An investigational testosterone prodrug resulted in improvements in skeletal muscles and quality, and reduced rates of hepatic encephalopathy in men with cirrhosis and sarcopenia, per a limited piece II pilot look.
In a modified plot-to-treat evaluation, men with cirrhosis had an extend within the L3-skeletal muscle index (L3-SMI) of 4.1 cm2/m2 after 24 weeks of therapy with LPCN 1148, as in contrast with a fall of 0.6 cm2/m2 within the L3-SMI amongst those that got a placebo (P<0.01), reported Arun Sanyal, MD, of the Virginia Commonwealth University in Richmond, on the European Association for the Uncover of the Liver in Milan.
The result represented a placebo-adjusted 9.9% extend within the L3-SMI within the LPCN 1148 neighborhood, and the extend was maintained by week 48, Sanyal told attendees.
Also, when the six individuals within the placebo neighborhood switched to therapy with LPCN 1148 at week 24, their L3-SMI elevated critically by 8.1 cm2/m2, or 16.7%, at week 48 (P<0.01).
“Sarcopenia is accepted in cirrhosis and impacts clinically meaningful outcomes,” he indispensable. “To boot, it increases healthcare helpful resource utilization.”
“There are extra than one mechanisms that make contributions to sarcopenia in cirrhosis,” Sanyal pointed out. “Of those, quite a lot of pathways are impacted by androgens, that are linked to muscles inhibit myostatin. Of fellows with cirrhosis, 90% have low-free testosterone.”
LPCN 1148 is an oral ester prodrug of bioidentical testosterone, testosterone dodecanoate. “Or no longer it is no longer an exogenous testosterone analog,” Sanyal emphasised. Consistent with its androgenic mechanism of action, it is anticipated that LPCN 1148 could maybe furthermore just have anabolic effects, equivalent to an extend in muscles, bone density, and improved nutritional status. It could per chance maybe furthermore just furthermore toughen liver characteristic, thereby lowering ammonia stages, and induce hematopoiesis.
‘Worth Pursuing Forward’
LPCN 1148 furthermore elevated excessive-quality muscle at week 24 by 12.1% as in contrast with an extend of 1.2% with placebo (P<0.05). Furthermore, the prodrug-treated patients had a lower in intramuscular adipose tissue of 19.7% versus a lower of 9.2% in placebo recipients (P<0.05).
Recurrence of overt hepatic encephalopathy (OHE) furthermore reduced amongst patients within the LPCN 1148 therapy neighborhood whereas on out of the ordinary medication for hepatic encephalopathy. At 24 weeks, those within the LPCN 1148 neighborhood had two OHE events versus six events within the placebo neighborhood (P<0.05). Also, average time to first OHE was longer within the therapy neighborhood, at 114 days, as in contrast with 35 days within the placebo neighborhood. For the period of the commence-mark extension, one extra case of OHE occurred in each and every therapy arm.
LPCN 1148 furthermore critically improved hemoglobin and anemia amongst individuals. At baseline, hemoglobin was 11.4 g/dL within the therapy neighborhood and elevated by 0.9 g/dL at week 24 (P<0.05 from baseline), whereas there was no extend in hemoglobin within the placebo neighborhood (P<0.05 between groups). The extend was maintained all the arrangement by 52 weeks of therapy. The patients within the placebo neighborhood who switched to LPCN 1148 at 24 weeks furthermore skilled a well-known extend in hemoglobin stages.
Of new, the Liver Frailty Index (LFI) discover, per grip strength, timed chair stands, and balance, was roughly 4 in both groups at baseline. No well-known changes were indispensable between the 2 palms by the live of the look. Alternatively, individuals who switched from placebo to LPCN 1148 at week 24 did have a nonsignificant lower of 0.32 on the LFI discover.
There were two deaths within the placebo arm versus one within the LPCN 1148 arm. Time spent within the scientific institution was 114 days within the placebo neighborhood versus about 51 to 54 days within the therapy neighborhood, Sanyal indispensable.
LPCN 1148 was well-tolerated, with identical entire, indispensable, and severe harmful events between the therapy and placebo groups. Importantly, there were no conditions of drug-introduced about liver damage, “which is continuously something we take into legend when the usage of a testosterone-address molecule in cirrhotic patients,” he mentioned.
In the LPCN 1148 neighborhood there were two conditions of hepatocellular carcinoma (HCC). One participant introduced with a 2.2-cm hepatic mass at 250 days after starting therapy and got ablation. But every other participant had pre-existing nodules seen on imaging quite a lot of months earlier than the look and was later classified as presumably having HCC on imaging. Alternatively, that affected person could maybe furthermore just tranquil were excluded from the trial at recruitment. “In future studies, there might maybe be a must display screen for conditions of HCC as an match of special passion,” he mentioned.
Sanyal acknowledged that the fundamental limitation of the look was its limited size. “But that was our impartial, to interrogate if there was a signal to interrogate whether LPCN 1148 is rate pursuing ahead,” Sanyal concluded. “General, we take into accout these recordsdata new that LPCN 1148 did toughen extra than one clinically relevant and surrogate outcomes whereas being well-tolerated up to 52 weeks in male patients with evolved cirrhosis.”
Uncover Miniature print
The proof-of-belief look enrolled 29 grownup males with cirrhosis and sarcopenia who were listed for liver transplantation. Sufferers were excluded if they had active severe encephalopathy, active an infection, uncontrolled or recurrent GI bleeding all the arrangement by the past 6 months, or a outdated or new HCC prognosis.
The indicate age at enrollment was about 58. Sufferers had a indicate BMI of 29, an L3-SMI of about forty five-48 cm2/m2 and a Mannequin for Cease-Stage Liver Disease discover of about 16-18. Most patients had on the least one prior decompensation match, 73% had a historical past of hepatic encephalopathy, most had ascites, and 53% to 57% had esophageal varices. Nearly all were on rifaximin and lactulose.
The look randomized patients to either oral LPCN 1148 (n=15) or placebo (n=14) for the first 24 weeks of the trial. In the placebo neighborhood, two patients died and two patients withdrew after liver transplantation. For the subsequent 28 weeks, the remaining 10 patients within the placebo were included within the therapy neighborhood, in an commence-mark fashion. At the live of 52 weeks, 9 patients within the LPCN 1148 and 7 within the placebo neighborhood had performed the look. Prognosis included a security dwelling and a modified plot-to-treat evaluation.
Disclosures
The look was subsidized by Lipocine. Some co-investigators are firm staff.
Sanyal disclosed extra than one relationships with industry.
Fundamental Source
European Association for the Uncover of the Liver
Source Reference: Sanyal AJ “Intervention with oral LPCN 1148 improves sarcopenia and hepatic encephalopathy (HE) in patients with cirrhosis: a 52-week piece 2 randomized clinical trial” EASL 2024; Presentation LBO-005.
