Oral androgen receptor agonist improves sarcopenia over 52 weeks in men with cirrhosis
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Key takeaways:
- At week 24, LPCN 1148 significantly improved the Skeletal Muscle Index at L3 vs. placebo (4.1 cm²/m² vs. –0.6 cm²/m²).
- This improvement was maintained through 52 weeks of treatment.
LPCN 1148, an oral androgen receptor agonist, improved sarcopenia in men with advanced cirrhosis as early as week 12 — with sustained improvement through 52 weeks — and reduced recurrence of encephalopathy, according to late-breaking data.
“Sarcopenia is common in cirrhosis and impacts clinically meaningful outcomes,” Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, said during a presentation at EASL Congress. “There are multiple mechanisms that contribute to sarcopenia in cirrhosis. Of these, several pathways are impacted by androgens. ... Of note, 90% of males with cirrhosis have low free testosterone.”
He continued: “LPCN 1148 is a novel testosterone prodrug that is being developed. It is an oral androgen receptor agonist and a dosage form comprising testosterone dodecanoate, which is a unique prodrug of the endogenous hormone. Based on its androgenic and testosterone-like biology, you would expect it to have anabolic effects, ammonia-lowering effects and other androgenic effects, some of which may be beneficial for the patient. This led us to develop a central hypothesis that LPCN 1148 would improve sarcopenia, sarcopenia-related outcomes and other clinically significant outcomes in patients with cirrhosis.”
In a phase 2, proof-of-concept study, Sanyal and colleagues assessed the short-term efficacy and safety of LPCN 1148 in 29 men (mean age, 59 years; mean BMI, 29 kg/m2) with advanced cirrhosis with sarcopenia who were awaiting liver transplantation. Patients were randomly assigned to oral LPCN 1148 (n = 15) or placebo (n = 14) for 24 weeks, followed by an open-label extension period, in which patients on LPCN 1148 continued treatment for another 28 weeks and those on placebo were switched to LPCN 1148.
At baseline, the mean MELD was 17 and 73% to 79% of patients had history of hepatic encephalopathy (HE).
The primary endpoint was improvement in baseline-adjusted Skeletal Muscle Index at L3 region (L3-SMI) at week 24, while secondary endpoints at weeks 24 and 52 included “feel and function” patient-reported outcomes, survival and biomarkers.
According to Sanyal, patients treated with LPCN 1148 met the primary endpoint as early as week 12, with a “significant increase” from baseline L3-SMI compared with those on placebo (3 cm2/m2 vs. 0.9 cm2/m2). At week 24, this improvement became “even more significant” (4.1 cm2/m2 vs. –0.6 cm2/m2).
In addition, patients on LPCN 1148 maintained an increase in muscle mass area through 52 weeks of treatment, while those who switched to LPCN 1148 from placebo had “highly significant” improvements in L3-SMI after week 24, Sanyal noted. Further, muscle quality, as measured by myosteatosis, improved with LPCN 1148.
“There was a significant increase in high quality muscle and a decrease in intramuscular adipose tissue in patients receiving the active therapy,” Sanyal told attendees.
In placebo-controlled analysis, recurrence of overt HE decreased with LPCN 1148 while on standard HE therapy compared with placebo (two events vs. six events), with a longer average time to first overt HE occurrence (114 days vs. 35 days). During the open-label extension, one additional overt HE event occurred in each treatment group.
Researchers also reported that LPCN 1148 was associated with improvement in encephalopathy, hemoglobin, anemia, patient-reported symptom severity and total hospitalization days, while Liver Frailty Index changes were comparable between groups.
According to Sanyal, LPCN 1148 was “fairly well-tolerated”, with similar adverse events reported between treatment and placebo groups and no cases of drug-induced liver injury. However, two cases of hepatocellular carcinoma were reported in the LPCN group.
“Overall, these data demonstrate that LPCN 1148 did improve multiple clinically relevant and surrogate outcomes while being well-tolerated up to 52 weeks in male patients with advanced cirrhosis,” Sanyal said. “These data further support our ongoing development activities.”
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Bruno B, et al. Intervention with oral LPCN 1148 improves sarcopenia and hepatic encephalopathy (HE) in patients with cirrhosis: A 52-week phase 2 randomized clinical trial. Presented at: EASL Congress; June 5-8,2024; Milan (hybrid meeting).
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