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An investigational testosterone prodrug resulted in improvements in skeletal muscle mass and quality, and lowered rates of hepatic encephalopathy in men with cirrhosis and sarcopenia, according to a small phase II pilot study.

In a modified intention-to-treat analysis, men with cirrhosis had an increase in the L3-skeletal muscle index (L3-SMI) of 4.1 cm²/m² after 24 weeks of treatment with LPCN 1148, compared with a drop of 0.6 cm²/m² in the L3-SMI among those who received a placebo (P<0.01), reported Arun Sanyal, MD, of the Virginia Commonwealth University in Richmond, at the European Association for the Study of the Liver in Milan.

The result represented a placebo-adjusted 9.9% increase in the L3-SMI in the LPCN 1148 group, and the increase was maintained through week 48, Sanyal told attendees.

Also, when the six participants in the placebo group switched to treatment with LPCN 1148 at week 24, their L3-SMI increased significantly by 8.1 cm²/m², or 16.7%, at week 48 (P<0.01).

"Sarcopenia is common in cirrhosis and impacts clinically meaningful outcomes," he noted. "In addition, it increases healthcare resource utilization."

"There are multiple mechanisms that contribute to sarcopenia in cirrhosis," Sanyal pointed out. "Of these, several pathways are impacted by androgens, which are linked to muscle mass inhibit myostatin. Of men with cirrhosis, 90% have low-free testosterone."

LPCN 1148 is an oral ester prodrug of bioidentical testosterone, . "It's not an exogenous testosterone analog," Sanyal emphasized. Based on its androgenic mechanism of action, it is expected that LPCN 1148 may have anabolic effects, such as an increase in muscle mass, bone density, and improved nutritional status. It may also improve liver function, thereby lowering ammonia levels, and induce hematopoiesis.

'Worth Pursuing Forward'

LPCN 1148 also increased high-quality muscle at week 24 by 12.1% compared with an increase of 1.2% with placebo (P<0.05). Moreover, the prodrug-treated patients had a decrease in intramuscular adipose tissue of 19.7% versus a decrease of 9.2% in placebo recipients (P<0.05).

Recurrence of overt hepatic encephalopathy (OHE) also decreased among patients in the LPCN 1148 treatment group while on standard medication for hepatic encephalopathy. At 24 weeks, those in the LPCN 1148 group had two OHE events versus six events in the placebo group (P<0.05). Also, average time to first OHE was longer in the treatment group, at 114 days, compared with 35 days in the placebo group. During the open-label extension, one additional case of OHE occurred in each treatment arm.

LPCN 1148 also significantly improved hemoglobin and anemia among participants. At baseline, hemoglobin was 11.4 g/dL in the treatment group and increased by 0.9 g/dL at week 24 (P<0.05 from baseline), whereas there was no increase in hemoglobin in the placebo group (P<0.05 between groups). The increase was maintained throughout 52 weeks of treatment. The patients in the placebo group who switched to LPCN 1148 at 24 weeks also experienced a significant increase in hemoglobin levels.

Of note, the Liver Frailty Index (LFI) score, based on grip strength, timed chair stands, and balance, was approximately 4 in both groups at baseline. No significant changes were noted between the two arms by the end of the study. However, participants who switched from placebo to LPCN 1148 at week 24 did have a nonsignificant decrease of 0.32 on the LFI score.

There were two deaths in the placebo arm versus one in the LPCN 1148 arm. Time spent in the hospital was 114 days in the placebo group versus about 51 to 54 days in the treatment group, Sanyal noted.

LPCN 1148 was well-tolerated, with similar total, serious, and severe adverse events between the treatment and placebo groups. Importantly, there were no cases of drug-induced liver injury, "which is always something we think about when using a testosterone-like molecule in cirrhotic patients," he said.

In the LPCN 1148 group there were two cases of hepatocellular carcinoma (HCC). One participant presented with a 2.2-cm hepatic mass at 250 days after starting treatment and received ablation. Another participant had pre-existing nodules seen on imaging several months prior to the study and was later classified as probably having HCC on imaging. However, that patient should have been excluded from the trial at recruitment. "In future studies, there is a need to monitor for cases of HCC as an event of special interest," he said.

Sanyal acknowledged that the primary limitation of the study was its small size. "But that was our goal, to see if there was a signal to see whether LPCN 1148 is worth pursuing forward," Sanyal concluded. "Overall, we believe 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."

Study Details

The proof-of-concept study enrolled 29 adult males with cirrhosis and sarcopenia who were listed for liver transplantation. Patients were excluded if they had active severe encephalopathy, active infection, uncontrolled or recurrent GI bleeding within the past 6 months, or a prior or current HCC diagnosis.

The mean age at enrollment was about 58. Patients had a mean BMI of 29, an L3-SMI of about 45-48 cm²/m² and a Model for End-Stage Liver Disease score of about 16-18. Most patients had at least one prior decompensation event, 73% had a history of hepatic encephalopathy, most had ascites, and 53% to 57% had esophageal varices. Nearly all were on rifaximin and lactulose.

The study randomized patients to either oral LPCN 1148 (n=15) or placebo (n=14) for the first 24 weeks of the trial. In the placebo group, two patients died and two patients withdrew after liver transplantation. For the next 28 weeks, the remaining 10 patients in the placebo were included in the treatment group, in an open-label fashion. At the end of 52 weeks, nine patients in the LPCN 1148 and seven in the placebo group had completed the study. Analysis included a safety set and a modified intention-to-treat analysis.

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