Present Clinical Data on oral T (LPCN 1144) at 2022 NASH-TAG Conference

[madman]

https://www.sec.gov/Archives/edgar/data/1535955/000149315221026815/ex99-4.htm

LPCN 1144 IMPROVES BODY COMPOSITION IN BIOPSY-CONFIRMED NASH PATIENTS

Background: Non-alcoholic Steatohepatitis (NASH) is a common cause of liver disease and rapidly rising to be the leading indication for liver transplantation. Sarcopenia, loss of muscle mass, occurs in 20-60% of patients with liver disease and reduces survival of cirrhotic patients. There is an unmet need for addressing adverse body composition (BC) in advanced NASH. A decrease in free testosterone (T) and an increase in Sex Hormone Binding Globulin (SHBG) are reported with the progression of NASH. LPCN 1144, an oral prodrug of endogenous T, is currently being investigated in an ongoing randomized, double-blind, paired biopsy, placebo-controlled, phase 2 study in men with NASH (LiFT, NCT04134091). Here, we present topline BC results post 20 weeks (w) of treatment.

Methods: biopsy-confirmed NASH (F1-F3) males were randomized 1:1:1 to three arms; 1) Treatment A: oral T twice daily (BID), 2) Treatment B: oral T with d-alpha-tocopherol BID, and 3) oral matching placebo (PL) BID. BC parameters, including appendicular lean muscle mass (APLM), whole-body fat mass (WBFM), and whole-body lean mass (WBLM), were evaluated using Dual Energy X-ray Absorptiometry (DEXA) scan at baseline and w20. Other key outcomes measured were changes in SHBG, hepatic fat fraction, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) at w12.

Results: APLM was significantly elevated with LPCN 1144 treatment compared to PL (p<0.05). Additionally, treatment with LPCN 1144 resulted in a significant reduction of WBFM compared to PL (p<0.01). Favorable BC changes, defined as a decrease in WBFM and an increase in WBLM, were observed in 64% of the subjects receiving LPCN 1144 compared to 15.4% in the PL arm(p<0.01). Furthermore, LPCN 1144 reduced progression of adverse muscle composition (AMC); 4% in the treatment arm vs 46.2% in the PL arm had an increase in WBFM and a decrease in WBLM (p<0.01). Treatment with LPCN 1144 significantly decreased SHBG from baseline compared to PL (p<0.001). Liver fat, ALT, and AST were also significantly reduced in both treatment arms compared to PL (p<0.001, <0.05, and <0.05, respectively).

Conclusion: LPCN 1144 significantly improved BC in biopsy-confirmed NASH male subjects. The forthcoming w36 data in the ongoing LiFT trial is expected to further elucidate the effects of LPCN 1144 on changes in BC. This significant impact of LPCN 1144 on BC can be beneficial in cirrhotic subjects. Larger longitudinal investigations may be required to study this potential effect in advanced liver disease.

 

[madman]

https://www.sec.gov/Archives/edgar/data/1535955/000149315221026815/ex99-3.htm

Safety and Tolerability of LPCN 1144 Treatment in Biopsy Confirmed NASH Subjects in the Phase 2 LiFT Study

Background: Non-alcoholic Steatohepatitis (NASH) is a common cause of liver disease and rapidly rising to be the leading indication for liver transplantation. An acceptable benefit to risk profile of therapeutics for chronic disease states including NASH is critical. LPCN 1144, an oral prodrug of endogenous testosterone (T), was investigated for safety and efficacy potential in a randomized, double-blind, paired biopsy, placebo-controlled, phase 2 study in men with NASH (LiFT, NCT04134091). Here, we present the safety results during 36 weeks of treatment.

Methods: biopsy-confirmed NASH (F1-F3) males were randomized 1:1:1 to three arms; 1) Treatment A (n=18): oral T twice daily (BID), 2) Treatment B (n=19): oral T with d-alpha-tocopherol BID, and 3) oral matching placebo (n=19) BID. An open-label extension of this study is ongoing to investigate the effects of treatment A for a total duration of 18 months. Safety outcomes were recorded throughout the study.

Results: LPCN 1144 treatment resolved NASH with no worsening of fibrosis. TEAEs were reported in 16 subjects (84%) in the placebo arm, 12 subjects (67%) in treatment A, and 11 subjects (58%) in treatment B. The most common adverse events were infections (7, 4, and 5 subjects in placebo, treatments A and B, respectively). Additionally, drug-related TEAEs were reported in 3, 2, and 3 subjects in placebo, treatments A and B, respectively. No more than one subject in each treatment arm experienced a drug-related TEAE in the same system organ class, and all were mild to moderate in severity. Four subjects in the placebo arm vs one subject total across both treatment arms discontinued the study drug due to TEAEs.

No cases of hepatocellular carcinoma, Drug-Induced Liver Injury (DILI), thromboembolic events, or sleep apnea were reported.

Changes in lipid levels including total cholesterol, triglyceride, LDL, and HDL in both treatment arms were similar to placebo. Cardiovascular events including myocardial infarction and cardiac arrest were well-balanced between arms. Additionally, rates of pedal edema, changes in PSA, and blood pressure were comparable among groups. Changes in weight and rates of GI events including nausea, vomiting, and diarrhea were similar between groups. Furthermore, one subject in treatment B had elevated hematocrit levels, and one subject in each placebo and treatment A experienced pruritis.

Conclusion: LPCN 1144 was well-tolerated in biopsy-confirmed NASH male subjects, with no observed signs of adverse androgenic effects, increased cardiovascular or hepatic risks. The observed benefit to risk profile warrants further investigation of LPCN 1144 in a larger trial with a longer duration.

 

[madman]

https://www.sec.gov/Archives/edgar/data/1535955/000149315221026815/ex99-2.htm

LPCN 1144 Therapy Demonstrates Histologic Benefits in the Phase 2 LiFT Study in Nonalcoholic Steatohepatitis (NASH) Subjects

Background and Aims: NASH is the fastest growing chronic liver disease and can progress to cirrhosis, HCC, and death. NASH is a serious condition with great unmet medical needs. Low testosterone (T) is associated with the presence of NASH. LPCN 1144 is an oral prodrug of endogenous T developed for noncirrhotic NASH treatment. The recently-completed LiFT (NCT04134091) study investigated LPCN 1144 for safety and efficacy in men with biopsy-confirmed NASH.

Methods: LiFT was a randomized, double-blind, placebo-controlled, 36-week treatment study that enrolled 56 men with NASH and F1-3 fibrosis. Subjects were randomized 1:1:1 to three arms administered twice daily (Treatment A: n=18, 142 mg T equivalent, Treatment B: n=19, 142 mg T equivalent with 238 mg of d-alpha-tocopherol equivalent, and Placebo: n=19, matching placebo). The primary endpoint was a change from baseline (BL) in hepatic fat fraction via MRI-PDFF at 12 weeks. A key secondary endpoint was the rate of NASH Resolution with no worsening of fibrosis at Week 36 (FDA Phase 3 guidance). Additionally, slides were digitized and analyzed using the FibroNest platform, which reports a continuous score for fibrosis severity. Reported p-values are comparisons to placebo.

Results: Liver fat was significantly reduced in both treatment groups at Week 12, with up to a mean absolute decrease of 9.4% (p<0.05) in subjects with BL MRI-PDFF >5%. Both LPCN 1144 treatment arms met the endpoint of proportion of subjects with NASH resolution and no worsening of fibrosis (Placebo: 0%; A: 46% (p<0.05); B: 69% (p<0.001). While there was no statistical difference in rates of fibrosis improvement by NASH CRN staging (p>0.05), digital pathology assessment revealed a numerical improvement in fibrosis (parenchymal tissue-normalized phenotypic fibrosis composite score) for both treatment arms. Statistically significant reductions of ALT and AST were observed during study visits: up to a mean of 24.5 U/L decreases (p<0.01) in ALT, and 12.3 U/L decreases (p<0.01) in AST.

During the 36 weeks of treatment, the observed rate and severity of Treatment-Emergent Adverse Events in both the treatment arms were comparable to the placebo arm. There were no reported cases of HCC or drug-induced liver injury.

Conclusion: LPCN 1144 resolved NASH with no worsening of fibrosis, improved liver injury markers, and reduced liver fat in men with biopsy-confirmed NASH and fibrosis in the LiFT study. LPCN 1144 was well tolerated, with rates and severity of AEs similar in all arms. These data support the potential for this novel approach as a treatment of NASH.

 

[madman]

NASH-TAG CONFERENCE 2022