IQIRVO 80mg film-coated tablets medication leaflet

Iqirvo 80 mg film-coated tablets

Each film-coated tablet contains 80 mg of elafibranor.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

The tablets are round, orange, approximately 8 mm diameter, debossed with ‘ELA 80’ on one side.

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

The recommended dose is 80 mg once daily.

If a dose of elafibranor is missed, the patient should not take the missed dose and instead take theirsubsequent dose at the next scheduled time point. The patient should not take a double dose to makeup for the missed dose.

No dose adjustment is necessary in patients older than 65 years of age (see section 5.2).

There is no relevant use of elafibranor in the paediatric population (below 18 years of age) for theindication of PBC.

No dose adjustment is necessary in patients with renal impairment (see section 5.2).

No dose adjustment is necessary in patients with mild (Child-Pugh A) or moderate (Child-Pugh B)hepatic impairment.

The safety and efficacy of elafibranor have not been established in patients with PBC with severehepatic impairment. Use in patients with severe hepatic impairment (Child-Pugh C) is notrecommended (see section 5.2).

For oral use.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Known or suspected pregnancy and in women of childbearing age who do not use contraception(see section 4.6).

Liver related events

Increases in liver biochemical tests including transaminases and bilirubin levels have been reported inparticipants receiving elafibranor.

Clinical and laboratory assessment of liver function should be done prior to initiation of elafibranortreatment and thereafter according to routine patient management.

If increases in liver biochemical tests and/or liver dysfunction are observed, prompt investigation ofthe cause is recommended and interruption of elafibranor treatment should be considered.

Elevated blood creatine phosphokinase and muscle injury

Increases in blood creatine phosphokinase (CPK) have been reported in participants receivingelafibranor (see section 4.8). CPK should be evaluated prior to initiation of elafibranor treatment andthereafter according to routine patient management. Periodic CPK measurements may be consideredin patients starting elafibranor treatment, especially those on concomitant HMG-CoA reductaseinhibitors. If increases in CPK or unexplained signs and symptoms of muscle injury are observed,prompt investigation of the cause is recommended and interruption of elafibranor treatment should beconsidered (see section 4.8).

Embryo-foetal toxicity

Based on data from animal studies, elafibranor is suspected to cause congenital malformations andreduced foetal survival when administered to a pregnant woman (see section 4.6). Therefore,elafibranor is contra-indicated in women with a known or suspected pregnancy and in women ofchildbearing age who do not use contraception (see section 4.3). Women with childbearing potentialshould be informed about this.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Based on in vitro and in vivo studies, no clinically relevant drug-drug interaction is expected by co-administering elafibranor with any other medicinal products (see section 5.2).

No human data on the effect of elafibranor on fertility are available. Animal studies do not indicateany direct or indirect effects on fertility or the ability to reproduce (see section 5.3).

Women of childbearing potential have to use effective contraception during and up to at least 3 weeksfollowing the final dose of elafibranor. The pregnancy status of patients of childbearing potentialshould be checked prior to initiation of elafibranor treatment (see section 4.4).

There is limited amount of data from the use of elafibranor in pregnant women.

Studies in pregnant animals with elafibranor have shown reproductive toxicity (foetal loss,malformations, stillbirths and/or perinatal deaths) at clinically relevant exposure (see sections 4.4and5.3).

Elafibranor is contraindicated during pregnancy (see section 4.3). If a patient becomes pregnant,treatment with elafibranor should be discontinued.

It is unknown whether elafibranor or its metabolites are excreted in human milk. There is noinformation on the excretion of elafibranor or its metabolites in animal milk, but adverse effects wereseen in offspring when elafibranor was administered to female rats during pregnancy (see section 5.3)and lactation at clinically relevant exposure.

A risk to the suckling child cannot be excluded.

Elafibranor should not be used during breastfeeding and for at least 3 weeks following last dose ofelafibranor.

Elafibranor has no influence on the ability to drive and use machines.

The most commonly reported adverse drug reactions associated with elafibranor treatment (n = 108)which occurred in more than 10% of participants and with a higher incidence than in the placebogroup (n = 53; difference >1%) were abdominal pain (11.1% versus 5.7%), diarrhoea (11.1% versus9.4%), nausea (11.1% versus 5.7%), and vomiting (11.1% versus 1.9%). These were non-serious, mildto moderate, occurred early in treatment and tended to resolve within days to a few weeks without anydose modification or supportive measures.

The most common adverse drug reaction leading to treatment discontinuation was blood CPKincreased (3.7%).

Within the system organ class, the adverse reactions are listed by frequency using the followingcategories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare(≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the availabledata).

System organ class Very common Com mon Uncom mon

Nervous system disorders Headache

Gastrointestinal disorders Abdominal paina Constipation

Nausea

Hepatobiliary disorders Cholelithiasis

Skin and subcutaneous tissue Rash pruriticdisorders

Musculoskeletal and Myalgiaconnective tissue disorders

Investigations Blood CPK Blood creatinineincreased increaseda includes abdominal pain upper and abdominal pain lower

In the pivotal phase 3 ELATIVE study, 9 (8.3%) participants in the elafibranor group and 6 (11.3%)participants in the placebo group experienced headache. However, within the first 10 days of studytreatment, more participants in the elafibranor group experienced headache compared to the placebogroup (3.7% compared to 0% respectively).

Blood CPK increased

In the pivotal phase 3 ELATIVE study, 4 (3.7%) participants in the elafibranor group and noparticipants in the placebo group had clinically significant blood CPK increase, leading to drugdiscontinuation. In 2 of the 4 participants, the CPK was >5 x upper limit of normal (ULN). All eventswere non-serious and mild to moderate in intensity. Two of the participants also experiencedassociated symptom of myalgia. At baseline, mean CPK values were similar between the treatmentgroups and within normal range; values at week 52 remained within normal range in both groups. Themean (standard deviation) change from baseline at week 52 was 6.2 (38.1) U/L in the elafibranorgroup and 12.3 (67.0) U/L in the placebo group.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.*

In the event of suspected overdose, patients should be carefully observed, and appropriatesymptomatic treatment and supportive care should be initiated.

Pharmacotherapeutic group: Bile and liver therapy, Other drugs for bile therapy

ATC code: A05AX06

Elafibranor and its main active metabolite GFT1007 are dual peroxisome proliferator-activatedreceptor (PPAR)α/δ agonists.

PPAR α/δ are thought to be key regulators of bile acid (BA) homeostasis, inflammation and fibrosis.

Activation of PPARα and PPARδ decreases bile toxicity and improve cholestasis by modulating BAsynthesis, detoxification and transporters.

Activation of PPARα and PPARδ also has anti-inflammatory effects by acting on different pathways.

In the pivotal phase 3 ELATIVE study, treatment with elafibranor resulted in a marked reduction frombaseline in alkaline phosphatase (ALP) as early as 4 weeks which was sustained through week 52. Inalignment with the observed biochemical response, greater reductions in biomarkers of BA synthesisincluding the BA precursor 7 alpha-hydroxy-4-cholesten-3-one (C4) and Fibroblast Growth Factor-19(FGF-19), a BA synthesis regulator, were observed with elafibranor treatment.

Thorough QT (TQT) analysis excluded any prolongation effect of elafibranor on QT/corrected QT(QTc) interval at repeat doses of up to 300 mg for 14 days.

In clinical studies, no clinically meaningful changes in vital signs or in electrocardiogram (ECG)(including QTc interval) were observed in participants treated with elafibranor.

The efficacy of elafibranor was evaluated in Study GFT505B-319-1 (ELATIVE), a phase 3,randomised, double blind (DB), placebo-controlled study in 161 adults with PBC with an inadequateresponse or intolerance to UDCA. Participants were randomised in a 2:1 ratio stratified across twofactors (ALP >3 x ULN or total bilirubin (TB) >ULN and PBC Worst Itch Numeric Rating Scale (WI-

NRS) score ≥4) to receive elafibranor 80 mg or placebo once daily for at least 52 weeks. Whenapplicable, participants continued their pre-study dose of UDCA throughout the study. Participantswere included in the study if their ALP was ≥ 1.67 x ULN and TB was ≤ 2 x ULN. Participants wereexcluded in case of decompensated cirrhosis or other causes of liver disease.

Overall, the mean age was 57.1 years, and the mean weight was 70.8 kg. The study population waspredominately female (96%) and white (91%). The baseline mean ALP concentration was 321.9 U/L,39% of participants had a baseline ALP concentration > 3 x ULN, and 35% of participants hadadvanced disease at baseline, defined as liver stiffness >10 kPa and/or bridging fibrosis or cirrhosis onhistology.

The median duration of exposure was 63.07 and 61.00 weeks in the elafibranor and placebo groups,respectively.

The mean baseline TB concentration was 9.6 µmol/L and 96% of participants had a baseline TBconcentration less than or equal to ULN. The mean baseline liver stiffness measurement by transientelastography was 10.1 kPa. The baseline mean PBC WI-NRS score was 3.3 and 41% had moderate-to-severe pruritus at baseline (PBC WI-NRS score ≥4); for those with moderate-to-severe pruritus, thebaseline mean PBC WI-NRS score was 6.2 for participants in the elafibranor 80 mg group and 6.3 forparticipants in the placebo group. The majority (95%) of participants received treatment incombination with UDCA or as monotherapy in 5% of participants who were unable to tolerate UDCA.

The primary endpoint was cholestasis response at week 52 as defined as the composite endpoint: ALP< 1.67 x ULN and TB ≤ ULN and ALP decrease ≥ 15%. The key secondary endpoints were ALPnormalization at week 52 and the change in pruritus from baseline through week 52 and through week24 based on the PBC WI-NRS score in participants with moderate-to-severe pruritus at baseline.

Table 1 shows the primary composite endpoint of cholestasis response and the key secondary endpointof ALP normalization.

Table 1. Percentage of Adult Participants with PBC Achieving the Primary Efficacy Composite

Endpoint of Cholestasis Response and Key Secondary Efficacy Endpoint of ALP Normalizationat Week 52

Analysis Elafibranor Placebo Treatment Odds Ratio P-value

Population 80 mg (N=53) Difference (95% CI) [4] [4](N=108) (95% CI) [3]

Primary composite endpoint: Cholestasis response [1]

ITT 51% 4% 47% 37.6(32, 57) (7.6, 302.2) <0.0001

First key secondary endpoint: ALP normalization [2]

ITT 15% 0 15% Infinity(6, 23) (2.8, infinity) 0.0019

ITT: Intention-to-treat[1] Cholestasis response is defined as ALP <1.67x ULN and TB ≤ULN and ALP decrease from baseline ≥ 15% atweek 52. Participants who stopped prematurely the study treatment (intercurrent event 1) or used rescue therapyfor PBC (intercurrent event 2) prior to week 52 assessment were considered as non-responders. In case ofmissing data at week 52 for participants without an intercurrent event, the closest non-missing assessment fromthe DB treatment period was taken into account.[2] Normalization of ALP at week 52 defined as proportion of participants with ALP ≤1.0× ULN. The approachto handle intercurrent events or missing data is the same as for the primary endpoint.[3] The response rate differences between the treatment groups and 95% CI were calculated using the Newcombemethod stratified by randomization strata for cholestasis response and unstratified for ALP normalization.[4] Odds ratios of response and p-values to compare treatments were from the exact Cochran-Mantel-Haenszel(CMH) test stratified by the randomization strata.

A significant decrease in ALP from baseline was seen as early as week 4 and was sustained over52 weeks of treatment in the elafibranor group compared to placebo (Figure 1).

Figure 1. Mean (Least Squares (LS) mean with 95% CI) Change from Baseline in ALP Over

Time - ITT analysis set

The primary endpoint of cholestasis response in participants with a baseline ALP ≤3 x ULN or TB<ULN was achieved in 71% of participants on elafibranor versus 6% of participants on placebo,compared to those with ALP >3 x ULN or TB >ULN where cholestasis response was achieved in 21%of participants on elafibranor versus 0% on placebo.

Among the 54 participants with advanced disease, 16/35 (46%) participants on elafibranor versus 0/19(0%) participants on placebo achieved the primary endpoint of cholestasis response. Due to the limitednumber of participants with advanced disease, these results should be interpreted with caution.

Patient- reported outcomes

In participants with moderate-to-severe pruritus at baseline, a greater decrease from baseline in PBC

WI-NRS score through week 52 and week 24 was observed in participants randomised to elafibranorcompared to placebo but this did not reach statistical significance (Table 2).

Table 2. Change in Pruritus from Baseline Through Week 52 and Week 24 as Measured by PBC

WI-NRS in those with Moderate-to-Severe Pruritus at Baseline

Elafibranor Placebo Treatment P-80 mg (N=22) Difference value(N=44)

Second key secondary endpoint: change through week 52 [1]

Least Squares Mean (95% CI) -1.9 (-2.6, -1.3) -1.1 (-2.1, -0.2) -0.8 (-2.0, 0.4) 0.1970

Third key secondary endpoint: change through week 24 [1]

Least Squares Mean (95% CI) -1.6 (-2.2, -1.0) -1.3 (-2.2, -0.3) -0.3 (-1.5, 0.8) -[1] Analysis used the mixed model for repeated measures (MMRM) with treatment, 4-week period and treatmentby 4-week period interaction as fixed factors and adjusting for baseline PBC WI-NRS and the stratificationfactor of ALP >3 x ULN or TB >ULN. An unstructured correlation structure is used. Treatment effect throughweek 52 is the average of NRS score changes from baseline for the thirteen 4-week periods. Treatment effectthrough week 52 and week 24 is the average treatment effects of NRS score changes from baseline over the firstthirteen 4-week periods and first six 4-week periods, respectively. The assessments of PBC WI-NRS scores afterparticipants stopped prematurely the study treatment or took a rescue therapy for pruritus were considered asmissing.

Treatment with elafibranor was associated with an improvement in pruritus as evidenced by areduction in the PBC-40 Itch and 5-D Itch total scores compared to placebo at week 52 (Table 3).

Table 3. Change in Pruritus from Baseline to Week 52 in PBC-40 Itch and 5-D Itch total scoresin those with Moderate-to-Severe Pruritus at Baseline

Elafibranor 80 mg Placebo Treatment Difference(N=44) (N=22)

PBC-40 Itch total score: change at week 52 [1]

Least Squares Mean -2.5 (-3.4, -1.6) -0.1 (-1.6, 1.3) -2.3 (-4.0, -0.7)(95% CI)5-D Itch total score: change at week 52 [1]

Least Squares Mean -4.2 (-5.6, -2.9) -1.2 (-3.3, 0.9) -3.0 (-5.5, -0.5)(95% CI)[1] Analysis uses the mixed model for repeated measures (MMRM) with treatment, visits (until week 52) andtreatment by visit interaction as fixed factor and adjusting for baseline score and the stratification factor of ALP> 3x ULN or TB > ULN.

Lipid parameters

Elafibranor demonstrated a favourable effect on lipid parameters. The mean reduction in very low-density lipoprotein-cholesterol (VLDL-C) and triglycerides (TG) was greater in participants treatedwith elafibranor compared to placebo at Week 52. The LS means difference from placebo in VLDL-Cwas -0.1 mmol/L [(95% CI: -0.2, -0.1); p<0.001] and for TG was -0.3 mmol/L [(95% CI: -0.4, -0.1)];p<0.001]. High-density lipoprotein-cholesterol (HDL-C) remained stable on treatment withelafibranor.

The European Medicines Agency has waived the obligation to submit the results of studies with Iqirvoin all subsets of the paediatric population in primary biliary cholangitis (see section 4.2 for informationon paediatric use).

This medicinal product has been authorised under a so-called 'conditional approval' scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review any new information on this medicinal product at leastevery year and this SmPC will be updated as necessary.

Elafibranor plasma exposure (AUC) increases proportionally from 50 to 360 mg (0.6 to 4.5 times therecommended dose). Steady state is achieved by day 14 following once daily dosing. Thepharmacokinetics (PK) of elafibranor and its major active metabolite GFT1007 was found to be time-independent after 16-day repeated administration. Elafibranor and its active metabolite exposure inparticipants with PBC are listed in Table 4.

Table 4. Elafibranor and GFT1007 exposures in participants with PBC at steady state following80 mg QD (once daily)

Cmax,ss (ng/mL) AUC0-24 (ng * h/mL) Accumulation ratio

Elafibranor 802 3758 2.9

GFT1007 2058 11985 1.3

Following repeated oral administration in participants with PBC, median peak plasma levels ofelafibranor and GFT1007 at doses of 80 mg occur within 1.25 hours.

When administered with a high-fat and high-calorie meal, there was a 30-minute delay in Tmax forelafibranor and a 1-hour delay for GFT1007 in fed compared to fasted conditions. The plasmaexposure (AUC) of elafibranor decreased by 15% and the plasma AUC of GFT1007 was notaffected. Given the higher circulating plasma levels of the pharmacologically active metabolite

GFT1007 compared to elafibranor, food intake was deemed to have limited clinical impact based onoverall exposure of parent and active metabolite.

Plasma protein binding of both elafibranor and GFT1007 is approximately 99.7% (mainly to serumalbumin). The mean apparent volume of distribution (Vd/F) of elafibranor in humans is 4731L,following single dose of elafibranor at 80 mg in fasted conditions.

In vitro, elafibranor is metabolised by 15-ketoprostaglandin 13-Δ reductase (PTGR1). In vitro neitherelafibranor nor GFT1007 show major metabolism by the main cytochrome P450 (CYP) and uridinediphosphate (UDP)-glucuronosyltransferase (UGT) isoforms.

Following oral administration of 14C radiolabelled elafibranor, it was rapidly hydrolysed to the activemetabolite GFT1007. Two major metabolites were identified in plasma, GFT1007 (active metabolite)and glucuronide conjugates (inactive metabolites).

Following single 80 mg dose under fasted conditions, mean elimination half-life is 68.2 hours forelafibranor, and 15.4 hours for metabolite GFT1007. Elafibranor mean apparent total clearance(CL/F) was 50.0 L/h after a single 80 mg dose under fasted conditions.

Excretion

Following a single 120 mg oral dose of 14C radiolabelled elafibranor in healthy participants,approximately 77.1% of the dose was recovered in faeces, primarily as elafibranor (56.7% of theadministered dose) and its active metabolite GFT1007 (6.08% of the administered dose).

Approximately 19.3% recovered in urine, primarily as glucuronide conjugates.

There was no evidence that age (from 18 to 80 years old), gender, race, Body Mass Index (BMI), andrenal status, had any clinically meaningful impact on elafibranor and GFT1007 PK.

The total drug exposure of the parent and active metabolite was not significantly different betweenparticipants with normal hepatic function and hepatically impaired participants (Child Pugh A, B and

C). No dose adjustment is required for patients with mild (Child Pugh A) or moderate (Child Pugh B)hepatic impairment. However, the unbound fraction of elafibranor and GFT1007 increased byapproximately 3-fold in the severe (Child Pugh C) hepatically impaired participants. Elafibranor is notrecommended for patients with severe hepatic impairment (Child-Pugh C).

Based on in vitro studies, CYP and UGT enzymes were shown not to play a major role in elafibranormetabolism. Drug-drug interactions (DDI) are expected to be minimal with drugs that significantlyalter CYP or UGT activity.

Clinical studies

Warfarin (CYP2C9 substrate):

Concomitant administration of elafibranor with warfarin resulted in no increase in exposure (AUC,

Cmax) of warfarin, and no difference in international normalized ratio (INR) compared to warfarinalone.

Simvastatin (CYP3A, Breast Cancer Resistance Protein (BCRP), organic anion transportingpolypeptides 1B1 (OATP1B1) and OATP1B3 substrates) and atorvastatin (CYP3A, organic aniontransporting polypeptides 1B1 (OATP1B1) and OATP1B3 substrates):

Concomitant administration of repeat doses of elafibranor with simvastatin, or atorvastatin, resulted inno increase in exposure (AUC, Cmax) of simvastatin or its β-Hydroxyacid metabolite, or atorvastatin.

Sitagliptin (dipeptidyl peptidase-IV (DPP-IV) inhibitor):

No clinically significant effects on blood levels of GLP-1 were observed when co-administering 100 mg of elafibranor as a DDI perpetrator once daily for 15 days with a single oral100 mg dose of sitagliptin during a meal test.

In Vitro Studies

Cytochrome P450 (CYP) inhibition and induction:

Elafibranor and GFT1007 were not considered inhibitors of main CYPs. No time dependent CYPinhibition was observed.

Elafibranor and GFT1007 did not cause induction on CYP1A2, CYP2B6, and CYP3A4.

UGT inhibition:

Based on in vitro data elafibranor and GFT1007 were not expected to inhibit main UGTs at clinicallysignificant concentrations.

Transporter systems:

Elafibranor was an inhibitor of OATP1B3 and BCRP. Based on the in vivo studies with simvastatinand atorvastatin, no clinical consequences are expected from the inhibition of OATP1B3 and BCRP.

Nonclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeat dose toxicity, genotoxicity and carcinogenic potential.

Reproduction and development toxicity

Elafibranor has shown evidence of developmental toxicity in both rats and rabbits.In rat pre- and post-natal study, maternal exposures to elafibranor (at or above 2-fold the AUC exposure at the maximumhuman recommended dose (MHRD)) led to reduced pup survival, developmental delay, or thrombosis.

In pregnant rabbits, maternal exposure (3-fold the AUC exposure at MHRD) to elafibranor causedmarked maternal toxicity, increased embryo-lethality, reduced foetal weight and a low incidence offoetal malformations.

Tablet content

Microcrystalline cellulose

Povidone

Croscarmellose sodium

Anhydrous colloidal silica

Magnesium stearate

Polyvinyl alcohol-part hydrolysed

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide yellow (E172)

Iron oxide red (E172)

Not applicable

3 years

This medicinal product does not require any special storage conditions.

40 mL high-density polyethylene (HDPE) bottle with a polypropylene child-resistant screw cap.

Each bottle contains 30 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Ipsen Pharma70 rue Balard 75015 Paris France

EU/1/24/1855/001

Date of first authorisation: 19 September 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu