The goal of this clinical trial is to learn about efficacy and safety of dual antiplatelet therapy in ischemic stroke with intracranial artery stenosis. The main question it aims to answer are:
whether aspirin combined with clopidogrel for 3 month is better than 1 months for patients with non-cardiogenic cerebral infarction with intracranial artery stenosis.
Participants will get dual antiplatelet therapy (aspirin plus clopidogrel) for 1 month or 3 months within 7 days of the first stroke.
Researchers will compare experimental group (3 months dual antiplatelet therapy) with comparison group (1 month dual antiplatelet therapy), to see if experimental group would reduce stroke recurrence or mortality, and increase bleeding and other adverse prognosis.

Start Date01 Jul 2024

Sponsor / Collaborator

Sichuan Provincial People's Hospital

NCT06454045 / Active, not recruitingNot ApplicableIIT

Evaluation of Platelet Aggregability in Patients With Previous Acute Myocardial Infarction or Concomitant Lower Extremity Peripheral Artery Disease

After an episode of acute ischemic syndrome, patients with concomitant peripheral arterial disease have a worse short- and long-term prognosis compared to patients with isolated coronary disease, but the mechanisms responsible are poorly understood. In this population, the presence of high platelet aggregability despite the use of antiplatelet drugs is related to a greater risk of future complications, including heart attack and death from all causes.
Thus, the main objective of the present project is to evaluate the role of platelet aggregability, analyzed by optical aggregometry using the AggRAM® equipment, in patients with a history of previous acute myocardial infarction with and without the presence of peripheral arterial disease. Among the secondary objectives, it is worth analyzing platelet aggregability, in both groups, using the Plateletworks® method. This is a case-control study, with groups differentiated by the presence or absence of peripheral arterial disease, matched by sex and age.
It is expected that, in the end, relevant aspects related to platelet aggregation will be better characterized in this high cardiovascular risk population, with a likely impact on new therapeutic strategies that can positively influence the morbidity and mortality of these patients.

Start Date13 May 2024

Sponsor / Collaborator

University of Sao Paulo

100 Clinical Results associated with Clopidogrel napadisilate

100 Translational Medicine associated with Clopidogrel napadisilate

100 Patents (Medical) associated with Clopidogrel napadisilate

2,815

Literatures (Medical) associated with Clopidogrel napadisilate

01 Mar 2024·Cardiovascular & hematological agents in medicinal chemistry

The Platelet Aggregation Inhibition Activity of Polyphenols can be Mediated by 67kda Laminin Receptor: A New Therapeutic Strategy For the Treatment of Venous Thromboembolism

Article

Author: Ghosh, Amit ; Prakash, Satya ; Kiran, Sheetal ; Nayek, Arnab

Background::

Thrombotic disease is still a major killer. Aspirin, Ticagrelor, Clopidogrel, etc. are the most widely used conventional antiplatelet drugs. The significant number of patients who are resistant to this drug shows a poor outcome.

Objective::

Developing a new antiplatelet agent with a stable antiplatelet effect and minimal bleeding risk is required for a patient who is resistant to antiplatelet drugs.

Methods::

Protein-ligand docking was performed using Autodock Vina 1.1.2 to study the interaction of 67LR with different Polyphenols.

Results::

Among the 18 polyphenols, thearubigin has the highest binding affinity towards 67LR and gallic acid shows the lowest binding affinity. Among the 18 molecules, the top 4 molecules from the highest to lowest binding affinity range from-10.6 (thearubigin) to -6.5 (Epigallocatechin).

Conclusion::

Polyphenols may inhibit platelet aggregation through 67 LR and can be an alternative treatment for Thrombotic Disease. Moreover, it will be interesting to know whether polyphenols interfere with the same pathways as aspirin and clopidogrel. Effective polyphenols could help prototype the compound development of novel antiplatelet agents.

01 Feb 2024·International journal of stroke : official journal of the International Stroke Society

Empiric treatment with aspirin and ticagrelor is the most cost-effective strategy in patients with minor stroke or transient ischemic attack

Article

Author: Chan, Jeremy ; Ang, Yoong Kwei ; De Silva, Deidre Anne ; Tan, Kelvin Bryan ; Narasimhalu, Kaavya

Background::

Patients with minor ischemic stroke or transient ischemic attacks (TIAs) are often treated with dual antiplatelet therapy regimens as part of secondary stroke prevention. Clopidogrel, an antiplatelet used in these regimens, is metabolized into its active form by the CYP2C19 enzyme. Patients with loss of function (LOF) mutations in CYP2C19 are at risk for poorer secondary outcomes when prescribed clopidogrel.

Aims::

We aimed to determine the cost-effectiveness of three different treatment antiplatelet regimens in ischemic stroke populations with minor strokes or TIAs and how these treatment regimens are influenced by the LOF prevalence in the population.

Methods::

Markov models were developed to look at the cost-effectiveness of empiric treatment with aspirin and clopidogrel versus empiric treatment with aspirin and ticagrelor, versus genotype-guided therapy for either 21 or 30 days. Effect ratios were obtained from the literature, and incidence rates and costs were obtained from the national data published by the Singapore Ministry of Health. The primary endpoints were the incremental cost-effectiveness ratios (ICERs).

Results::

Empiric treatment with aspirin and ticagrelor was the most cost-effective treatment. Genotype-guided therapy was more cost-effective than empiric aspirin and clopidogrel if the LOF was above 48%. Empiric ticagrelor and aspirin was cost saving when compared to genotype-guided therapy. Results in models of dual antiplatelet therapy for 30 days were similar.

Conclusion::

This study suggests that in patients with minor stroke and TIA planned for dual antiplatelet regimens, empiric ticagrelor and aspirin is the most cost-effective treatment regimen. If ticagrelor is not available, genotype-guided therapy is the most cost-effective treatment regimen if the LOF prevalence in the population is more than 48%.

01 Jan 2024·CPT: pharmacometrics & systems pharmacology

Population pharmacokinetic‐pharmacodynamic modeling of clopidogrel for dose regimen optimization based on CYP2C19 phenotypes: A proof of concept study

Article

Author: Park, Min Soo ; Chae, Dongwoo ; Kim, Choon Ok ; Jin, Byung Hak ; Jung, Yun Seob

Abstract:

Clopidogrel is an antiplatelet drug used to reduce the risk of acute coronary syndrome and stroke. It is converted by CYP2C19 to its active metabolite; therefore, poor metabolizers (PMs) of CYP2C19 exhibit diminished antiplatelet effects. Herein, we conducted a proof‐of‐concept study for using population pharmacokinetic‐pharmacodynamic (PK‐PD) modeling to recommend a personalized clopidogrel dosing regimen for individuals with varying CYP2C19 phenotypes and baseline P2Y12 reaction unit (PRU) levels. Data from a prospective phase I clinical trial involving 36 healthy male participants were used to develop the population PK‐PD model predicting the concentrations of clopidogrel, clopidogrel H4, and clopidogrel carboxylic acid, and linking clopidogrel H4 concentrations to changes in PRU levels. A two‐compartment model effectively described the PKs of both clopidogrel and clopidogrel carboxylic acid, and a one‐compartment model of those of clopidogrel H4. The CYP2C19 phenotype was identified as a significant covariate influencing the metabolic conversion of the parent drug to its metabolites. A PD submodel of clopidogrel H4 that stimulated the fractional turnover rate of PRU levels showed the best performance. Monte Carlo simulations suggested that PMs require three to four times higher doses than extensive metabolizers to reach the target PRU level. Individuals within the top 20th percentile of baseline PRU levels were shown to require 2.5–3 times higher doses than those in the bottom 20th percentile. We successfully developed a population PK‐PD model for clopidogrel considering the impact of CYP2C19 phenotypes and baseline PRU levels. Further studies are necessary to confirm actual dosing recommendations for clopidogrel.

News (Medical) associated with Clopidogrel napadisilate

06 Jun 2024

·www.biospace.com

Madrigal Pharmaceuticals Announces New Data from the Phase 3 MAESTRO-NASH Study of Rezdiffra™ (resmetirom) Presented at the EASL Congress

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

Clinical ResultPhase 3Drug ApprovalAccelerated Approval

29 May 2024

·www.globenewswire.com

Madrigal Pharmaceuticals to Present Multiple Rezdiffra™ (resmetirom) and Health Economics Outcomes Research Abstracts in NASH/MASH at the EASL Congress

CONSHOHOCKEN, Pa., May 29, 2024 (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a biopharmaceutical company focused on delivering novel therapeutics for nonalcoholic steatohepatitis (NASH), today announced ten data presentations at the upcoming European Association for the Study of the Liver (EASL) Congress, taking place from June 5-8, 2024 in Milan, Italy. “The data we will be presenting at EASL further support Rezdiffra as the foundational therapy in NASH and Madrigal as the leading company in the field," said Bill Sibold, Chief Executive Officer of Madrigal. "We look forward to sharing multiple new data analyses from the MAESTRO Phase 3 program, including the first quality of life data, further analysis of noninvasive test results, and the first look at Rezdiffra in patients with metabolic dysfunction- and alcohol associated liver disease (MetALD)." Mr. Sibold continued, “Additionally, we will be presenting important new real-world data examining the burden of uncontrolled NASH on patients and the health system. The serious human and economic costs of this disease are coming into focus, and we’re learning that patients can progress to cirrhosis and decompensated cirrhosis at a faster rate than previously understood.” 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. Madrigal data presentations at the EASL Congress 2024 Late-breaking oral presentation: “Identification and validation of pre-identified morphological baseline features for prediction of fibrosis progression in MAESTRO-NASH” [Friday, June 7 at 17:45 CEST. Presenter: Jörn Schattenberg]Oral presentation: “Assessment of resmetirom efficacy (80 mg vs. 100 mg) stratified by baseline body mass index and weight in patients from the MAESTRO-NASH trial” [Saturday, June 8 at 11:15 CEST. Presenter: Mazen Noureddin]Poster: “Health-related quality of life assessments in a 52-week, double-blind, randomized, placebo-controlled Phase 3 study of resmetirom in patients with NASH and fibrosis (MAESTRO-NASH)” [Presenter: Zobair Younossi]Poster: “Noninvasive predictive markers of resmetirom biopsy response” [Presenter: Jörn Schattenberg]Poster: “Resmetirom treatment of a subgroup of patients with possible MetALD enrolled in MAESTRO-NASH, a Phase 3 NASH/MASH serial liver biopsy study” [Presenter: Vlad Ratziu]Poster: “Analyses of fibrosis biomarkers PRO-C3 and ELF in resmetirom treated patients from MAESTRO-NASH, a 52 Week NASH/MASH serial liver biopsy study” [Presenter: Quentin Anstee]Poster: “Using machine learning models to predict baseline fibrosis stage in patients from phase 3 resmetirom trials (MAESTRO-NAFLD and MAESTRO-NASH)” [Presenter: Jörn Schattenberg]Poster: “Risk of nonalcoholic steatohepatitis disease progression to more severe liver disease in Medicare patients” [Presenter: Robert Gish]Poster: “Costs associated with nonalcoholic steatohepatitis disease progression in Medicare patients” [Presenter: Robert Gish]Poster: “Healthcare cost and resource utilization among patients with nonalcoholic steatohepatitis, stratified by glucagon-like peptide 1 receptor agonist use in real world data” [Presenter: Yestle Kim] 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 www.fda.gov/medwatch. 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 PharmaceuticalsMadrigal 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 www.madrigalpharma.com. Forward Looking StatementsThis 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 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; the initiation of the commercial launch of Rezdiffra, including statements regarding commercial insurance and the anticipated time to fill prescriptions; 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; possible or assumed future results of operations and expenses, business strategies and plans (including ex-US. Launch/partnering plans); 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 can be identified by terms such as “accelerate,” “achieve,” “allow,” “anticipates,” “appear,” “be,” “believes,” “can,” “confidence,” “continue,” “could,” “demonstrates,” ”design,” “estimates,” “expectation,” “expects,” “forecasts,” “future,” “goal,” “help,” “hopeful,” “inform,” inform,” “intended,” “intends,” “may,” “might,” “on track,” “planned,” “planning,” “plans,” “positions,” “potential,” “powers,” “predicts,” ”predictive,” “projects,” “seeks,” “should,” “will,” “will achieve,” “will be,” “would” or similar expressions and the negatives of those terms. Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to: the assumptions underlying the forward-looking statements; risks of obtaining and maintaining regulatory approvals, including, but not limited to, potential regulatory delays or rejections; the challenges with the commercial launch of a new product, particularly for a company that does not have commercial experience; risks associated with meeting the objectives of Madrigal’s clinical studies, including, but not limited to Madrigal’s ability to achieve enrollment objectives concerning patient numbers (including an adequate safety database), outcomes objectives and/or timing objectives for Madrigal’s studies; any delays or failures in enrollment, and the occurrence of adverse safety events; risks related to the effects of Rezdiffra’s (resmetirom’s) mechanism of action; enrollment and trial conclusion uncertainties; market demand for and acceptance of our product; the potential inability to raise sufficient capital to fund ongoing operations as currently planned or to obtain financings on terms similar to those arranged in the past; the ability to service indebtedness and otherwise comply with debt covenants; outcomes or trends from competitive studies; future topline data timing or results; our ability to prevent and/or mitigate cyber-attacks; the timing and outcomes of clinical studies of Rezdiffra (resmetirom); the uncertainties inherent in clinical testing; and uncertainties concerning analyses or assessments outside of a controlled clinical trial. 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 U.S. Securities and Exchange Commission, or 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. Madrigal specifically discusses these risks and uncertainties in greater detail in the sections appearing in Part I, Item 1A of its Annual Report on Form 10-K for the year ended December 31, 2023, filed with the 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. Investor Contact Tina Ventura, Madrigal Pharmaceuticals, Inc., IR@madrigalpharma.com Media ContactChristopher Frates, Madrigal Pharmaceuticals, Inc., media@madrigalpharma.com

Clinical ResultPhase 3Drug Approval

22 May 2024

·www.fiercepharma.com

Sanofi, Bristol Myers on the hook for $916M in do-over of Plavix marketing case in Hawaii

In the redo of a case that was overturned on an appeal, Bristol Myers Squibb and Sanofi have been ordered to pay $916 million to the state of Hawaii for their marketing of blood thinner Plavix. The award replaces a previous award of $834 million from three years ago. The companies will once again appeal. In the continuation of a decade-long legal battle, a Hawaii judge has ordered Bristol Myers Squibb and Sanofi to pay a combined $916 million to the state for failing to warn patients about the ineffectiveness of their blood thinner Plavix in some nonwhite patients. The award comes after a second trial in the case. Last year, following the first trial, which resulted in an $834 million award to the state in 2021, the Hawaii Supreme Court reversed in part and vacated in part the judgement, necessitating a redo. This time, the state court ruled in favor of Hawaii's allegation that the companies violated state consumer protection laws with their marketing of Plavix. In 2010, the FDA required Sanofi and BMS to include a boxed warning that Plavix could be less effective in nonwhite patients. Studies have shown that genetic differences—particularly in people of East Asian decent—can prevent some from metabolizing Plavix. The companies said they will appeal again. “Bristol Myers Squibb and Sanofi strongly disagree with the court’s penalty award,” the companies said in a joint statement. “The overwhelming body of scientific evidence demonstrates that Plavix is a safe and effective therapy, regardless of a patient’s race or genetics.” Judge James Ashford ruled that Sanofi and BMS knew that there was a risk “that about 30% of patients might have a diminished response to Plavix, but they did not update their label.” “The defendants created an environment where Hawaii prescribing physicians practiced for more than a decade without the necessary information needed to evaluate the serious limitations of this heart medication,” Ashford added. Plavix was approved in 1998, with generic versions (clopidogrel) controlling the market over the last decade. By way of settlements, Sanofi and BMS previously resolved lawsuits related to the drug in Louisiana, Mississippi, West Virginia and California. “The Hawai`i medical community recognizes the benefits of Plavix and continues to recommend it to Hawai`i patients without restrictions based on race, ethnicity or genetic status," the companies added. "The unprecedented penalties awarded in this case are unwarranted and out of proportion. This is the last remaining Plavix case and is a clear outlier given the companies’ successful defense of Plavix litigation in other states.”

Drug ApprovalPatent Infringement

100 Deals associated with Clopidogrel napadisilate

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KEGG	Wiki	ATC	Drug Bank
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10 top approved records.

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Indication	Country/Location	Organization	Date
Thrombosis	GB	Hanmi Pharmaceutical Co., Ltd.	23 Dec 2010

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


HOST-EXAM Extended (ESC2023)	Not Applicable	Thrombosis \| Hemorrhage Maintenance	-	Clopidogrel	ywafixuxqa(lshwggfrui): HR = 2.7 (95% CI, 2.29 - 3.18)	-	26 Aug 2023
				Aspirin
ALPHEUS Naive sub-study (ESC2023)	Not Applicable	Angina, Unstable	1,882	Ticagrelor	jblqzvecuw(sowxmhqzbi) = aycqizhnsn pkirdjvckz (clvhmheorl ) View more	-	26 Aug 2023
				Clopidogrel	jblqzvecuw(sowxmhqzbi) = xcoaijiiiz pkirdjvckz (clvhmheorl ) View more
TARDIS (ISC2023)	Not Applicable	Ischemic stroke	3,096	Clopidogrel	xjsamujoki(ilvrnvbbir) = onkswsexqf utrgbrowyy (uisdjjeycq )	-	01 Feb 2023
				Aspirin and dipyridamole	xjsamujoki(ilvrnvbbir) = oexqybxbxv utrgbrowyy (uisdjjeycq )
ASN2022	Not Applicable	Renal Insufficiency	-	Clopidogrel users	rewxydgcln(zqizhsrzvh): HR = 2.24 (95% CI, 2.21 - 2.27) View more	Positive	04 Nov 2022
				Clopidogrel
ESC2022	Not Applicable	Acute Coronary Syndrome	-	Clopidogrel SAPT	mejuojonjs(nghmhapnrl): HR = 0.72 (95% CI, 0.54 - 0.98)	-	28 Aug 2022
				Aspirin monotherapy
POPular AGE trial (Pubmed)	Not Applicable	Non ST segment elevation acute coronary syndrome	1,000	Clopidogrel	prppfueldi(oqfybofqij) = uyvvcbbwfg dapeaviqpc (ujbsrxwmnu )	-	20 Jun 2022
ISC2022	Not Applicable	-	-	Clopidogrel bolus	xpurvibspz(rgjuoklkzl) = xpxxuezuvn pfpjhbmouf (qttvltvbzx ) View more	Negative	01 Feb 2022
				Sustained clopidogrel pre-treatment	xpurvibspz(rgjuoklkzl) = ysyyhogwbx pfpjhbmouf (qttvltvbzx ) View more
ISC2021	Not Applicable	Intracranial Aneurysm	567	Clopidogrel (Patients undergoing coil embolization for IA)	hkmcjnuoow(yluoatnsba) = exmruswkqa rayaoaluja (iiypuxfcya )	-	01 Mar 2021
				Clopidogrel (Patients undergoing CAS)	hkmcjnuoow(yluoatnsba) = begxuxrazd rayaoaluja (iiypuxfcya )
NCT03381742 (SUPERIOR, Pubmed \| Platelets) Manual	Phase 2/3	Coronary Artery Disease	3,043	ticagrelor+clopidogrel	knlzovcbem(tyvvnnqubq) = There were no significant differences between T45BID and T90QD in the trough plasma concentrations of ticagrelor and its active metabolite uztrbdksmg (gzfzfpeqjh )	Positive	02 Jan 2021
				ticagrelor
NCT02317198 (POPular AG, Pubmed) Manual	Phase 4	Non ST segment elevation acute coronary syndrome	1,002	Clopidogrel	wsukkohucb(aqqdxjlzan) = utcyykfsfq fjqsywfprl (fmlgsiojxz ) View more	Positive	25 Apr 2020
				ticagrelor+prasugrel	wsukkohucb(aqqdxjlzan) = iooilfbpmv fjqsywfprl (fmlgsiojxz ) View more

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