Gemfibrozil

Over 100,000 patients in the United States have IPF, with two approved therapies available that only slow the course of disease progression Top line data expected in the second half of 2025 SILVER SPRING, Md. & RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)-- United Therapeutics Corporation (Nasdaq: UTHR), a public benefit corporation, announced full enrollment of the TETON 2 study evaluating the use of Tyvaso® (treprostinil) inhalation solution (nebulized Tyvaso) for the treatment of idiopathic pulmonary fibrosis (IPF). The TETON 2 study enrolled 597 patients and is part of the three-study global TETON clinical trial program evaluating the use of inhaled treprostinil in IPF and a similar condition, progressive pulmonary fibrosis (PPF). TETON 1 is evaluating the use of inhaled treprostinil in IPF in patients in the United States and Canada. TETON 2 is evaluating the use of inhaled treprostinil in IPF in patients outside the United States and Canada. TETON PPF is evaluating the use of inhaled treprostinil in PPF in patients globally. Patients in any of the TETON program studies may use nebulized Tyvaso alone as a monotherapy or in combination with one background therapy approved for the treatment of IPF or PPF. Enrollment in TETON 1 and TETON PPF is ongoing. “On behalf of my colleagues at United Therapeutics, I’d like to thank the patients and investigators around the world for the courage and determination to participate in the potentially revolutionary TETON 2 study,” said Peter Smith, Pharm. D., Vice President, Product Development at United Therapeutics and the lead for the global TETON program. “Our continued goal with the TETON program is to demonstrate that inhaled treprostinil can lead to better patient outcomes in this underserved, vulnerable patient population with fibrotic lung disease.” The TETON program in IPF and PPF was prompted by data from the INCREASE study of nebulized Tyvaso for the treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD), which demonstrated in a post-hoc analysis that treatment with nebulized Tyvaso resulted in significant improvements in percent predicted forced vital capacity (FVC) at weeks 8 and 16, with subjects having an underlying etiology of IPF showing the greatest improvement (week 8: 2.5%; p=0.038 and week 16: 3.5%; p=0.015). Further, open label extension data published in 2023 showed these improvements in FVC were sustained for at least 64 weeks. For those patients who received placebo during the INCREASE study, marked improvements in FVC were observed following transition to nebulized Tyvaso during the open-label extension study. These data points, combined with substantial preclinical evidence of antifibrotic activity of treprostinil, suggest that nebulized Tyvaso may offer a treatment option for patients with IPF and PPF. The TETON program is evaluating the use of nebulized Tyvaso, which is approved to improve exercise ability in patients with pulmonary arterial hypertension and PH-ILD. Tyvaso DPI® (treprostinil) Inhalation Powder is not being evaluated in the TETON program, but United Therapeutics intends to seek U.S. Food and Drug Administration (FDA) approval to expand the Tyvaso DPI label to include IPF and PPF following completion of the TETON studies and any FDA-required bridging studies. Tyvaso Inhalation Solution and Tyvaso DPI are not approved in any jurisdiction for the treatment of IPF or PPF patients who do not have documented pulmonary hypertension. About TETON 2 The TETON 2 study is a 597-patient, multicenter, randomized, double-blind, placebo-controlled phase 3 registration study to evaluate the safety and efficacy of nebulized Tyvaso in subjects with IPF over a 52-week period at sites outside of the United States and Canada. The study reached full enrollment in July 2024 and top-line data is expected in the second half of 2025. Subjects will be randomly allocated 1:1 to receive nebulized Tyvaso or placebo. All subjects will initiate nebulized Tyvaso or placebo at a dose of three breaths administered four times daily (QID) and will titrate to a target dosing regimen of 12 breaths QID. Study drug doses may be titrated up as tolerated, until the target dose or maximum clinically tolerated dose is achieved. The primary endpoint of the study is the change in FVC from baseline to week 52. Secondary endpoints include: (1) time to clinical worsening; (2) time to first acute exacerbation of IPF; (3) overall survival at week 52; (4) change in percent predicted FVC from baseline to week 52; and (5) change in the King’s Brief Interstitial Lung Disease questionnaire. Other data collected in the study will include the plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, supplemental oxygen use, and lung diffusion capacity. Safety assessments include the development of adverse events, serious adverse events, vital signs, clinical laboratory parameters, and electrocardiogram parameters. About IPF Idiopathic pulmonary fibrosis, or IPF, is a scarring disease of the lungs of an unknown (idiopathic) cause and is the most common of the idiopathic interstitial pneumonias. IPF is characterized by the progressive loss of the ability of the lungs to transfer oxygen into the blood, ultimately resulting in respiratory failure and death. While the precise causes of IPF remain unknown, IPF rarely presents before age 50 and can be associated with cigarette smoking and certain genetic dispositions. In addition, some evidence suggests that gastroesophageal reflux (acid reflux, or heartburn), certain viral infections, air pollution, and some exposures in the workplace may be risk factors for IPF. According to recent research, IPF is estimated to affect between 0.33 and 4.51 people per 10,000 persons worldwide. Further, United Therapeutics estimates there are over 100,000 IPF patients in the United States alone. Just two therapies are approved in the United States to treat IPF, and studies for both therapies have shown only a reduction in the rate of forced vital capacity, or FVC, decline in IPF patients. About Tyvaso® Inhalation Solution and Tyvaso DPI® Inhalation Powder INDICATION TYVASO (treprostinil) Inhalation Solution and TYVASO DPI (treprostinil) Inhalation Powder are prostacyclin mimetics indicated for the treatment of: Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with TYVASO establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%). The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities. While there are long-term data on use of treprostinil by other routes of administration, nearly all clinical experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with TYVASO was limited to 12 weeks in duration. Pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with TYVASO establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%). IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS TYVASO and TYVASO DPI are pulmonary and systemic vasodilators. In patients with low systemic arterial pressure, either product may produce symptomatic hypotension. Both products inhibit platelet aggregation and increase the risk of bleeding. Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness. Like other inhaled prostaglandins, TYVASO and TYVASO DPI may cause acute bronchospasm. Patients with asthma or chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk for bronchospasm. Ensure that such patients are treated optimally for reactive airway disease prior to and during treatment with TYVASO and TYVASO DPI. DRUG INTERACTIONS/SPECIFIC POPULATIONS The concomitant use of either product with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer, rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8. Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality. There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production. Safety and effectiveness in pediatric patients have not been established. Across clinical studies used to establish the effectiveness of TYVASO in patients with PAH and PH‑ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety pro in geriatric patients were similar to younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy. ADVERSE REACTIONS Pulmonary Arterial Hypertension (WHO Group 1) In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most common adverse reactions seen with TYVASO in ≥4% of PAH patients and more than 3% greater than placebo were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%). In addition, adverse reactions occurring in ≥4% of patients were dizziness and diarrhea. In a 3-week, open-label, single-sequence, safety and tolerability study (BREEZE) conducted in 51 patients on stable doses of TYVASO who switched to a corresponding dose of TYVASO DPI, the most commonly reported adverse events seen with TYVASO DPI in ≥4% of PAH patients during the 3-week treatment phase included cough (35.3%), headache (15.7%), dyspnea (7.8%), and nausea (5.9%). Pulmonary Hypertension Associated with ILD (WHO Group 3) In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions with TYVASO were similar to the experience in studies of PAH. Please see Full Prescribing Information for TYVASO or TYVASO DPI, Instructions for Use manuals for TD-100 and TD-300 TYVASO® Inhalation System and TYVASO DPI™ Inhalation Powder, and additional information at or call 1‑877‑UNITHER (1-877-864-8437). TYVISIhcpMAY2022revised United Therapeutics: Enabling Inspiration At United Therapeutics, our vision and mission are one. We use our enthusiasm, creativity, and persistence to innovate for the unmet medical needs of our patients and to benefit our other stakeholders. We are bold and unconventional. We have fun, we do good. We are the first publicly-traded biotech or pharmaceutical company to take the form of a public benefit corporation (PBC). Our public benefit purpose is to provide a brighter future for patients through (a) the development of novel pharmaceutical therapies; and (b) technologies that expand the availability of transplantable organs. You can learn more about what it means to be a PBC here: unither.com/pbc. Forward-Looking Statements Statements included in this press release that are not historical in nature are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, among others, our plans concerning the TETON program, including our plans to release top-line data from the TETON 2 study in 2025, our plans to seek FDA approval of nebulized Tyvaso and Tyvaso DPI to treat IPF and PPF, the potential for inhaled treprostinil to lead to better patient outcomes in patients with fibrotic lung disease, our efforts to innovate for the unmet medical needs of our patients, to benefit our other stakeholders, and to pursue our public benefit purpose of developing novel pharmaceutical therapies and technologies that expand the availability of transplantable organs. These forward-looking statements are subject to certain risks and uncertainties, such as those described in our periodic reports filed with the Securities and Exchange Commission, that could cause actual results to differ materially from anticipated results. Consequently, such forward-looking statements are qualified by the cautionary statements, cautionary language, and risk factors set forth in our periodic reports and documents filed with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. We claim the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. We are providing this information as of July 10, 2024, and assume no obligation to update or revise the information contained in this press release whether as a result of new information, future events or any other reason. TYVASO and TYVASO DPI are registered trademarks of United Therapeuitcs Corporation.

Late-breaking AI-based analysis of MAESTRO-NASH biopsy data demonstrates Rezdiffra improved key fibrotic features that are predictive of progression to decompensated cirrhosis Noninvasive test data through three years of treatment demonstrate durable treatment response to Rezdiffra; 91% of patients achieved improvement or stabilization of liver stiffness First analysis of health-related quality of life data from MAESTRO-NASH demonstrates Rezdiffra improved patient worry, health distress and stigma First analysis of Rezdiffra treatment in MetALD demonstrates patients achieved similar rates of fibrosis improvement and steatohepatitis resolution compared to the NASH population CONSHOHOCKEN, Pa., June 06, 2024 (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a biopharmaceutical company focused on delivering novel therapeutics for nonalcoholic steatohepatitis (NASH), today announced results from new analyses of the Phase 3 MAESTRO-NASH trial of Rezdiffra being presented at the EASL Congress, which takes place from June 5-8, 2024 in Milan, Italy. Rezdiffra is a once-daily, oral, liver-directed thyroid hormone receptor (THR)-β agonist designed to target key underlying causes of NASH. It is the first approved medication for the treatment of NASH. In the pivotal Phase 3 MAESTRO-NASH biopsy trial, Rezdiffra achieved both fibrosis improvement and NASH resolution primary endpoints, and 80% of patients treated with Rezdiffra 100 mg experienced improvement or stabilization of fibrosis. Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials. Bill Sibold, Chief Executive Officer of Madrigal, stated, “The ten abstracts Madrigal will be presenting at the EASL Congress further advance our leadership position in NASH. Our late-breaking oral presentation leverages innovative AI technology to provide deeper insight into the antifibrotic effects of Rezdiffra and the critical role of THR-β as a suppressor of NASH disease progression. This analysis is particularly meaningful in light of emerging health economics data indicating patients with NASH can progress more rapidly than previously thought to decompensated cirrhosis. Additionally, new analyses of the MAESTRO-NASH data broaden our understanding of Rezdiffra treatment response across a range of parameters, including noninvasive measures of fibrosis and steatosis through three years of therapy and health-related quality of life. These data reinforce Rezdiffra’s role as the foundational therapy in NASH.” Becky Taub, M.D., Chief Medical Officer and President of Research & Development of Madrigal, added, “Madrigal continues to advance ambitious scientific research that will help shape the future of the NASH field. We also look forward to presenting our first abstract examining Rezdiffra treatment in patients with probable metabolic dysfunction and alcohol-associated liver disease (MetALD), a population that has historically been underrepresented in clinical research.” Late-breaking AI-based analysis of MAESTRO-NASH biopsy data demonstrates Rezdiffra improved key fibrotic features that may be predictive of progression to decompensated cirrhosis An AI-driven fibrosis assessment methodology, qFibrosis (Histoindex), has identified 30 specific fibrotic features on NASH liver biopsies that may be predictive of progression to cirrhosis and decompensated cirrhosis based on the SteatoSITE database. SteatoSITE contains integrated clinical and pathological data from 940 cases across the NASH spectrum with outcome data from electronic health record and pathologist-assigned fibrosis stage and RNA on baseline biopsy. In an analysis of MAESTRO-NASH data featured in a late-breaking presentation at EASL, total qFibrosis score showed a highly significant improvement in fibrosis with Rezdiffra treatment and less progression of fibrosis as compared with placebo; results were similar to pathologist scoring. Six qFibrosis progression features with the strongest correlations between baseline pathologist scoring and noninvasive tests were identified. At week 52, patients treated with Rezdiffra showed reduction from baseline in these key features compared to placebo, with the most marked reductions occurring in the F3 population. In a previous study, baseline biopsy RNA analyses and annotated patient timelines from SteatoSITE in histologically identical high risk fibrosis stages (F3 and F4) identified THR-β as a potential master regulator of fibrosis progression. Patients with low THR-β activity in their liver at baseline had the highest chance of progression to decompensated cirrhosis. “The qFibrosis data provide support for Rezdiffra’s potential in benefiting patients with NASH with moderate to advanced liver fibrosis by reversing fibrosis and preventing progression to more advanced liver disease,” said Jörn M. Schattenberg, M.D., Professor of Medicine and Director of the Department of Medicine at the University Medical Center Homburg and University of the Saarland in Germany. “These results, coupled with earlier analyses of the SteatoSITE database which found that reduced THR-β activity predicts future hepatic decompensation in patients with NASH, are highly encouraging as we await results from two ongoing Phase 3 outcomes studies of Rezdiffra, a THR-β agonist.” Noninvasive test data through three years of treatment demonstrate durable treatment response to Rezdiffra In analyses of noninvasive test results from MAESTRO-NASH, changes in vibration-controlled transient elastography (VCTE; an ultrasound-based measure of liver stiffness, a surrogate for fibrosis), controlled attenuation parameter (CAP; an ultrasound-derived measure of fat content in the liver), and magnetic resonance imaging-proton density fat fraction (MRI-PDFF; an MRI-based measure of triglyceride content in the liver) were assessed in the Rezdiffra 80mg, Rezdiffra 100mg, and placebo groups. Liver stiffness as measured by VCTE improved over time (up to three years) relative to placebo in Rezdiffra-treated patients, with both doses showing a similar durable response. At year three, 91% of patients treated with Rezdiffra had improved or stable liver stiffness, as compared to 9% who experienced a ≥30% increase in liver stiffness. CAP improvement was also stable over time, with both Rezdiffra doses showing a similar durable response through three years of treatment. CAP and MRI-PDFF improvements in patients treated with Rezdiffra predicted achieving both fibrosis improvement and NASH resolution responses on histology. However, CAP and MRI-PDFF improvements in placebo-treated patients did not predict fibrosis improvement, highlighting the importance of reducing liver fat directly in hepatocytes through THR-β agonism. Rezdiffra improved health-related quality of life in patients with NASH In the first analysis of health-related quality of life (HRQL) data from patients participating in the MAESTRO-NASH trial, changes in HRQL scores from baseline were evaluated in patients receiving Rezdiffra versus placebo and compared between patients with versus without biopsy response. By weeks 24 and 52, patients receiving both doses of Rezdiffra experienced improvement of HRQL scores in the Worry domain of the Chronic Liver Disease Questionnaire-NASH. At week 52, Rezdiffra-treated patients who achieved fibrosis improvement or NASH resolution experienced improvement in several HRQL domains, including domains for Worry, Health Distress and Stigma. The improvement in HRQL among Rezdiffra biopsy responders was contrasted by no similar improvement in the placebo group. Biopsy responders with stage F3 fibrosis at baseline had similar or more pronounced improvements of HRQL in comparison to those responders with F2 or F1B fibrosis at baseline. Rezdiffra improved fibrosis and resolved steatohepatitis in patients with MetALD The first analysis of Rezdiffra treatment in MetALD included 75 patients from the Phase 3 MAESTRO-NASH study who were believed to have significant alcohol consumption in addition to NASH. Patients with probable MetALD were identified based on Carbohydrate Deficient Transferrin (CDT), a biomarker for chronic alcohol consumption, collected longitudinally through the study, and phosphatidylethanol (PEth) tests performed in patients suspected of increased alcohol consumption. Rezdiffra-treated patients in the MetALD group achieved rates of fibrosis improvement and steatohepatitis resolution that were similar to the positive results observed in the overall MAESTRO-NASH population and to patients with NASH with low alcohol consumption. In the MetALD group, 88% of patients treated with Rezdiffra 100 mg and 81% treated with Rezdiffra 80 mg showed a ≥30% reduction from baseline in MRI-PDFF, compared to 14% in the placebo group. About the Phase 3 MAESTRO-NASH Trial of Rezdiffra MAESTRO-NASH is an ongoing Phase 3 trial that enrolled 1759 patients with biopsy-confirmed NASH. Patients were randomly assigned in a 1:1:1 ratio to receive once-daily Rezdiffra at a dose of 80 mg or 100 mg or placebo. The two primary endpoints at week 52 were NASH resolution with no worsening of fibrosis and an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score. The key secondary endpoint was the percent change from baseline in LDL cholesterol at week 24. Rezdiffra achieved both primary endpoints and the key secondary endpoint of the MAESTRO-NASH trial. Additionally, Rezdiffra improved liver enzymes, fibrosis biomarkers and imaging tests as compared with placebo. The primary results of the trial were published in the New England Journal of Medicine in February 2024. Patients enrolled in the MAESTRO-NASH trial continue on therapy after the initial 52-week treatment period for up to 54 months to accrue and measure hepatic clinical outcome events including progression to cirrhosis on biopsy and hepatic decompensation events, as well as all-cause mortality. The 54-month outcomes portion of the trial is designed to generate confirmatory data that, if positive, will help verify Rezdiffra’s clinical benefit and may support full approval. About NASH Nonalcoholic steatohepatitis (NASH) is a more advanced form of nonalcoholic fatty liver disease (NAFLD). NASH is a leading cause of liver-related mortality and an increasing burden on healthcare systems globally. Additionally, patients with NASH, especially those with more advanced metabolic risk factors (hypertension, concomitant type 2 diabetes), are at increased risk for adverse cardiovascular events and increased morbidity and mortality. Once patients progress to NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), the risk of adverse liver outcomes increases dramatically. NASH is rapidly becoming the leading cause of liver transplantation in the U.S. Madrigal estimates that approximately 1.5 million patients have been diagnosed with NASH in the U.S., of which approximately 525,000 have NASH with moderate to advanced liver fibrosis. Madrigal plans to focus on approximately 315,000 diagnosed patients with NASH with moderate to advanced liver fibrosis under the care of the liver specialist physicians during the launch of Rezdiffra. NASH is also known as metabolic dysfunction associated steatohepatitis (MASH). In 2023, global liver disease medical societies and patient groups came together to rename the disease, with the goal of establishing an affirmative, non-stigmatizing name and diagnosis. Nonalcoholic fatty liver disease (NAFLD) was renamed metabolic dysfunction-associated steatotic liver disease (MASLD); NASH was renamed MASH; and an overarching term, steatotic liver disease (SLD), was established to capture multiple types of liver diseases associated with fat buildup in the liver. In addition to liver disease, patients with MASH have at least one related comorbid condition (e.g., obesity, hypertension, dyslipidemia, or type 2 diabetes). About Rezdiffra What is Rezdiffra? Rezdiffra is a prescribed medicine used along with diet and exercise to treat adults with nonalcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), but not with cirrhosis of the liver. It is not known if Rezdiffra is safe and effective in children (under 18 years old). This indication is approved based on improvement of NASH and liver scarring (fibrosis). There are ongoing studies to confirm the clinical benefit of Rezdiffra. Before you take Rezdiffra, tell your healthcare provider about all of your medical conditions, including if you: have any liver problems other than NASH. have gallbladder problems or have been told you have gallbladder problems, including gallstones. are pregnant or plan to become pregnant. It is not known if Rezdiffra will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if Rezdiffra passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Rezdiffra. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Rezdiffra and other medicines may affect each other, causing side effects. Rezdiffra may affect the way other medicines work, and other medicines may affect how Rezdiffra works. Especially tell your healthcare provider if you take medicines that contain gemfibrozil to help lower your triglycerides, or cyclosporine to suppress your immune system, because Rezdiffra is not recommended in patients taking these medicines. Tell your healthcare provider if you are taking medicines such as clopidogrel to thin your blood or statin medicines to help lower your cholesterol. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. What are the possible side effects of Rezdiffra? Rezdiffra may cause serious side effects, including: liver injury (hepatotoxicity). Stop taking Rezdiffra and call your healthcare provider right away if you develop the following signs or symptoms of hepatotoxicity: tiredness, nausea, vomiting, fever, rash, your skin or the white part of your eyes turns yellow (jaundice), pain or tenderness in the upper middle or upper right area of your stomach (abdomen). gallbladder problems. Gallbladder problems such as gallstones, inflammation of the gallbladder, or inflammation of the pancreas from gallstones can occur with NASH and may occur if you take Rezdiffra. Call your healthcare provider right away if you develop any signs or symptoms of these conditions including nausea, vomiting, fever, or pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen to your back and the pain may happen with or without vomiting. The most common side effects of Rezdiffra include: diarrhea, nausea, itching, stomach (abdominal) pain, vomiting, dizziness, constipation. These are not all the possible side effects of Rezdiffra. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or . You may also report side effects to Madrigal at 1-800-905-0324. Please see the full Prescribing Information, including Patient Information, for Rezdiffra. About Madrigal Pharmaceuticals Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) is a biopharmaceutical company pursuing novel therapeutics for nonalcoholic steatohepatitis (NASH), a liver disease with high unmet medical need. Madrigal’s medication, Rezdiffra (resmetirom), is a once-daily, oral, liver-directed THR-β agonist designed to target key underlying causes of NASH. For more information, visit . Forward Looking Statements This press release includes “forward-looking statements” made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, that are based on Madrigal’s beliefs and assumptions and on information currently available to it but are subject to factors beyond its control. Forward-looking statements can be identified by terms such as “anticipates,” “believes,” “can,”“could,” “demonstrates,” “estimates,” “expects,” “forecasts,” “future,” “goal,” “help,” “hopeful,” “intends,” “may,” “might,” “on track,” “plans,” “positions,” “potential,” “predicts,” “projects,” “seeks,” “should,” “will,” “would” or similar expressions and the negatives of those terms. Forward-looking statements reflect management’s current knowledge, assumptions, judgment and expectations regarding future performance or events. Forward-looking statements include all statements that are not historical facts; statements referenced by forward-looking statement identifiers; and statements regarding: Rezdiffra (resmetirom) and its expected use for treating NASH with moderate to advanced fibrosis; analysis of Rezdiffra treatment in MetALD; estimates of patients diagnosed with NASH and market opportunities; the relationship between NASH progression and adverse patient outcomes; the estimated clinical burden of uncontrolled NASH; analyses for patients with NASH with moderate to advanced fibrosis concerning potential progression to cirrhosis, decompensated cirrhosis, liver transplant or death; cardiovascular risks, comorbidities and outcomes; health economics assessments or projections; indicating Rezdiffra has been shown to improve the fibrosis that is associated with progression to cirrhosis and its complications and resolve the underlying inflammation that drives the disease; projections or objectives for obtaining full approval for Rezdiffra (resmetirom), including those concerning potential clinical benefit to support potential full approval; regarding post-approval requirements and commitments; reduced risk of progression to cirrhosis, liver failure, need for liver transplant and premature mortality; treatment paradigm; improved liver enzymes, fibrosis biomarkers and imaging tests; the potential efficacy and safety of Rezdiffra (resmetirom) for noncirrhotic NASH patients and cirrhotic NASH patients; research and development activities, the timing and results associated with the future development of Rezdiffra (resmetirom), the timing and completion of projected future clinical milestone events, including enrollment, additional studies, the potential to support an additional indication for Rezdiffra (resmetirom) in patients with well-compensated NASH cirrhosis; optimal dosing levels for Rezdiffra (resmetirom); potential NASH or NAFLD and potential patient benefits with Rezdiffra (resmetirom), including future NASH resolution, safety, fibrosis treatment, cardiovascular effects, lipid treatment, and/or biomarker effects with Rezdiffra (resmetirom); and strategies, objectives and commercial opportunities, including potential prospects or results. Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to those risks and uncertainties discussed in Part I, Item 1A of its Annual Report on Form 10-K for the year ended December 31, 2023, filed with the U.S. Securities and Exchange Commission, or SEC, on February 28, 2024, and Part II, Item 1A of its Quarterly Report on Form 10-Q for the quarter ended March 31, 2024, filed with the SEC on May 7, 2024, and as updated from time to time by Madrigal’s other filings with the SEC.. Undue reliance should not be placed on forward looking statements, which speak only as of the date they are made. Madrigal undertakes no obligation to update any forward-looking statements to reflect new information, events, or circumstances after the date they are made, or to reflect the occurrence of unanticipated events. Please refer to Madrigal’s submissions filed with the SEC for more detailed information regarding these risks and uncertainties and other factors that may cause actual results to differ materially from those expressed or implied. Investor Contact Tina Ventura, Madrigal Pharmaceuticals, Inc., IR@madrigalpharma.com Media Contact Christopher Frates, Madrigal Pharmaceuticals, Inc., media@madrigalpharma.com