Healthful Living Rx: MASH Clinical Perspectives

REZDIFFRA ® (resmetirom) Brief Summary of full Prescribing Information INDICATIONS AND USAGE

Adverse Reactions Leading to Discontinuations The exposure-adjusted incidence rates (EAIRs) per 100 person-years (PY) for treatment discontinuation due to any adverse reaction were higher in the REZDIFFRA dosage arms: 4 per 100 PY, 5 per 100 PY, and 8 per 100 PY in placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Diarrhea and nausea were the most common causes of treatment discontinuation. Common Adverse Reactions Table 1 displays EAIRs per 100 PY for the common adverse reactions that occurred in at least 5% of patients with F2 or F3 fibrosis treated in either drug arm with REZDIFFRA and were greater than that reported for placebo. Table 1: Exposure-Adjusted Incidence Rates (EAIR) of Common Adverse Reactions Reported with REZDIFFRA in Adult Patients with Noncirrhotic NASH (Trial 1) a, b, c Adverse Reactions Leading to Discontinuations The exposure-adjusted incidence rates (EAIRs) per 100 person-years (PY) for treatment discontinuation due to any adverse reaction were higher in the REZDIFFRA dosage arms: 4 per 100 PY, 5 per 100 PY, and 8 per 100 PY in placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Diarrhea and nausea were the most common causes of treatment discontinuation. Common Adverse Reactions Table 1 displays EAIRs per 100 PY for the common adverse reactions that occurred in at least 5% of patients with F2 or F3 fibrosis treated in either drug arm with REZDIFFRA and were greater than that reported for placebo. Table 1: Exposure-Adjusted Incidence Rates (EAIR) of Common Adverse Reactions Reported with REZDIFFRA in Adult Patients with Noncirrhotic NASH (Trial 1) a, b, c

REZDIFFRA is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of NASH and fibrosis [see Clinical Studies (14) in the full Prescribing Information] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitations of Use Avoid use of REZDIFFRA in patients with decompensated cirrhosis [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) in the full Prescribing Information] . CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hepatotoxicity Hepatotoxicity has been observed with use of REZDIFFRA. One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received REZDIFFRA 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted. After reinitiating REZDIFFRA, the patient had elevations of ALT, AST, and TB. Peak values observed were 58 x upper limit of normal (ULN) for ALT, 66 x ULN for AST, 15 x ULN for TB, with no elevation of alkaline phosphatase (ALP). Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels, suggesting drug-induced autoimmune-like hepatitis (DI-ALH). The liver tests returned to baseline following hospitalization and discontinuation of REZDIFFRA without any therapeutic intervention. Monitor patients during treatment with REZDIFFRA for elevations in liver tests and for the development of liver-related adverse reactions. Monitor for symptoms and signs of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue REZDIFFRA and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting REZDIFFRA. If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests. Gallbladder-Related Adverse Reactions In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in REZDIFFRA-treated patients than in placebo- treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, interrupt REZDIFFRA treatment until the event is resolved [see Adverse Reactions (6.1) in the full Prescribing Information] . Drug Interaction with Certain Statins An increase in exposure of atorvastatin, pravastatin, rosuvastatin and simvastatin was observed when concomitantly administered with REZDIFFRA [see Clinical Pharmacology (12.3) in the full Prescribing Information] , which may increase the risk of adverse reactions related to these drugs. Dosage adjustment for certain statins is recommended [see Drug Interactions (7.2) in the full Prescribing Information] . Monitor for statin-related adverse reactions including but not limited to elevation of liver tests, myopathy, and rhabdomyolysis. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hepatotoxicity [see Warnings and Precautions (5.1) in the full Prescribing Information] • Gallbladder-Related Adverse Reactions [see Warnings and Precautions (5.2) in the full Prescribing Information] 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 with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of REZDIFFRA was evaluated in two randomized, double-blind, placebo- controlled trials that enrolled a total of 2019 patients. Trial 1 Trial 1 included patients who had noncirrhotic NASH with stages F2 and F3 fibrosis at eligibility (n=888) [see Clinical Studies (14) in the full Prescribing Information] . Trial 1 included patients who had noncirrhotic NASH with stages F2 and F3 fibrosis at eligibility (n=888) [see Clinical Studies (14) in the full Prescribing Information] . An increase in exposure of atorvastatin, pravastatin, rosuvastatin and simvastatin was observed when concomitantly administered with REZDIFFRA [see Clinical Pharmacology (12.3) in the full Prescribing Information] , which may increase the risk of adverse reactions related to these drugs. Dosage adjustment for certain statins is recommended [see Drug Interactions (7.2) in the full Prescribing Information] . Monitor for statin-related adverse reactions including but not limited to elevation of liver tests, myopathy, and rhabdomyolysis. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hepatotoxicity [see Warnings and Precautions (5.1) in the full Prescribing Information] • Gallbladder-Related Adverse Reactions [see Warnings and Precautions (5.2) in the full Prescribing Information] 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 with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of REZDIFFRA was evaluated in two randomized, double-blind, placebo- controlled trials that enrolled a total of 2019 patients. Trial 1 Monitor patients during treatment with REZDIFFRA for elevations in liver tests and for the development of liver-related adverse reactions. Monitor for symptoms and signs of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue REZDIFFRA and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting REZDIFFRA. If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests. Gallbladder-Related Adverse Reactions In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in REZDIFFRA-treated patients than in placebo- treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, interrupt REZDIFFRA treatment until the event is resolved [see Adverse Reactions (6.1) in the full Prescribing Information] . Drug Interaction with Certain Statins REZDIFFRA is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of NASH and fibrosis [see Clinical Studies (14) in the full Prescribing Information] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitations of Use Avoid use of REZDIFFRA in patients with decompensated cirrhosis [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) in the full Prescribing Information] . CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hepatotoxicity Hepatotoxicity has been observed with use of REZDIFFRA.One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received REZDIFFRA 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted.After reinitiating REZDIFFRA, the patient had elevations of ALT,AST, and TB. Peak values observed were 58 x upper limit of normal (ULN) for ALT, 66 x ULN for AST, 15 x ULN for TB, with no elevation of alkaline phosphatase (ALP). Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels,suggesting drug-induced autoimmune-like hepatitis (DI-ALH).The liver tests returned to baseline following hospitalization and discontinuation of REZDIFFRA without any therapeutic intervention.

REZDIFFRA 80 mg Once Daily N=298 n (EAIR d )

REZDIFFRA 100 mg Once Daily N=296 n (EAIR d )

Placebo N=294 n (EAIR d )

Adverse Reaction

Diarrhea Nausea Pruritus Vomiting

52 (14)

78 (23) 65 (18)

98 (33) 51 (15) 36 (10)

36 (9) 18 (4) 15 (4) 18 (4) 18 (4)

24 (6) 27 (7) 20 (5) 22 (5)

24 (6) 27 (7) 20 (5) 22 (5) 17 (4)

30 (8) 28 (8) 27 (7)

Constipation

Abdominal pain

Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions was higher for the REZDIFFRA drug arms compared to placebo. The EAIRs for gastrointestinal adverse reactions were 57 per 100 PY, 73 per 100 PY, and 89 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, REZDIFFRA 100 mg once daily arms, respectively. Diarrhea typically began early in treatment initiation and was mild to moderate in severity. The median time (Q1 to Q3) to a diarrheal event was 39 (2 to 195) days, 17 (3 to 70) days, and 6 (2 to 54) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Diarrhea typically began early in treatment initiation and was mild to moderate in severity.The median time (Q1 to Q3) to a diarrheal event was 39 (2 to 195) days, 17 (3 to 70) days, and 6 (2 to 54) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Median duration of diarrhea was 9 days for placebo compared to 20 days for both REZDIFFRA 80 mg once daily and REZDIFFRA 100 mg once daily dosage arms. Nausea also began early in treatment and was mild to moderate in severity. Among patients with nausea, the median time (Q1 to Q3) to a nausea event was 85 (24 to 347) days, 28 (2 to 162) days, and 5 (2 to 40) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respec- tively. Median duration of nausea was 17 days, 26 days, and 28 days for patients in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Vomiting and abdominal pain adverse reactions were mild to moderate in severity. Hypersensitivity Reactions Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were observed in patients receiving REZDIFFRA. The EAIRs for urticaria were 0.2 per 100 PY, 0.7 per 100 PY, and 1.5 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. The EAIRs for rash were 3 per 100 PY in the placebo and REZDIFFRA 80 mg once daily arms compared to 5 per 100 PY in the REZDIFFRA 100 mg once daily arm. Gallbladder-Related Adverse Reactions A higher incidence of cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the EAIRs for these events were less than 1 per 100 PY for all treatment arms. Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the REZDIFFRA arms compared to placebo, in less than 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrhythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy, abnormal uterine bleeding. Dizziness 17 (4) a Population includes adult patients with noncirrhotic NASH with liver fibrosis (stages F2 and F3 at eligibility). b Median exposure duration was 68 weeks for placebo, 74 weeks for REZDIFFRA 80 mg once daily, and 66 weeks for REZDIFFRA 100 mg once daily. c EAIRs are per 100 person-years (PY) where total PYs were 435, 435, and 407 for placebo, 80 mg once daily, and 100 mg once daily arms, respectively. 6 (1) 17 (4) a Population includes adult patients with noncirrhotic NASH with liver fibrosis (stages F2 and F3 at eligibility). b Median exposure duration was 68 weeks for placebo, 74 weeks for REZDIFFRA 80 mg once daily, and 66 weeks for REZDIFFRA 100 mg once daily. c EAIRs are per 100 person-years (PY) where total PYs were 435, 435, and 407 for placebo, 80 mg once daily, and 100 mg once daily arms, respectively. 17 (4) d The EAIR per 100 PY can be interpreted as an estimated number of first occur- rences of the adverse reaction of interest if 100 patients are treated for one year. Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years; NASH, nonalcoholic steatohepatitis d The EAIR per 100 PY can be interpreted as an estimated number of first occur- rences of the adverse reaction of interest if 100 patients are treated for one year. Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years; NASH, nonalcoholic steatohepatitis Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions was higher for the REZDIFFRA drug arms compared to placebo.The EAIRs for gastrointestinal adverse reactions were 57 per 100 PY, 73 per 100 PY, and 89 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, REZDIFFRA 100 mg once daily arms, respectively. Median duration of diarrhea was 9 days for placebo compared to 20 days for both REZDIFFRA 80 mg once daily and REZDIFFRA 100 mg once daily dosage arms. Nausea also began early in treatment and was mild to moderate in severity. Among patients with nausea, the median time (Q1 to Q3) to a nausea event was 85 (24 to 347) days, 28 (2 to 162) days, and 5 (2 to 40) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respec- tively. Median duration of nausea was 17 days, 26 days, and 28 days for patients in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively.Vomiting and abdominal pain adverse reactions were mild to moderate in severity. Hypersensitivity Reactions Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were observed in patients receiving REZDIFFRA.The EAIRs for urticaria were 0.2 per 100 PY, 0.7 per 100 PY, and 1.5 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively.The EAIRs for rash were 3 per 100 PY in the placebo and REZDIFFRA 80 mg once daily arms compared to 5 per 100 PY in the REZDIFFRA 100 mg once daily arm. Gallbladder-Related Adverse Reactions A higher incidence of cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the EAIRs for these events were less than 1 per 100 PY for all treatment arms. Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the REZDIFFRA arms compared to placebo, in less than 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrhythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy, abnormal uterine bleeding. Dizziness 6 (1)

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