Regulatory Decision Summary for Lyvdelzi

Gilead Sciences Canada Inc. filed a New Drug Submission (NDS) to obtain market authorization for Lyvdelzi (seladelpar) 10 mg capsules, to be given orally, for the treatment of primary biliary cholangitis (PBC), including pruritis, in adults in combination with ursodeoxycholic acid (UDCA) who have an inadequate response to UDCA alone, or as monotherapy in those unable to tolerate UDCA.

Upon review of the submitted data package, Health Canada authorized Lyvdelzi for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA alone, or as monotherapy in those unable to tolerate UDCA

The submission was filed and reviewed under Advance Consideration, Notice of Compliance with Conditions (NOC/c) Guidance.

Primary biliary cholangitis (PBC) is a serious and potentially life-threatening chronic, progressive, autoimmune cholestatic liver disease characterized by inflammation and destruction of intrahepatic bile ducts. Approximately 50-60% of patients are asymptomatic at diagnosis, with symptoms developing within 2 to 4 years in the majority of patients. Clinical symptoms include pruritus, fatigue, hypercholesterolemia, and osteoporosis. In advanced PBC, patients may develop progressive jaundice, portal hypertension, and liver failure, progressing to liver related death in the absence of liver transplant. Lyvdelzi is an agonist of peroxisome proliferator activated receptor δ intended to reduce bile-acid toxicity in PBC to slow disease progression.

The efficacy and safety of Lyvdelzi for the proposed indication was supported by the pivotal Phase 3 double-blind, placebo-controlled trial, CB8025-32048 (RESPONSE). A total of 193 adults with PBC, aged 18-75 with inadequate responses to ursodeoxycholic acid (UDCA) (94% of patients) or UDCA intolerance (6% of patients) were randomized 2:1 to Lyvdelzi 10 mg (n = 128) or placebo (n = 65) once daily for ≥52 weeks. Patients were stratified by baseline alkaline phosphatase (ALP) (<350 U/L vs. >350 U/L) and presence of pruritus (baseline pruritus numerical rating scale (NRS) score <4 vs. >4).

The pivotal trial met its primary endpoint of composite biochemical response at month 12, defined as ALP <1.67x upper limit of normal (ULN), an ALP decrease of at least 15% from baseline and total bilirubin <1.0x ULN. This endpoint is consistent with international specialty guidance, regulatory precedent, and published prognostic literature. At month 12, 61.7% of patients who received Lyvdelzi achieved the composite biochemical response compared to 20% of patients who received placebo (p <0.0001). The response was primarily driven by patients who met the endpoint of ALP <1.67× ULN (65.6% Lyvdelzi vs. 26.2% placebo) and ≥15% decrease in ALP (83.6% Lyvdelzi vs. 32.3% placebo). At baseline, 87% of patients had a total bilirubin ≤ULN, therefore, improvement in ALP was the main contributor to the biochemical response rate.

Prespecified key secondary endpoints included ALP normalization at month 12 and improvement in averaged pruritus NRS in patients with baseline pruritus NRS, >4 at month 6. Treatment with Lyvdelzi led to a significantly higher percentage of patients achieving ALP normalisation at month 12 relative to placebo (25.0% vs. 0%, p <0.0001). Of those patients with baseline average pruritus NRS >4 (n = 72), treatment with Lyvdelzi led to a statistically significant improvement in pruritus NRS compared with placebo. The mean change from baseline was -3.2 in those who received seladelpar (n = 49) versus -1.7 in the placebo arm (p = 0.0047). These results are considered statistically significant as well as clinically relevant and offer support for the clinical effectiveness of seladelpar.

Primary support of safety was provided by the pivotal trial RESPONSE and included 128 patients who received 10 mg Lyvdelzi in the proposed indication. The mean duration of exposure to Lyvdelzi was 50.5 weeks. Overall, incidence of treatment-emergent adverse events (TEAEs) were similar between Lyvdelzi and placebo: total TEAEs (87% vs. 85%), study-drug related (17% vs. 12%), severe (11 vs. 8%), serious (7% vs. 6%). No serious adverse events (SAE) were considered to be treatment-related. All SAE were individually reported with the exception of COVID-19 which occurred in 1 patient in each arm. A total of 7 (3.6%) patients discontinued treatment due to TEAEs, including 4 patients (3 %) in the Lyvdelzi group and 3 patients (5%) in the placebo group. There were no deaths in the study.

Adverse reactions occurring in >5% of patients and with higher frequency than placebo were headache (8% vs. 3%), abdominal pain (7% vs. 2%), nausea (6% vs. 5%) and abdominal distension (6% vs. 3%). Adverse events of special interest included liver-related, muscle-related, renal-related and pancreatic- related TEAEs. TEAE potentially reflecting liver-related toxicity were reported for 6% of patients in the Lyvdelzi arm vs. 9.2% of patients in the placebo arm. Among patients with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above ULN at baseline, increases to >2× baseline AST or ALT values were observed in 2.3% of seladelpar patients compared with 6.2% of placebo patients. One patient treated with Lyvdelzi was identified as meeting potential Hy’s Law criteria and was not considered consistent with drug-induced liver injury (DILI) related to study drug. An analysis of renal safety laboratory parameters demonstrated that more patients treated with Lyvdelzi had decreases in estimated glomerular filtration rate (eGFR) of ≥25% compared with patients treated with placebo (9.4% vs. 1.5%). These changes were associated with comparable increases in serum creatinine however were not associated with renal-related TEAEs or drug interruption. There were no muscle or pancreatic safety signals identified.

Patients with advanced disease, decompensated hepatic impairment (Child-Pugh B or C), complications of cirrhosis, portal hypertension or laboratory findings that would be consistent with severe disease were excluded from the trial. As such, the safety of Lyvdelzi in these populations has not been established. Given that PBC is a progressive disease, treatment discontinuation should be considered if the patient progresses to moderate hepatic impairment, and use is not recommended in patients with severe hepatic impairment. This is reflected in the Risk Management Plan (RMP) and in the Product Monograph (PM).

Supportive data was provided from the uncontrolled open label extension (OLE) study CB8025-31731-RE (ASSURE) and the prematurely terminated placebo-controlled phase 3 trial CB8025-31735 (ENHANCE), neither of which demonstrated additional safety signals. In total, 461 patients with PBC received at least one dose of seladelpar 10 mg with a mean duration of treatment of 77.2 weeks.

The toxicology, non-clinical pharmacology and clinical pharmacology review did not raise any issues that would preclude approval of Lyvdelzi for the proposed indication.

The chemistry and manufacturing information submitted for Lyvdelzi demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Comparative bioavailability was reviewed and demonstrated differences in the rate of absorption and elimination of seladelpar. These were considered unlikely to be clinically significant or relevant and Lyvdelzi may be taken with or without food.

A RMP for Lyvdelzi was submitted by Gilead Sciences Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimise risks associated with the product.

The inner and outer labels, package insert and PM approved with this New Drug Submission are compliant with Food and Drug Regulations and associated guidance documents and, therefore, meet all necessary requirements.

The demonstrated beneficial effect of Lyvdelzi in the treatment of PBC is based on a biochemical surrogate endpoint that is considered reasonably likely to translate into improved clinical outcomes and has the potential to offer a statistically significant and clinically relevant improvement in benefit/risk profile over existing therapies on the Canadian market to treat PBC, a serious, life-threatening disease. Lyvdelzi presents an acceptable and manageable safety profile in consideration of the intended population. Based on the benefit-risk-uncertainty profile of the product, it is recommended that Lyvdelzi be granted authorization with confirmatory evidence required for full approval.

Confirmatory Study CB8025-41837 (AFFIRM) is a currently ongoing, 3-year fixed duration multicenter placebo-controlled trial designed to provide complementary safety and efficacy data in patients with PBC and compensated cirrhosis, restricted to Child-Pugh (CP)-A or CP-B. The primary objective of the study is to evaluate the effect of seladelpar compared to placebo on event-free survival (EFS) where EFS is defined as the time from start of treatment to the first occurrence of any of the following adjudicated events up to Week 156: death by any cause, liver transplantation, model for end-stage liver disease (MELD) score ≥15, ascites requiring treatment or hospitalization for any of the following qualifying events: esophageal or gastric variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis. Additionally, the ongoing study CB8025-31731-RE will continue collecting open-label long term efficacy and safety data for up to 5 years.

Overall, the benefit-harm-uncertainty profile was considered favorable for Lyvdelzi 10 mg daily for the approved indication. Therefore, a Notice of Compliance with Conditions-Qualifying Notice (NOC/c-QN) was recommended in accordance with the Guidance Document: Notice of Compliance with Conditions (NOC/c) and the sponsor was requested to verify the benefit of Lyvdelzi with confirmatory studies.

For further details about Lyvdelzi, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.