Drug Trials Snapshots: LIVDELZI
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the LIVDELZI Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
LIVDELZI (seladelpar)
liv del’ zee
CymaBay Therapeutics, Inc.
Original Approval date: August 14, 2024
DRUG TRIALS SNAPSHOT SUMMARY
What is the drug for?
LIVDELZI is a peroxisome proliferator-activated receptor (PPAR)-delta agonist that is used to treat primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.
LIVDELZI is not recommended for patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, or hepatic encephalopathy).
How is this drug used?
LIVDELZI is a capsule that is taken once daily.
Who participated in the clinical trials?
The FDA approved LIVDELZI based on evidence from a clinical trial of 193 patients with PBC with an inadequate response or intolerance to UDCA. The trial was conducted at 90 sites in 24 countries including Argentina, Australia, Austria, Belgium, Canada, Chile, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Mexico, New Zealand, Poland, Romania, Russia, South Korea, Spain, Switzerland, Turkey, the United Kingdom, and the United States. Approximately 32% (61) of the patients were from the United States.
The same trial was used to assess efficacy and safety.
How were the trials designed?
LIVDELZI was evaluated in Trial 1 (NCT04620733), a 12-month, randomized, double-blind, placebo-controlled trial of 193 patients with PBC with an inadequate response or intolerance to UDCA. Patients received LIVDELZI 10 mg or placebo once daily. The benefit of LIVDELZI was evaluated based on the percentage of patients who achieved biochemical response at Month 12, where biochemical response measures liver enzymes (alkaline phosphatase [ALP] and total bilirubin [TB]) that are found in blood or serum.
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.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes the percentage of male and female patients enrolled in the clinical trial that evaluated the safety and efficacy of LIVDELZI.
Figure 1. Baseline Demographics by Sex, Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes the percentage of patients by race enrolled in the clinical trial that evaluated the safety and efficacy of LIVDELZI.
Figure 2. Baseline Demographics by Race, Efficacy Population
Source: Adapted from FDA Review
Missing: The Applicant stated that “Race and ethnicity were not collected for participants enrolled in France due to prohibition by local regulations.”
Figure 3 summarizes the percentage of patients by age enrolled in the clinical trial that evaluated the safety and efficacy of LIVDELZI. Notably, the disease affects predominantly women (approximately 90%) in their 50s and 60s.
Figure 3. Baseline Demographics by Age, Efficacy Population
Source: Adapted from FDA Review
Figure 4 summarizes the percentage of patients by ethnicity enrolled in the clinical trial that evaluated the safety and efficacy of LIVDELZI.
Figure 4. Baseline Demographics by Ethnicity, Efficacy Population
Source: Adapted from FDA Review
Missing: The Applicant stated that “Race and ethnicity were not collected for participants enrolled in France due to prohibition by local regulations.”
Who participated in the trials?
Table 1. Baseline Demographics, Efficacy Population
| Demographic Parameters | LIVDELZI N=128 |
Placebo N=65 |
Total N=193 |
| Sex, n (%) | |||
| Female | 123 (96.1) | 60 (92.3) | 183 (94.8) |
| Male | 5 (3.9) | 5 (7.7) | 10 (5.2) |
| Age, years | |||
| Mean (SD) | 56.6 (10.0) | 57.0 (9.2) | 56.7 (9.7) |
| Median | 57.0 | 58.0 | 57.0 |
| Min, max | 28.0, 75.0 | 33.0, 75.0 | 28.0, 75.0 |
| Age category, years, n (%) | |||
| <65 | 99 (77.3) | 53 (81.5) | 152 (78.8) |
| ≥65 | 29 (22.7) | 12 (18.5) | 41 (21.2) |
| Race, n (%) | |||
| American Indian or Alaska Native | 3 (2.3) | 3 (4.6) | 6 (3.1) |
| Asian | 7 (5.5) | 4 (6.2) | 11 (5.7) |
| Black or African American | 2 (1.6) | 2 (3.1) | 4 (2.1) |
| White | 114 (89.1) | 56 (86.2) | 170 (88.1) |
| Missing1 | 2 (1.6) | 0 | 2 (1.0) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 29 (22.7) | 27 (41.5) | 56 (29.0) |
| Not Hispanic or Latino | 97 (75.8) | 38 (58.5) | 135 (69.9) |
| Missing1 | 2 (1.6) | 0 | 2 (1.0) |
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?
More patients achieved biochemical response after 12 months of treatment with LIVDELZI compared to those who were treated with placebo. Biochemical response is a lowering of the levels of liver enzymes (ALP) that are found in the blood or serum, and that are elevated in patients with PBC.
Among patients with elevated itching, patients treated with LIVDELZI had greater improvement in itching after six months of treatment compared to those treated with placebo.
LIVDELZI was approved under FDA’s accelerated approval program, which provides earlier patient access to a promising new drug while the company continues to conduct clinical trials to confirm that the drug works well.
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
| Parameter | LIVDELZI N=128 |
Placebo N=65 |
Risk Difference % (95% CI)4 |
| Biochemical response rate, n (%)1, 3 | 79 (62) | 13 (20) | 42 (28, 53) |
| Components of biochemical response | |||
| ALP less than 1.67-times ULN, n (%) | 84 (66) | 17 (26) | 39 (25, 52) |
| ALP decrease of greater than or equal to 15%, n (%) | 107 (84) | 21 (32) | 51 (37, 63) |
| TB less than or equal to ULN, n (%) | 104 (81) | 50 (77) | 4 (-7, 17) |
| ALP normalization, n (%)2, 3 | 32 (25) | 0 (0) | 25 (18, 33) |
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
| Parameter | LIVDELZI N=49 |
Placebo N=23 |
| Baseline average itching score, mean (SD) | 6.1 (1.4) | 6.6 (1.4) |
| Change from baseline to Month 6 | ||
| Mean (SE) | -3.2 (0.3) | -1.7 (0.4) |
| Mean difference vs. placebo (95% CI)1 | -1.5 (-2.5, -0.5) | |
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?
- Sex: The number of males was small; therefore, differences between sexes in how LIVDELZI worked could not be determined.
- Race: The number of patients of races other than White was small; therefore, differences in how LIVDELZI worked among races could not be determined.
- Age: LIVDELZI worked similarly in patients younger and older than 65 years of age.
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
| Subgroup | LIVDELZI N=128 n/Ns (%) |
Placebo N=65 n/Ns (%) |
Risk Difference % (95% CI) |
| Sex | |||
| Female | 76/123 (62) | 12/60 (20) | 42 (27, 54) |
| Male | 3/5 (60) | 1/5 (20) | 40 (-23, 79) |
| Age category, years | |||
| <65 | 61/99 (62) | 10/53 (19) | 43 (27, 56) |
| ≥65 | 18/29 (62) | 3/12 (25) | 37 (3, 62) |
| Race1 | |||
| American Indian or Alaska Native | 2/3 (67) | 0/3 (0) | 67 (-17, 95) |
| Asian | 7/7 (100) | 0/4 (0) | 100 (44, -) |
| Black or African American | 0/2 (0) | 0/2 (0) | - (-, -) |
| White | 68/114 (60) | 13/56 (23) | 36 (21, 49) |
| Missing | 2/2 (100) | 0 | - (-, -) |
| Ethnicity1 | |||
| Hispanic or Latino | 14/29 (48) | 6/27 (22) | 26 (1, 48) |
| Not Hispanic or Latino | 63/97 (65) | 7/38 (18) | 47 (29, 60) |
| Missing | 2/2 (100) | 0 | - (-, -) |
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?
The most common side effects that occurred ≥5% in LIVDELZI-treated patients compared with placebo were headaches, abdominal pain, nausea, abdominal distension, and dizziness.
The label includes warnings for fractures, liver test abnormalities, and biliary obstruction.
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 1a, Safety Population
| Adverse Reactionb | LIVDELZI N=128 n (%) |
Placebo N=65 n (%) |
| Headache | 10 (8) | 2 (3) |
| Abdominal painc | 9 (7) | 1 (2) |
| Nauseac | 8 (6) | 3 (5) |
| Abdominal distensionc | 8 (6) | 2 (3) |
| Dizziness | 6 (5) | 1 (2) |
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 among sex, race, and age?
- Sex: The number of males was small; therefore, differences in side effects of LIVDELZI between sexes could not be determined.
- Race: The number of patients other than White was small; therefore, differences in side effects of LIVDELZI among races could not be determined.
- Age: Observed side effects from LIVDELZI relative to placebo were greater in patients older than 65 years of age than in younger patients. Because of limited data, this difference may be due to chance.
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
| Subgroup | LIVDELZI N=128 n/Ns (%) |
Placebo N=65 n/Ns (%) |
Risk Difference % (95% CI) |
| Sex | |||
| Female | 107/123 (87.0) | 51/60 (85.0) | 2.0 (8.0, 14.2) |
| Male | 4/5 (80.0) | 4/5 (80.0) | 0.0 (-51.7, 51.7) |
| Age group, years | |||
| <65 | 86/99 (86.9) | 48/53 (90.6) | -3.7 (-13.7, 8.4) |
| ≥65 | 25/29 (86.2) | 7/12 (58.3) | 27.9 (0.3, 57.0) |
| Age group ≥75, years | |||
| ≥75 | 2/2 (100) | 1/1 (100) | 0.0 (-74.2, 85.2) |
| Race | |||
| American Indian or Alaska Native | 2/3 (66.7) | 2/3 (66.7) | 0.0 (-65.3, 65.3) |
| Asian | 6/7 (85.7) | 3/4 (75.0) | 10.7 (-37.2, 62.1) |
| Black or African American | 1/2 (50.0) | 2/2 (100) | -50.0 (-92.4, 46.8) |
| White | 100/114 (87.7) | 48/56 (85.7) | 2.0 (-8.2, 14.6) |
| Missing | 2/2 (100) | 0/0 (NA) | NA |
| Ethnicity | |||
| Hispanic or Latino | 27/29 (93.1) | 22/27 (81.5) | 11.6 (-6.7, 31.2) |
| Not Hispanic or Latino | 82/97 (84.5) | 33/38 (86.8) | -2.3 (-13.9, 13.1) |
| Missing | 2/2 (100) | 0/0 (NA) | NA |
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
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.