Iptacopan

Risk Summary

Available data from clinical trials with iptacopan use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH in pregnancy (see Clinical Considerations). The use of iptacopan in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits.

In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4 to 6-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Consideration

Disease-Associated Maternal and/or Embryo/Fetal Risk

PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery.

Data

Animal Data

In an embryo-fetal development study in rats, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC.

In an embryo-fetal development study in rabbits, oral administration of iptacopan during organogenesis did not cause embryo-fetal toxicity when given up to the highest dose of 450 mg/kg/day, which corresponds to 6-times the MRHD based on AUC.

In a pre- and postnatal development study in rats, oral administration of iptacopan during gestation, parturition, and lactation did not cause adverse effects in offspring when given up to the highest dose of 1,000 mg/kg/day, which corresponds to 4-times the MRHD based on AUC.

There are no data on the presence of iptacopan or its metabolite in either human or animal milk, the effects on the breastfed child or on milk production. Since many medicinal products are secreted into human milk, and because of the potential for serious adverse reactions in a breastfed child, breastfeeding should be discontinued during treatment and for 5 days after the final dose.

Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays.

Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential. The highest exposure to iptacopan in rats corresponds to ~9-times the MRHD based on AUC.

In a fertility study in male rats, iptacopan did not adversely impact fertility up to the highest tested dose of 750 mg/kg/day, which corresponds to 4-times the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and cellular debris in epididymis) were observed in repeat-dose toxicity studies with oral administration in dogs at doses ≥ 2-times the MRHD based on AUC, with no clear effects on sperm numbers, morphology or motility. In a fertility and early embryonic developmental study in female rats, oral administration of iptacopan caused increased pre- and post-implantation losses when given at the highest dose of 1,000 mg/kg/day orally, which corresponds to ~11-times the MRHD based on AUC.

• Serious Infections Caused by Encapsulated Bacteria.
• Hyperlipidemia.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Paroxysmal Nocturnal Hemoglobinuria

The data described below reflects the exposure in adults with PNH who received iptacopan (n = 62) or anti-C5 treatment (US-approved and non-US-approved eculizumab product or US-approved and non-US-approved ravulizumab product, n = 35) in APPLY-PNH [NCT04558918] and adults who received iptacopan (n = 40) in APPOINT-PNH [NCT04820530] at the recommended dosing regimen for 24 weeks. In APPLY-PNH, serious adverse reactions were reported in 2 (3%) patients with PNH receiving iptacopan. Serious adverse reactions included pyelonephritis, urinary tract infection and COVID-19. In APPOINT-PNH, serious adverse reactions were reported in 2 (5%) patients with PNH receiving iptacopan. Serious adverse reactions included COVID-19 and bacterial pneumonia. The most common adverse reactions (≥ 10%) with iptacopan were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash.

Table 1 describes the adverse reactions that occurred in > 5% of patients treated with iptacopan in the APPLY-PNH or APPOINT-PNH studies.

Table 1. Adverse Reactions Reported in > 5% of Patients Treated with Iptacopan in APPLY-PNH or APPOINT-PNH Studies (24-Week Treatment Period):

^a Includes similar terms.
^b Nasopharyngitis contains: rhinitis allergic, upper respiratory tract infection, pharyngitis, rhinitis.
^c Bacterial infection contains: pyelonephritis, urinary tract infection, bronchitis bacterial, bronchitis haemophilus, cholecystitis, folliculitis, cellulitis, arthritis bacterial, sepsis, klebsiella infection, staphylococcal infection, Pseudomonas infection, hordeolum, pneumonia bacterial.
^d Viral infection contains: COVID-19, herpes zoster, oral herpes, nasal herpes, influenza A virus test positive, influenza.
^e Lipid Disorder contains: dyslipidemia, blood cholesterol increased, low density lipoprotein increased, hypercholesterolemia, blood triglycerides increased, hyperlipidemia.
^f Rash contains: dermatitis allergic, acne, erythema multiforme, rash maculo-papular, rash erythematous.

Clinically relevant adverse reactions reported in less than or equal to 5% of patients includes urticaria in one patient (3%) in APPOINT-PNH.

Description of Select Adverse Reactions (graded per NCI CTCAE Version 4.03 unless noted otherwise)

Platelet Count Decreased

Of the 37 iptacopan-treated patients who had normal platelet counts at baseline in APPLY-PNH, 43% experienced any Grade thrombocytopenia during the randomized treatment period. Three iptacopan-treated patients in APPLY-PNH experienced decreased platelets that worsened to Grade ≥ 3 from baseline (one patient with normal platelets that worsened to Grade 4, one patient with baseline Grade 1 that worsened to Grade 4; and one patient with baseline Grade 3 that worsened to Grade 4).