Regulatory Decision Summary for Iqirvo

Ipsen Biopharmaceuticals Canada Inc. filed a New Drug Submission (NDS) to obtain market authorization pursuant to section C.08.0004 of the Food and Drugs Regulations, for Iqirvo (elafibranor) for the treatment of adults with primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

The submission was filed and reviewed under the Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance. The Canadian regulatory decision on the review of Iqirvo was based on a critical assessment of the data package submitted to Health Canada. The primary source of evidence that supported the efficacy and safety of Iqirvo is a phase 3 randomized controlled trial in adult PBC patients with inadequate responses to UDCA, or UDCA intolerance. The foreign reviews completed by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were used as additional references.

Primary biliary cholangitis (PBC) is a chronic, progressive, autoimmune, and cholestatic liver disease. Patients are often asymptomatic at initial presentation but over time develop itch, fatigue, and mucous-membrane dryness, and later cirrhosis and liver failure which can be fatal. Iqirvo (elafibranor) is an agonist of peroxisome proliferator activated receptor α and δ intended to reduce bile-acid toxicity in PBC to slow disease progression.

The efficacy and safety of Iqirvo as second line treatment for PBC was evaluated in the pivotal phase 3 Study 319 (GFT505B-319-1). Study 319 was a randomized, double-blind, placebo-controlled trial in 161 adults with PBC with either inadequate responses to ursodeoxycholic acid (UDCA) (95% of patients) or intolerance to UDCA (5% of patients). Patients were randomized 2:1 to elafibranor 80 mg (n = 108) or placebo (n = 53) once daily for ≥52 weeks. UDCA-tolerant patients continued their pre-study UDCA dose. Patients were included if the alkaline phosphatase (ALP) was ≥1.67 x upper limit of normal (ULN) and total bilirubin (TB) was ≤2 x ULN. Patients were 96% female and 91% white. Mean age was 57 years old and patients were an average of 8 years from their PBC diagnosis.

The primary endpoint was the proportion of patients at 52 weeks with biochemical cholestasis response: TB ≤ ULN, ALP <1.67 x ULN, and ALP decrease ≥15%. This surrogate endpoint was considered acceptable as it was consistent with international specialty guidelines, regulatory precedent, and published prognostic literature. Key secondary endpoints at 52 weeks were the proportion of patients with ALP normalization, and the change from baseline in PBC Worst Itch Numerical Rating Scale scores among the 66 patients with moderate-to-severe pruritis.

In Study 319, 50.9% of Iqirvo patients and 3.8% of placebo patients had cholestasis responses: a risk difference of 47.2% (95% confidence interval [CI]: 32.0 to 56.9%). 14.8% of elafibranor patients and 0% of placebo patients had ALP normalization (p = 0.0019). The pruritic patients’ least squares mean pruritis change from baseline trended 0.784 lower with elafibranor than with placebo (95% CI -1.986, 0.418). After 52 weeks, the absolute change from baseline in modelled 15-year transplant-free survival was higher with elafibranor versus placebo per the United Kingdom PBC Score (+1.95%) and the GLOBE score (+4.26%).

The overall safety population exposed to elafibranor (n = 2,588) included 138 patients with PBC, 1,615 with metabolic-dysfunction-associated steatohepatitis (MASH), and 835 “other” (healthy participants, elderly participants, participants with renal impairment, hepatic impairment, obesity and/or abnormal glucose tolerance, diabetes mellitus, and patients with dyslipidemia). Elafibranor doses ranged from 30 mg to 300 mg daily. The primary safety population consisted of 161 patients from the pivotal trial (Study 319).

In Study 319 (n = 161: primary safety population), the incidence of treatment-emergent adverse events (TEAEs) was similar with elafibranor and placebo: the total TEAEs (96% vs 91%), study-drug related (39% vs 40%), mild (37% vs 32%), moderate (49% vs 47%), severe (10% vs 11%), serious (10% vs 13%), serious and study-drug-related (2.8% vs 1.9%), and leading to treatment discontinuation (10% vs 9%). Two TEAEs led to death with elafibranor, and 0 with placebo. Both deaths were judged unrelated to study drug.

The very common TEAEs were gastrointestinal: vomiting (11% vs 2%), nausea (11% vs 6%), abdominal pain (11% vs 6%), and diarrhea (11% vs 9%). Severe adverse reactions included fracture, cholelithiasis, and rhabdomyolysis (1 each). There was one possible drug-induced liver injury (DILI) with Iqirvo that may have been precipitated by rhabdomyolysis. Increases in liver transaminases and bilirubin were observed in 6% of both Iqirvo- and placebo-treated patients.

Data in human pregnancy was very limited: 1 healthy birth and 2 spontaneous abortions occurred were reported in MASH Studies 212-7 (80 mg daily) and 315-1 (120 mg daily). The non-clinical data showed that elafibranor-treated pregnant animals experienced fetal loss, malformations, stillbirths, and perinatal deaths at clinically relevant exposures. Thus, Iqirvo was contraindicated in pregnancy, and effective contraception recommended. Other contraindications were hypersensitivity and decompensated cirrhosis.

No significant Quality issues were noted during this review.

Comparative bioavailability Study N^o. GFT505-119-17 was submitted to bridge the clinical formulation (N^o. 5), which was administered in the Phase 3 trial, to the commercial formulation (N^o. 6). The New Drug Quality Division (NDQD) confirmed that the comparative in vitro data met the acceptance criteria. The Division of Biopharmaceutics Evaluation (DBE)1 further confirmed that the pharmacokinetic results (provided by the sponsor) for Study N^o. GFT505-119-17 indicated that there would be no anticipated difference in in vivo absorption between formulations N^o. 5 and N^o. 6. Given the above, a full review of Study N^o. GFT505-119-17 was not conducted. Comparative bioavailability Study N^o. CLIN-60190-452 investigated the effect of food on the elafibranor exposure from the commercial formulation of the 80 mg Iqirvo tablet. Based on the DBE1 review, the Product Monograph (PM) for Iqirvo has been revised and includes wording to reflect the results from Study N^o. CLIN-60190-452, under Section 9.5 Drug-Food Interactions.

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

An updated Risk Management Plan (RMP) for Iqirvo was reviewed by Health Canada and considered acceptable. Risks have been communicated in the approved PM and will continue to be monitored post-market as outlined in the Risk Management Plan, with routine and additional pharmacovigilance activities, including Study 319, Study 454 (ELFIDENCE), and Study 461 (ELFINITY) for the safety concerns of hepatic events including DILI, rhabdomyolysis, and long-term safety, and Study 471 (10-year non-interventional descriptive study) for fetotoxicity and/or teratogenicity.

Based on the totality of evidence presented in the NDS, including the use of surrogate efficacy endpoints to demonstrate likely clinical benefit, the data was considered promising rather than substantial. Iqirvo 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. Iqirvo also presents an acceptable and manageable safety profile in consideration of the intended population. Further evidence is needed to verify the clinical benefit and further characterize the benefit-harm-uncertainly profile of Iqirvo. Based on the benefit-risk-uncertainty profile of the product, 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 Iqirvo with confirmatory studies.

A letter of undertaking (LoU) was subsequently submitted by the Sponsor and reviewed by Health Canada. In the LoU, the sponsor agreed to complete the requested confirmatory studies to potentially remove the conditions which will include data from the long term extension (LTE) of Study 319 and Study 454. The ongoing Study 319 LTE will provide complementary safety and efficacy data for up to 5 years of follow up with Iqirvo 80 mg daily. Study 454 in cirrhotic PBC patients will evaluate the efficacy of daily oral Iqirvo 80 mg in extending hepatic event-free survival (time to decompensation of cirrhosis, Model of End-stage Liver Disease [MELD] 3.0 score increasing from ≤12 to ≥15, liver transplant, or death).

Following thorough of review of the Response to QN, the Sponsor’s final Letter of Undertaking (LoU) addressed Health Canada’s Qualifying Notice (QN) requirements and was considered acceptable. The Sponsor has committed to verify the benefit of Iqirvo suggested by biochemical surrogate endpoints by conducting confirmatory studies with more clinically relevant indicators of hepatic injury and/or insufficiency.

In sum, the benefit-harm-uncertainty profile for Iqirvo for the recommended indication was favourable; thus, a Notice of Compliance with Conditions (NOC/c) was recommended in accordance with the Guidance Document: Notice of Compliance with Conditions (NOC/c).

Further detail about Iqirvo is in the Product Monograph, available through the Drug Product Database.