Positive Topline Phase II Results from Ongoing LiFT Study
Lipocine Inc. (NASDAQ:LPCN) announced positive topline data from LiFT (1), a Phase II study of its candidate LPCN 1144 in biopsy-confirmed, non-cirrhotic male Non-alcoholic Steatohepatitis (NASH) patients with F1-F3 fibrosis. LiFT reported that both treatment arms met the primary endpoint with a high single digit absolute and low to mid 40% relative reduction in liver fat at week 12. It enrolled 56 men with confirmed NASH and had three arms with 1:1:1 randomization. The arms included Treatment A, 142 mg testosterone equivalent twice daily, Treatment B, which was the same as Treatment A but with the addition of 217 mg of d-alpha tocopherol (Vitamin E) equivalent twice daily, and a placebo arm with twice-daily administration. A summary of the data is provided below. We are in the process of developing a comparison of LiFT results with other NASH candidates to place these data in perspective to be published shortly.
Exhibit I – Absolute Change in Liver Fat (%) (2)
LPCN 1144 is an oral pro-drug of endogenous testosterone intended for a patient population with outstanding clinical need. The drug is being investigated in the LiFT study which is examining the impact on liver fat. 12-week results for the study were positive generating statistically significant improvements in change of hepatic fat fraction, quantified via MRI-PDFF (3). The results follow a string of failed NASH treatment attempts by other companies, including Gilead, whose anti-fibrosis drug selonsertib failed in Phase III, Ionis, with its delayed result release for their antisense gene therapy and Intercept’s Ocaliva that failed to achieve statistical significance in the clinic. There are other NASH candidates that remain in contention, including entries by 89bio (ETNB) with a Phase IIb program expecting to start in 1H:21, Madrigal Pharma (MDGL) with a Phase III currently recruiting, Inventiva (IVA.PA) just announcing the design of its Phase III, NGM Bio (NGM) is planning a topline readout of its Phase II in 2Q:21, Viking (VKTX) has a Phase IIb trial underway and Akero Therapeutics (AKRO) presented positive Phase IIa data last November.
In contrast, Lipocine’s LPCN 1144 has shown robust, statistically significant efficacy its primary endpoint of reduction of hepatic fat fraction and secondary endpoints including assessment of histological change for NASH resolution and/or fibrosis improvement.
LiFT Study Design
LiFT (Liver Fat intervention with oral Testosterone) is a Phase II trial designed to evaluate LPCN 1144 oral testosterone in men with biopsy-confirmed NASH. It enrolled 56 men with confirmed NASH in three arms with 1:1:1 randomization. The arms included Treatment A, 142 mg testosterone equivalent twice daily, Treatment B, which was the same as Treatment A but with the addition of 217 mg of d-alpha tocopherol (Vitamin E) equivalent twice daily, and a placebo arm with twice-daily administration. LiFT has a duration of 36 weeks at which time biopsy confirmation will be performed.
Exhibit II – LiFT Trial Timeline (4)
The primary endpoint for LiFT is the change in hepatic fat fraction, evaluated using MRI-PDFF at week 12. Secondary endpoints included change in NASH activity and fibrosis via liver biopsy scoring at week 36, change in hepatic fat fraction via MRI-PDFF at week 36, change in liver injury markers, anthropomorphic measurements, lipids, insulin resistance and inflammatory/fibrosis markers, and Patient Reported Outcomes (PROs) including quality of life and global impression scores (PGI). In the update, Lipocine included preliminary data addressing liver biomarkers.
Baseline characteristics were presented that recounted the number of subjects, number completing the 12-week study, age, BMI, diabetes and hypertension, as well as baseline measurements of endpoint factors.
Exhibit III – Baseline Characteristics (5)
Primary endpoint for LiFT was change in hepatic fat fraction. As reported, there was a statistically significant decrease in hepatic fat, significant at the 0.01% level for both Treatment A and Treatment B arms. The percentage of subjects with greater than 30% reduction in liver fat was statistically significant at better than 1% in both arms vs placebo.
Exhibit IV – Mean Absolute Liver Fat Change Using MRI-PDFF (6)
Exhibit V – Mean Relative Liver Fat Using MRI-PDFF (Liver Fat ≥5% at Baseline (7)
Absolute and relative change in liver fat percentage in subjects with baseline liver fat in excess of 5% was statistically significant at 0.01% for both arms vs placebo.
Exhibit VI - ALT and AST Levels in Active and Placebo Arms at 12 Weeks (8)
Liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were both improved over placebo at statistically significant levels. ALT levels were 13.0 U/L lower in the Treatment B arm as compared to the A arm with the difference significant at the 0.5% level. This compares with AST which was 5.5 U/L better between in the B arm compared with the A arm; however, the difference was not significant in the AST comparison. Addition of d-alpha tocopherol appeared to reduce liver injury markers ALT and AST beyond LPCN 1144 alone, although, as the difference was present, yet less dramatic in other measures such as hepatic fat fraction reduction, to what extent d-alpha tocopherol is augments the action of LPCN 1144 is unknown.
Finally, longitudinal analysis of changes in the two liver injury markers showed that as early as week four, for AST, and week 8 for both ALT and AST, combination LPCN 1144 and d-alpha tocopherol showed statistically significant changes, making the treatment not only successful where other NASH therapies have struggled, but also conveniently orally administrated, and timely in its efficacy.
Adverse events were comparable to placebo arm with no observed tolerability issues. Three subjects in placebo group and one in a treatment arm discontinued study due to treatment emergent adverse events (TEAE).
The LiFT study will continue on for the next 24 weeks until the biopsy measurement and we expect to see the next set of data in mid-2021. These data will include histological change in NASH activity and fibrosis, MRI-PDFF liver fat data, body composition DXA scans at week 20 and 36, liver and other markers including those related to fibrosis and inflammation and PROs. Patients will also have access to LPCN 1144 through an open label extension study (NCT04685993). The extension study will enable the collection of additional data on LPCN 1144 for up to a total of 72 weeks of therapy.
Lipocine’s LPCN 1144 may succeed where other NASH therapies have struggled. The primary endpoint readout is an impressive improvement over placebo in a space where there are no other approved therapies. While the drug is only appropriate for the male NASH population, it has shown a favorable safety profile and is bioidentical to testosterone, a well-understood hormone. Lipocine has conducted many safety studies for the same compound in its Tlando trials, which ultimately achieved approval from the FDA. We see a higher safety hurdle by the FDA for treatment of low testosterone as compared to NASH, which gives us confidence that the agency will look favorably on this. Combined with the convenience and safety of oral administration, the topline results suggest advancement of the candidate towards Phase III studies of LPCN 1144. We are assembling a comparison of LPCN 1144’s results with other NASH assets in development by peers to illustrate the strong results shown here. In other efforts, Lipocine continues efforts related to its lead candidate, Tlando, which just received tentative approval that resulted in an increase to our price target. The tentative nature of the approval is a function of exclusivity granted by the FDA to Tlando competitor Jatenzo, marketed by Clarus. Clarus and Lipocine are currently litigating alleged patent infringement that appears to be in Lipocine’s favor, the next anticipated court date, February 8, 2021, for which has recently been postponed due to uncertainty regarding the pandemic. Please see our latest report for our target price and a review of the FDA’s recent tentative approval for Tlando.
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1. Liver Fat Intervention with oral Testosterone (LiFT)
2. Lipocine LPCN 1144 Presentation January 12, 2021
3. Magnetic Resonance imaging Proton Density Fat Fraction
4. Lipocine LPCN 1144 Presentation January 12, 2021
5. Lipocine LPCN 1144 Presentation January 12, 2021
6. Source: Lipocine Press Release, January 12, 2021
7. Source: Lipocine Press Release, January 12, 2021
8. Source: Lipocine Press Release, January 12, 2021