LPCN 1144 Resolves NAFLD in Hypogonadal Males

Abstract

Hypogonadism affects hepatic lipid metabolism and is expected to promote nonalcoholic fatty liver disease (NAFLD). The aims of this study were to determine (1) the prevalence of NAFLD in hypogonadal males and (2) the impact of correction of hypogonadism by LPCN 1144 (Lipocine, Inc., Salt Lake City, UT), an oral testosterone prodrug, on NAFLD in this population. Data were derived from a multicenter open-label single-arm trial of LPCN 1144 for hypogonadal males, in which a subset (n = 36) had serial magnetic resonance imaging-proton density fat fraction measurements (National Clinical Trial 03868059). NAFLD prevalence, defined by magnetic resonance imaging-proton density fat fraction ≥5%, was 66%. Eighty-one percent of those with baseline liver fat (BL) ≥5% had improvement in liver fat content, and NAFLD resolved in 33% of subjects at 8 weeks (mean relative reduction: 45%) and 48% (mean relative reduction: 55%) after 16 weeks of LPCN 1144 therapy. The reduction in liver fat was greater in those with higher BL (BL ≥5%: 71%; BL ≥8%: 80%; and BL ≥10%: 75%). Normalization rate of alanine aminotransferase and gamma-glutamyltransferase greater than the upper limit of normal range were 100% and 50% of treated patients, respectively. LPCN 1144 was not associated with major adverse events. Conclusion: Treatment with LPCN 1144 (oral T prodrug) in hypogonadal males with NAFLD resolved NAFLD in approximately half of the affected patients without any safety signals. Further studies are needed to validate its use in hypogonadal males with nonalcoholic steatohepatitis. (Hepatology Communications 2020;4:1430-1440). T he clinical and histological spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis, and eventually to cirrhosis. (1) The prevalence of NAFLD is rising rapidly and is now recognized as a leading indication for liver transplantation worldwide. (2) NAFLD is linked with visceral fat accumulation and metabolic syndrome, (3,4) and is associated with increased risk of cardiovascular disease and mortality. (5) Obesity, type 2 diabetes, and dyslipidemia are the main metabolic risk factors for NAFLD. (6) There are several lines of evidence suggesting a potential role of sex hormones in the genesis and

A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism

“…The improvement of liver injury markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma‐glutamyl transferase) in the majority of subjects was consistent with the results from a clinical study also utilizing the same dosing regimen of oral TU with no titration for four months that measured hepatic fat content. 19 As an analysis result of secondary efficacy endpoints evaluating T Cmax outliers, two of the three secondary endpoints (1.8 × ULN ≤ T Cmax ≤ 2.5 × ULN in ≤5% of subjects, and T Cmax > 2.5 × ULN in zero subjects) were met (5% and 0%, respectively) while the third secondary endpoint was not met but nearly achieved (82% with T Cmax ≤ 1.5 × ULN, target ≥85%). The results of secondary endpoints were comparable with a recently approved oral TU product with titration (83% with T Cmax ≤ 1.5 × ULN, 3% with 1.8 × ULN ≤ T Cmax ≤ 2.5 × ULN, and 3% with T Cmax > 2.5 × ULN).…”

Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations

“…Our results are consistent with a recent study in which 32 men with low serum testosterone, of whom 8 (25%) had type 2 diabetes, were given a novel oral testosterone preparation LPCN 1144 for 16 wk. In this study, 21/32 patients met diagnostic criteria for NAFLD, and a mean relative reduction in liver fat of 33% as measured by MRI-PDFF was demonstrated in 17 of these 21 patients[ 16 ]. However, in contrast to our study, the LPCN 1144 study did not include a control group.…”

“…A placebo controlled study of obese men with severe obstructive sleep apnoea and testosterone concentrations that ranged from low normal to normal demonstrated that testosterone therapy reduced liver fat as measured by computed tomography[ 15 ]. A study of 21 men with low serum testosterone concentrations and NAFLD reported that treatment with a novel oral testosterone prodrug improved liver fat as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 81% of patients[ 16 ]. Two small studies of testosterone therapy in men with type 2 diabetes and low testosterone concentrations and one in men with mobility limitation and low testosterone concentrations conversely showed no significant change in hepatic fat compared to placebo as measured by MRI[ 17 - 19 ].…”

Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model

“…Noteworthy, the general improvement in liver histological and mRNA expression of markers related to the inflammation, steatosis and fibrosis was substantiated by the significant reduction of liver triglycerides content. In a recently performed 16-week clinical trial with LPCN 1144 in hypogonadal patients with NAFLD, LPCN 1144 reduced liver fat contents (measured by Magnetic Resonance Imaging Proton Density Fat Fraction, MRI-PDFF) by about 40% from baseline and resolved NAFLD in about half of the population [ 51 ]. The observation of the reduction of liver triglyceride content in this pre-clinical study supports the findings in the clinical study.…”