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Therapeutic Potential of LPCN 1144 in NAFLD/NASH
Male hypogonadism is an underappreciated comorbidity in non-alcoholic
fatty liver disease (NAFLD)/ steatohepatitis (NASH). A significant overlap of comorbidities such as obesity, hypertension, hypertriglyceridemia,
type 2 diabetes, and metabolic syndrome, exists between hypogonadism and NAFLD/NASH.
Herein we report the prevalence of NAFLD in hypogonadal patients
and the potential utility of orally bioavailable prodrug of bioidentical testosterone (LPCN1144), delivered lymphatically, in NAFLD/NASH.
The Liver Fat Study (LFS) is a 16-week open-label, multi-center,
single arm study with LPCN 1144 treatment in subjects (N=36) assessing potential NAFLD/NASH prevalence and liver fat (LF) changes.
The Study of Androgen Replacement (SOAR) trial was an active
controlled (topical testosterone gel) randomized multicenter 52-week study with LPCN 1144.
In the LFS, about 58 %
of hypogonadal patients were identified as having NAFLD. Among the patients with NAFLD, obesity was the most prevalent comorbidity.
NAFLD was about 2-fold overrepresented in hypogonadal patients compared to US general population.
At interim visit (8 weeks) mean absolute and relative liver
fat reduction in patients with LF 10 % at baseline were 7.6% and 38%, respectively. 28% of NAFLD (LF 5 %) confirmed subjects
experienced NAFLD resolution with LPCN 1144.
In the SOAR trial, subjects with elevated baseline serum liver
enzymes (ALT, GGT) and cardiovascular risk markers (TG, Lp-PLA2, LDL-C) experienced significant reductions. Significant rates of
patients with above-normal levels of liver enzymes and lipids at BL ended with normal levels post LPCN 1144 therapy: ALT = 52%,
GGT = 31%, TG = 34%, and LDL-C = 56%.
Changes of TG for patients with above-normal levels at BL were
reduced with oral LPCN 1144 compared with topical T gel: -64 mg/dL vs. +13 mg/dL, respectively. SHBG change for all patients with
oral LPCN 1144 and Topical T gel: -19.5% vs. +8.3%, respectively.
Greater reductions of TG and ALP were observed with oral LPCN
1144 as in patients key comorbidities compared with topical T gel.
LPCN 1144, with up to 52 weeks exposure, exhibited no adverse
drug reaction in the Hepatobilliary System Organ Class (e.g., peliosis hepatitis, hepatic neoplasms, cholestatic hepatitis and
jaundice), no major adverse cardiac events (MACE), no signs of increased skeletal fragility or nephrotoxicity, and good gastrointestinal
Evaluation of NAFLD/NASH
should be considered in hypogonadal males. LPCN 1144 therapy meaningfully reduces liver fat in hypogonadal males, suggesting utility
as a NAFLD/NASH therapy. Biomarker data support unique benefits of oral over topical testosterone options.