Positive Topline Phase II Results from Ongoing LiFT Study, Update Includes Comparison
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 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 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. A summary of Lipocine’s primary endpoint data is provided below.
Exhibit I – LiFT Trial 12-week Absolute Change in Liver Fat (%) (2)
We add to our previous article with a summary of other NASH programs’ Phase II data to place the LiFT results in context. We provide 12-week data for eight different competing therapies that provided data on change in liver fat relative to baseline, seven of which are in NASH and one in NAFLD. Lipocine is in one of the oral offerings in the group which includes Cymabay’s seladelpar, Madrigal’s resmetirom, Viking’s VK2809 (3) and Intercept’s OCA which promise easier and more convenient dosing as compared to the subcutaneous injection offered by others. There are several entries in the subcutaneous injection group including 89bio’s BIO89-100, NGM Biopharmaceutical’s aldafermin and Akero’s efruxifermin.
We note that the trials included in the comparison are not identically structured and presented different baseline characteristics which make direct comparisons difficult. Despite this, LPCN 1144 results are favorable against the other oral candidates. LPCN 1144 achieved a placebo adjusted 6.2 percentage point reduction in the 142 mg testosterone arm, and a 7.7 percentage point reduction in the 142 mg testosterone and Vitamin E arm. Madrigal’s resmetirom achieved a placebo adjusted 4.3 percentage point reduction and Intercept’s obeticholic acid obtained a placebo adjusted 3.4 percentage point reduction. Cymabay went the other direction with seladelpar and generated a placebo adjusted increase in liver fat. Subcutaneous candidates provided a stronger showing with 89bio’s BIO89-100 clinching a 14.9 percentage point reduction in liver fat relative to placebo, while Akero’s efruxifermin produced a 13.8 percentage point reduction. NGM Bio’s aldafermin delivered a 5.0 percentage point reduction, lagging the other subcutaneous offerings.
Exhibit II – Summary of Phase II Liver Fat Changes in NASH Patients (4)
Safety was a strong point for LPCN 1144 and we note the substantial amount of safety data generated for testosterone as compared to the other candidates. Treatment with LPCN 1144 and d-alpha tocopherol (Vitamin E) provided liver benefits as evidenced by the lower levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and did not negatively impact tolerability. Adverse events for LPCN 1144 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). Full safety data was not available on many of the other candidates; however, we do note that resmetirom generated a higher incidence of gastrointestinal events including diarrhea and nausea. Efruxifermin was also associated with negative gastrointestinal side effects and injection site reactions. Neither readout has provided a quantified summary of adverse events and side effects.
LPCN 1144 is an oral pro-drug of endogenous testosterone intended for a patient population with outstanding clinical need. 12-week results were positive generating statistically significant improvements in change of hepatic fat fraction, quantified via MRI-PDFF (5). 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 and was issued a complete response letter (CRL) by the FDA. There are other NASH candidates that remain in contention which are included in our review, 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) which is designing its Phase III, NGM Bio (NGM) which is planning a topline readout of its Phase II in 2Q:21, Viking (VKTX) which is conducting a Phase IIb trial and Akero Therapeutics (AKRO) which presented positive Phase IIa data last November.
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) (6) equivalent twice daily, and a placebo arm with twice-daily administration. LiFT has a duration of 36 weeks.
Exhibit III – LiFT Trial Timeline (7)
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 participants, completion, age, BMI, diabetes and hypertension, as well as baseline measurements of endpoint factors.
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 (p < 0.0001) for both Treatment A and Treatment B arms. The percentage of subjects with greater than 30% reduction in liver fat was statistically significant (p ≤ 0.01) in both arms vs placebo.
Exhibit IV – Mean Absolute Liver Fat Change Using MRI-PDFF (8)
Exhibit V – Mean Relative Liver Fat Using MRI-PDFF (Liver Fat ≥ 5% at Baseline (9)
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. Although the liver fat percentage change data between Treatment A and Treatment B were not statistically different, the addition of d-alpha tocopherol in Treatment B further improved liver injury markers ALT and AST compared to Treatment A.
Exhibit VI – ALT and AST Levels in Active and Placebo Arms at 12 Weeks (10)
ALT and AST levels were improved in both treatment arms over placebo at statistically significant levels. ALT levels were 13.0 U/L lower in the Treatment B arm as compared to the Treatment A arm with the a significant difference at the 0.005 level. This trend has been shown in AST changes, which was 5.5 U/L lower in the B arm as compared with the A arm; however, the difference between the treatment arms was not significant. 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 potentiates LPCN 1144 remains speculative. Antioxidant activity of d-alpha tocopherol may be expected as a potential mechanism, although it is not completely understood.
A review of other oral NASH agents on ALT level changes finds a placebo adjusted improvement from baseline of 3 U/L for resmetirom, 20 U/L for seladelpar and 18 U/L for obeticholic acid. This compares to an 11.1 U/L and 24.1 U/L improvement in LPCN 1144 excluding and including Vitamin E. AST levels were improved by 4.8 U/L for resmetirom, 2.4 U/L for seladelpar and 8 U/L for obeticholic acid. LPCN 1144 performed relatively better in AST improvement with a placebo-adjusted 7.7 U/L improvement in the monotherapy and a 13.2 U/L improvement in the LPCN 1144 and Vitamin E group.
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 may succeed where other NASH therapies have struggled. The primary endpoint readout is a solid improvement over placebo in a space where there are no other approved therapies. The 12-week results show a better result in liver fat improvement compared to other oral candidates, although, we caution that these are not head to head trials and the populations have dissimilar characteristics. While the drug is only appropriate for the male NASH population, it has shown a favorable safety profile and is bioidentical to testosterone. Lipocine has conducted many safety studies for the same compound in its TLANDO trials, which ultimate achieved approval from the FDA. We see a higher safety hurdle for treatment of low testosterone as compared to NASH, which gives us confidence the FDA will look favorably on the safety side of the equation. These topline results combined with forthcoming anticipated favorable biopsy data, suggests advancement of the candidate towards Phase III studies of LPCN 1144.
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1. Liver Fat Intervention with oral Testosterone (LiFT)
2. Lipocine LPCN 1144 Presentation January 12, 2021. This analysis was based on the intent to treat (ITT) set for all patients.
3. Note that Viking’s VK2809 and the related trial is being conducted in Non-Alcoholic Fatty Liver Disease (NAFLD) patients.
4. Source: Data sourced from Lipocine compiled data and Zacks’ analyst work. Note that Viking’s VK2809 is for NAFLD rather than NASH. Data for Lipocine includes subjects with BL ≥ 5% liver fat, which do not include one subject (BL < 5%) and three subjects missing data, in contrast to Exhibit I data.
5. Magnetic Resonance imaging Proton Density Fat Fraction
6. Vitamin E used along has demonstrated a benefit in NASH patients, reducing oxidative stress and improving levels of ALT and AST. A journal article here provides a review of studies performed up to mid-2018 on the topic. It is unclear if the benefit from Vitamin E in the LPCN 1144 trial is synergistic with the investigational drug or additive.
7. Lipocine LPCN 1144 Presentation January 12, 2021
8. Source: Lipocine Press Release, January 12, 2021
9. Source: Lipocine Press Release, January 12, 2021
10. Source: Lipocine Press Release, January 12, 2021