Livdelzi Drug Information
Generic name: SELADELPAR LYSINE
Uses of Livdelzi
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). Limitations of Use Use of LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).
Dosage & Administration of Livdelzi
Recommended Dosage and Administration
The recommended dosage of LIVDELZI is 10 mg orally once daily. Administer LIVDELZI with or without food.
Administration Modification for Bile Acid Sequestrants Administer LIVDELZI at least 4 hours before or 4 hours after taking bile acid sequestrants, or at as great an interval as possible.
Side Effects of Livdelzi
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. LIVDELZI or placebo was administered in combination with UDCA in 94% of patients and as monotherapy in 6% of patients who were unable to tolerate UDCA. Common Adverse Reactions Table 1 presents common adverse reactions that occurred in Trial 1.
Baseline bone mineral density was not obtained. The median time to fracture after receiving LIVDELZI was 295 days (range: 89–349). Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the LIVDELZI-treated patients compared to placebo, but in less than 5% of patients, included dyspepsia, rash, alopecia, anemia, and cough.
Laboratory Abnormalities Estimated Glomerular Filtration Rate In Trial 1, LIVDELZI-treated patients developed decreased estimated glomerular filtration rate (eGFR) (serum creatinine elevations) more frequently compared to placebo-treated patients. Ten percent (n=12) of LIVDELZI-treated patients had a decline in eGFR of at least 25%, compared to 2% (n=1) of placebo-treated patients. None of the patients experienced an eGFR decline of 50% or more.
The decline in eGFR stabilized or returned towards baseline with ongoing LIVDELZI treatment. None of the patients required discontinuation of LIVDELZI and there were no clinical findings associated with the observed changes in eGFR.
| Adverse Reaction 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. | LIVDELZI 10 mg Once Daily (N=128) % (n) | PLACEBO (N=65) % (n) |
|---|---|---|
| Headache | 8% (10) | 3% (2) |
| Abdominal pain The gastrointestinal adverse reactions were mild to moderate without the need for discontinuation of LIVDELZI. | 7% (9) | 2% (1) |
| Nausea | 6% (8) | 5% (3) |
| Abdominal distension | 6% (8) | 3% (2) |
| Dizziness | 5% (6) | 2% (1) |
Warnings & Cautions for Livdelzi
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 (aspartate aminotransferase and alanine aminotransferase ) levels greater than 3-times upper limit of normal (ULN) in PBC patients receiving 50 mg once daily (5-times higher than the recommended dosage) and 200 mg (20-times higher than the recommended dosage) once daily. Transaminase levels returned to pretreatment levels upon LIVDELZI discontinuation. LIVDELZI 10 mg once daily did not show a similar pattern for increases in transaminase levels.
Obtain baseline clinical and laboratory assessments at treatment initiation with LIVDELZI and monitor thereafter according to routine patient management. Interrupt LIVDELZI treatment if the liver tests (ALT, AST, total bilirubin, and/or alkaline phosphatase ) worsen, or the patient develops signs and symptoms consistent with clinical hepatitis (e.g., 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.
Drug Interactions with Livdelzi
Effect of Other Drugs on LIVDELZI Table 2 includes clinically significant drug interactions affecting LIVDELZI. Table 2: Clinically Significant Interactions Affecting LIVDELZI Bile acid sequestrants may interfere with the action of LIVDELZI by reducing its absorption and systemic exposure, which may reduce LIVDELZI efficacy. Administer LIVDELZI at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible.
| Concomitant Drug or Class | Potential Effect on Seladelpar Exposure ↑ = Increase, ↓ = Decrease. | Clinical Intervention |
|---|---|---|
| Probenecid | ↑ seladelpar | Avoid concomitant administration of LIVDELZI with probenecid. |
| Strong CYP2C9 Inhibitors | ↑ seladelpar | Monitor patients for adverse effects during concomitant use of LIVDELZI with strong CYP2C9 inhibitors. |
| Dual Moderate CYP2C9 and Moderate or Strong CYP3A4 Inhibitors (e.g., fluconazole) | ↑ seladelpar | Monitor patients for adverse effects during concomitant use of LIVDELZI with drugs that are dual moderate CYP2C9 and moderate or strong CYP3A4 inhibitors. |
| CYP2C9 Poor Metabolizers Using Moderate or Strong CYP3A4 Inhibitors | ↑ seladelpar | Monitor patients who are CYP2C9 poor metabolizers for adverse effects during concomitant use of LIVDELZI with moderate or strong CYP3A4 inhibitor. |
| Dual or Multiple Clinical Inhibitors of Drug Transporters OATP1B1, OATP1B3, and BCRP (e.g, cyclosporine) | ↑ seladelpar | Monitor patients for adverse effects during concomitant use of LIVDELZI with dual or multiple clinical inhibitors of drug transporters OATP1B1, OATP1B3, and BCRP. |
| Rifampin | ↓ seladelpar | Concomitant use of LIVDELZI with rifampin, an inducer of metabolizing enzymes, may result in delayed or suboptimal LIVDELZI biochemical response. Monitor the biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during LIVDELZI treatment. |
| Bile Acid Sequestrants | ↓ seladelpar | Bile acid sequestrants may interfere with the action of LIVDELZI by reducing its absorption and systemic exposure, which may reduce LIVDELZI efficacy. Administer LIVDELZI at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible [see Dosage and Administration (2.2) ]. |
Pregnancy Safety for Livdelzi
Pregnancy Risk Summary 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. In animal reproduction studies, no malformations or effects on embryo-fetal survival occurred in pregnant rats or rabbits after seladelpar treatment at exposures of up to 176-times and 49-times the recommended dose based on AUC (area under the plasma concentration-time curve), respectively. Reduction of fetal growth associated with maternal toxicity occurred in pregnant rabbits at 49-times the recommended dose based on AUC, but not at 3-times the recommended dose.
In a pre- and postnatal development study in rats with maternal dosing of seladelpar during organogenesis through lactation, postnatal growth and pre-weaning survival of offspring was reduced at 115-times the recommended dose based on AUC, but not at the lower exposure of 16-times the recommended dose (see Data ). The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Report pregnancies to Gilead Sciences, Inc. at 1-800-445-3235. Data Animal Data No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day seladelpar (176-times the recommended dose based on AUC) during the period of organogenesis.
Oral administration of 40 mg/kg/day seladelpar in pregnant rabbits (49-times the recommended dose based on AUC) during organogenesis resulted in reduced fetal body weight, which was likely due to maternal toxicity (i.e., decreases in food consumption, body weight, and gravid uterine weight) and distended stomach. No adverse effects on embryo-fetal development were observed at 10 mg/kg/day (3-times the recommended dose based on AUC). Treatment with 5 mg/kg/day or higher (4-times the recommended dose based on AUC) resulted in a dose-dependent reduction in pup body weight during the pre-weaning period.
The weight reduction in offspring was associated with delays in developmental milestones (i.e., eye opening and pinna unfolding at 5 mg/kg/day and higher; hair growth and sexual maturity at 100 mg/kg/day). Reduction in pup body weight at 100 mg/kg/day (115-times the recommended dose based on AUC), which continued into the post-weaning maturation period, was associated with a slight decrease in pre-weaning survival and was considered adverse. No adverse effects were found in clinical observations, neurobehavioral assessment, or reproductive performance testing in the offspring of females treated with seladelpar.
At 20 mg/kg/day (16-times the recommended dose based on AUC), none of the observed effects in offspring were considered to be adverse.
Pediatric Use of Livdelzi
Pediatric Use The safety and effectiveness of LIVDELZI in pediatric patients have not been established.
Overdosage Information for Livdelzi
PBC patients who received 5-times the recommended dosage or 20-times the recommended dosage of LIVDELZI experienced an increase in liver transaminases, muscle pain, and/or elevations in creatine phosphokinase, which resolved upon LIVDELZI discontinuation. There is no specific treatment for overdose with LIVDELZI. General supportive care of the patient is indicated, as appropriate.
If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because seladelpar is highly bound to plasma proteins, hemodialysis should not be considered.
Clinical Studies of Livdelzi
The efficacy of LIVDELZI was evaluated in Trial 1 (NCT04620733), a 12-month, randomized, double-blind, placebo-controlled trial. The trial 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 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. 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.
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. There was a trend of lower ALP in LIVDELZI arm compared to placebo arm starting at Month 1 through Month 12.
ALP in Adult Patients with PBC over 12 Months in Trial 1 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. Figure 1 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.
| LIVDELZI 10 mg Once Daily (N=128) | Placebo (N=65) | Treatment Difference % (95% CI) 95% unstratified Miettinen and Nurminen confidence intervals (CIs) are provided. | |
|---|---|---|---|
| Patients who discontinued treatment prior to Month 12 or who had missing data were considered as non-responders. | |||
| Biochemical Response Rate, n (%), p<0.0001 for LIVDELZI 10 mg 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 pruritus NRS (<4 versus ≥4). | 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) |
| Decrease in ALP of at least 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 (%), ALP normalization is defined as ALP less than or equal to ULN. | 32 (25) | 0 (0) | 25 (18, 33) |
| LIVDELZI 10 mg Once Daily (N=49) | Placebo (N=23) | |
|---|---|---|
| Baseline Average Pruritus Score, Mean (SD) | 6.1 (1.4) | 6.6 (1.4) |
| Change from Baseline in Pruritus Score at Month 6 | ||
| Mean (SE) | -3.2 (0.3) | -1.7 (0.4) |
| Mean difference vs. placebo (95% CI) | -1.5 (-2.5, -0.5) p=0.0051 | |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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