Iqirvo

IQIRVO 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 reduction of alkaline phosphatase (ALP)

[see

14 CLINICAL STUDIES

The efficacy of IQIRVO was evaluated in Study 1 (NCT04526665), a multi-center, randomized, double-blind, placebo-controlled study. The study included 161 adults with PBC with an inadequate response or intolerance to UDCA. Patients were randomized to receive IQIRVO 80 mg (n=108) or placebo (n=53) once daily for at least 52 weeks. When applicable, patients continued their pre-study dose of UDCA throughout the study. Patients were included in the study if their ALP was greater than or equal to 1.67-times the ULN and TB was less than or equal to 2-times the ULN. Patients were excluded if they had other liver disease or in case of decompensated cirrhosis.

The mean age of patients in Study 1 was 57 (Range: 36, 76) years, and the mean weight was 70.8 (Range: 43, 134) kg. The study population was predominately female (96%) and White (91%). The baseline mean ALP concentration was 321.9 (Range: 151, 1398) U/L, and 39% of patients had a baseline ALP concentration greater than 3-times the ULN.

The mean baseline TB concentration was 0.56 (Range: 0.15, 1.76) mg/dL, and 96% of patients had a baseline TB concentration less than or equal to ULN. The baseline mean concentration of ALT was 50 (Range: 11 to 188) U/L and mean baseline concentration for AST was 46 (Range: 14 to 203) U/L.

Most patients (95%) received study treatment (IQIRVO or placebo) in combination with UDCA. There were 6 (6%) in the IQIRVO-treated patients and 2 (4%) in the placebo-treated patients who were unable to tolerate UDCA and received IQIRVO as monotherapy. At baseline, 12 (11%) of the IQIRVO-treated patients and 8 (15%) of the placebo-treated patients met at least one of the following criteria: serum albumin < 3.5g/dL, INR >1.3, TB > 1-time ULN, Fibroscan >16.9 kPa, or historical biopsy suggestive of cirrhosis.

The primary endpoint was biochemical response at Week 52, where biochemical response was defined as achieving ALP less than 1.67-times ULN, TB less than or equal to ULN, and ALP decrease greater than or equal to 15% from baseline. The ULN for ALP was defined as 129 U/L for males and 104 U/L for females. The ULN for TB was defined as 1.20 mg/dL. ALP normalization (i.e., ALP less than or equal to ULN) at Week 52 was a key secondary endpoint.

Table 6 presents results at Week 52 for the percentage of patients who achieved biochemical response, achieved each component of biochemical response, and achieved ALP normalization. IQIRVO demonstrated greater improvement on biochemical response and ALP normalization at Week 52 compared to placebo. Overall, 96% of patients had a baseline TB concentration less than or equal to ULN. Therefore, improvement in ALP was the main contributor to the biochemical response rate results at Week 52.

Table 6: Percentage of Adult Patients with PBC Achieving Biochemical Response and ALP Normalization at Week 52 in Study 1Patients who prematurely stopped the study treatment or used rescue therapy for PBC prior to the Week 52 assessment were considered non-responders. For two other patients with missing data at Week 52, the closest non-missing assessment from the double-blind treatment period was used.

	IQIRVO 80mg Once Daily (N=108)	Placebo (N=53)	Treatment Difference, % (95% CI)For biochemical response and its components: calculated using the Newcombe method stratified by (1) ALP > 3-times ULN or TB > ULN (Yes/No) and (2) 14-day baseline average PBC Worst Itch Numeric Rating Scale score ≥ 4 (Yes/No). For ALP normalization: calculated using unstratified Newcombe method.
Biochemical response rate, n (%)Biochemical response is defined as ALP <1.67-times ULN and TB ≤ULN and ALP decrease from baseline ≥ 15% at Week 52. The p-value from the exact Cochran–Mantel–Haenszel (CMH) test was <0.0001.	55 (51)	2 (4)	47 (32, 57)
Components of biochemical response
ALP less than 1.67-times ULN, n (%)	56 (52)	5 (9)	42 (27, 53)
Decrease in ALP of at least 15%, n (%)	81 (75)	9 (17)	58 (43, 69)
TB less than or equal to ULN, n (%)The mean baseline total bilirubin was 0.56 mg/dL, and was less than or equal to the ULN in 96% of the enrolled patients.	92 (85)	44 (83)	2 (-9, 16)
ALP normalization, n (%)Normalization of ALP at Week 52 is defined as ALP ≤1-time ULN. The p-value from the exact CMH test was 0.0019.	16 (15)	0 (0)	15 (6, 23)

Figure 1 depicts the mean (95% confidence interval) ALP levels over 52 weeks. There was a trend of lower ALP in the IQIRVO group compared to the placebo group starting by Week 4 through Week 52.

Figure 1: Mean ALP (+/- 95% Confidence Interval) in Adult Patients with PBC Over 52 Weeks in Study 1

Missing data and data following study treatment discontinuation was imputed by multiple imputation.

Figure 1

]

• Before treatment, evaluate for muscle pain or myopathy, and/or verify that females of reproductive potential are not pregnant. (
  2.1 Recommended Evaluation Before Initiating IQIRVO

  Before initiating IQIRVO:

  • Evaluate for muscle pain or myopathy
    [see Warnings and Precautions (5.1)]
    .
  • Verify that females of reproductive potential are not pregnant prior to initiating treatment with IQIRVO [
    see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)]
    .
  )
• The recommended dosage is 80 mg orally once daily with or without food. (
  2.2 Recommended Dosage and Administration

  The recommended dosage of IQIRVO is 80 mg taken orally once daily with or without food

  [see Clinical Pharmacology (12.3)]

  .
  )

Tablets: 80 mg, round, orange, film-coated tablets, debossed with "ELA 80" on one side and plain on the other side.

• Lactation: Advise not to breastfeed during treatment and for 3 weeks after last dose. (
  8.2 Lactation

  Risk Summary

  There are no data available on the presence of elafibranor or its metabolites in human or animal milk, or on effects of the drug on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise patients not to breastfeed during treatment with IQIRVO, and for 3 weeks after the last dose.
  )
• Hepatic Impairment: Monitor patients with cirrhosis for evidence of decompensation. Consider discontinuation if patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C). (
  8.7 Hepatic Impairment

  No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A)

  [see Clinical Pharmacology (12.3)]

  .

  The safety and efficacy of IQIRVO in patients with decompensated cirrhosis have not been established. Use of IQIRVO is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). Monitor patients with cirrhosis for evidence of decompensation. Consider discontinuing IQIRVO if the patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C).
  )

• Myalgia, Myopathy, and Rhabdomyolysis
  : Assess for muscle pain and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement). Interrupt IQIRVO if there is new onset or worsening of muscle injury, or muscle pain. (
  5.1 Myalgia, Myopathy, and Rhabdomyolysis

  Rhabdomyolysis resulting in acute kidney injury occurred in one IQIRVO-treated patient who had cirrhosis at baseline and was also taking a stable dose of an HMG-CoA reductase inhibitor (statin). Myalgia or myopathy, with or without CPK elevations, occurred in patients treated with IQIRVO alone or treated concomitantly with a stable dose of an HMG-CoA reductase inhibitor

  [see Adverse Reactions (6.1)]

  .

  Assess for myalgia and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement) during treatment with IQIRVO, especially in those who have signs and symptoms of new onset or worsening of muscle pain or myopathy. Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain, or myopathy, or rhabdomyolysis.
  )
• Fractures:
  The risk of fracture should be considered in the care of patients treated with IQIRVO. Apply current standards of care for assessing and maintaining bone health. (
  5.2 Fractures

  Fractures occurred in 6% of IQIRVO-treated patients compared to no placebo-treated patients

  [see Adverse Reactions (6.1)]

  .

  Consider the risk of fracture in the care of patients treated with IQIRVO and monitor bone health according to current standards of care.
  )
• Adverse Effects on Fetal and Newborn Development
  : May cause fetal harm. Verify that a female of reproductive potential is not pregnant prior to initiating IQIRVO. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  5.3 Adverse Effects on Fetal and Newborn Development

  Based on findings from animal reproduction studies, IQIRVO may cause fetal harm when administered during pregnancy. Treatment of pregnant rats with elafibranor at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body.

  For females of reproductive potential, verify that the patient is not pregnant prior to initiation of therapy. Advise females of reproductive potential to use effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives during treatment with IQIRVO and for 3 weeks following the last dose of IQIRVO

  [see Drug Interactions (7.1), Use in Specific Populations (8.1, 8.3)]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on data from animal reproduction studies, IQIRVO may cause fetal harm when administered during pregnancy. Treatment of pregnant rats with elafibranor during organogenesis through lactation resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body, which occurred at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose (

  see Data

  ). There are insufficient data from human pregnancies exposed to IQIRVO to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

  The background risk of major birth defects and miscarriage for the indicated population is 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 2-4% and 15-20%, respectively.

  Report pregnancies to Ipsen Pharmaceuticals, Inc. Adverse Event reporting line at 1-855-463-5127 and [https://www.ipsen.com/contact-us/].

  Data

  Animal Data

  No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 300 mg/kg/day elafibranor (15-times the recommended dose based on combined AUC [area under the plasma concentration-time curve] for elafibranor and GFT1007) during the period of organogenesis.

  No adverse effects on embryo-fetal development were observed in pregnant rabbits treated orally with doses up to 100 mg/kg/day elafibranor, which produced systemic exposures (combined AUC for elafibranor and GFT1007) during the period of organogenesis that were less than the human exposure. Administration of 300 mg/kg/day (3.9-times the recommended dose based on combined AUC for elafibranor and GFT1007) produced marked maternal toxicity, embryo-lethality, reduced fetal weight, and a low incidence of fetal malformations. Variations in ossification of distal limb bones occurred at 100 mg/kg/day, which was associated with strong signs of maternal toxicity (e.g., body weight loss).

  A pre- and postnatal development study was performed using oral administration of 10, 30, or 100 mg/kg/day elafibranor in female rats during organogenesis through lactation. All doses produced a reduction in pup survival (during postnatal days 1-4 at 100 mg/kg/day and postnatal days 5-21 at 10 mg/kg/day and higher), a decrease in pup body weight (dose-dependent, up to -28% on postnatal day 1), blue/black discoloration of the caudal section of body, and developmental delays based on evaluation of physical landmarks and functional tests. The developmental delays were likely caused by the decrease in body weight. Adverse effects in the offspring occurred at maternal exposures at or above 0.6-times the recommended dose based on combined AUC for elafibranor and GFT1007. Stillbirths were observed in the 30 and 100 mg/kg/day groups (1.3 and 4.9-times the recommended dose, respectively, based on combined AUC for elafibranor and GFT1007). Aortic or iliac arterial thrombosis was found in decedent pups from females treated with 30 or 100 mg/kg/day. The surviving adult offspring showed no effects on learning and memory, reflex development, or reproductive capability.
  ,
  8.3 Females and Males of Reproductive Potential

  Based on animal data, IQIRVO may cause fetal harm when administered during pregnancy

  [see Use in Specific Populations (8.1)]

  .

  Pregnancy Testing

  For females of reproductive potential, verify that the patient is not pregnant prior to initiating IQIRVO.

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception (non-hormonal) or add a barrier method of contraception when using hormonal contraceptives during treatment with IQIRVO and for 3 weeks after the last dose.
  )
• Drug-Induced Liver Injury
  : Obtain clinical and laboratory assessments at treatment initiation and monitor thereafter according to routine patient management. Interrupt the treatment if liver tests worsen, or patients develop signs and symptoms consistent with clinical hepatitis. Consider permanent discontinuation if liver tests worsen after restarting IQIRVO. (
  5.4 Drug-Induced Liver Injury

  Drug-induced liver injury (DILI) occurred in one patient who took IQIRVO 80 mg once daily

  [see Adverse Reactions (6.1)]

  and two patients who took IQIRVO at 1.5-times the recommended dosage. In one patient who developed DILI while taking IQIRVO at 1.5-times the recommended dosage, the clinical presentation was drug-induced autoimmune-like hepatitis (DI-ALH). The median time to onset of elevation in liver tests was 85 days (range: day 57 to 288). In Study 1, increases in transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≥ 5× ULN) occurred in 6% of IQIRVO-treated patients compared to 6% of placebo-treated patients, and total bilirubin (TB) elevation (> 3× ULN) occurred in 2% of IQIRVO-treated patients compared to no placebo-treated patients

  .

  Obtain baseline clinical and laboratory assessments at treatment initiation with IQIRVO and monitor thereafter according to routine patient management. Interrupt IQIRVO treatment if liver tests (ALT, AST, TB, and/or alkaline phosphatase [ALP]) 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 IQIRVO.
  )
• Hypersensitivity Reactions
  : If severe hypersensitivity reactions occur, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor until signs and symptoms resolve. (
  5.5 Hypersensitivity Reactions

  Hypersensitivity reactions have occurred in a clinical trial with IQIRVO at 1.5-times the recommended dosage. Three patients (0.2%) had rash or unspecified allergic reaction that occurred 2 to 30 days after IQIRVO initiation, with positive dechallenges and rechallenges. Hypersensitivity reactions resolved after discontinuation of IQIRVO and treatment with steroids and/or antihistamines.

  If a severe hypersensitivity reaction occurs, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor the patient until signs and symptoms resolve. If a hypersensitivity reaction recurs after IQIRVO rechallenge, then permanently discontinue IQIRVO.
  )
• Biliary Obstruction
  : Avoid use in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated. (
  5.6 Biliary Obstruction

  Avoid use of IQIRVO in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated

  [see Adverse Reactions (6.1)]

  .
  )