Hepatology Month in Review: March 2024

The month of March was nothing short of groundbreaking in the field of hepatology, owed largely to a landmark US Food and Drug Administration (FDA) decision with the approval of resmetirom (Rezdiffra) as the first and only treatment for metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH). Our March 2024 month in review spotlights HCPLive’s extensive pre- and post-approval coverage of the decision as well as other notable hepatic pipeline updates for MASH, cirrhosis, and hepatitis B virus (HBV).

FDA Approves First MASH/NASH Treatment

Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH

On March 14, resmetirom became the first and only FDA-approved MASH treatment, earning accelerated approval in patients with noncirrhotic MASH and moderate to advanced fibrosis following 18 clinical studies in the oral, thyroid hormone receptor (THR)-β selective agonist’s clinical development program.

Results from MAESTRO-NASH, 1 of resmetirom’s 4 phase 3 clinical studies, showed NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the resmetirom 80 mg group and 29.9% of those in the resmetirom 100 mg group, compared to 9.7% of those in the placebo group (P <.001). Fibrosis improvement by ≥ 1 stage with no worsening of the NAFLD activity score was also superior in the resmetirom 80 mg (24.2%) and resmetirom 100 mg (25.9%) groups versus the placebo group (14.2%; P <.001). Additionally, the change in LDL cholesterol levels from baseline to week 24 was −13.6% in the resmetirom 80 mg group and −16.3% in the resmetirom 100 mg group, as compared with 0.1% in the placebo group (P <.001).

Stephen Harrison, MD: FDA Approval of Resmetirom Ends Lengthy Road to First NASH Treatment

For further insight into resmetirom’s road to approval, we spoke with lead MAESTRO-NASH investigator Stephen Harrison, MD, founder and chairman of Pinnacle Clinical Research and Summit Clinical Research. In this interview with HCPLive, Harrison reflected on Intercept Pharmaceuticals’ Complete Response Letter for obeticholic acid (OCA) last year, noting “we learned a lot” from its FDA failure. Specifically, he pointed to the importance of adverse event profiles and treatment safety, noting that in comparison, resmetirom showed far more efficacy with fewer safety concerns than OCA.

In a second interview segment, Harrison discussed the role of glucagon-like peptide 1 (GLP-1)-based therapies in NASH management and situations where resmetirom may be a better option. He cited GLP-1 agonists’ lack of meaningful, timely impact on fibrosis and highlighted the need for liver-directed therapies with a faster, more direct impact, especially in patients with F2 or F3.

How Approval of Resmetirom Impacts Management, Screening for NASH

In this 5-part HCPLive peer-to-peer video series, a pair of experts in hepatology, Juan Pablo Arab, MD, and Rajarshi Banerjee, MD, PhD, MSc, discuss resmetirom’s impact on NASH management and screening for the progressive liver disease. Topics discussed range from the recent change in nomenclature and the MAESTRO-NASH data supporting resmetirom’s approval to how they anticipate it will alter the current hepatic landscape.

In the Pipeline

Pegozafermin Enters Phase 3 Clinical Trial Program for MASH, Fibrosis

Just a few days prior to the approval of Madrigal Pharmaceuticals’ resmetirom, 89bio announced the initiation of its phase 3 ENLIGHTEN program evaluating the efficacy and safety of pegozafermin in patients with noncirrhotic MASH and fibrosis stage F2-F3. Co-primary endpoints for improvement in fibrosis with no worsening of MASH and MASH resolution with no worsening of fibrosis will be measured at week 52 and are intended to support a filing for the specifically engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21)’s accelerated approval in the US.

T Cell Vaccine Demonstrates Safety as Functional Cure for Hepatitis B Virus in Phase 1 Trial

Data from a first-in-human trial of a novel, first-in-class, checkpoint modifier immunotherapy called VRON-0200 presented at the Asian Pacific Association for the Study of the Liver (APSAL) meeting suggests the agent, intended to be a functional cure for HBV, was well tolerated among a cohort of 10 patients with chronic HBV infection. Results from cohort 1 of the phase 1b trial showed VRON-0200 did not cause any serious adverse events, had no observed safety concerns, and no unexpected laboratory abnormalities, including for liver function tests.

LPCN 1148 Achieves Phase 2 Study Endpoints in Cirrhosis Management

Topline results from a phase 2 study of LPCN 1148 showed the oral drug candidate achieved its primary endpoints in the clinical management of cirrhosis, including the prevention of overt hepatic encephalopathy (OHE) recurrence and the treatment of sarcopenia. Findings showed individuals on LPCN 1148 therapy demonstrated an increase in Skeletal Muscle Index (SMI) at 24 weeks, with maintenance through 52 weeks, and fewer OHE events compared to placebo-treated patients. Based on these results, Lipocine Inc. has announced plans to meet with the FDA to evaluate a development path to filing a New Drug Application (NDA).

Positive Phase 2 Data Shows Benefit of Lanifibranor with Empagliflozin for MASH, T2D

Results from an interim analysis of the phase 2, proof-of-concept LEGEND trial evaluating lanifibranor in combination with empagliflozin in patients with MASH and poorly controlled T2D suggest the potential benefit of combination therapy with the sodium-glucose cotransporter-2 (SGLT2) inhibitor and peroxisome proliferator-activated receptor (PPAR) agonist. The trial achieved its primary efficacy endpoint by significantly lowering hemoglobin A1c (HbA1c) in both the lanifibranor arm and in the lanifibranor with empagliflozin arm compared to placebo, also achieving statistical significance for multiple markers of liver injury, markers of glucose and lipid metabolism, and hepatic steatosis.