EPL Improves Steatosis, Fatigue in Patients With MASLD, With Zobair Younossi, MD

In EXCEL, the first double-blind, randomized, placebo-controlled clinical trial to assess the impact of essential phospholipids (EPL) in addition to standard of care on liver steatosis and quality of life in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic comorbidities, treatment with EPL resulted in a statistically significant reduction in hepatic steatosis compared with placebo, meeting the study's primary endpoint.

Measured by controlled attenuation parameter (CAP), a noninvasive FibroScan-based assessment of hepatic fat content, the reduction in steatosis was evident as early as 3 months and remained significant through 3 months after treatment discontinuation.

“There has been a lack of understanding and awareness about this disease at all levels of the health system in the United States, as well as the rest of the world,” Zobair Younossi, MD, chairman of the Global NASH Council and professor of medicine and chairman of the Global Center for Liver Outcomes & Policy Research at Georgetown University School of Medicine, told HCPLive.

The standard of care for first-line MASLD management remains lifestyle intervention, including dietary modification and physical activity. More recently, the treatment landscape has expanded with FDA approvals for metabolic liver disease, including resmetirom (Rezdiffra) for adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced fibrosis and semaglutide (Wegovy) for MASH in adults with moderate-to-advanced fibrosis.

MASLD Burden

The prevalence of MASLD continues to rise alongside obesity and type 2 diabetes mellitus (T2DM), with estimates suggesting approximately 38% of adults globally are affected. Individuals with MASLD, particularly those with MASH and hepatic fibrosis, are at increased risk for T2DM, cardiovascular disease, chronic kidney disease, and several extrahepatic malignancies.

Recently, a Consensus Report from the American Diabetes Association addressed the MASLD nomenclature change, risk stratification, current treatment approaches, and long-term monitoring strategies while emphasizing the need for multidisciplinary disease management.

Beyond its clinical burden, MASLD substantially affects health-related quality of life (HRQoL), with common symptoms including fatigue, abdominal discomfort, and sleep disturbances.

“A lot of these patients actually do have significant fatigue,” Younossi said. “The problem is that they may not recognize that fatigue to be associated with their liver disease.”

Why EPL?

The phosphatidylcholine pathway is an important driver of MASLD pathogenesis. Patients with MASLD and MASH have been shown to have lower levels of polyunsaturated phosphatidylcholine, an important component of hepatocyte cell membranes involved in lipid transport and membrane integrity.

EPL, or polyene phosphatidylcholine, is derived from highly purified soybean extracts and contains >72% 3-sn-phosphatidylcholine, with 1,2-dilinoleoylphosphatidylcholine as its primary active component. Previous studies evaluating EPL in patients with MASLD have suggested benefits on liver enzyme levels, lipid profiles, and hepatic steatosis, although robust placebo-controlled data have been limited.

EXCEL Design

EXCEL was a phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the efficacy and safety of EPL added to standard of care in patients with MASLD and at least 1 metabolic comorbidity, including T2DM, hyperlipidemia, or obesity.

The primary endpoint was change in hepatic steatosis from baseline to month 6, assessed by CAP score. Secondary endpoints included changes in HRQoL and symptom assessments for asthenia, depressed mood, abdominal pain or discomfort, and fatigue. Safety assessments included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest.

Eligible patients were 18-70 years of age with MASLD, steatosis grades S1-S3 (CAP score >248 dB/m), liver fibrosis stages F1-F3 based on liver stiffness measurement scores of 5-13 kPa by vibration-controlled transient elastography, and at least 1 metabolic comorbidity.

In the intention-to-treat population, 193 patients were randomized 1:1 to EPL (n = 97) or placebo (n = 96). The modified intention-to-treat population included 165 patients with evaluable baseline and postbaseline CAP assessments who received study treatment (EPL, n = 82; placebo, n = 83).

Baseline characteristics were balanced between treatment groups. More than three-quarters of patients were obese, more than 80% had severe steatosis (CAP ≥280 dB/m), and most had mild fibrosis at study entry.

Results

A statistically significant reduction in CAP score was observed among patients treated with EPL compared with placebo.

At 6 months, the mean change from baseline in CAP score was −23.0 dB/m (standard deviation [SD], 46.50) in the EPL arm and −11.5 dB/m (SD, 42.83) in the placebo arm. Least-squares mean changes were −24.6 dB/m and −9.8 dB/m, respectively, corresponding to a least-squares mean difference (LSMD) of −14.81 dB/m (standard error [SE], 6.63; 95% CI, −27.89 to −1.72; P = .0269).

Notably, improvements in steatosis were evident by month 3 and remained significant 3 months after treatment discontinuation. At month 3, the LSMD was −16.11 dB/m (SE, 5.65; 95% CI, −27.27 to −4.96; P = .0049), while the post-treatment assessment showed an LSMD of −15.19 dB/m (SE, 6.65; 95% CI, −28.29 to −2.09; P = .0234).

Subgroup analyses demonstrated significant CAP score reductions among patients with baseline HbA1c <8.0% (LSMD, −15.39 dB/m; SE, 7.39; 95% CI, −30.02 to −0.77; P = .0392) and among those with baseline BMI <30 kg/m² (LSMD, −41.0 dB/m; SE, 18.89; 95% CI, −79.8 to −2.19; P = .0392).

Investigators also observed significant improvements in glycemic control. At 6 months, EPL was associated with a significant reduction in HbA1c compared with placebo (LSMD, −0.55%; SE, 0.20; 95% CI, −0.95 to −0.15; P = .0069), with the effect persisting numerically through the 9-month follow-up period.

The mean change from baseline to 6 months in the QoL total score was greater in the EPL arm than the placebo arm, although the difference did not reach statistical significance (LSMD, 0.17; SE, 0.08; P = .2445). Numerical improvements in QoL were observed at months 3, 6, and 9 among patients receiving EPL.

When analyzed by symptom subscore, EPL treatment was associated with a statistically significant improvement in fatigue at 6 months compared with placebo (LSMD, 0.31; SE, 0.13; 95% CI, 0.04-0.58; P = .0229).

Safety and Patient Satisfaction

Overall, 56.7% of patients receiving EPL and 52.1% of those receiving placebo experienced at least 1 TEAE. The most commonly reported TEAEs were headache, diarrhea, and nasopharyngitis.

Investigators reported a safety profile comparable to placebo, with no new safety concerns identified during the study.

At 6 months, a greater proportion of patients receiving EPL reported high satisfaction with treatment effectiveness compared with placebo (53.7% vs 50.6%), while fewer patients reported dissatisfaction (1.2% vs 9.6%). However, differences in total satisfaction scores were not statistically significant (OR, 1.14; 95% CI, 0.62-2.10; P = .6709).

Although EPL did not significantly improve liver stiffness measurements, a post hoc analysis demonstrated a significant improvement in FibroScan-AST (FAST) score compared with placebo at 6 months (LSMD, −0.05; SE, 0.03; 95% CI, −0.10 to −0.00; P = .0437), suggesting a potential benefit in reducing the risk of progressive MASH.

Editor’s Note: Younossi reports relevant disclosures with Boehringer Ingelheim, Ipsen, Gilead Sciences, BMS, GSK, NovoNordisk, Siemens, Madrigal Pharmaceuticals, Merck, and Abbott.