Madrigal Announces New Two-Year Data from the Compensated MASH Cirrhosis Arm of the MAESTRO-NAFLD-1 Trial Demonstrating Potential Benefit of Rezdiffra™ (resmetirom) in Patients with Compensated MASH Cirrhosis
Madrigal Pharmaceuticals (NASDAQ:MDGL) has reported positive two-year results from the open-label compensated MASH cirrhosis arm of the Phase 3 MAESTRO-NAFLD-1 trial of Rezdiffra™ (resmetirom). The study showed significant improvements in liver health markers:
- Patients achieved a mean 6.7 kPa reduction in liver stiffness after two years of treatment
- 51% of patients achieved ≥25% reduction in liver stiffness
- Mean liver stiffness at baseline was 25 kPa
The safety and tolerability profile remained consistent with previous trials, showing low discontinuation rates due to adverse events. While Rezdiffra is currently approved for treating adults with noncirrhotic MASH with F2 to F3 fibrosis, it is not yet approved for MASH cirrhosis patients. The company's ongoing MAESTRO-NASH OUTCOMES trial aims to establish safety and efficacy for cirrhosis treatment.
Madrigal Pharmaceuticals (NASDAQ:MDGL) ha riportato risultati positivi a due anni dall'armata MASH cirrosi in aperto compensato dello studio di Fase 3 MAESTRO-NAFLD-1 per Rezdiffra™ (resmetirom). Lo studio ha mostrato miglioramenti significativi nei marcatori della salute epatica:
- I pazienti hanno ottenuto una riduzione media di 6,7 kPa nella rigidità epatica dopo due anni di trattamento
- Il 51% dei pazienti ha raggiunto una riduzione ≥25% nella rigidità epatica
- La rigidità epatica media al basale era di 25 kPa
Il profilo di sicurezza e tollerabilità è rimasto coerente con studi precedenti, mostrando basse percentuali di interruzione a causa di eventi avversi. Sebbene Rezdiffra sia attualmente approvato per il trattamento di adulti con MASH non cirrotica con fibrosi F2 a F3, non è ancora approvato per i pazienti con cirrosi MASH. L'attuale studio MAESTRO-NASH OUTCOMES dell'azienda mira a stabilire la sicurezza e l'efficacia per il trattamento della cirrosi.
Madrigal Pharmaceuticals (NASDAQ:MDGL) ha reportado resultados positivos a dos años del brazo de cirrosis MASH compensada en abierto del ensayo de Fase 3 MAESTRO-NAFLD-1 de Rezdiffra™ (resmetirom). El estudio mostró mejoras significativas en los marcadores de salud hepática:
- Los pacientes lograron una reducción media de 6.7 kPa en la rigidez hepática después de dos años de tratamiento
- El 51% de los pacientes logró una reducción ≥25% en la rigidez hepática
- La rigidez hepática media al inicio era de 25 kPa
El perfil de seguridad y tolerabilidad se mantuvo consistente con ensayos anteriores, mostrando bajas tasas de interrupción debido a eventos adversos. Aunque Rezdiffra está actualmente aprobado para tratar a adultos con MASH no cirrótica con fibrosis F2 a F3, aún no está aprobado para pacientes con cirrosis MASH. El ensayo en curso MAESTRO-NASH OUTCOMES de la compañía tiene como objetivo establecer la seguridad y eficacia para el tratamiento de la cirrosis.
마드리갈 제약 (NASDAQ:MDGL)은 Rezdiffra™ (레즈메티롬)의 3상 MAESTRO-NAFLD-1 시험에서 오픈 라벨 보상 MASH 간경변 팔의 2년 긍정적 결과를 보고했습니다. 이 연구는 간 건강 지표에서 중요한 개선을 보여주었습니다:
- 환자들은 2년 치료 후 6.7 kPa의 평균 감소를 간 경직도에서 달성했습니다
- 환자의 51%가 간 경직도에서 ≥25% 감소를 달성했습니다
- 기준선에서의 평균 간 경직도는 25 kPa였습니다
안전성과 내약성 프로필은 이전 연구와 일관되게 유지되었으며, 부작용으로 인한 낮은 중단율을 보였습니다. Rezdiffra는 현재 F2에서 F3 섬유증이 있는 비간경변 MASH 성인을 치료하기 위해 승인되었지만, MASH 간경변 환자에게는 아직 승인되지 않았습니다. 회사의 진행 중인 MAESTRO-NASH OUTCOMES 시험은 간경변 치료의 안전성과 효능을 확립하는 것을 목표로 하고 있습니다.
Madrigal Pharmaceuticals (NASDAQ:MDGL) a rapporté des résultats positifs sur deux ans du bras de cirrhose MASH compensée en ouvert de l'essai de Phase 3 MAESTRO-NAFLD-1 pour Rezdiffra™ (resmetirom). L'étude a montré des améliorations significatives dans les marqueurs de santé hépatique :
- Les patients ont obtenu une réduction moyenne de 6,7 kPa de la rigidité hépatique après deux ans de traitement
- 51 % des patients ont atteint une réduction ≥25 % de la rigidité hépatique
- La rigidité hépatique moyenne au départ était de 25 kPa
Le profil de sécurité et de tolérabilité est resté cohérent avec les essais précédents, montrant de faibles taux d'interruption en raison d'événements indésirables. Bien que Rezdiffra soit actuellement approuvé pour le traitement des adultes atteints de MASH non cirrhotique avec fibrose F2 à F3, il n'est pas encore approuvé pour les patients atteints de cirrhose MASH. L'essai en cours MAESTRO-NASH OUTCOMES de l'entreprise vise à établir la sécurité et l'efficacité pour le traitement de la cirrhose.
Madrigal Pharmaceuticals (NASDAQ:MDGL) hat positive Ergebnisse nach zwei Jahren aus dem offenen, kompensierten MASH-Leberzirrhose-Arm der Phase-3-Studie MAESTRO-NAFLD-1 zu Rezdiffra™ (Resmetirom) berichtet. Die Studie zeigte signifikante Verbesserungen bei den Lebergesundheitsmarkern:
- Die Patienten erreichten eine durchschnittliche Reduktion von 6,7 kPa bei der Lebersteifigkeit nach zwei Jahren Behandlung
- 51% der Patienten erreichten eine Reduktion von ≥25% bei der Lebersteifigkeit
- Die durchschnittliche Lebersteifigkeit zu Beginn betrug 25 kPa
Das Sicherheits- und Verträglichkeitsprofil blieb konsistent mit früheren Studien und zeigte niedrige Abbruchraten aufgrund von unerwünschten Ereignissen. Während Rezdiffra derzeit zur Behandlung von Erwachsenen mit nicht-zirrhotischer MASH mit F2- bis F3-Fibrose zugelassen ist, ist es noch nicht für Patienten mit MASH-Leberzirrhose zugelassen. Die laufende MAESTRO-NASH OUTCOMES-Studie des Unternehmens zielt darauf ab, Sicherheit und Wirksamkeit für die Behandlung von Leberzirrhose zu etablieren.
- Largest reported reduction in liver stiffness (6.7 kPa) for MASH cirrhosis patients
- 51% of patients achieved clinically significant improvement
- Low rate of adverse event discontinuations
- Potential expansion of Rezdiffra indication to cirrhosis patients pending OUTCOMES trial
- Rezdiffra not yet approved for MASH cirrhosis treatment
- Continued approval contingent on verification in confirmatory trials
Insights
Madrigal Pharmaceuticals' new two-year data from the MAESTRO-NAFLD-1 trial represents a significant clinical and commercial development for Rezdiffra in compensated MASH cirrhosis patients. The mean 6.7 kPa reduction in liver stiffness and 51% responder rate (≥25% reduction) are particularly impressive as they suggest potential to modify disease progression in this high-risk population.
From a market perspective, this data strengthens Madrigal's expansion strategy beyond their current F2-F3 fibrosis approval into the F4c cirrhotic segment. The cirrhotic MASH population represents approximately 20-30% of the total MASH market, with higher treatment urgency given their 42× increased mortality risk. With no approved treatments for this segment, successful completion of the MAESTRO-NASH OUTCOMES trial could add $1-2 billion in peak sales potential to Rezdiffra's commercial outlook.
The consistent safety profile is reassuring, though the full risk-benefit profile in cirrhotic patients will only be established through the OUTCOMES trial. Investors should note that full approval remains contingent on confirmatory trial results, creating some regulatory uncertainty despite these positive surrogate endpoint data.
This data strengthens Madrigal's competitive positioning against emerging competitors like Viking Therapeutics and Akero Therapeutics, who are developing similar THR-β agonists but remain years behind in development. The robust VCTE data also provides differentiation in a space where non-invasive testing is increasingly preferred over liver biopsies for monitoring.
The expanded label potential and strengthened efficacy evidence make Madrigal an increasingly attractive acquisition target for larger pharmaceutical companies seeking to enter the MASH market, potentially creating near-term shareholder value beyond the organic commercial opportunity.
The two-year data from Madrigal's compensated MASH cirrhosis arm represents a potential breakthrough for this high-risk patient population. The mean 6.7 kPa reduction in liver stiffness is clinically significant, as VCTE measurements directly correlate with portal hypertension risk and disease progression rates. For context, each 5 kPa increase in liver stiffness approximately doubles the risk of liver-related complications, making this 6.7 kPa reduction potentially life-extending.
The 51% responder rate achieving ≥25% improvement in liver stiffness is particularly meaningful because longitudinal studies have shown this threshold correlates with reduced clinical events. In practical terms, many patients likely moved from the high-risk category (>20 kPa) to moderate risk ranges, potentially delaying or preventing complications like varices, ascites, and hepatic decompensation.
Rezdiffra's mechanism as a thyroid hormone receptor-β agonist appears to address the underlying pathophysiology of MASH by reducing hepatic fat, inflammation, and subsequently fibrosis. This contrasts with symptomatic treatments that don't address disease progression.
While these results are encouraging, several important limitations must be considered:
- This was an open-label study without a control arm
- VCTE, while validated, remains a surrogate endpoint
- The study doesn't address whether improvements persist if treatment is discontinued
- The safety profile in cirrhotic patients requires careful monitoring for hepatic decompensation risks
The ongoing MAESTRO-NASH OUTCOMES trial will provide important data on whether these VCTE improvements translate to the endpoints that matter most: preventing progression to decompensated cirrhosis, reducing need for liver transplantation, and improving survival. This represents the first real hope for pharmacological intervention in a patient population previously managed primarily through transplant waiting lists.
- Patients achieved a mean 6.7 kPa reduction in liver stiffness as measured by vibration-controlled transient elastography (VCTE); this represents the largest reduction in liver stiffness reported in a compensated MASH cirrhosis patient population
51% of patients achieved a ≥25% reduction in liver stiffness; a reduction of this magnitude has been associated with reduced progression to end-stage liver disease- Company to review topline data during its fourth-quarter and full-year 2024 financial results conference call today, February 26, 2025, at 8 a.m. EST
CONSHOHOCKEN, Pa., Feb. 26, 2025 (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a biopharmaceutical company focused on delivering novel therapeutics for metabolic dysfunction-associated steatohepatitis (MASH), today reported positive two-year results from the open-label compensated MASH cirrhosis (F4c) arm of the Phase 3 MAESTRO-NAFLD-1 trial of Rezdiffra (resmetirom). Patients treated with Rezdiffra achieved marked reductions in liver stiffness, a surrogate for fibrosis, measured by vibration-controlled transient elastography (VCTE).
The Phase 3 MAESTRO-NAFLD-1 trial of Rezdiffra included an open-label active treatment arm of patients with compensated MASH cirrhosis. Madrigal previously reported one-year results from this cohort. Following two years of treatment, 101 patients had VCTE results for analysis. Mean liver stiffness at baseline was 25 kPa and patients achieved a mean 6.7 kPa reduction in liver stiffness at two years (6.1 kPa at one year), which was statistically significant compared to baseline. This represents the largest reduction in liver stiffness reported to date in an F4c MASH population.
Mazen Noureddin, M.D., M.H.Sc., Professor of Medicine, Director Houston Research Institute and C.S.O. Summit Clinical Research, stated, “These data demonstrating patients with compensated MASH cirrhosis achieved marked reductions in VCTE are highly encouraging. We use the ‘Baveno rule of 5 kPa’ to stratify risk of liver-related events in patients with MASH, so a mean 6.7 kPa reduction suggests that many patients are moving into a lower risk category. The results are particularly meaningful in light of recently published, multi-center, longitudinal studies1,2 demonstrating VCTE is a strong predictor of clinical outcomes and may be more predictive of clinical outcomes than fibrosis stage assessed by liver biopsy.”
In a responder analysis examining ≥
The safety and tolerability profile of Rezdiffra in the compensated MASH cohort of MAESTRO-NAFLD-1 was consistent with other Rezdiffra clinical trials, with a low rate of discontinuations due to adverse events.
Becky Taub, M.D., Chief Medical Officer and President of Research & Development of Madrigal, stated, “Patients with MASH who progress to cirrhosis face a 42 times higher risk of liver-related mortality, so there is an urgent need to improve care for this underserved population with no approved treatment options. The new two-year data from MAESTRO-NAFLD-1 reinforce our confidence in the ongoing, fully enrolled MAESTRO-NASH OUTCOMES trial of Rezdiffra in patients with compensated MASH cirrhosis. If our OUTCOMES trial is successful, Rezdiffra has the potential to become the first therapy for F2-F4c MASH. It is important to remember that Rezdiffra should not be used for the treatment of patients with compensated MASH cirrhosis until safety and efficacy are established in our Phase 3 trial and the medication receives approval for this indication from regulatory authorities.”
Draft FDA guidance recommends that Phase 3 clinical trials in MASH cirrhosis use outcomes as an endpoint, as opposed to biopsy-based surrogate endpoints. This guidance, along with data from the open-label compensated MASH cirrhosis arm of MAESTRO-NAFLD-1, informed the design of the ongoing Phase 3 MAESTRO-NASH OUTCOMES trial.
Madrigal plans to present additional results from the compensated MASH cirrhosis arm of the MAESTRO-NAFLD-1 trial at a future medical conference.
Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic MASH 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. Rezdiffra is not approved for the treatment of patients with MASH cirrhosis.
About MASH
Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is a serious liver disease that can progress to cirrhosis, liver failure, liver cancer, need for liver transplantation, and premature mortality. MASH is expected to become the leading cause of liver transplantation in the U.S. and is already the leading cause of liver transplantation among women.
Once patients progress to MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), the risk of adverse liver outcomes increases dramatically: these patients have a 10-17 times higher risk of liver-related mortality as compared to patients without fibrosis. Those who progress to cirrhosis face a 42 times higher risk of liver-related mortality, underscoring the need to treat MASH before complications of cirrhosis develop. MASH is also an independent driver of cardiovascular disease, the leading cause of mortality for patients.
An estimated 1.5 million patients have been diagnosed with MASH in the U.S., and Madrigal is focused on reaching approximately 315,000 patients with moderate to advanced fibrosis who are under the care of liver specialists. As MASH disease awareness improves and disease prevalence increases, the number of diagnosed patients with MASH with moderate to advanced fibrosis is expected to grow.
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 the Rezdiffra Phase 3 Program
Madrigal is currently conducting multiple Phase 3 clinical trials to evaluate the safety and efficacy of Rezdiffra for the treatment of moderate to advanced fibrosis (consistent with fibrosis stages F2-F3) and compensated MASH cirrhosis (consistent with F4c):
- The pivotal MAESTRO-NASH (Moderate to Advanced Fibrosis) trial included a 52-week biopsy assessment that supported accelerated approval and an ongoing 54-month outcomes trial designed to generate confirmatory data that, if positive, will help verify the clinical benefit of Rezdiffra and support full approval. The primary results of the MAESTRO-NASH trial were published in the New England Journal of Medicine in February 2024.
- MAESTRO-NASH OUTCOMES (Compensated Cirrhosis) evaluates progression to liver decompensation events in patients with compensated NASH cirrhosis treated with Rezdiffra versus placebo. A positive outcome is expected to support the full approval of Rezdiffra for noncirrhotic MASH and expand the eligible patient population for Rezdiffra with an additional indication in patients with compensated MASH cirrhosis.
- The MAESTRO-NAFLD-1 (Safety) trial was designed to noninvasively evaluate the safety and tolerability of Rezdiffra and provide a larger safety database to support regulatory benefit-risk assessment. The primary results from the MAESTRO-NAFLD-1 trial were published in Nature Medicine in October 2023. MAESTRO-NAFLD-OLE, an open-label active treatment extension of MAESTRO-NAFLD-1, is ongoing to collect additional safety data in patients with noncirrhotic NASH and patients with compensated NASH cirrhosis.
Data from the 52-week portion of MAESTRO-NASH, together with data from MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, Phase 2 and Phase 1 data, including safety parameters, formed the basis for accelerated approval of Rezdiffra for treatment of MASH with moderate to advanced liver fibrosis.
About Madrigal
Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) is a biopharmaceutical company focused on delivering novel therapeutics for metabolic dysfunction-associated steatohepatitis (MASH), 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 MASH. Rezdiffra is the first and only medication approved by the FDA for the treatment of MASH with moderate to advanced fibrosis (consistent with stages F2 to F3). An ongoing Phase 3 outcomes trial is evaluating Rezdiffra for the treatment of compensated MASH cirrhosis (consistent with stage F4c). For more information, visit www.madrigalpharma.com.
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, as amended, including Rezdiffra’s potential ability to treat patients with compensated MASH cirrhosis, Madrigals intentions to present data from the MAESTRO-NAFLD-1 trial at a medical conference and expectations regarding the MAESTRO NASH OUTCOMES trial. 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; our history of operating losses and the possibility that we may never achieve or maintain profitability; 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 Rezdiffra; the potential inability to raise sufficient capital to fund ongoing operations as currently planned or to obtain financing on acceptable terms; 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; uncertainties concerning analyses or assessments outside of a controlled clinical trial; and changes in laws and regulations applicable to our business and our ability to comply with such laws and regulations. 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 September 30, 2024, filed with the SEC on October 31, 2024, and as updated from time to time by Madrigal’s other filings with the SEC.
1. Lin H, Lee HW, Yip TC, et al. Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease. JAMA. 2024;331(15):1287–1297.
2. Gawrieh, S, et al. Increases and Decreases in Liver Stiffness Measurement are independently associated with the risk of liver-related events in NAFLD. Journal of Hepatology. 2024;81(4):600–608.
Investor Contact
Tina Ventura, IR@madrigalpharma.com
Media Contact
Christopher Frates, media@madrigalpharma.com
FAQ
What were the key results of Madrigal's (MDGL) two-year MAESTRO-NAFLD-1 trial for Rezdiffra?
Is Rezdiffra approved for treating MASH cirrhosis patients?
What is the significance of the 6.7 kPa reduction in liver stiffness achieved in the MDGL trial?
How many patients showed improvement in the Madrigal (MDGL) MAESTRO-NAFLD-1 trial?
