PALSONIFY

1 INDICATIONS AND USAGE PALSONIFY is indicated for the treatment of adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option. PALSONIFY is a somatostatin receptor agonist indicated for the treatment of adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option ( 1 ).

2 DOSAGE AND ADMINISTRATION Take orally once daily with water on an empty stomach (at least 6 hours after a meal) and at least 1 hour before the next meal ( 2.1 ). Recommended initial dosage is 40 mg once daily. During initiation, PALSONIFY may be temporarily reduced to 20 mg once daily if needed, based on tolerability. Once adverse reactions have resolved, resume PALSONIFY 40 mg once daily ( 2.2 ). After 2 to 4 weeks, based on IGF-1 levels, titrate to 60 mg once daily ( 2.2 ). 2.1 Important Administration Instructions Take PALSONIFY orally once daily with water on an empty stomach, at least 6 hours after a meal (e.g., after overnight fasting) and at least 1 hour before the next meal [see Clinical Pharmacology ( 12.3 )] . 2.2 Recommended Dosage, Titration, and Monitoring The recommended initial dosage of PALSONIFY is 40 mg once daily. During initiation period, PALSONIFY may be temporarily reduced to 20 mg once daily if needed, based on tolerability [see Adverse Reactions ( 6.1 )] . Once adverse reactions have resolved, resume PALSONIFY 40 mg once daily. After 2 to 4 weeks on PALSONIFY 40 mg once daily, based on IGF-1 levels, titrate to a PALSONIFY dosage of 60 mg once daily. 2.3 Dosage Modifications for Drug Interactions Concomitant Use with Strong CYP3A4 Inducers Patients taking strong CYP3A4 inducers may require an increased dosage of PALSONIFY. Do not exceed three-fold the PALSONIFY dosage prior to concomitant use or 120 mg daily, whichever is less [see Drug Interactions ( 7.1 )] . Concomitant Use with Moderate CYP3A4 Inducers Patients taking moderate CYP3A4 inducers may require an increased dosage of PALSONIFY. Do not exceed two-fold the PALSONIFY dosage prior to concomitant use or 120 mg daily, whichever is less [see Drug Interactions ( 7.1 )] . Concomitant Use with Proton Pump Inhibitors Patients taking proton pump inhibitors may require an increased dosage of PALSONIFY. Avoid concomitant use of proton pump inhibitors in patients who are already on PALSONIFY 60 mg [see Drug Interactions ( 7.1 )] .

3 DOSAGE FORMS AND STRENGTHS PALSONIFY Tablets: 20 mg: pink, biconvex oval tablets, debossed with “PAL” on one side and “20” on the other side; contains 20 mg paltusotine free base. 30 mg: yellow, biconvex oval tablets, debossed with “PAL” on one side and “30” on the other side; contains 30 mg paltusotine free base. Tablets: 20 mg, 30 mg ( 3 )

4 CONTRAINDICATIONS None. None ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions ( 5.1 )] Hyperglycemia and Hypoglycemia [see Warnings and Precautions ( 5.2 )] Cardiovascular Abnormalities [see Warnings and Precautions ( 5.3 )] Thyroid Function Abnormalities [see Warnings and Precautions ( 5.4 )] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions ( 5.5 )] Changes in Vitamin B 12 Levels [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (≥5%) are diarrhea, abdominal pain, nausea, decreased appetite, sinus bradycardia, hyperglycemia, palpitations, and gastroenteritis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Crinetics Pharmaceuticals, Inc. at toll-free phone 1-833-CRN-INFO or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PALSONIFY was evaluated in adults with acromegaly in two randomized, double-blind, placebo-controlled Phase 3 studies. Study 1 was a 24-week, randomized, placebo-controlled study in 111 adults who were naive or previously treated on a somatostatin analog and biochemically uncontrolled at randomization. Participants in Study 1 had a mean age of 47 years (range: 18 to 80 years) and were randomized to PALSONIFY (n=54) or placebo (n=57) [see Clinical Studies ( 14.1 )] . Study 2 was a 36-week, randomized, placebo-controlled study in 58 adults who were biochemically controlled on injectable depot formulations of octreotide or lanreotide. Participants in Study 2 had a mean age of 55 years (range: 29 to 84 years) and were randomized to PALSONIFY (n=30) or placebo (n=28) [see Clinical Studies ( 14.2 )] . Adverse Reactions Adverse reactions that occurred in ≥5% of PALSONIFY-treated participants and 5% greater incidence than placebo in the randomized-controlled phase of Study 1 and Study 2 are presented in Table 1 and Table 2 , respectively. Adverse reactions presented in Table 1 and Table 2 exclude events which occurred after a participant received rescue therapy (Study 1 PALSONIFY n=1, placebo n=13; Study 2 PALSONIFY n=1, placebo n=17). Table 1. Adverse Reactions Occurring in ≥5% of PALSONIFY-Treated Participants and 5% Greater Incidence than Placebo-Treated Participants During the Randomized Controlled Period of Study 1 a Abdominal pain also includes abdominal discomfort. b Hyperglycemia also includes impaired fasting glucose and diabetes mellitus. Adverse Reaction PALSONIFY N=54 n (%) Placebo N=57 n (%) Diarrhea 18 (33) 8 (14) Abdominal pain a 10 (19) 3 (5) Nausea 5 (9) 1 (2) Sinus bradycardia 4 (7) 0 Hyperglycemia b 4 (7) 1 (2) Table 2. Adverse Reactions Occurring in ≥5% of PALSONIFY-Treated Participants and 5% Greater Incidence than Placebo-Treated Participants During the Randomized Controlled Period of Study 2 a Decreased appetite also includes early satiety. Adverse Reaction PALSONIFY N=30 n (%) Placebo N=28 n (%) Diarrhea 7 (23) 3 (11) Nausea 4 (13) 1 (4) Decreased appetite a 3 (10) 0 Palpitations 2 (7) 0 Gastroenteritis 2 (7) 0 Gastrointestinal Gastrointestinal adverse reactions, including diarrhea, nausea, and abdominal pain were reported in participants from Studies 1 and 2 (see Table 1 and Table 2 ). Most gastrointestinal adverse reactions occurred within the first two months of PALSONIFY treatment initiation and had a median duration ranging between 6 to 18 days. Other Adverse Reactions from Studies 1 and 2 Cholelithiasis and its Complications Cholelithiasis and its complications were reported in 10/173 (6%) participants during Studies 1 and 2 as follows: cholelithiasis (n=8), acute cholecystitis, biliary colic, and bile duct stone (on …

7 DRUG INTERACTIONS Strong CYP3A4 Inducers: may decrease paltusotine exposure. May require PALSONIFY dosage increase ( 2.3 , 7.1 ). Moderate CYP3A4 Inducers: may decrease paltusotine exposure. May require PALSONIFY dosage increase ( 2.3 , 7.1 ). Proton Pump Inhibitors: may decrease paltusotine exposure. May require PALSONIFY dosage increase ( 2.3 , 7.1 ) Cyclosporine: may decrease cyclosporine exposure. May require cyclosporine dosage adjustment ( 7.2 ). 7.1 Effect of Other Drugs on PALSONIFY Table 3. Clinically Significant Interactions Affecting PALSONIFY Strong CYP3A4 Inducers Intervention Concomitant use of PALSONIFY with strong CYP3A4 inducers may require an increased dosage of PALSONIFY, not to exceed three-fold the dose prior to concomitant use or 120 mg daily, whichever is less. Clinical Impact Concomitant use of PALSONIFY with strong CYP3A4 inducers reduced paltusotine exposure and may affect therapeutic response [see Clinical Pharmacology ( 12.3 )]. Moderate CYP3A4 Inducers Intervention Concomitant use of PALSONIFY with moderate CYP3A4 inducers may require an increased dosage of PALSONIFY, not to exceed two-fold the dose prior to concomitant use or 120 mg daily, whichever is less. Clinical Impact Concomitant use of PALSONIFY with moderate CYP3A4 inducers resulted in a decrease in paltusotine exposure [see Clinical Pharmacology ( 12.3 )]. Proton Pump Inhibitors Intervention Concomitant use of PALSONIFY with PPIs may require an increased dosage of PALSONIFY. Patients who are already on PALSONIFY 60 mg should avoid concomitant use with proton pump inhibitors. Clinical Impact Concomitant use of PALSONIFY with proton pump inhibitors demonstrated a dose-dependent decrease in paltusotine exposure [see Clinical Pharmacology ( 12.3 )]. 7.2 Effect of PALSONIFY on Other Drugs Table 4. Clinically Significant Interactions Affecting Other Drugs Cyclosporine Intervention Adjustment of cyclosporine dose to maintain therapeutic levels may be necessary. Follow recommended therapeutic drug monitoring for cyclosporine. Clinical Impact Concomitant use of PALSONIFY with cyclosporine resulted in a decrease in cyclosporine bioavailability [see Clinical Pharmacology ( 12.3 )].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The available data with PALSONIFY use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no malformations were observed with oral administration of paltusotine to pregnant rats and rabbits during organogenesis at exposures 11 and 3 times the human exposure at the maximum recommended human dose (MRHD) of 60 mg once daily, respectively (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant rats, paltusotine was administered orally at 25, 75, and 500 mg/kg/day during the period of organogenesis from gestation Day 7 to 17. The NOAEL for maternal and embryo-fetal developmental toxicity was 500 mg/kg/day, as no paltusotine-related effects were observed on any ovarian, uterine or litter parameters (approximately 11 times the MRHD based on AUC). In an embryo-fetal development study in pregnant rabbits, paltusotine was administered orally at 10, 25, and 75 mg/kg/day during the period of organogenesis from gestation Day 7 to 19. Maternal findings included an increased incidence of spontaneous abortions at 75 mg/kg/day, with decreased body weight gain, body weights, and food consumption. No fetal abnormalities were observed at any dose. Lower fetal body weight was noted at 75 mg/kg/day. The NOAEL for maternal and embryo-fetal developmental toxicity was 25 mg/kg/day (approximately 3 times the MRHD based on AUC). In a pre- and postnatal development study, pregnant rats were given paltusotine orally at the doses of 25, 75, and 500 mg/kg/day from gestation Day 6 to lactation Day 20. Paltusotine had no effect on the growth and development of offspring up to the highest tested dose of 500 mg/kg (5 times MRHD based on AUC). In a single dose pharmacokinetic study, oral administration of paltusotine at 25 mg/kg or 500 mg/kg paltusotine to pregnant rats showed measurable paltusotine concentrations in embryos and fetuses, demonstrating placental transfer. Overall, the embryo and fetal concentrations were generally low when compared to maternal concentrations. 8.2 Lactation Risk Summary There is no information available on the presence of paltusotine in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Paltusotine is present in animal milk (see Data ). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PALSONIFY and any potential adverse effects on the breastfed infant from PALSONIFY or from the underlying maternal condition. Data Paltusotine concentrations were elevated 2.4- to 3.8-fold in rat milk compared to plasma during animal studies. Paltusotine concentrations in plasma and maternal milk suggest that rat pups were likely exposed in utero and/or via lactational transfer. The concentration of paltusotine in animal milk does not necessarily predict the concentration of paltusotine in human milk. 8.4 Pediatric Use The safety and efficacy of PALSONIFY have not been established in pediatric patients. 8.5 Geriatric Use In the Phase 3 studies 17/84 (20.2%) PALSONIFY-treated participants were ≥65 years of age. No overall differences in safety or effectiveness of PALSONIFY have been observed between participants 65 years of age and older and younger adult participants. No dose adjustments are required based on age [see Clinical Pharmacology ( 12.3 )] . 8.6 Hepatic Impairm …

12.1 Mechanism of Action Similar to the natural hormone somatostatin, paltusotine suppresses growth hormone (GH) and insulin-like growth factor-1 (IGF-1) secretion. Paltusotine exerts its pharmacological activity via selective agonism (>4000-fold) at somatostatin receptor 2 (SSTR2) and exhibits little or no affinity for other SST receptor subtypes. Paltusotine inhibited cyclic adenosine monophosphate accumulation via human SSTR2 activation with an average drug (agonist) concentration that results in half-maximal response (EC 50 ) of 0.25 nM.

11 DESCRIPTION PALSONIFY tablets contain paltusotine hydrochloride, a somatostatin receptor agonist. Paltusotine is known chemically as 3-[4-(4-Amino-1-piperidinyl)-3-(3,5-difluorophenyl)-6-quinolinyl]-2-hydroxybenzonitrile hydrochloride. The molecular weight of paltusotine hydrochloride is 492.95 g/mol (C 27 H 22 F 2 N 4 O·HCl). PALSONIFY tablets for oral administration contain 20 mg of paltusotine (equivalent to 21.6 mg of paltusotine hydrochloride) or 30 mg of paltusotine (equivalent to 32.4 mg of paltusotine hydrochloride). Each tablet contains the following inactive ingredients: colloidal silicon dioxide, copovidone, crospovidone, magnesium stearate, mannitol, and microcrystalline cellulose. Additionally, the 20 mg tablets contain Opadry pink coating (hypromellose, iron oxide red, iron oxide yellow, titanium dioxide, and triacetin) and the 30 mg tablets contain Opadry yellow coating (hypromellose, iron oxide yellow, titanium dioxide, and triacetin). Figure

10 OVERDOSAGE Overdose with somatostatin analogs may result in hyperglycemia or hypoglycemia, bradycardia, arrhythmia, diarrhea, vomiting, and other gastrointestinal symptoms. If overdose is suspected, initiate supportive treatment as dictated by patient's clinical status.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied PALSONIFY is provided in two strengths: 20 mg and 30 mg. Table 8. PALSONIFY Configurations and NDC Numbers Strength Tablet Color/Shape Imprint NDC Package Size 20 mg Pink; biconvex oval shape “PAL” on one side; “20” on other side 84015-920-60 Bottle of 60 tablets 30 mg Yellow; biconvex oval shape “PAL” on one side; “30” on other side 84015-930-60 Bottle of 60 tablets Storage and Handling PALSONIFY tablets are packaged in a child-resistant container; keep out of reach of children. Store tablets at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Excursions permitted 15°C to 30°C (59°F to 86°F). Store and dispense in original container or USP equivalent tight container.