Review LIVDELZI safety, tolerability, and side effects data1
Safety and tolerability profile demonstrated with LIVDELZI1
In RESPONSE, LIVDELZI was studied in a broad population of patients taking a wide range of concomitant medications. The safety profile included adverse reactions of patients without cirrhosis and those with compensated cirrhosis in both treatment arms.2-4
Most common adverse reactions (≥5%) in patients with PBC1*
| Adverse reaction† | LIVDELZI 10 mg ± UCDA(n=128) % (n) | Placebo ± UDCA(n=65)% (n) |
|---|---|---|
| Headache | 8% (10) | 3% (2) |
| Abdominal pain‡ | 7% (9) | 2% (1) |
| Nausea‡ | 6% (8) | 5% (3) |
| Abdominal distension‡ | 6% (8) | 3% (2) |
| Dizziness | 5% (6) | 2% (1) |
*In the RESPONSE trial, 12 patients (6%) were intolerant to UDCA and initiated treatment as monotherapy: 8 patients (6%) in the LIVDELZI 10 mg arm and 4 patients (6%) in the placebo arm.1
†Adverse reactions occurred in ≥5% of patients in the LIVDELZI arm and at an incidence of ≥1% higher than in the placebo arm.1
‡Gastrointestinal adverse reactions were mild to moderate without the need for discontinuation of LIVDELZI.1
Primary endpoint1
Composite biochemical response at 12 months:
- ALP <1.67 x ULN
- ≥15% decrease in ALP from baseline
- TB ≤1 x ULN
Key secondary endpoints1
- ALP normalization at 12 months, defined as ALP ≤1.0 x ULN
- Change from baseline in mean pruritus NRS score at 6 months was analyzed using a mixed-effect model for repeated measures#
Select secondary endpoint2
- Mean change in ALP at 12 months
Inclusion criteria1,2
- PBC with an inadequate response or intolerance to UDCA (on treatment ≥12 months; last dose >3 months prior to screening)
- ALP <1.67 x ULN
- TB ≤2 x ULN
- ALT/AST ≤3 x ULN
Exclusion criteria1
- Other chronic liver diseases
- Clinically important hepatic decompensation
- Portal hypertension with complications
- Cirrhosis with complications (MELD score ≥12, known esophageal varices or variceal bleeds, history of hepatorenal syndrome)
After 12 months, patients from both arms of the RESPONSE trial could enroll in an open-label, long-term study2
§Patients were randomized in a 2:1 ratio.1
¶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.1
#The pruritus NRS is a scale ranging from 0 (no itch) to 10 (worst itch imaginable).1
Safety data from open-label, pooled analysis5
Overall exposure-adjusted adverse event (AE) rates observed in ≥3 patients per 100 patient-years (N=337; E=575.7 years*): COVID-19 (11.5), pruritus (6.8), nausea (5.2), fatigue (4.9), urinary tract infection (4.7), diarrhea (4.5), headache (4.5), arthralgia (4.0), nasopharyngitis (4.0), abdominal pain upper (3.7), abdominal pain (3.5), patients with ≥1 AE (50.2).5†
Limitations: This is an open-label extension study that lacked a treatment comparator and was not designed to address potential bias. These data should be considered descriptive only and conclusions should not be drawn around long-term safety up to 3 years.5
*E=patients’ sum of exposure.
†ASSURE includes patients who rolled over from both arms of the pivotal RESPONSE study as well as patients who were previously enrolled in prior LIVDELZI PBC clinical studies (legacy studies). Interim safety results have been reported in a pooled analysis with a data cutoff of January 31, 2024.5
ASSURE is an ongoing, open-label extension (OLE) study evaluating the long-term efficacy and safety results of LIVDELZI. Patients from both arms of the pivotal RESPONSE study or those who were enrolled in a prior LIVDELZI PBC clinical study (legacy studies) were invited to participate in ASSURE. Interim 30-month efficacy and safety results have been reported in a pooled analysis.5‡
ASSURE phase 3 open-label study design5,6
Inclusion criteria:
- Participated in a PBC study with LIVDELZI
Exclusion criteria§:
- AST or ALT >3 x ULN
- Total bilirubin >2 x ULN
- MELD score ≥12
- Evidence of advanced PBC
- eGFR ≤45 mL/min/1.73 m2
- Use of certain other treatments within 2-3 months prior to screening
- History of malignancy diagnosed or treated within 2 years
- Use of immunosuppressant therapies
- Evidence of advanced PBC
- eGFR ≤45 mL/min/1.73 m2
- Use of certain other treatments within 2-3 months prior to screening
- History of malignancy diagnosed or treated within 2 years
- Use of immunosuppressant therapies
Initial data were reported based on exposure to LIVDELZI either upon entry to ASSURE or RESPONSE.
‡Data cutoff of January 31, 2024.5
§Exclusion criteria are only applicable when patients have a study drug interruption of >4 weeks prior to day 1 and for patients who participated in the Phase 1b Hepatic Impairment Study.6
¶Legacy seladelpar studies include Phase 2 Dose-Ranging Study (NCT02955602), Phase 3 Long-Term Safety Study (NCT03301506), Phase 3 ENHANCE (NCT03602560), and Phase 1b Hepatic Impairment Study (NCT04950764). Most patients from legacy studies had a treatment gap between their initial use of LIVDELZI and entering the ASSURE study.5,6
#Patients from the placebo arm of the RESPONSE pivotal study switched to active treatment with LIVDELZI in the ASSURE study.6
**54 patients rolled over from the RESPONSE placebo arm and 104 patients rolled over from the RESPONSE LIVDELZI 10 mg arm.5
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate aminotransferase; eGFR=estimated glomerular filtration rate; MELD=Model for End-Stage Liver Disease; NRS=Numerical Rating Scale; OLE=open-label extension; PBC=primary biliary cholangitis; TB=total bilirubin; UDCA=ursodeoxycholic acid; ULN=upper limit of normal.
Tap for Important Safety Information, including warnings for fractures, liver test abnormalities, and biliary obstruction
LIVDELZI is indicated for the treatment of primary biliary cholangitis (PBC), in combination with ursodeoxycholic acid (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.
This indication is approved under accelerated approval based on a reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Limitation of use: Use of LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (eg, ascites, variceal bleeding, hepatic encephalopathy).
IMPORTANT SAFETY INFORMATION
Warnings and Precautions
- Fractures: Fractures occurred in 4% of LIVDELZI-treated patients compared to no placebo-treated patients. Consider the risk of fracture in the care of patients treated with LIVDELZI and monitor bone health according to current standards of care.
- Liver Test Abnormalities: LIVDELZI has been associated with dose-related increases in serum transaminase (AST and ALT) levels >3x ULN in patients receiving 50 mg and 200 mg once daily (5x and 20x higher than the recommended dosage of 10 mg once daily). Perform baseline clinical and laboratory testing when starting LIVDELZI and monitor thereafter according to routine patient management. Interrupt treatment if the liver tests (ALT, AST, total bilirubin, and/or ALP) worsen, or if the patient develops signs and symptoms of clinical hepatitis (eg, jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting LIVDELZI.
- Biliary Obstruction: Avoid use of LIVDELZI in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt LIVDELZI and treat as clinically indicated.
Adverse Reactions
- The most common adverse reactions (≥5%) with LIVDELZI were headache (8%), abdominal pain (7%), nausea (6%), abdominal distension (6%), and dizziness (5%).
Drug Interactions
- OAT3 Inhibitors and Strong CYP2C9 Inhibitors: Avoid coadministration with LIVDELZI due to increased LIVDELZI exposure.
- Rifampin: Monitor biochemical response (eg, ALP and bilirubin) when patients initiate rifampin during LIVDELZI treatment. Coadministration may result in delayed or suboptimal biochemical response of LIVDELZI.
- Dual Moderate CYP2C9 and Moderate-to-Strong CYP3A4 Inhibitors and BCRP Inhibitors (eg, cyclosporine): Monitor closely for adverse effects. Concomitant administration with LIVDELZI may increase LIVDELZI exposure.
- CYP2C9 Poor Metabolizers Using Moderate-to-Strong CYP3A4 Inhibitors: Monitor more frequently for adverse reactions as concomitant use of a moderate-to-strong CYP3A4 inhibitor in patients who are CYP2C9 poor metabolizers may increase LIVDELZI exposure and risk of LIVDELZI adverse reactions.
- Bile Acid Sequestrants: Administer LIVDELZI at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible.
Pregnancy and Lactation
- Pregnancy: There are insufficient data from human pregnancies exposed to LIVDELZI to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Gilead Sciences, Inc., at 1-800-445-3235.
- Lactation: There are no data on the presence of LIVDELZI in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LIVDELZI and any potential adverse effects on the breastfed infant from LIVDELZI.
Please see full Prescribing Information for LIVDELZI.
References
- LIVDELZI [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2024.
- Hirschfield GM, Bowlus CL, Mayo MJ, et al; RESPONSE Study Group. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med. 2024;390(9):783-794. doi:10.1056/NEJMoa2312100
- Hirschfield GM, Bowlus CL, Mayo MJ, et al; RESPONSE Study Group. A phase 3 trial of seladelpar in primary biliary cholangitis [supplementary appendix]. N Engl J Med. 2024;390(9):783-794. doi:10.1056/NEJMoa2312100
- Data on file. Gilead Sciences, Inc.; 2024.
- Lawitz EJ, Trivedi PJ, Kowdley KV, et al. Long-term efficacy and safety of open-label seladelpar treatment in patients with primary biliary cholangitis: pooled interim results for up to 3 years from the ASSURE study. Poster presented at: The Liver Meeting, American Association for the Study of Liver Diseases; November 15-19, 2024; San Diego, CA.
- Yimam K, Levy C, Kowdley KV, et al. ASSURE study in progress: an open-label long-term extension study to evaluate the safety and tolerability of seladelpar in subjects with primary biliary cholangitis (PBC). Poster presented at: Liver Connect Conference; April 4-6, 2024; Scottsdale, AZ.