Naim Alkhouri, MD, is Chief Academic Officer at Summit Clinical Research and the Director of the Steatotic Liver Disease Program at the Clinical Research Institute of Ohio.

Naim Alkhouri, MD

Using Noninvasive Testing to Guide MASH Treatment Decisions, With Naim Alkhouri, MD

The rapid emergence of pharmacologic options for metabolic dysfunction-associated steatohepatitis (MASH) has introduced a new set of clinical challenges, particularly around identifying which patients are appropriate candidates for treatment.

With both resmetirom and semaglutide now approved by the US Food and Drug Administration for patients with F2-F3 fibrosis, professional societies have emphasized the need for careful noninvasive assessment to avoid treating individuals with cirrhosis until more data become available. However, the practical application of these recommendations is not always straightforward, as liver stiffness thresholds commonly used to exclude patients may inadvertently prevent some individuals with advanced fibrosis from receiving therapies that have the potential to reverse disease progression.

“We know from clinical practice that many patients with liver stiffness above 20, between 20 to 25, may actually have stage 3 fibrosis, not cirrhosis, and if you exclude them automatically, they will miss the opportunity to be treated with the treatment that can reverse fibrosis,” Naim Alkhouri, MD, chief academic officer of Summit Clinical Research and director of the Steatotic Liver Program at North Shore Gastroenterology, explained to 

American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025

, Alkhouri presented research examining the performance of noninvasive tests (NITs) in identifying F2/F3 or F4 fibrosis in patients with LSM 15-25 kPa in a large multicenter database of patients with biopsy-proven MASH.

Patients with LSM 15-20 kPa or LSM 20-25 kPa were identified for further analysis. Comparisons were made between those found to have F2/F3 on biopsy versus F4, and NIT performance was compared to biopsy results.

Of 18,402 patients reviewed, 4326 had baseline liver biopsy and LSM results, 882 of whom had LSM between 15-25. Among patients with LSM between 15-20 kPa (n = 586, 66%; n = 354 F2/F3 and n = 232 F4) and 20-25 kPa (n = 296, 34%; n = 141 F2/F3 and n = 155 F4), patients with F4 fibrosis were significantly older (

In patients with LSM 15-20 kPa, investigators noted model performance was highest using Agile 4 (AUC, 0.76; 95% CI, 0.69-0.83), followed by platelet count (AUC, 0.71; 95% CI, 0.66-0.76) and FIB-4 (AUC, 0.69; 95% CI, 0.64-0.75). Among the LSM 20-25 kPa group, platelet count had superior performance (AUC, 0.75; 95% CI, 0.69-0.82), followed by FIB-4 (AUC, 0.73; 95% CI, 0.66-0.80), and Agile 4 (AUC, 0.70; 95% CI, 0.60-0.79).

Combining all tests resulted in an AUC of 0.76 (95% CI, 0.69-0.82) in the 15-20 kPa group and 0.75 (95% CI, 0.66-0.84) in the 20-25 kPa group. To reach ≥90% sensitivity, for the Agile 4 score, a cutoff value of 0.104 was needed in the 15-20 kPa group and 0.099 in the 20-25 kPa group.

“We hope that these recommendations will be useful to providers when they have elevated liver stiffness and they're not sure if they need to proceed with treatment with resmetirom or semaglutide or say no because this patient has cirrhosis,” Alkhouri said.

Editors’ note: Alkhouri reports relevant disclosures with Altimmune, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Rivus, Takeda, and others.

Alkhouri N, Schattenberg J, Patil R, et al. Utility of FIB-4, Agile 4, and Platelet Count to Rule Out Cirrhosis on Biopsy in Patients with LSM Between 15-25 kPa: A Multi-Center Cohort Study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed November 20, 2025. 

https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed November 20, 2025. 

https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash

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Alkhouri explains the importance of differentiating F3 from cirrhosis and the utility of different noninvasive tests for identifying these patients.

WAYFIND: Exploring Combination Therapy for MASH Cirrhosis, With Naim Alkhouri, MD

While cirrhosis has traditionally been viewed as an irreversible stage of chronic liver disease, emerging data from pharmacologic trials have begun to challenge that notion. Among these, the phase 2 WAYFIND trial has drawn considerable attention for testing a novel combination approach in patients with biopsy-proven 

metabolic dysfunction-associated steatohepatitis (MASH)

 cirrhosis, with results recently presented at the 

In the past 2 years, the MASH treatment landscape has seen the addition of the first 2 US Food and Drug Administration approved therapies in the form of resmetirom and semaglutide. However, neither agent indicated for patients with cirrhotic MASH, representing a substantial unmet need for this population.

Seeking to address this therapeutic gap, the Naim Alkhouri, MD, chief academic officer of Summit Clinical Research and director of the Steatotic Liver Program at North Shore Gastroenterology, and investigators on the WAYFIND trial assessed the efficacy and safety of semaglutide alone and in fixed-dose combination with cilofexor and firsocostat in patients with compensated cirrhosis due to MASH. The multicenter, double-blind, phase 2b study randomly assigned adults with biopsy-proven F4C due to MASH in a 3:3:3:2 ratio to receive semaglutide 2.4 mg/week + cilofexor 30 mg/firsocostat 20 mg/day, semaglutide 2.4 mg/week, cilofexor 30 mg/firsocostat 20 mg/day, or placebo for 72 weeks.

The primary endpoint was the proportion of patients with fibrosis improvement without MASH worsening at week 72 with semaglutdie+cilofexor/firsocostat versus placebo. Secondary (with prespecified testing hierarchy) and exploratory efficacy endpoints and safety were also assessed.

Of 457 patients who were randomized in the trial, 453 had ≥1 study drug dose. Their mean age was 62 years, 68.2% had type 2 diabetes, and mean platelets were 191×109/L.

Investigators noted there was no significant difference in the proportions of patients with fibrosis improvement without MASH worsening at week 72 with semaglutide+cilofexor/firsocostat versus placebo (13.7% vs 8.3%; 

= .2289). However, fibrosis improvement was observed with cilofexor/firsocostat versus placebo (20.3% vs 8.3%; 

Further analysis with PathAI analysis revealed a difference with semaglutide+cilofexor/firsocostat versus placebo (21.0% vs 6.0%; 

= .0011). Investigators noted MASH resolution was greater with semaglutide+cilofexor/firsocostat versus cilofexor/firsocostat or placebo and with semaglutide versus placebo in both pathologist and PathAI analyses.

The most frequent adverse events (AEs) occurring more often with semaglutide+cilofexor/firsocostat versus placebo were nausea (47.6% vs 22.6%), diarrhea (27.4% vs 17.9%), constipation (24.2% vs 8.3%), vomiting (21.8% vs 7.1%), and decreased appetite (15.3% vs 6.0%). Serious AEs and AEs leading to study discontinuation were similar across all groups. A single death occurred in each of the semaglutide and cilofexor/firsocostat groups.

“In my opinion, these data speak to the potential of reversing cirrhosis, [which has a] very high unmet need, and although we did not hit the primary endpoint, I think we see several secondary endpoints that improved with these treatments,” Alkhouri said.

Alkhouri N, Kowdley K, Lawitz E, et al. A randomized, placebo-controlled, phase 2 study of the safety and efficacy of combination treatment with semaglutide, cilofexor and firsocostat in patients with compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis (WAYFIND). Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed November 18, 2025. 

Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed November 18, 2025. 

Alkhouri explains findings from the phase 2 WAYFIND trial suggesting the potential of semaglutide and cilofexor/firsocostat for MASH cirrhosis.

Resmetirom’s Potential Role in MASH Cirrhosis, With Naim Alkhouri, MD

Just a few years ago, there were no US Food and Drug Administration (FDA)-approved pharmacologic treatments for 

, leaving patients and clinicians to rely solely on lifestyle changes with diet and exercise for disease management. Recently, the field has seen unprecedented progress in the form of 2 FDA-approved treatments, resmetirom (Rezdiffra) and semaglutide (Wegovy), and the success of several other agents in clinical development.

“The data have been very encouraging, and I think these medications have the potential to change the natural history of this disease and prevent the development of major adverse liver outcomes,” Naim Alkhouri, MD, chief academic officer of Summit Clinical Research and director of the Steatotic Liver Program at North Shore Gastroenterology, explained to 

, describing 2025 as having been “a good year for patients living with MASH.”

Despite the therapeutic progress seen in MASH for patients with moderate to advanced fibrosis, a major unmet need remains for patients with cirrhotic MASH, as neither resmetirom or semaglutide are currently indicated for use in this patient population.

 assessed resmetirom’s use in a cohort of patients with compensated MASH cirrhosis. Specifically, a total of 122 patients with Child Pugh A MASH cirrhosis, defined based on MASH F4 on historic biopsy >66% or clinical diagnosis, were treated with 80 mg resmetirom for up to 2 years in MAETRO-NAFLD-1 and its open-label extension.

Of note, patients experienced a mean gap of 77 (58) days in resmetirom treatment between years 1 and 2. Investigators analyzed non-invasive biomarkers and imaging at baseline and out to 2 years to assess durability of responses and the impact of treatment interruption.

Among the cohort, the mean age was 61.3 (9.1) years, 56% of patients were female, and 27% were Hispanic. The median VCTE was 20.1 (interquartile range [IQR], 17.1 to 31.3)kPa, ELF was 10.7 (IQR, 10.0-11.5), and MRI-PDFF was 8.6% (IQR, 6.0% to 11.5%). Clinically significant portal hypertension or probable clinically significant portal hypertension was predicted in 49%, 93% with platelets(PLT)<100k; 35%, PLT≥100K. Spleen volume in patients with PLT count <100k (n = 30) and ≥100k (n = 92) were 867 (319) and 487 (220), respectively.

Results showed treatment interruption after year 1 resulted in loss of resmetirom biomarker effects including lipids, MRI-PDFF, VCTE, adiponectin and spleen volume. Treatment with resmetirom restored year 1 biomarker effects except in some with baseline PLT<100K. Of 6 total decompensation events, 5 occurred in patients with PLT<100K and elevated spleen volume.

“This speaks to the fact that when we achieve response to resmetirom, continuation of treatment is key in this very advanced population with cirrhosis,” Alkhouri explained.

Resmetirom effects at year 2 compared to baseline included the following in patients with PLT count <100K and ≥100k, respectively:

VCTE: -7.9 (95% CI, -14.1 to -1.8) and -6.4 (95% CI, -8.7 to -4.0) kPa

ALT: 6%(95% CI, -11% to 23%) and -25%(95% CI, -32% to -19%)

AST: 31% (95% CI, 8% to 54%) and -18% (95% CI, -25% to -11%)

GGT: -19% (95% CI, -39% to 0) and -40% (95% CI, -47% to -33%) (baseline ALT ≥ 30 IU/L)

LDL: -9% (95% CI, -19% to 1%) and -17% (95% CI, -23% to -12%)

ApoB: -12% (95% CI, -19% to -6%) and -22% (95% CI, -25% to -18%)

TGs: -13% (95% CI, -35% to 9%) and -20% (95% CI, -27% to -14%)

Adiponectin: 63% (95% CI, 31% to 94%) and 36% (95% CI, 26% to 46%)

Spleen volume: 5% (95% CI, 1% to 9%) and -6% (95% CI, -9% to -2%).

Investigators additionally noted high Agile shifted to lower Agile (35%) and clinically significant portal hypertension shifted to a lower clinically significant portal hypertension risk score in 65%. The treatment discontinuation rate was 8%, with mild gastrointestinal disorders being the most common adverse events.

Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed November 13, 2025. 

Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed November 13, 2025. 

Alkhouri N, Taub R, Lu X, et al. Two-year time course of biomarker and imaging responses in well-compensated MASH cirrhosis patients treated with resmetirom. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Alkhouri breaks down recent therapeutic progress in MASH and explains new data on resmetirom’s use in patients with compensated MASH cirrhosis.

Phase 3 MAESTRO-NAFLD-1 Data for Resmetirom in MASH Cirrhosis, with Naim Alkhouri, MD

In 2024, the US Food and Drug Administration granted accelerated approval to Madrigal Pharmaceuticals’ resmetirom (Rezdiffra) for the treatment of noncirrhotic 

 in patients with moderate to advanced fibrosis.

However, as MASH progresses and cirrhosis develops, therapeutic options become increasingly limited, as the selective thyroid hormone receptor-β agonist is not yet approved for MASH cirrhosis. New positive 2-year results from the open-label compensated MASH cirrhosis (F4c) arm of the phase 3 MAESTRO-NAFLD-1 trial suggest a new, much-needed indication may be on its way.

The trial included an open-label active treatment arm of patients with compensated MASH cirrhosis. After one year, patients were given the option to enroll in an open-label extension trial; 122 patients enrolled and 113 completed 2 years of treatment.

“The most exciting finding was what we saw with changes in liver stiffness,” Naim Alkhouri, MD, Chief Academic Officer at Summit Clinical Research and the Director of the Steatotic Liver Disease Program at the Clinical Research Institute of Ohio, explained to 

. “After 2 years of treatment, we show reduction in liver stiffness measurement with FibroScan by 6.7 kilopascals. In my mind, this is very clinically meaningful, because if you reduce your liver stiffness by 25% or more from baseline, this has been shown to predict less progression to liver outcomes, and we were able to do this in over 50% of patients after 2 years of treatment.”

Further analysis revealed patients achieved significant improvements from baseline in liver fat, fibrosis biomarkers, liver volume, and risk scores for clinically significant portal hypertension (CSPH).

At baseline, 35% of patients met Baveno criteria for CSPH, 14% for probable CSPH and 51% for no/low CSPH. Among those with CSPH at baseline, 65% moved into lower risk categories by year 2, including 42% to no/low CSPH and 23% to probable CSPH. Among patients with probable CSPH at baseline, 57% moved into the no/low CSPH category as compared to 14% who moved into the CSPH category by year 2.

Of note, similar shifts to lower risk categories were observed in an analysis using a more stringent modified Baveno criteria that incorporates magnetic resonance elastography and the Enhanced Liver Fibrosis test as additional evidence for CSPH risk.

“Overall, we're very pleased with the results of this open label extension trial, and I hope that this will be solidified when we see the results of the MAESTRO NASH OUTCOMES phase 3 trial. This is fully enrolled, and we expect the results hopefully by the end of 2027,” Alkhouri said.

Editors’ note: Alkhouri has relevant disclosures with Altimmune, Chronwell, Cytodyne, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Rivus, Takeda, and Terns.

Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. 

. March 14, 2024. Accessed June 4, 2025. 

Madrigal Pharmaceuticals. Madrigal Announces New Clinical Data Demonstrating Rezdiffra™ (resmetirom) Significantly Improved Multiple Noninvasive Tests and Portal Hypertension Risk in Patients with Compensated MASH Cirrhosis. May 10, 2025. Accessed June 4, 2025. 

https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-announces-new-clinical-data-demonstrating-rezdiffratm

Alkhouri reviews data from the trial’s open-label compensated MASH cirrhosis arm demonstrating resmetirom’s impact on liver stiffness and CSPH.

Naim Alkhouri, MD

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