Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis

Abstract

Introduction: This study is to evaluate the safety and pharmacokinetics (PK) of larsucosterol (DUR-928 or 25HC3S) in subjects with alcohol-associated hepatitis (AH), a devastating acute illness without US Food and Drug Administration-approved therapies.

Methods: This phase 2a, multicenter, open-label, dose escalation study evaluated the safety, PK, and efficacy signals of larsucosterol in 19 clinically diagnosed subjects with AH. Based on the model for end-stage liver disease (MELD) score, 7 subjects were considered to have moderate AH and 12 to have severe AH. All subjects received 1 or 2 intravenous infusions (72 hours apart) of larsucosterol at a dose of 30, 90, or 150 mg and were followed up for 28 days. Efficacy signals from a subgroup of subjects with severe AH were compared with those from 2 matched arms of those with severe AH treated with standard of care (SOC), including corticosteroids, from a contemporaneous study.

Results: All 19 larsucosterol-treated subjects survived the 28-day study. Fourteen (74%) of all subjects including 8 (67%) of the subjects with severe AH were discharged ≤72 hours after receiving a single infusion. There were no drug-related serious adverse events nor early terminations due to the treatment. PK profiles were not affected by disease severity. Biochemical parameters improved in most subjects. Serum bilirubin levels declined notably from baseline to day 7 and day 28, and MELD scores were reduced at day 28. The efficacy signals compared favorably with those from 2 matched groups treated with SOC. Lille scores at day 7 were <0.45 in 16 of the 18 (89%) subjects with day 7 samples. Lille scores from 8 subjects with severe AH who received 30 or 90 mg larsucosterol (doses used in phase 2b trial) were statistically significantly lower ( P < 0.01) than those from subjects with severe AH treated with SOC from the contemporaneous study.

Discussion: Larsucosterol was well tolerated at all 3 doses in subjects with AH without safety concerns. Data from this pilot study showed promising efficacy signals in subjects with AH. Larsucosterol is being evaluated in a phase 2b multicenter, randomized, double-blinded, placebo-controlled (AHFIRM) trial.

Trial registration: ClinicalTrials.gov NCT03432260 NCT01809132 NCT02655510.

Graphical abstract

Figure 1.

The study schema. The study was conducted in 2 parts using a staggered parallel design. Part A included subjects with MELD scores of 11–20 (moderate AH), while part B included subjects with MELD scores of 21–30 (severe AH). The study was initiated with 4 subjects with moderate AH receiving 30 mg of larsucosterol by infusion. Dose escalation to 90 mg within part A was permitted after a review of safety and PK data by the DEC, including the study PI, the Medical Monitor, and the Sponsor. In parallel, enrollment of 4 subjects with severe AH (part B) for the low-dose (30 mg) group was only initiated once safety and PK results review of the 30 mg in subjects with moderate AH (part A) had been completed. Part A was terminated when part B enrollment met the prespecified enrollment goal. Subjects were followed up for 28 days and were assessed for safety, PK, and efficacy signals. AH, alcohol-associated hepatitis; DEC, Dose Escalation Committee; MELD, model for end-stage liver disease; PI, principal investigator; PK, pharmacokinetics.

Figure 2.

Plasma concentrations of larsucosterol over time in subjects with AH. Plasma samples were taken before, during, and after a 2-hour infusion of larsucosterol in subjects with moderate and severe AH. (a, left) Plasma concentrations of larsucosterol over time in subjects with moderate AH (mean ± SD). Four subjects received 30 mg of larsucosterol (solid round) and 3 received 90 mg of larsucosterol (solid square). (b, right) Plasma concentrations of larsucosterol over time in subjects with severe AH (mean ± SD). Four subjects each received 30 mg (empty round), 90 mg (shaded square), or 150 mg of larsucosterol (empty triangle). AH, alcohol-associated hepatitis.

Figure 3.

Serum total bilirubin levels over time in subjects with AH. Serum total bilirubin levels (mg/dL) from individual subjects (who returned for sample collection) were determined at baseline, day 7, and day 28 (end of the study) after the first infusion. Shaded circles represent subjects who received 30 mg of larsucosterol, empty circles are those who received 90 mg of larsucosterol, and shaded squares show those who received 150 mg of larsucosterol. (a, left) Subjects with moderate AH, and (b, right) Subjects with severe AH. *Represents P < 0.05 by t test. AH, alcohol-associated hepatitis.

Figure 4.

MELD scores over time in subjects with AH. MELD scores from individual subjects (who returned for sample collection) were determined at baseline, day 7, and day 28 (end of the study) after the first infusion. Shaded circles represent subjects who received 30 mg of larsucosterol, empty circles are those who received 90 mg of larsucosterol, and shaded squares show those who received 150 mg of larsucosterol. (a, left) Subjects with moderate AH, and (b, right) Subjects with severe AH. *Represents P < 0.05 by t test. AH, alcohol-associated hepatitis; MELD, model for end-stage liver disease.

Figure 5.

Lille scores and baseline MELD scores in subjects with AH. Lille scores were calculated on day 7 from individual subjects who returned for sample collection and were plotted against their corresponding baseline MELD scores. At the baseline, subjects with moderate AH had MELD scores of 11–20, while subjects with severe AH had MELD scores of 21–30. Shaded circles represent subjects who received 30 mg of larsucosterol, empty circles are those who received 90 mg of larsucosterol, and shaded squares show those who received 150 mg of larsucosterol. AH, alcohol-associated hepatitis; MELD, model for end-stage liver disease.

Figure 6.

Comparative Lille scores of subjects with severe AH from contemporaneous studies. Lille scores at day 7 are shown from selected subjects with severe AH after treatment with SOC, including CS, in an observational arm of the NIH-funded DASH study (n = 8, solid circle); larsucosterol at 30 or 90 mg doses (n = 8, solid square); and SOC, including CS, in a comparison arm of the DASH study (n = 16, solid triangle). **Represents P < 0.01 by t test. AH, alcohol-associated hepatitis; CS, corticosteroids; DASH, Defeat Alcoholic Steatohepatitis; NIH, National Institutes of Health; SOC, standard of care.

Figure 7.

MELD scores over time in subjects with severe AH. MELD scores from subjects with AH were calculated at baseline (a, left), day 7 (b, middle), and day 28 (c, right) after the initiation of treatment. Treatment was SOC, including CS, in an observational arm of the NIH-funded DASH study (n = 8, solid round); larsucosterol at 30 and 90 mg doses (n = 8, solid square); and SOC, including CS, in a larger comparison arm (n = 16, solid triangle) of the DASH study. Only 1 patient in the observational arm had follow-up laboratory tests at day 28. AH, alcohol-associated hepatitis; CS, corticosteroids; DASH, Defeat Alcoholic Steatohepatitis; MELD, model for end-stage liver disease; NIH, National Institutes of Health; SOC, standard of care.

Figure 8.

Serum AST levels over time in subjects with severe AH. Serum AST levels (IU/L) were determined at baseline (a, left), day 7 (b, middle), and day 28 (c, right) after treatment with SOC, including CS, in an observational arm of the NIH-funded DASH study (n = 8, solid circle); larsucosterol at 30 and 90 mg doses (n = 8, solid square); and SOC, including CS, in a larger comparison arm (n = 16, solid triangle) from the DASH study. Only 1 patient in the observational arm had follow-up laboratory tests at day 28. AH, alcohol-associated hepatitis; AST, aspartate aminotransferase; CS, corticosteroids; DASH, Defeat Alcoholic Steatohepatitis; NIH, National Institutes of Health; SOC, standard of care.

Figure 9.

Serum ALT levels over time in subjects with severe AH. Serum ALT levels (IU/L) were determined at baseline (a, left), day 7 (b, middle), and day 28 (c, right) after treatment with SOC, including CS, in an observational arm of the NIH-funded DASH study (n = 8, solid circle); larsucosterol at 30 and 90 mg doses (n = 8, solid square); and SOC, including CS, in a larger comparison arm (n = 16, solid triangle) of the DASH study. Only 1 patient in the observational cohort had follow-up laboratory tests at day 28. **Represents P < 0.01 by t test. ****Represents P < 0.0001 by t test. AH, alcohol-associated hepatitis; ALT, alanine aminotransferase; CS, corticosteroids; DASH, Defeat Alcoholic Steatohepatitis; NIH, National Institutes of Health; SOC, standard of care.