Hepatology Month in Review: July 2024

July was a strong start to the second half of what has been a historic year in hepatology thus far, suggesting the latter portion of 2024 will be a fitting continuation of a busy first 6 months of the year. Our month in review spotlights some of the top news from the past few weeks, including pipeline updates, advances in hepatic diagnostic and prognostic approaches, and new research about factors impacting health outcomes across a range of chronic liver diseases.

In the Pipeline

FDA Approves Label Expansion for Maralixibat (Livmarli) in PFIC

The sole hepatic FDA approval in July came in the form of a label expansion for maralixibat (Livmarli) to include use in patients with progressive familial intrahepatic cholestasis (PFIC) 12 months of age and older. Previously, the orally administered, once-daily ileal bile acid transporter (IBAT) inhibitor was granted approval for the treatment of cholestatic pruritus in patients 5 years of age or older with PFIC in its second rare liver disease indication, the first being for cholestatic pruritus in patients with Alagille syndrome ≥ 3 months of age.

“The launch of LIVMARLI in PFIC is going well and we are thrilled that it will now be available for patients 12 months and older,” Chris Peetz, chief executive officer at Mirum, said in a press release. “PFIC is generally diagnosed when children are young, and initiating treatment quickly after diagnosis will help to ensure they have fewer days suffering from pruritus associated with this rare liver disease.”

SEQUOIA: Fazirsiran Reduces Serum, Liver Z-AAT Concentrations, Improves Hepatic Globule Burden

Phase 2 data for fazirsiran in adult patients with the PiZZ genotype of alpha-1 antitrypsin deficiency (AATD) and liver fibrosis made waves in the hepatology pipeline in July.

A hepatocyte-targeted investigational RNA interference therapeutic, fazirsiran contains a synthetic, double-stranded, small interfering RNA duplex and was designed to degrade AAT and Z-AAT messenger RNA in hepatocytes, subsequently reducing protein synthesis and inhibiting further accumulation of Z-AAT polymers to allow normal cellular mechanisms to dispose of mutant proteins. One-year findings from the ongoing randomized, placebo-controlled, phase 2 SEQUOIA study highlight sustained, dose-dependent reductions in Z-AAT concentration and improved histological findings, including periodic acid-Schiff staining with diastase digestion globule burden, with fazirsiran.

SPRING: CM-101, A CCL24-Neutralizing Antibody, Impresses in Phase 2 PSC Trial

Other notable phase 2 data announced in July were positive topline results from the SPRING trial assessing CM-101, a first-in-class CCL24-neutralizing antibody, in patients with primary sclerosing cholangitis (PSC). In the phase 2 trial, treatment with CM-101 achieved the primary endpoint of safety and tolerability and demonstrated anti-fibrotic, anti-inflammatory, and anti-cholestatic effects across a range of disease-related secondary efficacy endpoints, making it the first investigational drug being developed for PSC to exhibit broad, clinically relevant effects on all 3 components of the disease.

“We are thrilled to report the positive results of the Phase 2 SPRING trial that represent a major milestone for Chemomab and establish clear clinical proof-of-concept for CM-101 in PSC and potentially other fibrotic diseases,” Adi Mor, PhD, co-founder, chief executive officer and chief scientific officer of Chemomab, said in a press release.1 “We believe these results provide strong support for advancing CM-101 to a Phase 3 PSC trial, which we are planning to initiate in 2025 after our interactions with the FDA later this year.”

Diagnostic, Prognostic Advances in Hepatology

Circulating Z-Polymer Levels Show Potential as Prognostic Biomarker in AATD

New research suggests circulating polymerized mutant Z-alpha-1 antitrypsin (Z-polymer) levels may have prognostic value as a biomarker of clinically relevant disease in individuals with AATD. In the study, increased circulating Z-polymer levels were associated with a greater risk of having an adverse clinical outcome and positively correlated with baseline liver stiffness measurement in adults with the PiZZ genotype. Findings build upon previous research about circulating Z-polymer levels’ association with liver fibrosis on biopsy, now providing evidence about their impact on long-term clinically relevant adverse outcomes.

Diagnostic Nomogram Enables Noninvasive Detection of HBV-Related Cirrhosis

A recent study identified age, diameter of right hepatic vein, presence or absence of nodules, and liver parenchymal echo grading as independent risk factors for early cirrhosis related to chronic hepatitis B virus (HBV) infection and used these variables to construct a diagnostic nomogram for noninvasive diagnosis without liver biopsy. Of note, the nomogram showed greater diagnostic accuracy than aspartate aminotransferase to platelet ratio index (APRI), FIB-4, international normalized ratio-to-platelet ratio (INPR), and liver stiffness measurement (LSM).

Factors Impacting Hepatic Health, Outcomes

Cirrhosis Linked to Greater Health Care Cost, Comorbidity Burden in MASH

Findings from this retrospective, observational study provide insight into the health and economic burden of metabolic dysfunction-associated steatohepatitis (MASH), especially among patients with cirrhosis, who generally face an increased prevalence of comorbidities and greater annual total health care costs.

“These results complement previous findings demonstrating that early diagnosis and prevention of disease progression could reduce the comorbidity and economic burden associated with MASH,” investigators wrote.

Lower Income Associated with Greater Mortality Risk in Chronic Liver Disease

Income has a notable impact on mortality risk in individuals with nonalcoholic fatty liver disease (NAFLD) and viral hepatitis, according to findings from this analysis of National Health and Nutrition Examination Surveys (NHANES) data. Specifically, findings suggest lower-income, foreign-born, and racial/ethnic minority groups are disproportionately represented among those with chronic liver disease, with individuals with chronic liver disease and lower income having twice the mortality risk compared to their higher-income counterparts.

Medicaid Direct-Acting Antiviral Restrictions Linked to Reduced HCV Treatment Rates

Medicaid nonexpansion status, fibrosis restrictions, and sobriety restrictions have notable negative impacts on hepatitis C treatment rates among Medicaid recipients, with findings from this study suggesting that removing restrictive direct-acting antiviral prior authorization policies could improve timely access to treatment while also reducing disparities in treatment access and enhancing health equity among people who use drugs or alcohol, people experiencing poverty, and people without access to specialty care.