The efficacy of LIVDELZI was evaluated in Trial 1 (NCT04620733), a 12-month, randomized, double-blind, placebo-controlled trial. The study included 193 adult patients with PBC with an inadequate response or intolerance to UDCA. Patients were included in the trial if their ALP was greater than or equal to 1.67-times the ULN and total bilirubin (TB) was less than or equal to 2-times the ULN. Patients were excluded from the trial if they had other chronic liver diseases, clinically important hepatic decompensation including portal hypertension with complications, or cirrhosis with complications (e.g., Model for End Stage Liver Disease [MELD] score of 12 or greater, known esophageal varices or history of variceal bleeds, history of hepatorenal syndrome).

Patients were randomized to receive LIVDELZI 10 mg (N=128) or placebo (N=65) once daily for 12 months. LIVDELZI or placebo was administered in combination with UDCA in 181 (94%) patients during the trial, or as a monotherapy in 12 (6%) patients who were unable to tolerate UDCA.

Baseline Demographics and Characteristics

The mean age of patients was 57 (Range: 28 to 75) years; 95% were female; 88% were White, 6% Asian, 2% Black or African American, and 3% American Indian or Alaska Native. Twenty-nine percent of the patients, 23% in the LIVDELZI 10 mg arm and 42% in the placebo arm, identified as Hispanic/Latino. Thirty-two percent of the patients, 38% in the LIVDELZI 10 mg arm and 20% in the placebo arm, were enrolled in the US.

At baseline, 18 (14%) of the LIVDELZI-treated patients and 9 (14%) of the placebo-treated patients met at least one of the following criteria: Fibroscan >16.9kPa; historical biopsy or radiological evidence suggestive of cirrhosis; platelet count < 140,000/µL with at least one additional laboratory finding including serum albumin < 3.5 g/dL, INR > 1.3, or TB > 1-time ULN; or clinical determination of cirrhosis by the investigator.

The mean baseline ALP concentration was 314 (Range: 161 to 786) units per liter (U/L), corresponding to 2.7-times ULN. The mean baseline TB concentration was 0.8 (Range: 0.3 to 1.9) mg/dL and was less than or equal to the ULN in 87% of the patients. Other mean baseline liver biochemistries were 48 (Range: 9 to 115) U/L for ALT and 40 (Range: 16 to 94) U/L for AST.

Biochemical Results

The primary endpoint was biochemical response at Month 12, where biochemical response was defined as achieving ALP less than 1.67-times ULN, an ALP decrease of greater than or equal to 15% from baseline, and TB less than or equal to ULN. ALP normalization (i.e., ALP less than or equal to ULN) at Month 12 was a key secondary endpoint. The ULN for ALP was defined as 116 U/L. The ULN for TB was defined as 1.1 mg/dL.

Table 3 presents results at Month 12 for the percentage of patients who achieved biochemical response, achieved each component of biochemical response, and achieved ALP normalization. LIVDELZI demonstrated greater improvement on biochemical response and ALP normalization at Month 12 compared to placebo. Overall, 87% of patients had a baseline of TB concentration less than or equal to ULN. Therefore, improvement in ALP was the main contributor to the biochemical response rate results at Month 12.

Figure 1 shows the mean (95% CI) levels of ALP over 12 months. There was a trend of lower ALP in LIVDELZI arm compared to placebo arm starting at Month 1 through Month 12.

Biochemical response at Month 3 comparing LIVDELZI as a monotherapy to placebo was evaluated in a pooled analysis of a subset of patients from Trial 1 and another randomized, double-blind, placebo-controlled trial in a similar patient population. There was a trend of improvement on biochemical response at Month 3 in the LIVDELZI monotherapy group compared to the placebo group.

Pruritus

A single-item patient-reported outcome (PRO), the pruritus Numerical Rating Scale (NRS), evaluated patients' daily worst itching intensity on an 11-point rating scale with scores ranging from 0 ("no itching") to 10 ("worst itching imaginable") in Trial 1. The pruritus NRS was administered daily in a 14-day run-in period prior to randomization through Month 6.

Table 4 presents the results of the comparison between LIVDELZI and placebo on the key secondary endpoint evaluating the change from baseline in pruritus score at Month 6 in patients with baseline average pruritus scores greater than or equal to 4. The baseline average pruritus score for each patient was calculated by averaging the pruritus NRS scores administered in the run-in period and on Day 1 before treatment initiation. The pruritus scores at Month 6 for each patient were calculated by averaging the pruritus NRS scores within the last week in the month. Patients treated with LIVDELZI demonstrated greater improvement in pruritus compared with placebo.