adrenal Androgens (e.g., A4) 21-hydroxylase negative feedback 17-OHP CRF AVP Hypothalamus Pituitary Stress ACTH Be
Slide 6: Disruptions in the HPA Axis Lead to Diseases of Excess ACTH
Normal Cushing’s Disease (CD) Congenital Adrenal Hyperplasia (CAH) Cause ACTH-secreting pituitary tumor Inability to produce cortisol leads to loss of negative feedback & excess ACTH US Prevalence (global incidence per 100,000) 10k (2.5-3.8) 27k (6.7-10.0) Symptoms Central obesity and round face; Do
Slide 7: Excess ACTH and Adrenal Activation Lead to Excess Cortisol in Cushing's and A4 in CAH
Normal Cushing’s Disease (CD) Congenital Adrenal Hyperplasia (CAH) Negative Feedback Unable to Regulate Excess ACTH from Tumor CRF AVP Pituitary Tumor Effect: Elevated Cortisol 1 Raff et al. Compr Physiol 2015, 2 Petersen Acta Pediatr Scand 1981, 3 NBIX ENDO Online 2020 presentation, 4 Oster et al.,
Slide 8: Current HPA Therapeutics Have Limited Efficacy and/or Safety Issues
Cortisol ACTH Pituitary Gland Pituitary Directed Agents to Suppress ACTH Secretion Available: glucocorticoids, pasireotide, cabergoline Limited efficacy Safety issues In Development: CRF antagonists (CAH only) Target Cells Glucocorticoid Receptor Antagonist Available: mifepristone Efficacy difficult
Slide 9: CRN04894: The First-in-Class ACTH Antagonist for ACTH Driven Diseases
Cortisol Pituitary Gland Pituitary Directed Agents to Suppress ACTH Secretion Available: glucocorticoids, pasireotide, cabergoline Limited efficacy Safety issues In Development: CRF antagonists (CAH only) Target Cells Glucocorticoid Receptor Antagonist Available: mifepristone Efficacy difficult to a
Slide 10: Healthy Volunteer MAD Study Designed to Build on SAD Pharmacologic POC Data
CRN04894 Healthy Volunteer MAD Study Designed to Build on SAD Pharmacologic POC Data MAD cohorts include 6 treated and 3 placebo per cohort MAD: Multiple-ascending dose; SAD: Single-ascending dose; POC: Proof-of-concept; PD: Pharmacodynamic; QD: Once daily; BID: Twice daily Follows Crinetics’ core e
Slide 11: Healthy Volunteer MAD Study Design
CRN04894 Healthy Volunteer MAD Study Designed to Build on SAD Pharmacologic POC Data ACTH Challenge (06:00) Screening d1 Baseline (d-1) d2 d3 d4 d5 d6 d7 d8 d9 24:00 24:00 24:00 24:00 24:00 24:00 24:00 24:00 24:00 24:00 24:00 24h profile 24h profile 24h profile ‘4894 or PBO* 24:00 t=-480’ (22:00) t=
Slide 12: CRN04894 was Well Tolerated: No Discontinuations due to Treatment Related AEs
CRN04894 was Well Tolerated: No Study Drug Discontinuations due to Treatment Related AEs As expected, glucocorticoid deficiency, defined as 08:00 cortisol level <5 mcg/dL, was the most common treatment related adverse event and seen only in MAD cohorts (8 during dosing, 4 after completion of dosing)
Slide 13: PK Supports Goal of Once Daily Oral Dosing
PK Supports Goal of Once Daily Oral Dosing Data represent mean ± SEM. N=1 subject was an outlier and excluded in 60 mg cohort; MAD: Multiple-ascending dose; SAD: Single-ascending dose; PK: Pharmacokinetics; BID: Twice daily Steady State PK Oral bioavailability Favorable half-life of ~24 hours Rapidl
Slide 14: Healthy Volunteers Have Expected Circadian Rhythm of Adrenal Activity at Baseline
Healthy Volunteers Have Expected Circadian Rhythm of Adrenal Activity (Cortisol) at Baseline Data represent mean ± SEM. Excluding subjects (n=1 in PBO, n=3 in active) with COVID-19 infection. PBO=placebo
Slide 15: CRN04894 Suppressed Peak Adrenal Activity Below Normal Levels in HVs
Administration of CRN04894 Suppressed Peak Adrenal Activity Below Normal Levels in HVs d2 d3 d4 d5 d6 d7 d8 d9 ‘4894 or PBO (22:00) Data represent mean ± SEM. Includes data from two subjects that required glucocorticoid replacement as per protocol (AM cortisol less than 5 mcg/dL) Cortisol (Hydrocort
Slide 16: Dose-Dependent Suppression of Serum Cortisol Below Normal Levels
Dose-Dependent Suppression of Serum Cortisol Below Normal Levels Day 9 Cortisol Profiles Change in Cortisol from Baseline ‘4894 or PBO AUC (0-24h) -17% -29% -37% 2% * * * * Data represent mean ± SEM. White asterisks in graph on upper right represent values for subjects who received glucocorticoid re
Slide 17: CRN04894 Potently Suppressed Adrenal Activity as Measured by Urinary Free Cortisol
CRN04894 Potently Suppressed Adrenal Activity as Measured by Urinary Free Cortisol Data shown are median ± IQR. Includes data from subjects receiving GC rescue 24-Hour Urinary Free Cortisol (day 9) Normalization of 24-hour urinary free cortisol has been the registrational endpoint for previously app
Slide 18: Loss of Cortisol Negative Feedback Resulted in Disease-Like ACTH
Loss of Cortisol Negative Feedback Resulted in HV ACTH Comparable to That Seen in Disease States Data shown are mean±SEM using Luminex assay which reports values ~3.9-fold lower than more commonly used clinical Roche assay; All subjects receiving GC add back (in addition to ‘4894) are pooled across
Slide 19: CRN04894 Maintained Cortisol Below Normal Levels After ACTH Challenge
CRN04894 Maintained Cortisol Below Normal Levels After ACTH Challenge Test on Top of Sustained Elevated ACTH Data shown are mean ± SEM; one subject in 80 mg MAD arm did not receive ACTH challenge; Placebo ACTH Challenge ‘4894 or PBO ACTH Challenge (1 mcg) Normal range for Healthy Volunteers at 06:00
Slide 20: CRN04894 Suppressed Adrenal Activity in Presence of Sustained, Disease-like ACTH Levels
CRN04894 Suppressed Adrenal Activity in Presence of Sustained, Disease-like ACTH Levels Adrenal Gland cholesterol Cortisol Adrenal Cortical Cell MC2/MRAP cortisol suppressed steroidogenesis Loss of negative feedback 17-OHP Adrenal Androgens (e.g., A4) CRN04894 21-hydroxylase CRF AVP Hypothalamus Pit
Slide 21: Results from Completed CRN04894 Phase 1 Program (SAD & MAD Cohorts)
Results from Completed CRN04894 Phase 1 Program (SAD & MAD Cohorts) Objectives Evaluate safety and tolerability Evaluate drug-like Pharmacokinetics Evaluate PK/PD for suppression of ACTH-induced adrenal activity Enable patient clinical studies CRN04894 was well tolerated in the Phase 1 program Achie
Slide 22: Key Treatment Goal for Cushing's Disease Patients
Key Treatment Goal for Cushing’s Disease Patients CD Treatment Objective Inhibit excessive cortisol secretion, which is associated with serious complications such as: Weight gain, obesity Insulin resistance, diabetes mellitus Hypertension Muscle weakness Neuropsychiatric disorders Impaired reproduct
Slide 23: Key Treatment Goals for CAH Patients
Key Treatment Goals for CAH Patients Figure adapted from: Merke D, Auchus R. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. New England Journal of Medicine. 2020;383(13):1248-1261.DOI: 10.1056 / NEJMra1909786 CAH Treatment Objectives Normalization of adrenal androgens (e.g., andros
Slide 24: Phase 1 Data Supports Advancing to Studies in Both CAH and Cushing's Disease Patients
Phase I Data Supports Advancing to Studies in Both CAH and Cushing’s Disease Patients CAH: Congenital adrenal hyperplasia; CD: Cushing’s disease Initiate clinical program in patients (anticipated 2H22) CAH: Targeting single efficacious QD dose Cushing’s Disease: Targeting patient specific QD dose ra
Slide 25: 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 PROGRAM Development Stage (Potential Registrational Endpoints) Prevalence Preclin Phase 1 Phase 2 Phase 3 US Total Global Range per
Slide 26: 2021 Accomplishments and Anticipated 2022 Milestones
2021 Accomplishments and Anticipated 2022 Milestones 2021 Accomplishments 2022 Accomplishments & Anticipated Milestones Strategic partnership for paltusotine in Japan CRN04777 MAD data in 1Q22 CRN04894 MAD data in 2Q22 Strengthened balance sheet CRN04777 patient program initiation in 2H22 CRN04894 p
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Slide 28: Dose-Dependent Suppression of Cortisol Below Normal Levels Despite Elevated ACTH
Dose-Dependent Suppression of Cortisol Below Normal Levels Despite Elevated ACTH -17% -29% -37% 2% AUC (0-24h) Day 9 Cortisol Profiles Change in Cortisol from Baseline ‘4894 or PBO * * * * Data represent mean ± SEM. White asterisks in graph on right represent values for subjects who received glucoco
Slide 29: Dose-Dependent Suppression of Cortisol Below Normal Levels Despite Elevated ACTH (8:00 Peak)
Dose-Dependent Suppression of Cortisol Below Normal Levels Despite Elevated ACTH -14% -50% -53% 1% 8:00 Peak Cortisol Day 9 Cortisol Profiles Change in Cortisol from Baseline ‘4894 or PBO Data represent mean ± SEM. White asterisks in graph on right represent values for subjects who received glucocor
Slide 30: Cushing's Disease and CAH Comparison with Normal HPA Axis
Normal Cushing’s Disease (CD) Congenital Adrenal Hyperplasia (CAH) Cause ACTH-secreting pituitary tumor Inability to produce cortisol leads to loss of negative feedback & excess ACTH US Prevalence (global incidence per 100,000) 10k (2.5-3.8) 27k (6.7-10.0) Symptoms Central obesity and round face; Do
Slide 31: CRN04894 Suppresses ACTH-Stimulated Cortisol Production
CRN04894 Suppresses ACTH-Stimulated Cortisol Production Add 40 mg AM dosing -40% -46% -46% -35% 0% Add # each group on GC replacement
Slide 32: Consider re-introducing 4894 as did in SAD
Consider re-introducing 4894 as did in SAD Preclinical potency Ph1 SAD PK Ph1 SAD PD at 2 hrs