Slide 1: CRN04894: Phase 1 Multiple Ascending Dose (MAD) Preliminary Results
‘Crinetics Pharmaceuticals CRNO4894: PHASE 1 MULTIPLE ASCENDING DOSE (MAD) PRELIMINARY RESULTS May 25, 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: CRN04894 MAD Results Support Moving to Patient Studies in Both CAH and Cushing's
CRNO4894 MAD Results Support Moving to Patient Studies in Both CAH and Cushing's Well tolerated at doses from 40 mg to 80 mg administered daily for 10 days * No Serious Adverse Events; All Adverse Events considered mild/moderate * MTD not reached: may allow further dose escalation in some patients i
Slide 4: Crinetics' Endocrine Development Strategy: Hormone Levels from Preclinical to Approval
Crinetics’ Endocrine Development Strategy: Hormone Levels from Preclinical to Approval Leveraging Highly Conserved Biology and Purpose-Built Molecules to Optimize Probability of Success in Diseases of High Unmet Need Phase 2,3 Safety, Preclinical POC Disease Efficacy AHormones, AHormones, PROs, PK,
Slide 5: The Hypothalamic-Pituitary-Adrenal (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 & ACTH Circadian aps a? . cholesterol ACTH acts exclusively through MC2/MRAP at adrenal gland ACTH Receptor (MC2/MRAP) 17-OHP. Vv / Q p week i | 0. or) Adrenal negative y oom ele Androgens ee
Slide 6: Disruptions in the HPA Axis Lead to Diseases of Excess ACTH and Excess Adrenal Activation
Disruptions in the HPA Axis Lead to Diseases of Excess ACTH and Excess Adrenal Activation | Normal =| Cushing's Disease (cd) | Cushing's Disease (CD) Congenital Adrenal Hyperplasia (CAH) Hypothalamus Negative Hypothalamus Feedback Unable to Regulate Negative Excess ACTH Loss of Feedback Negative fro
Slide 7: Cortisol profile: placebo vs '4894
20 Randomized to PBO (n=9) Randomized to '4894 (n=18) [Cortisol] (mcg/dL) 15 10 5 0 22:00 0 : 0 0 6 :0 0 1 2 :0 0 1 8 :0 0 2 4 :0 0 Clock Time
Slide 8: Pituitary Directed Agents to Suppress ACTH Secretion
Pituitary Directed Agents to Adrenal Steroidogenesis Glucocorticoid Receptor Suppress ACTH Secretion Inhibitors Antagonist Available: glucocorticoids, Available: ketoconazole/ Available: mifepristone pasireotide, cabergoline levoketoconazole • Efficacy difficult to assess • Limited efficacy metyrapo
Slide 9: CRN04894
Pituitary Directed Agents to ACTH Adrenal Steroidogenesis Glucocorticoid Receptor Suppress ACTH Secretion Receptor Inhibitors Antagonist Antagonist Available: glucocorticoids, Available: ketoconazole/ Available: mifepristone pasireotide, cabergoline levoketoconazole, • Efficacy difficult to assess •
Slide 10: CRN04894 Healthy Volunteer MAD Study Designed to Build on SAD Pharmacologic POC Data
CRNO04894 Healthy Volunteer MAD Study Designed to Build on SAD Pharmacologic POC Data Follows Crinetics’ core endocrine strategy of using hormonal biomarkers to drive development MAD Study Goals Evaluated Dosing Regimens + Evaluate safety and tolerability with repeat dosing * QD08:00 (8 am) dosing:
Slide 11: CRN04894 Healthy Volunteer MAD Study Designed to Build on SAD Pharmacologic POC Data
CRNO04894 Healthy Volunteer MAD Study Designed to Build on SAD Pharmacologic POC Data v v v v Vv v Vv v v 24h profile 24h profile 24h profile 24h profile [71 J 1 1 1 1 1 1 1 1 T T T T T T T Screening 24:00 24:00 2400 24:00 24:00 24:00 24:00 Baseline dl d2 d3 d4 d5 (d-1) 24h Profile GC Replacement Pr
Slide 12: CRN04894 was Well Tolerated: No Study Drug Discontinuations due to Treatment Related AEs
CRNO4894 was Well Tolerated: No Study Drug Discontinuations due to Treatment Related AEs No Serious Adverse Events. All Adverse events considered mild/moderate Treatment emergent adverse events in 22 ‘4894 treated subjects * As expected, glucocorticoid deficiency, defined as 08:00 Most Frequent Plac
Slide 13: CRN04894 Plasma Conc. (ng/mL)
• CRN04894 Plasma Conc. (ng/mL) • 1000 • • M2 40 mg (n=6) • M3 60 mg (n=5) M4 80 mg (n=6) 100 0 4 8 12 16 20 24 Time (hr)
Slide 14: Cortisol profile: placebo vs '4894
20 Randomized to PBO (n=9) Randomized to '4894 (n=18) [Cortisol] (mcg/dL) 15 10 5 0 22:00 0 : 0 0 6 :0 0 1 2 :0 0 1 8 :0 0 2 4 :0 0 Clock Time
Slide 15: Cortisol at 08:00 by day
20 [Cortisol] (mcg/dL) 15 10 5 0 Baseline 08:00 08:00 08:00 08:00 08:00 08:00 08:00 08:00 08:00 08:00 d2 d3 d4 d5 d6 d7 d8 d9 PBO (n=15) '4894 80 mg (n=6)
Slide 16: Cortisol 24h AUC percent change from baseline
Day 9-10, CORT 24h AUC Perchage Change from Baseline (%CFB) 20 25% 0 25% [Cortisol] (mcg/dL) 15 CORT %CFB -25% 0 10 CORT %CFB 25% -50% -25% 5 -75%0 -50% CORT %CFB -25% -100% 0 -75% PBO MAD2 MAD3 MAD4 22:00 0 : 0 0 6 :0 0 1 2 :0 0 1 8 :0 0 2 4 :0 0 (n=15) 40 mg 60 mg 80 mg -50% Nighttime Nighttime Ni
Slide 17: CRN04894 Potently Suppressed Adrenal Activity as Measured by Urinary Free Cortisol
CRNO4894 Potently Suppressed Adrenal Activity as Measured by Urinary Free Cortisol 24-Hour Urinary Free Cortisol (day 9) pol eee cece seeescecvevececseeeesesestvsvevesseveees Normalization of 24-hour urinary free cortisol has been the registrational endpoint for previously approved Cushing's disease
Slide 18: ACTH(1-39) (pg/mL)
• 100 ACTH(1-39) (pg/mL) • 50 • 0 22:00 0 : 0 0 6 :0 0 1 2 :0 0 1 8 :0 0 2 4 :0 0 Clock Time • PBO (n=9) '4894 80 mg (n=4) Subject on GC (n=4)
Slide 19: Cortisol after ACTH challenge
PBO (n=12) 20 '4894 80 mg nighttime (n=5) [Cortisol] (mcg/dL) 15 10 5 0 22:00 06:00 06:15 06:30 07:00 07:30 08:00 Time (min) ±
Slide 20: CRN04894 Suppressed Adrenal Activity in Presence of Sustained, Disease-like ACTH Levels
CRNO4894 Suppressed Adrenal Activity in Presence of Sustained, Disease-like ACTH Levels Adrenal Gland (i) ae ACTH Circadian (Elevated) 5 ACTH acts exclusively Go" through MC2/MRAP at wo adrenal gland cholesterol CRNO4894 Cortisol Q OH / Adrenal HOLA, Dat Androgens pb? A Aya Loss of A - — Multiple pa
Slide 21: Results from Completed CRN04894 Phase 1 Program (SAD & MAD Cohorts)
Results from Completed CRNO4894 Phase 1 Program (SAD & MAD Cohorts) Objectives CRNO04894 was well tolerated in the Phase 1 program + Evaluate safety and tolerability Achieved targeted pharmacokinetic profile Y + Rapidly absorbed after oral administration (t,,3, ~1-2 hrs) Evaluate drug-like + Dose pr
Slide 22: Key Treatment Goal for Cushing's Disease Patients
Key Treatment Goal for Cushing's Disease Patients Goal: prevent complications of excessive cortisol secretion CD Treatment Objective Select Comorbidities Associated with CD ————_ Neuropsychiatric Disorders Inhibit excessive cortisol secretion, which is associated with serious complications such as:
Slide 23: Key Treatment Goals for CAH Patients
Key Treatment Goals for CAH Patients Goal: reduce symptoms of androgen excess and excess glucocorticoid treatment-related complications CAH Treatment Objectives CAH Symptoms/Complications — & Brain + Androgenization effects + Glucocorticoid effects + Decreased quality of life + Increased anxiety and
Slide 24: Phase 1 Data Supports Advancing to Studies in Both CAH and Cushing's Disease Patients
Phase | Data Supports Advancing to Studies in Both CAH and Cushing's Disease Patients Next Steps Review ‘4894 data package and discuss patient program with global regulators * Seek confirmation of proposed dose range (40 to >8Omg QD) * Feedback on P2 trial designs * Seek guidance on registration req
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 PROGRAM Development Stage (Potential Registrational Endpoints) Preclin Phase 1 Phase 2 Phase 3 Prevalence Global Range per 100,000 Paltusotine (SST2 agonist) Pharmacologic POC Acromegaly ; _ ; 26K 28
Slide 26: 2021 Accomplishments and Anticipated 2022 Milestones
2021 Accomplishments and Anticipated 2022 Milestones 2021 Accomplishments 2022 Accomplishments & Anticipated Milestones Initiated Ph 3 PATHFNDR program inei Strategic partnership for paltusotine in Japan of paltusotine in acromegaly gic p P for p p CRNO4777 MAD data in 1Q22 JY Phase 1 POC data for C