Jascayd nerandomilast 9 mg Tablet, Film Coated, 60-count — NDC 0597-2465-41 (Billing 00597-2465-41)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Nerandomilast is an inhibitor of phosphodiesterase 4 (PDE4) with at least nine-fold preferential inhibition of the PDE4B isoenzyme over PDE4A, PDE4C, and PDE4D based on in vitro data. PDE4 hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP). Nerandomilast exerts both antifibrotic and immunomodulatory effects as PDE4B inhibition elevates intracellular cAMP levels and reduces the expression of profibrotic growth factors and inflammatory cytokines, which are overexpressed in IPF and PPF.

12.2Pharmacodynamics Exposure-Response Increases in nerandomilast steady state trough concentrations were associated with better efficacy, as indicated by a smaller reduction in forced vital capacity (FVC) from baseline over 52 weeks. Cardiac Electrophysiology At 2.1 times the maximal concentration provided by the maximum recommended dose of nerandomilast, clinically significant QTc interval prolongation was not observed.

12.3Pharmacokinetics Nerandomilast exposure increased in a dose proportional manner following administration of single doses of 0.0032 to 2.6 times a single dose of 18 mg and multiple doses of 0.056 to 1 times the maximum recommended dose of 18 mg twice daily. Following administration of multiple doses of 18 mg twice daily, C max increases 1.3-fold and AUC tau increases 1.38-fold. Nerandomilast steady state is reached in approximately 4 days.

No clinically relevant differences in nerandomilast pharmacokinetics were observed between healthy subjects, patients with IPF, and patients with PPF. Absorption The absolute oral bioavailability of nerandomilast is 73%. Nerandomilast median (min, max) time to maximum plasma concentration (T max ) is 1 to 1.25 hours (range 0.5 to 4 hours).

Effect of Food No clinically relevant differences in nerandomilast pharmacokinetics were observed following administration with a high-fat meal (1000 calories, 50% fat). Distribution Nerandomilast steady state apparent (oral) central volume of distribution is 93 L (CV 37%). In vitro , nerandomilast plasma protein binding is 77% and is not concentration dependent.

Nerandomilast blood-to-plasma ratio is approximately 0.6 to 0.8. Elimination The geometric mean (CV%) elimination half-life of nerandomilast is 17 hours (46%) with an apparent (oral) clearance of

15.2L/h. Metabolism Nerandomilast is primarily metabolized by CYP3A and to a lesser extent by multiple UGT enzymes. After oral administration of nerandomilast, chiral inversion from the pharmacologically active R-enantiomer to the pharmacologically inactive S-enantiomer occurs via metabolism.

The S-enantiomer was identified as a minor metabolite of nerandomilast. The R-enantiomer is the predominant circulating enantiomer. Excretion After a single oral dose of radiolabeled nerandomilast, approximately 58% of the dose was recovered in feces (14% as unchanged nerandomilast) and 36% of the dose was recovered in urine (13% as unchanged nerandomilast).

Specific Populations No clinically significant differences in the pharmacokinetics of nerandomilast were observed based on age (range: 18 to 90 years), body weight (range: 31 to 143 kg), sex, race (63% White and 35% Asian), mild (eGFR ≥60 to <90 mL/min/1.73 m 2 [calculated according to Chronic Kidney Disease Epidemiology Collaboration]), moderate (eGFR ≥30 to <60 mL/min/1.73 m 2 ), or severe renal impairment (eGFR ≥15 to <30 mL/min/1.73 m 2 ), or mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Subjects with end stage renal disease or severe hepatic impairment (Child-Pugh Class C) have not been studied [see Use in Specific Populations (8.6 , 8.7) ] . Drug Interaction Studies Strong CYP3A Inhibitors : Nerandomilast C max increased by 1.3-fold and AUC increased by 2.2-fold following concomitant administration with itraconazole (a strong CYP3A and P-gp inhibitor) 200 mg oral solution once daily for 4 days [see Drug Interactions (7.1) ] . Strong or Moderate CYP3A Inducers… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Nerandomilast is an inhibitor of phosphodiesterase 4 (PDE4) with at least nine-fold preferential inhibition of the PDE4B isoenzyme over PDE4A, PDE4C, and PDE4D based on in vitro data. PDE4 hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP). Nerandomilast exerts both antifibrotic and immunomodulatory effects as PDE4B inhibition elevates intracellular cAMP levels and reduces the expression of profibrotic growth factors and inflammatory cytokines, which are overexpressed in IPF and PPF.

12.3Pharmacokinetics Nerandomilast exposure increased in a dose proportional manner following administration of single doses of 0.0032 to 2.6 times a single dose of 18 mg and multiple doses of 0.056 to 1 times the maximum recommended dose of 18 mg twice daily. Following administration of multiple doses of 18 mg twice daily, C max increases 1.3-fold and AUC tau increases 1.38-fold. Nerandomilast steady state is reached in approximately 4 days.

No clinically relevant differences in nerandomilast pharmacokinetics were observed between healthy subjects, patients with IPF, and patients with PPF. Absorption The absolute oral bioavailability of nerandomilast is 73%. Nerandomilast median (min, max) time to maximum plasma concentration (T max ) is 1 to 1.25 hours (range 0.5 to 4 hours).

Effect of Food No clinically relevant differences in nerandomilast pharmacokinetics were observed following administration with a high-fat meal (1000 calories, 50% fat). Distribution Nerandomilast steady state apparent (oral) central volume of distribution is 93 L (CV 37%). In vitro , nerandomilast plasma protein binding is 77% and is not concentration dependent.

Nerandomilast blood-to-plasma ratio is approximately 0.6 to 0.8. Elimination The geometric mean (CV%) elimination half-life of nerandomilast is 17 hours (46%) with an apparent (oral) clearance of

15.2L/h. Metabolism Nerandomilast is primarily metabolized by CYP3A and to a lesser extent by multiple UGT enzymes. After oral administration of nerandomilast, chiral inversion from the pharmacologically active R-enantiomer to the pharmacologically inactive S-enantiomer occurs via metabolism.

The S-enantiomer was identified as a minor metabolite of nerandomilast. The R-enantiomer is the predominant circulating enantiomer. Excretion After a single oral dose of radiolabeled nerandomilast, approximately 58% of the dose was recovered in feces (14% as unchanged nerandomilast) and 36% of the dose was recovered in urine (13% as unchanged nerandomilast).

Specific Populations No clinically significant differences in the pharmacokinetics of nerandomilast were observed based on age (range: 18 to 90 years), body weight (range: 31 to 143 kg), sex, race (63% White and 35% Asian), mild (eGFR ≥60 to <90 mL/min/1.73 m 2 [calculated according to Chronic Kidney Disease Epidemiology Collaboration]), moderate (eGFR ≥30 to <60 mL/min/1.73 m 2 ), or severe renal impairment (eGFR ≥15 to <30 mL/min/1.73 m 2 ), or mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Subjects with end stage renal disease or severe hepatic impairment (Child-Pugh Class C) have not been studied [see Use in Specific Populations (8.6 , 8.7) ] . Drug Interaction Studies Strong CYP3A Inhibitors : Nerandomilast C max increased by 1.3-fold and AUC increased by 2.2-fold following concomitant administration with itraconazole (a strong CYP3A and P-gp inhibitor) 200 mg oral solution once daily for 4 days [see Drug Interactions (7.1) ] . Strong or Moderate CYP3A Inducers : Nerandomilast C max decreased by 31% and AUC decreased by 51% following concomitant administration with carbamazepine (a strong CYP3A inducer) 600 mg once daily for 5 days.

Nerandomilast trough concentration at steady state (C trough,ss ) is predicted to decrease by approximately 70% [see Drug Interactions (7.1) ]. Nerandomilast C max decreased by 15% and AUC decreased by 41% following concomitant administration with bosentan (a moderate CYP3A inducer) 125 mg twice daily for 3 days. Nerandomilast C trough,ss is predicted to decrease by approximately 58% [see Drug Interactions (7.1) ].

Pirfenidone : Nerandomilast C trough,ss decreased by approximately 50% following concomitant administration with pirfenidone [see Drug Interactions (7.1) ] . Other Drugs : No clinically significant differences in nerandomilast C trough,ss were observed when used concomitantly with nintedanib. No clinically significant differences in the pharmacokinetics of the following drugs were o… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Exposure-Response Increases in nerandomilast steady state trough concentrations were associated with better efficacy, as indicated by a smaller reduction in forced vital capacity (FVC) from baseline over 52 weeks. Cardiac Electrophysiology At 2.1 times the maximal concentration provided by the maximum recommended dose of nerandomilast, clinically significant QTc interval prolongation was not observed.

14 CLINICAL STUDIES

14.1Idiopathic Pulmonary Fibrosis The efficacy of JASCAYD for idiopathic pulmonary fibrosis (IPF) was evaluated in two randomized, double-blind, placebo-controlled trials (FIBRONEER-IPF [NCT05321069] and Trial 2 [NCT04419506]). FIBRONEER-IPF enrolled a total of 1,177 adult patients with IPF with or without background antifibrotic treatments (nintedanib or pirfenidone). They were randomized in a 1:1:1 ratio to receive JASCAYD 9 mg twice daily, JASCAYD 18 mg twice daily, or placebo twice daily until the last patient received treatment for 52 weeks (blinded trial duration up to 91 weeks; end of trial duration up to 109 weeks).

Randomization was stratified by the presence or absence of background antifibrotic treatments (nintedanib or pirfenidone) at baseline. The FIBRONEER-IPF trial consisted of 83% male and 17% female patients with a mean age of 70 years (age range: 42 to 90 years). The trial population included 68% White, 32% Asian, and <1% Black or African American.

For ethnicity, 8% of patients identified as Hispanic or Latino. At baseline, the mean FVC was 78% of predicted normal; 78% of the patients were on stable antifibrotic treatment (nintedanib 46%, pirfenidone 32%) and 22% were not on either treatment (15% treatment naïve, 7% previously discontinued treatment). Trial 2 was a 12-week trial that enrolled a total of 147 adult patients with IPF with or without background antifibrotic treatments (nintedanib or pirfenidone) and were randomized 2:1 to receive JASCAYD 18 mg twice daily or placebo twice daily for 12 weeks.

Randomization was stratified by the presence or absence of background antifibrotic treatments (nintedanib or pirfenidone) at baseline. The trial population in Trial 2 consisted of 77% male, and mean age of 70 years (age range: 40 to 85 years). The trial population included 78% White and 22% Asian.

For ethnicity, 9% of patients identified as Hispanic or Latino. At baseline, the mean FVC was 78% of predicted normal; 50% of the patients were on stable antifibrotic treatment (nintedanib 29%, pirfenidone 21%). In both the FIBRONEER-IPF trial and Trial 2, patients were required to have a diagnosis of IPF based on ATS/ERS/JRS/ALAT criteria.

Diagnosis was confirmed by the investigator based on chest high-resolution computed tomography (HRCT) scan and, if available, lung biopsy, and usual interstitial pneumonia (UIP) or probable UIP HRCT pattern consistent with the clinical diagnosis of IPF. Patients were also required to be greater than or equal to 40 years of age with an FVC greater than or equal to 45% of predicted and a carbon monoxide diffusing capacity (DLCO, corrected for hemoglobin) greater than or equal to 25% of predicted. Prior to Visit 1 and during screening, patients had to be on stable treatment with nintedanib or pirfenidone (no dose changes for at least 12 weeks) and planned to stay on this background antifibrotic treatment after randomization.

Alternatively, patients were required to be naïve to or have previously discontinued nintedanib or pirfenidone for at least 8 weeks and did not plan to start or re-start background antifibrotic treatment. Patients with active vasculitis, severe depression or suicidal behavior or ideation, or use of immunomodulatory medications (other than prednisone ≤15 mg/day or equivalent) were excluded. Change from Baseline in Forced Vital Capacity The primary endpoint in FIBRONEER-IPF trial was the absolute change from baseline in forced vital capacity (FVC) in milliliters (mL) at 52 weeks for JASCAYD compared with placebo.

In the FIBRONEER-IPF trial population, there was less decline in absolute change from baseline in FVC in patients who received JASCAYD compared with patients who received placebo (accounting for mortality), and this reduction in decline was statistically significant. The adjusted mean decline in patients receiving JASCAYD 18 mg or JASCAYD 9 mg was -106 mL and -122 mL, respectively, whereas in the placebo group, an adjusted mean declin… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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 104 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).