Summary Basis of Decision for Iqirvo

Clinical Pharmacology

Elafibranor (the medicinal ingredient in Iqirvo) and its main active metabolite, GFT1007, are first-in-class dual peroxisome proliferator-activated receptor (PPAR) α/𝛿 agonists. The activation of PPARα and PPAR𝛿 modulate complementary pathways involved in the pathogenesis of primary biliary cholangitis (PBC).

The activation of PPARα decreases bile acid (BA) synthesis, increases BA detoxification, and modulates BA output. This results in decreased bile toxicity and less injury to cholangiocytes and hepatocytes. The activation of PPAR𝛿 also regulates transporters that absorb and secrete bile components, contributing to decreased bile toxicity and improved cholestasis.

The liver-specific activation of PPARα and PPAR𝛿 by elafibranor also has anti-inflammatory effects by acting on different pathways of inflammation, nuclear factor kappa B (NF-κB) and B-cell lymphoma 6 (BCL6) pathways, respectively.

The pharmacokinetics of elafibranor and its potential for drug-drug interactions were studied in patient populations and in healthy subjects. Studies were also conducted to characterize the pharmacology of GFT1007 and the inactive metabolites GFT3351 and GFT4775.

The mean exposures of elafibranor and GFT1007, as measured by the area under the plasma concentration-time curve (AUC) from time 0 to 24 hours (AUC_0-24h) increased linearly with a daily intake of elafibranor ranging from 40 mg to 300 mg (0.5 to 3.75 times the indicated dose). With once-daily dosing, steady state was achieved by Day 14 for elafibranor and by Day 7 for GFT1007. The pharmacokinetics of both elafibranor and GFT1007 are independent of time after 16 days of repeated oral administration.

The major aspects of absorption, distribution, metabolism, and elimination were adequately characterized. Elafibranor is rapidly absorbed, with median peak plasma levels of elafibranor and GFT1007 occurring within 1.25 hours in patients with PBC receiving a once-daily dose of 80 mg. Elafibranor can be taken with or without food, as the pharmacokinetic differences between fed and fasted conditions were determined to have limited clinical impact. Orally administered ¹⁴C radiolabelled elafibranor was rapidly hydrolyzed to the active metabolite, GFT1007. In addition to GFT1007, glucuronide conjugates (inactive metabolites) were also identified in plasma. Following a single 80 mg dose under fasted conditions, the mean elimination half-life was 68.2 hours for elafibranor, and 15.4 hours for GFT1007. In healthy subjects, approximately 77.1% of a single 120 mg orally administered ¹⁴C radiolabelled dose of elafibranor was recovered in feces. It was recovered primarily as elafibranor and GFT1007 (56.7% and 6.08% of the administered dose, respectively). Approximately 19.3% was recovered in urine, primarily as glucuronide conjugate GFT3351 (11.8% of the administered dose).

No dosing adjustments are required for patients with mild or moderate (Child Pugh A or B) hepatic impairment. However, Iqirvo is not recommended for patients with severe hepatic impairment (Child Pugh C).

No dosing adjustments are required for patients with renal impairment.

There was no evidence that age (from 18 to 80 years old), gender, race, body mass index (BMI), or renal status had any clinically meaningful impact on the pharmacokinetics of elafibranor and GFT1007.

In healthy volunteers, daily doses of elafibranor up to 300 mg did not cause clinically significant corrected QT (QTc) interval prolongation.

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

Clinical Efficacy

The clinical efficacy of Iqirvo as a second-line treatment for primary biliary cholangitis (PBC) was mainly evaluated in Study 319, a randomized, double-blind, placebo-controlled, Phase III study in 161 adult patients with PBC. Ninety-five percent (95%) of patients had an inadequate response to ursodeoxycholic acid (UDCA), while 5% of patients were intolerant to UDCA. Patients were randomized in a 2:1 ratio to receive 80 mg elafibranor (108 patients) or placebo (53 patients) once daily for at least 52 weeks. Patients with UDCA tolerance continued their pre-study UDCA dose.

Patients were included in the study if their alkaline phosphatase level was greater than or equal to 1.67 times the upper limit of normal (ULN) and their total bilirubin level was less than or equal to 2 times the ULN. Patients were excluded from the study for decompensated cirrhosis, for other significant medical conditions, or for the potential to become pregnant without highly effective contraception. Ninety-six percent (96%) of patients were female, and 91% of patients were white. The mean age of patients was 57 years, and patients were an average of 8 years from their PBC diagnoses.

The primary endpoint was the proportion of patients with a biochemical cholestasis response at 52 weeks. This response was defined as a total bilirubin level less than or equal to the ULN, an alkaline phosphatase level less than 1.67 times the ULN, and a decrease in alkaline phosphatase by 15% or more. The endpoint is consistent with international specialty guidance, regulatory precedent with obeticholic acid (another treatment for PBC), and published prognostic literature.

Key secondary endpoints were the proportion of patients with alkaline phosphatase normalization after 52 weeks and the change from baseline to 52 weeks in the PBC Worst Itch Numerical Rating Scale (PBC WI NRS) scores among the 66 patients with moderate-to-severe pruritus (baseline PBC WI NRS score of 4 or higher).

At 52 weeks, 50.9% of Iqirvo-treated patients and 3.8% of placebo-treated patients had a cholestasis response (risk difference of 47.2%, 95% confidence interval [CI]: 32.0% to 56.9%). Alkaline phosphatase normalization was observed in 14.8% of Iqirvo-treated patients and 0% of placebo-treated patients (p = 0.0019). In patients with pruritus, the least squares mean pruritus change from baseline trended lower by 0.784 points in Iqirvo-treated patients than in placebo-treated patients (95% CI: -1.986, 0.418). Additionally, after 52 weeks, the absolute change from baseline in the modelled 15-year transplant-free survival rate trended higher with Iqirvo than with placebo based on the United Kingdom PBC score (+1.95%, unadjusted p = 0.0026) and the GLOBE score (+4.26%, unadjusted p<0.0001).

Indication

The New Drug Submission for Iqirvo was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Iqirvo (elafibranor) is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

For more information, refer to the Product Monograph for Iqirvo, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Iqirvo was evaluated primarily in the 161 patients in Study 319, described above in the Clinical Efficacy section. The full safety population exposed to elafibranor included 138 patients with PBC, 1,615 patients with metabolic dysfunction-associated steatohepatitis (MASH), and 835 other patients (healthy participants, elderly participants, participants with renal impairment, hepatic impairment, obesity and/or abnormal glucose tolerance, diabetes mellitus, and patients with dyslipidemia).

The incidence of treatment-emergent adverse events (TEAEs) was similar between patients that received Iqirvo and placebo, with respect to the total incidence of TEAEs (96% versus 91%), study medication-related TEAEs (39% versus 40%), mild TEAEs (37% versus 32%), moderate TEAEs (49% versus 47%), severe TEAEs (10% versus 11%), serious TEAEs (10% versus 13%), serious and study medication-related TEAEs (2.8% versus 1.9%), and TEAEs leading to treatment discontinuation (10% versus 9%). Fatal TEAEs occurred in two Iqirvo-treated patients, but both deaths were determined to be unrelated to the study medication. No fatal TEAEs occurred in placebo-treated patients.

Gastrointestinal TEAEs were very common, and included vomiting (11% versus 2%), nausea (11% versus 6%), abdominal pain (11% versus 6%), and diarrhea (11% versus 9%). Less frequent but more significant adverse reactions included fracture (6% versus 0%), cholelithiasis (3% versus 0%), and rhabdomyolysis (1% versus 0%) in the context of more frequent creatinine phosphokinase elevation (3% versus 0%).

Two major adverse cardiac events (MACE) were reported in Study 319 in patients treated with Iqirvo, which were associated with death but determined to be unrelated to the study drug. No MACE were reported in placebo-treated patients. Major adverse cardiac events were also observed in a Phase III study in patients with MASH (Study 315), in which 1,437 patients were treated with Iqirvo, 720 patients were treated with placebo, 61% of patients were male, and patients with PBC were excluded. The administered dose was 1.5 times higher (120 mg in Study 315 in patients with MASH versus 80 mg in Study 319 in patients with PBC), however, it was comparable when measured as mg/kg. The hazard ratio for MACE in Study 315 was 2.45 (95% CI: 1.02, 5.91), with MACE rates of 2.0% in Iqirvo-treated patients and 0.8% in placebo-treated patients. The higher frequency of MACE observed in patients with MASH is included in the Product Monograph for Iqirvo.

The submitted data used surrogate efficacy endpoints to demonstrate likely clinical improvement. The data reviewed indicate that Iqirvo has the potential to offer a statistically significant and clinically relevant improvement in the benefit/risk profile over existing therapies on the Canadian market to treat PBC; a serious, life-threatening disease. Additionally, Iqirvo presents an acceptable and manageable safety profile in the intended patient population. Based on the benefit-harm-uncertainty profile of the product, it is recommended that Iqirvo be authorized with conditions.

The completion of two studies is required for full approval of Iqirvo: a long-term extension (LTE) of Study 319 (ongoing; final report expected by November 2028), and Study 454 (final report expected by May 2030). The ongoing LTE of Study 319 is expected to provide complementary safety and efficacy data from up to 5 years of follow-up on an 80 mg daily dose of Iqirvo, following the double-blind period of Study 319.

Study 454 will evaluate the efficacy of a daily oral dose of 80 mg Iqirvo in extending hepatic event-free survival in patients with cirrhotic PBC. The time to hepatic event-free survival is defined as the time to either decompensation of cirrhosis (e.g., variceal bleed), a Model of End-Stage Liver Disease (MELD) version 3.0 score increasing from ≤12 to ≥15, liver transplant, or mortality. Recruitment is ongoing at the time of authorization. The sponsor is expected to provide secondary analyses of time to a composite endpoint of the primary endpoint or other significant adverse events, such as MACE. If the additional data from the Study 319 LTE and Study 454 confirm overall net clinical benefit, the conditions associated with this authorization may be removed.

For more information, refer to the Product Monograph for Iqirvo, approved by Health Canada and available through the Drug Product Database.

The general toxicology of elafibranor was assessed after single and repeat dose oral administration, for up to 6 months in rats and 12 months in monkeys. Studies were also conducted in mice.

Elafibranor had a favourable safety profile when administered to rats and mice as single oral doses in acute toxicity studies. In a 6-month repeat-dose study in rats, higher liver weights, hepatocellular hypertrophy, and/or liver necrosis were observed in rats exposed to doses of 3 mg/kg/day or higher. The relevance to humans of the liver findings in this study is uncertain, as they may be attributed to the expected rodent-specific peroxisome proliferator-activated receptor (PPAR)α-related liver toxicity. Excluding the liver effects, the no-observed-adverse-effect level (NOAEL) was determined to be 100 mg/kg/day (15.4 times the recommended human dose [RHD]).

No adverse effects were observed in the 12-month monkey repeat-dose study up to the maximum tested dose of 50 mg/kg/day (15.7 times the RHD). In addition, up to the highest doses tested, elafibranor did not show any relevant effects on organs and systems previously described as being a safety concern with PPARγ agonists (weight gain, hemodilution, fluid retention leading to congestive heart failure, bladder cancer).

No safety issues were identified when assessing the potential effects of elafibranor on the cardiovascular, respiratory, and central nervous systems.

Carcinogenicity was evaluated in two studies in mice and rats, with elafibranor administered through oral gavage at doses of 1, 3, 10, or 30 mg/kg/day for up to two years. Tumours were detected in the liver of mice and rats starting at the lower dose levels tested, and may be attributed to the expected rodent-specific PPARα-related liver toxicity. Therefore, the relevance of these findings to humans is uncertain.

Elafibranor, its principal active metabolite GFT1007, and the acyl glucuronide metabolite racemic GFT3351 are unlikely to pose a significant genotoxic risk to humans.

In a fertility and early embryonic development study in male and female rats, a lower fertility index, a lower mean percentage of live concepti, and a higher rate of post-implantation loss were observed at a dose of 100 mg/kg/day. The NOAEL for fertility in rats was 30 mg/kg/day (5.3 times the RHD). Evidence of developmental toxicity has been observed in both rats and rabbits administered elafibranor.

In pregnant rats, no effects were observed on embryofetal development following the administration of elafibranor at doses up to 300 mg/kg/day (approximately 100 times the RHD) during the period of organogenesis (from gestation days 6 to 17). At the 1,000 mg/kg/day dose level (approximately 167 times the RHD), observations included higher rates of post-implantation loss and total resorptions, lower numbers of live fetuses and lower number of fetuses per dam, lower fetal body weights, and visceral and skeletal variations (short innominate artery and incomplete ossification). However, no fetal malformations were observed at this dose level.

In pregnant rabbits, the administration of elafibranor during organogenesis at the high dose of 300 mg/kg/day (3 times the RHD) was associated with marked maternal toxicity, increased embryolethality, and reduced fetal weight plus fetal malformations. Despite maternal toxicity observed at the mid dose of 100 mg/kg/day (0.5 times the RHD), no effects were observed on embryofetal survival, fetal weight, or fetal malformations. The only finding was fetal ossification variations in the distal limb bones. No adverse effects were observed on embryofetal development at the low dose of 30 mg/kg/day (approximately 0.1 times the RHD).

A pre- and postnatal study was conducted in rats, in which maternal exposures to elafibranor (at or above 2 times the RHD) was associated with reduced pup survival, blue/black discolouration of the caudal section of some pups, lower pup body weights, and developmental delays at all doses. Low levels of plasma GFT1007 (the active metabolite of elafibranor) were detected in 2 pups who had been maternally exposed at the highest dose level. Therefore, elafibranor could potentially be transferred via lactation.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Iqirvo. Considering the intended use of Iqirvo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Iqirvo, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Iqirvo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Iqirvo is of human or animal origin.