Drug Trials Snapshots: LIVDELZI

How were the trials designed?

The safety and efficacy of LIVDELZI were evaluated in one 12-month, randomized, double-blind, placebo-controlled clinical trial (Trial 1) in patients with PBC with 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 upper limit of normal (ULN) and 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, or history of hepatorenal syndrome). Patients were randomized in a 2:1 ratio to receive either LIVDELZI 10 mg (N=128) or placebo (N=65) once daily.

The primary endpoint was the percentage of patients achieving biochemical response at Month 12, where biochemical response measures liver enzymes that are found in the blood or serum. The key secondary endpoints were ALP normalization at Month 12 and change from baseline in itching score at Month 6 in patients with baseline average itching score greater than or equal to 4.

Who participated in the trials?

Table 1. Baseline Demographics, Efficacy Population

_{Source: Adapted from FDA Review
1 The Applicant stated that “Race and ethnicity were not collected for participants enrolled in France due to prohibition by local regulations.”
Abbreviations: SD, standard deviation}

What are the benefits of this drug (results of trials used to assess efficacy)?

The primary efficacy endpoint was the percentage of patients achieving biochemical response at Month 12, with biochemical response defined as ALP less than 1.67-times ULN, and TB less or equal to ULN, and ALP decrease greater than or equal to 15%. The key secondary efficacy endpoints were ALP normalization at Month 12 and change from baseline in itching score at Month 6 in patients with baseline average itching score greater than or equal to 4.

Table 2 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 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.

Table 2. Biochemical Response and ALP Normalization Results at Month 12, Efficacy Population

_{Source: Adapted from FDA Review
¹ Biochemical response is defined as ALP <1.67×ULN, an ALP decrease of ≥15%, and total bilirubin ≤ULN.
² ALP normalization is defined as ALP less than or equal to ULN.
³ P<0.0001 for LIVDELZI versus placebo. P-values were obtained using the Cochran–Mantel–Haenszel Test stratified by baseline ALP level (<350 U/L versus ≥350 U/L), and baseline average itching score (<4 versus ≥4).
⁴ 95% unstratified Miettinen and Nurminen CIs are provided.
Abbreviations: ALP, alkaline phosphatase; CI, confidence interval; TB, total bilirubin; ULN, upper limit of normal}

Table 3 presents results for the change from baseline in itching score at Month 6 in patients with baseline average itching scores greater than or equal to 4. Patients reported their daily worst itching intensity using the itching Numerical Rating Scale (NRS) with scores ranging from 0 ("no itching”) to 10 (“worst itching imaginable”) in a 14-day run-in period prior to randomization through Month 6. The baseline average itching score for each patient was calculated by averaging the itching NRS scores in the run-in period and on Day 1 before treatment initiation. The itching scores at Month 6 for each patient were calculated by averaging the itching NRS scores within the last week in the month. LIVDELZI demonstrated greater improvement on itching at Month 6 compared to placebo.

Table 3. Change From Baseline in Itching Score at Month 6, Efficacy Population With Baseline Average Itching Score ≥4

_{Source: Adapted from FDA Review
P=0.01 for LIVDELZI 10 mg versus placebo. P-value was obtained from a mixed-effect model for repeated measures (MMRM) for change from baseline in itching scores at Months 1, 3, and 6 adjusting for baseline average itching score, baseline randomization stratum for ALP level (<350 U/L versus ≥350 U/L), treatment group, month as a categorical variable, and treatment-by-month interaction.
Abbreviations: ALP, alkaline phosphatase; CI, confidence interval; SD, standard deviation; SE, standard error}

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Table 4 summarizes efficacy results by sex, age, race, and ethnicity in Trial 1 for the endpoint of achieving biochemical response at Month 12. The treatment effect of LIVDELZI compared to placebo appeared consistent across age groups. The observed effect of LIVDELZI was larger for not Hispanic or Latino patients than Hispanic or Latino patients; because of limited data, this difference may be due to chance. There was an insufficient number of male patients and patients of races other than White to determine whether LIVDELZI worked differently in different sexes and races.

Table 4. Efficacy Results by Sex, Age, Race, and Ethnicity, Efficacy Population

_{Source: Adapted from FDA Review
¹ Unable to calculate the percentage of responders or to construct the 95% CIs when the number of patients in the treatment arm in the subgroup is small.
Abbreviations: CI, confidence interval; N, number of patients in treatment arm; n, number of patients meeting criteria; Ns, total number of patients for each specific subgroup and were assigned to that specific arm}

What are the possible side effects (results of trials used to assess safety)?

Table 5. Common Adverse Reactions Occurring Through Week 52 in Adult Patients With PBC, Trial 1^a, Safety Population

_{Source: Adapted from LIVDELZI Prescribing Information
^a Included 12 patients (6%) who were intolerant to UDCA and initiated treatment as monotherapy: 8 patients (6%) in the LIVDELZI arm and 4 patients (6%) in the placebo arm.
^b Occurring in greater than or equal to 5% of patients in the LIVDELZI treatment arm and at an incidence greater than or equal to 1% higher than in the placebo arm.
^c The gastrointestinal adverse reactions were mild to moderate without the need for discontinuation of LIVDELZI.
Abbreviations: PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid}

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Table 6 shows the side effects by subgroup. The observed proportion of patients with side effects for LIVDELZI relative to placebo was greater in patients older than 65 years of age than in younger patients. Because of limited data, this difference may be due to chance.

Table 6. Side Effects by Subgroup, Trial 1, Safety Population

_{Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; N, number of patients in treatment arm; n, number of patients with adverse event; NA, not applicable; Ns, total number of patients for each specific subgroup and were assigned to that specific arm}