Oral LPCN 1148 improves sarcopenia and hepatic encephalopathy in male patients with cirrhosis: A randomized, placebo-controlled phase 2 trial

Abstract

Background and aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes, including HE. Androgen receptor agonists, androgen receptor agonists, can address these conditions through multimodal mechanisms of action; however, their safety and efficacy in patients with cirrhosis have not been well established.

Approach and results: In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral Androgen Receptor Agonist LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary end point was the change from baseline to 24 weeks in skeletal muscle index measured by a CT scan of the L3 region, analyzed with a prespecified modified intent-to-treat population. The secondary end point was the number of overt HE events. Twenty-nine participants (mean age=59 y, MELD=17) received at least 1 dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary end point analysis demonstrated an increase in L3-skeletal muscle index measured by a CT scan of the L3 region in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm 2 /m 2 (95% CI: 1.3-7.4 cm 2 /m 2 , p =0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (Common Terminology Criteria for Adverse Events grade ≥2; p =0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms.

Conclusions: LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.

Keywords: CT; androgen; intramuscular adipose tissue; liver disease; muscle loss.

Graphical abstract

FIGURE 1

Consort diagram for stage 1 of LPCN 1148-21-001 investigating LPCN 1148 in men with cirrhosis of the liver and sarcopenia (NCT# 04874350). The safety set included all randomized participants who received at least 1 dose of study drug. The mITT set was based on prespecified conditions including having a pos-baseline CT scan and compliance criteria. Analyses based on CT parameters (eg, skeletal muscle index of the third lumbar) used the mITT set, whereas all other analyses used the Safety set. Black arrows represent the flow of study events. *Note one screen failed participant was randomized in error and was removed from the study prior to receiving any intervention. Abbreviations: LT, liver transplant; mITT, modified intent-to-treat.

FIGURE 2

Change in L3-SMI following LPCN 1148 treatment. Data are LS mean (95% CI), and last observation carried forward for the change in L3-SMI at weeks 12 (left) and 24 (right). Filled and open symbols represent the LPCN 1148 and Placebo groups, respectively. Baseline mean L3-SMI was not different between LPCN 1148 and placebo groups at week 12 (49.0±1.7 vs. 45.6±2.2 cm²/m²) or 24 (47.8±1.8 vs. 45.8±2.3 cm²/m²) analyses, respectively. *p<0.05 for change from baseline; ^p=0.007 versus Placebo. Abbreviation: L3-SMI, skeletal muscle index of the third lumbar region.