Nerandomilast

There are no available data on nerandomilast use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are maternal and fetal risks associated with untreated idiopathic pulmonary fibrosis during pregnancy.

Based on findings from animal reproduction studies, nerandomilast may increase the risk for fetal loss. In an embryo-fetal development study in rats, oral administration of nerandomilast to pregnant rats during organogenesis at an exposure approximately 5 times the maximum recommended human dose (MRHD) of 36 mg/day resulted in an increase in embryo-fetal losses. Advise pregnant women and females of reproductive potential of the potential risk of fetal loss.

The estimated 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 is 2% to 4% and miscarriage in clinically recognized pregnancies is 15% to 20%.

There are no data on the presence of nerandomilast or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Nerandomilast is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for nerandomilast and any potential adverse effects on the breastfed infant from nerandomilast or from the underlying maternal condition.

Carcinogenesis

The carcinogenic potential of nerandomilast was assessed in Tg.rasH2 mice and Wistar Han rats. No evidence of tumorigenicity was observed in male and female Tg.rasH2 mice that received nerandomilast for 26 weeks at oral doses up to 60 and 100 mg/kg/day, respectively. No evidence of tumorigenicity was observed in male or female rats that received nerandomilast for up to 102 weeks at oral doses up to 2 mg/kg/day (approximately 2 times the MRHD on an AUC basis).

Mutagenesis

Nerandomilast was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo rat micronucleus assay.

Impairment of Fertility

Nerandomilast had no effect on fertility in male or female rats at oral doses up to 6 mg/kg/day (approximately 3 or 4 times the MRHD on an AUC basis, respectively). Decreased mating, pregnancy, and fertility indices at the highest tested dose of 9 mg/kg/day (approximately 4 or 9 times the MRHD on an AUC basis) were attributed to excessive general toxicity.

Sexually mature female monkeys administered nerandomilast by the oral route for 39 weeks showed sporadic menstrual cycle prolongation at dose levels of 10 mg/kg/day and 30 mg/kg/day (approximately 3- and 10 times the MRHD on an AUC basis, respectively). Menstrual cycles were not affected in monkeys at oral doses of 3 mg/kg/day (equivalent to the MRHD on an AUC basis).

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 clinical trials of another drug and may not reflect the rates observed in practice.

The safety of nerandomilast was based on a randomized, placebo-controlled, double-blind trial (FIBRONEER-IPF), which included 1,177 adult patients with IPF who were randomized in a 1:1:1 ratio to receive nerandomilast 9 mg twice daily, nerandomilast 18 mg twice daily, or matching placebo. Patients received nerandomilast or placebo with or without background antifibrotic treatment (nintedanib or pirfenidone) for at least 52 weeks. The median duration of exposure was 14 months in each treatment arm.

Discontinuation due to adverse reactions occurred more frequently in patients treated with nerandomilast (with or without background antifibrotic treatment) 18 mg (15%) and 9 mg (12%) compared to placebo (11%). The most frequent adverse reaction leading to discontinuation of nerandomilast 18 mg and 9 mg was diarrhea (6% and 2%, respectively).

The following table lists the most common adverse reactions from the studied population with an incidence of greater than or equal to 5% in nerandomilast-treated patients and more common than the placebo group.

Adverse Reactions with Nerandomilast with Incidence of ≥5% and More Common than Placebo in Patients¹ with IPF (FIBRONEER-IPF Trial):

¹ Studied population including patients who received nerandomilast with or without background antifibrotic treatment (nintedanib or pirfenidone)
² Includes depression, depressed mood, depression rating scale score increased, suicidal ideation, adjustment disorder with depressed mood, depressive symptom
BID: twice daily; COVID-19: infection with SARS-CoV-2 virus

Specific Adverse Reactions of Nerandomilast with or without Concomitant Use of Nintedanib or Pirfenidone

Diarrhea

Diarrhea was more common in patients using nerandomilast with concomitant nintedanib. In patients taking nintedanib, diarrhea occurred in 62%, 50%, and 28% of patients treated with nerandomilast 18 mg twice daily, nerandomilast 9 mg twice daily, and placebo, respectively. In patients using concomitant pirfenidone, diarrhea occurred in 24% and 8% of patients treated with nerandomilast 18 mg twice daily, and placebo, respectively. In patients without concomitant antifibrotic treatment, diarrhea occurred in 26%, 17%, and 8% of patients using nerandomilast 18 mg twice daily, nerandomilast 9 mg twice daily, and placebo, respectively.

Diarrhea was the most common adverse reaction associated with treatment discontinuation, and most common with nerandomilast used concomitantly with nintedanib: discontinuation occurred in 13%, 2%, and 1% of patients treated with nerandomilast 18 mg twice daily, nerandomilast 9 mg twice daily, and placebo, respectively. No treatment discontinuations due to diarrhea occurred in patients treated with background pirfenidone and nerandomilast 18 mg twice daily or background pirfenidone with placebo. Diarrhea leading to treatment discontinuation occurred in 1% of patients treated with nerandomilast 18 mg twice daily and in no patients treated with nerandomilast 9 mg or placebo without concomitant antifibrotic treatment.

In most patients treated with nerandomilast, diarrhea was of mild to moderate intensity and generally occurred within the first 3 months of treatment.

Weight Decrease

Weight decrease was most common in patients who received nerandomilast concomitantly with nintedanib in the studied population: in patients taking nintedanib, weight decrease occurred in 16%, 14%, and 12% of patients treated with nerandomilast 18 mg twice daily, nerandomilast 9 mg twice daily, and placebo, respectively. In patients using concomitant pirfenidone, weight decrease occurred in 6% and 5% of patients treated with nerandomilast 18 mg twice daily and placebo, respectively. In patients without background antifibrotic therapy, weight decrease occurred in 8%, 2%, and 6% of patients treated with nerandomilast 18 mg twice daily, nerandomilast 9 mg twice daily, and placebo, respectively.

Decreased Appetite

In patients taking nintedanib, decreased appetite occurred in 7%, 10%, and 4% in nerandomilast 18 mg twice daily, nerandomilast 9 mg twice daily, and placebo, respectively. In patients using concomitant pirfenidone, decreased appetite occurred in 13% and 10% of patients treated with nerandomilast 18 mg twice daily and placebo, respectively. In patients without concomitant antifibrotic treatment, decreased appetite occurred in 9%, 6%, and 0% of patients treated with nerandomilast 18 mg twice daily, nerandomilast 9 mg twice daily, and placebo, respectively.

Less Common Adverse Reactions

Less common adverse reactions in the studied population following administration of nerandomilast included asthenia (5% nerandomilast 18 mg twice daily, 4% nerandomilast 9 mg twice daily, and 2% placebo), amylase increased (1% nerandomilast 18 mg twice daily, 1% nerandomilast 9 mg twice daily, and 0% placebo), and vasculitis (1% nerandomilast 18 mg twice daily, 1% nerandomilast 9 mg twice daily, and 0% placebo).