Jascayd 9 mg film-coated tablet

Jascayd is indicated for the treatment of adult patients with Idiopathic Pulmonary Fibrosis (IPF).

Jascayd is indicated for the treatment of adult patients with Progressive Pulmonary Fibrosis (PPF).

Posology

The recommended dosage of Jascayd is 18 mg twice daily, administered approximately 12 hours apart.

Based on individual patient tolerability, the dosage may be reduced to 9 mg twice daily.

Concomitant use with CYP3A inhibitors

If used concomitantly with strong CYP3A inhibitors, the dosage of Jascayd must be reduced to 9 mg twice daily (see section 4.5).

Concomitant use with CYP3A inducers

If used concomitantly with strong or moderate CYP3A inducers, the recommended dosage of Jascayd is 18 mg twice daily and must not be reduced to 9 mg twice daily (see section 4.5).

Concomitant use with pirfenidone

Concomitant use of Jascayd with pirfenidone decreased nerandomilast exposure by approximately 50% (see section 4.5). In patients using pirfenidone, the recommended dosage of Jascayd is 18 mg twice daily and must not be reduced to 9 mg twice daily.

Missed dose

If a dose of Jascayd is missed, the next dose should be taken at the next scheduled time.

The patient should not take an additional dose. The recommended maximum dosage of 18 mg twice daily should not be exceeded.

Special populations

Elderly patients

No overall differences in safety and efficacy were observed for patients aged below or above 65 years. No dose adjustment is required in elderly patients (see section 5.2).

Renal impairment

No dose adjustment is necessary in patients with mild, moderate, or severe renal impairment (eGFR ≥15 and <90 mL/min/1.73 m², based on CKD-EPI formula) (see section 5.2).

The pharmacokinetics, safety, and efficacy in patients with end stage renal disease (eGFR <15 mL/min/1.73 m²) have not been investigated. Treatment of patients with end stage renal disease (eGFR <15 mL/min/1.73 m²) with Jascayd is not recommended.

Hepatic impairment

No dose adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment (see section 5.2).

The pharmacokinetics, safety, and efficacy of nerandomilast in patients with severe (Child-Pugh class C) hepatic impairment have not been investigated. Treatment of patients with severe hepatic impairment with Jascayd is not recommended.

Paediatric patients

The safety and efficacy in paediatric patients have not been established.

Method of administration

Jascayd is for oral use. The tablets should be swallowed whole with water.

Jascayd can be taken with or without food (see section 5.2).

Alternative method of administration

For patients who have difficulty swallowing the whole tablet, a tablet of Jascayd may be dispersed in a glass with approximately 100 mL of non-carbonated, room temperature drinking water. No other liquids should be used. The tablet should be dropped in water without crushing it and stirred regularly for approximately 15-20 min until the tablet is dispersed into very small pieces (the tablets will not completely dissolve). The resultant dispersion should be drunk within 2 hours of mixing. If the dispersion is not drunk immediately, patients must stir again before drinking. The glass should be rinsed with approximately 100 mL of water which should also be drunk to ensure the full dose is administered.

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

Jascayd contains lactose

Each tablet of Jascayd 9 mg contains lactose monohydrate equivalent to 81.1 mg lactose anhydrous.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Jascayd contains sodium

Jascayd contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.

Strong cytochrome P450 3A (CYP3A) inhibitors

Moderate or strong cytochrome P450 3A (CYP3A) inducers

Pirfenidone

Nintedanib

Cytochrome P450 substrates

Contraception

Based on findings in animal studies, Jascayd may cause loss of pregnancy (see section Pregnancy below and section 5.3).

Females of reproductive potential should be advised to avoid becoming pregnant and to use effective contraceptive methods during treatment with Jascayd.

Pregnancy

There are no data from the use of Jascayd in pregnant women. Based on findings in animal studies, Jascayd may cause loss of pregnancy. In rats, embryo-foetal loss was observed at 5‑times human exposure at the maximum recommended human dose (MRHD); this effect was not observed at approximately 3-times human exposure (see section 5.3).

Females of reproductive potential should be advised to avoid becoming pregnant while taking Jascayd. Jascayd is not recommended during pregnancy.

Female patients should be advised to notify their health care provider if they become pregnant or suspect they may be pregnant during therapy with Jascayd. Pregnant women and females of reproductive potential should be advised of the potential risk of foetal loss.

Breast-feeding

There are no data on the presence of nerandomilast in human milk or its effects on either the breast-fed child or on milk production. Studies in rats have shown evidence of excretion of nerandomilast in milk (see section 5.3).

A risk to the breast-fed infant cannot be excluded. Breast-feeding should be discontinued during treatment with Jascayd.

Fertility

There are no data on the impact of nerandomilast on human fertility. No adverse effects on fertility were observed in male and female rats at 4-times human exposure (see section 5.3).

Jascayd has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The safety of Jascayd has been studied in a randomised, placebo-controlled, double-blind trial (FIBRONEER-IPF), in which 1177 adult patients with IPF were randomised in a 1:1:1 ratio to receive Jascayd 9 mg twice daily, Jascayd 18 mg twice daily, or matching placebo in the presence or absence of background IPF treatment (nintedanib or pirfenidone) for at least 52 weeks.

In patients with Progressive Pulmonary Fibrosis (PPF), the safety of Jascayd has been studied in a randomised, placebo-controlled, double-blind trial (FIBRONEER-ILD), in which 1178 adult patients with PPF were randomised in a 1:1:1 ratio to receive Jascayd 9 mg twice daily, Jascayd 18 mg twice daily, or matching placebo in the presence or absence of background PPF treatment (nintedanib) for at least 52 weeks.

The safety data provided in the following are based on 52-week data.

In clinical trials, the most frequent adverse reaction associated with Jascayd was diarrhoea.

Tabulated list of adverse reactions

Table 1 shows the frequencies of adverse drug reactions (ADRs) of Jascayd in FIBRONEER-IPF and FIBRONEER-ILD trials with twice daily Jascayd doses of 18 mg. ADRs are listed by MedDRA System Organ Class (SOC) and frequency category using the following convention.

Table 1. Adverse reactions for Jascayd and corresponding frequencies as observed in FIBRONEER-IPF and FIBRONEER-ILD trials with twice daily Jascayd doses of 18 mg

^a see section Description of selected adverse reactions

Description of selected adverse reactions

Diarrhoea

IPF

In patients treated with Jascayd in the FIBRONEER-IPF trial, the frequency of diarrhoea depended on the presence and type of background IPF treatment. In patients on background nintedanib treatment, the frequency was 62% in patients treated with Jascayd 18 mg, 49% in patients treated with Jascayd 9 mg versus 27% in patients receiving placebo. In patients without background IPF treatment, diarrhoea was reported in 26% of patients treated with Jascayd 18 mg, 17% of patients treated with Jascayd 9 mg versus 8% of patients receiving placebo. In patients on background pirfenidone treatment, the frequency was 23%, in patients treated with Jascayd 18 mg, versus 8% in patients receiving placebo.

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

In the FIBRONEER-IPF trial diarrhoea was the most common adverse reaction associated with treatment discontinuation and occurred most frequently in patients treated with Jascayd 18 mg concomitantly with background nintedanib therapy (13%) versus patients receiving Jascayd 9 mg (2%) or placebo (1%) and background nintedanib. In patients without background IPF treatment, diarrhoea led to treatment discontinuation in 1% of patients treated with Jascayd 18 mg, and no patients receiving Jascayd 9 mg or placebo. In patients receiving background pirfenidone treatment, there were no treatment discontinuations in patients receiving nerandomilast 18 mg or placebo.

PPF

In patients treated with Jascayd in the FIBRONEER-ILD trial, the frequency of diarrhoea depended on the presence or absence of background nintedanib treatment. In patients on background nintedanib treatment, the frequency was 49% in patients treated with Jascayd 18 mg, 48% in patients treated with Jascayd 9 mg versus 36% in patients receiving placebo. In patients without background nintedanib treatment, diarrhoea was reported in 27% of patients treated with Jascayd 18 mg, 15% of patients treated with Jascayd 9 mg versus 16% of patients receiving placebo.

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

In the FIBRONEER-ILD trial, diarrhoea was the most common adverse reaction associated with treatment discontinuation and occurred most frequently in patients treated with Jascayd 18 mg concomitantly with background nintedanib therapy (4%) versus patients receiving Jascayd 9 mg (3%) or placebo (1%) and background nintedanib. In patients without background nintedanib treatment, diarrhoea led to treatment discontinuation in 1% of patients treated with Jascayd 18 mg, and no patients receiving Jascayd 9 mg or placebo.

Weight decrease

IPF

In the FIBRONEER-IPF trial, the mean absolute change in body weight from baseline to week 52 was -2.6 kg for patients treated with Jascayd 18 mg, -2.4 kg for patients treated with Jascayd 9 mg, and -1.8 kg for patients receiving placebo.

The frequency of reported weight decrease depended on the presence and type of background IPF treatment. In patients on background nintedanib treatment, the frequency was 16% in patients treated with Jascayd 18 mg, 13% in patients treated with Jascayd 9 mg versus 11% in patients receiving placebo. In patients without background IPF treatment, weight decrease was reported in 7% of patients treated with Jascayd 18 mg, 1% of patients treated with Jascayd 9 mg versus 6% of patients receiving placebo. In patients on background pirfenidone treatment, the frequency was similar in patients treated with Jascayd 18 mg and placebo (5%).

PPF

In the FIBRONEER-ILD trial, the mean absolute change in body weight from baseline to week 52 was -3.2 kg for patients treated with Jascayd 18 mg, -2.0 kg for patients treated with Jascayd 9 mg and -2.0 kg for patients receiving placebo.

In patients on background nintedanib treatment, the frequency of weight decrease was 11% in patients treated with Jascayd 18 mg, 9% in patients treated with Jascayd 9 mg versus 8% in patients receiving placebo. In patients without background nintedanib treatment, weight decrease was reported in 10% of patients treated with Jascayd 18 mg, 5% of patients treated with Jascayd 9 mg versus 4% of patients receiving placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Symptoms

Single doses of up to 48 mg of nerandomilast were well tolerated in clinical trials with healthy volunteers. No clinically relevant changes in vital signs or ECG changes were observed.

In clinical trials, cases of accidental overdose of Jascayd were reported in patients who received doses up to 72 mg/day for up to 17 days. No serious adverse events were reported as a result of the overdosage.

Therapy

In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment is provided.

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA61

Mechanism of action

Nerandomilast is a selective inhibitor of phosphodiesterase 4 (PDE4) with at least 9-fold preferential inhibition of the PDE4B isoenzyme over PDE4A, C and D based on in vitro data. PDE4 hydrolyses and inactivates cyclic adenosine monophosphate (cAMP). Nerandomilast exerts both anti-fibrotic and immunomodulatory effects as preferential PDE4B inhibition elevates intracellular cAMP levels and reduces the expression of pro-fibrotic growth factors and inflammatory cytokines, which are overexpressed in fibrotic lung disease.

Pharmacodynamic effects

Anti-fibrotic and immunomodulatory activity

In cellular and animal models, nerandomilast was shown to reduce inflammatory cytokines, influx of neutrophils, extra-cellular matrix components, fibroblast-to-myofibroblast transformation, and fibroblast proliferation (synergistic with nintedanib).

Nerandomilast also showed efficacy in lung fibrosis models in mice and rats.

In clinical studies in healthy volunteers and in IPF patients, nerandomilast inhibited the Lipopolysaccharide-stimulated release of pro-inflammatory cytokines TNFa and IFNg using an ex vivo whole blood assay.

Cardiac electrophysiology

At single doses of nerandomilast up to 48 mg (2.2-times the estimated C_max,ss exposure at the maximum recommended human dose), clinically significant QTc interval prolongation was not observed.

Clinical efficacy and safety

Idiopathic Pulmonary Fibrosis (IPF)

A randomised, double-blind, placebo-controlled trial (FIBRONEER-IPF) evaluated the clinical efficacy and safety of Jascayd in adult patients with IPF with or without receiving background treatment of nintedanib or pirfenidone. 1177 patients were randomised in a 1:1:1 ratio to receive Jascayd 9 mg twice daily, Jascayd 18 mg twice daily, or placebo twice daily for at least 52 weeks. Randomisation was stratified by the presence of nintedanib or pirfenidone versus the absence of these background treatments at baseline. The primary endpoint of the trial was the absolute change from baseline in Forced Vital Capacity (FVC) in mL at 52 weeks compared with placebo. The key secondary endpoint was the time to the first occurrence of any of the components of the composite endpoint: first acute IPF exacerbation, first hospitalisation for respiratory cause, or death over the duration of the trial. At the time of main analysis, median exposure was 14.6 months; at the end-of trial analysis, median exposure was 17.0 months.

The study population consisted of 83% men and 17% women with a mean age of 70 years (range: 42 to 90 years). 68% of the study population were White, 32% Asian and 0.5% Black/African American. For ethnicity, 8% of patients identified as Hispanic or Latino. At baseline, the mean FVC was 2843 mL and 78% of predicted normal. 78% of the patients were on stable treatment with nintedanib (46%) or with pirfenidone (32%) and 22% were on none of these treatments (15% of patients were treatment naïve and 8% previously discontinued treatment with nintedanib or pirfenidone).

Change from baseline in FVC

Overall, the primary endpoint of absolute change from baseline in FVC (in mL) at 52 weeks in patients receiving Jascayd was statistically significantly improved compared with patients receiving placebo. The adjusted mean decline in patients receiving 18 mg or 9 mg Jascayd twice daily was -115 mL and -139 mL, respectively, whereas in the placebo group, an adjusted mean decline of -183 mL was observed. The respective treatment difference compared with the placebo group was 69 mL (95% CI: 30, 107; p-value: 0.0005) and 45 mL (95% CI: 6, 83; p-value: 0.0222).

The primary analysis was consistent with all sensitivity and supplementary analyses as well as across pre-specified subgroups of age, gender, race, ethnicity, bodyweight, and baseline FVC.

A drug-drug interaction was observed in patients receiving pirfenidone as background IPF treatment (see section 4.5). In these patients, no treatment effect was observed when receiving 9 mg nerandomilast twice daily.

Results for the primary endpoint in the overall population and by background IPF treatment for the Jascayd 18 mg and 9 mg doses versus matching placebo are presented in Figure 1 and Figure 2, respectively.

Figure 1. Absolute change from baseline in FVC (mL) at 52 weeks for patients receiving 18 mg Jascayd compared to placebo in the FIBRONEER-IPF study

For patients who died before week 52, a lowest 10th percentile change from baseline value was assigned.

bid = twice daily

Figure 2. Absolute change from baseline in FVC (mL) at 52 weeks for patients receiving 9 mg Jascayd compared to placebo in the FIBRONEER‑IPF study

For patients who died before week 52, a lowest 10th percentile change from baseline value was assigned.

bid = twice daily

Figure 3 shows the change in FVC from baseline over 52 weeks in patients receiving Jascayd 18 mg twice daily compared to matching placebo. When the adjusted mean of absolute change from baseline in FVC was plotted over time, the curves started to separate at week 2 and continued to diverge up to week 52. This effect over time was consistently observed across the subgroups by background IPF treatment.

Figure 3. Change from baseline in FVC (mL) over 52 weeks in the FIBRONEER‑IPF study

bid = twice daily

Percent change from baseline in FVC

Figure 4 presents the percent change from baseline in FVC in mL at week 52. More patients on Jascayd 18 mg showed stability or improvement in lung function compared to patients receiving placebo. These results were consistent regardless of background IPF treatment.

Figure 4. Histogram of the percent change in FVC (mL) from baseline to week 52 in percent increments or decrements of 5 in the FIBRONEER-IPF study^a

^a Patients classified as having missing FVC data at week 52 are those with no FVC assessment, including due to death, between day 338 and day 393.

bid = twice daily

Time to first acute ILD exacerbation, first hospitalisation for respiratory cause, or death

The key secondary composite endpoint was the time to the first event of acute IPF exacerbation, hospitalisation for respiratory cause, or death over the duration of the trial. Acute IPF exacerbation was defined as acute worsening or development of dyspnoea typically less than 1 month duration, computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with IPF, and deterioration not fully explained by cardiac failure or fluid overload. Neither acute IPF exacerbations nor respiratory hospitalisations were adjudicated. Overall, there was no statistically significant treatment difference for the Jascayd 18 mg or 9 mg groups compared to placebo for the key secondary composite endpoint (At time of main analysis for 18 mg and 9 mg dose, respectively: HR 1.17 (95% CI: 0.86, 1.59; p-value: 0.3102) and HR 1.03 (95% CI: 0.75, 1.41; p-value: 0.8568); and at time of end-of trial analysis for 18 mg and 9 mg dose, respectively: HR 0.99 (95% CI: 0.75, 1.31) and HR 0.92 (95% CI: 0.69, 1.22).

See Figure 5 for results of Jascayd 18 mg versus placebo for the key secondary endpoint, its components, and related endpoints 'first acute IPF exacerbation or death' and 'first hospitalisation for respiratory cause or death' over the duration of the FIBRONEER-IPF study at the time of the end-of trial analysis.

Figure 5. Acute IPF exacerbation, hospitalisation for respiratory cause or death over the duration of the FIBRONEER-IPF study

bid = twice daily

Survival

In the pre-specified analysis of survival over the duration of the FIBRONEER-IPF study, the HR for all-cause mortality was 0.95 in the Jascayd 9 mg group compared with matching placebo at the time of end-of trial analysis (95% CI: 0.61, 1.49) see Figure 6; the risk for all-cause mortality was numerically lower by 34% in the Jascayd 18 mg group compared with matching placebo at the time of end-of trial analysis (HR 0.66 (95% CI: 0.41, 1.08)), see Figure 7.

Figure 6. Cumulative incidence of death over the duration of the FIBRONEER-IPF study (nerandomilast 9 mg vs placebo)

Figure 7. Cumulative incidence of death over the duration of the FIBRONEER-IPF study (nerandomilast 18 mg vs placebo)

bid = twice daily

Absolute Decline from Baseline in FVC Percent Predicted >10% or Death

Over the duration of the trial, at the time of end-of trial analysis, the risk of deterioration in absolute FVC % predicted by >10% or death was reduced in patients treated with Jascayd 18 mg versus placebo (30% vs. 39%) (HR 0.75 (95% CI: 0.59, 0.95)).

Progressive Pulmonary Fibrosis (PPF)

A randomised, double-blind, placebo-controlled trial (FIBRONEER-ILD) evaluated the clinical efficacy and safety of Jascayd in adult patients with PPF. Patients with PPF were selected if they had relevant fibrosis (greater than 10% fibrotic features) on high resolution computed tomography (HRCT) and presented with clinical signs of progression (defined as FVC decline greater than or equal to 10%, FVC decline greater than or equal to 5% and less than 10% with worsening of respiratory symptoms or imaging, or worsening of respiratory symptoms and worsening imaging all in the 24 months prior to screening). Patients were required to have an FVC greater than or equal to 45% of predicted and a diffusing capacity of the lungs for carbon monoxide (DLCO) greater than or equal to 25% of predicted normal corrected for haemoglobin (Hb). Eligible patients were or were not on stable background treatment with nintedanib.

1178 patients were randomised in a 1:1:1 ratio to receive Jascayd 9 mg twice daily, Jascayd 18 mg twice daily, or placebo twice daily for at least 52 weeks. Randomisation was stratified by the presence or absence of background treatment with nintedanib and by high resolution computed tomography (HRCT) pattern (UIP or UIP-like fibrotic pattern vs Other fibrotic patterns) using central review. The primary endpoint of the trial was the absolute change from baseline in Forced Vital Capacity (FVC) in mL at 52 weeks compared with placebo. The key secondary endpoint was the time to the first occurrence of any of the components of the composite endpoint: the first acute Interstitial Lung Disease (ILD) exacerbation, first hospitalisation for respiratory cause, or death over the duration of the trial.

At the time of the main analysis, median observation was 15.4 months; at the end-of trial analysis, median observation time was 17.2 months.

The study population consisted of 56% men and 44% women with a mean age of 66 years (range: 26 to 88 years). 58% of the study population were White, 39% Asian and 1% Black or African American. For ethnicity, 14% of patients identified as Hispanic or Latino.

At baseline, the mean FVC was 2353 mL and 70% of predicted normal. 44% of the patients were on stable treatment with nintedanib and 56% not treated with nintedanib (44% of patients were treatment naïve and 12% previously discontinued nintedanib treatment). On baseline HRCT, 71% of the patients had UIP or UIP-like fibrotic pattern and 29% of the patients had other fibrotic patterns. The underlying clinical ILD diagnoses were autoimmune ILDs (28%), hypersensitivity pneumonitis (20%), unclassifiable idiopathic interstitial pneumonia (20%), idiopathic nonspecific interstitial pneumonia (19%), and other ILDs (14%).

Change from baseline in FVC

Overall, the primary endpoint of absolute change from baseline in FVC (in mL) at 52 weeks in patients receiving Jascayd was statistically significantly improved compared with patients receiving placebo.

The adjusted mean decline in patients receiving 18 mg or 9 mg Jascayd twice daily was -99 mL and -85 mL, respectively, whereas in the placebo group, an adjusted mean decline of -166 mL was observed. The respective treatment difference compared with the placebo group was 67 mL (95% CI: 32, 102; p-value: 0.0002) and 81 mL (95% CI: 46, 116; p-value: <0.0001).

The primary analysis was consistent with all sensitivity and supplementary analyses as well as across pre-specified subgroups by presence or absence of nintedanib background treatment, HRCT pattern, and underlying clinical ILD diagnoses. See Figure 7 and Figure 8.

Figure 8. Absolute change from baseline in FVC (mL) at 52 weeks for patients receiving 18 mg Jascayd compared to placebo in the FIBRONEER-ILD study

For patients who died before week 52, a lowest 10th percentile change from baseline value was assigned.

bid = twice daily

Figure 9. Absolute change from baseline in FVC (mL) at 52 weeks for patients receiving 9 mg Jascayd compared to placebo in the FIBRONEER‑ILD study

For patients who died before week 52, a lowest 10th percentile change from baseline value was assigned.

bid = twice daily

The results of the primary endpoint were generally consistent across the other pre-specified subgroups (defined by age, gender, race, ethnicity, bodyweight, baseline FVC).

Figure 10 shows the change in FVC from baseline over 52 weeks in patients receiving Jascayd 18 mg twice daily compared to matching placebo. When the adjusted mean of absolute change from baseline in FVC was plotted over time, the curves started to separate at week 2 and separation was maintained up to week 52. This effect over time was consistently observed regardless of background nintedanib treatment.

Figure 10. Change from baseline in FVC (mL) over 52 weeks in the FIBRONEER-ILD study

bid = twice daily

Percent Change from Baseline in FVC

Figure 11 presents the percent change from baseline in FVC in mL at week 52. More patients on Jascayd 18 mg showed stability or improvement in lung function compared to patients receiving placebo. These results were consistent regardless of background nintedanib treatment.

Figure 11. Histogram of the percent change in FVC (mL) from baseline to week 52 in percent increments or decrements of 5 in the FIBRONEER-ILD study^a

^a Patients classified as having missing FVC data at week 52 are those with no FVC assessment, including due to death, between day 338 and day 393.

bid = twice daily

Time to first acute ILD exacerbation, first hospitalisation for respiratory cause, or death

The key secondary composite endpoint was the time to the first event of acute ILD exacerbation, hospitalisation for respiratory cause, or death over the duration of the trial. Acute ILD exacerbation was defined as acute worsening or development of dyspnoea typically less than 1 month duration, computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILD, and deterioration not fully explained by cardiac failure or fluid overload. Neither acute ILD exacerbations nor respiratory hospitalisations were adjudicated.

At the time of main analysis, the risk for the key secondary endpoint was numerically lower for Jascayd 18 mg or 9 mg groups, respectively, compared to placebo: HR 0.77 (95% CI: 0.59, 1.01; p-value: 0.0602) and HR 0.88 (95% CI: 0.68, 1.14; p-value: 0.3398). The end-of trial analysis resulted in HR 0.77 (95% CI: 0.60, 0.99) and HR 0.78 (95% CI: 0.61, 1.00) for the 18 mg and 9 mg dose, respectively.

See Figure 12 for results of Jascayd 18 mg versus placebo for the key secondary endpoint, its components, and related endpoints 'first acute ILD exacerbation or death' and 'first hospitalisation for respiratory cause or death' over the duration of the FIBRONEER-ILD study at the time of the end-of trial analysis.

Figure 12. Acute ILD exacerbation, hospitalisation for respiratory cause or death over the duration of the FIBRONEER-ILD study

bid = twice daily

The results of the key secondary endpoint were generally consistent regardless of background nintedanib treatment or HRCT pattern and across the other pre-specified subgroups (defined by age, gender, race, ethnicity, bodyweight, baseline FVC).

Survival

In the pre-specified analysis of survival over the duration of the FIBRONEER-ILD study, the risk for all-cause mortality was 49% lower in the Jascayd (either 18 mg or 9 mg) group compared with matching placebo at the end-of trial analysis (HR 0.51 (95% CI: 0.34, 0.78), see Figure 12 and Figure 13. Across treatment groups, the majority of deaths (64%) were adjudicated as respiratory related (86 of 134 deaths, 64%).

In a post hoc analysis, the risk for adjudicated respiratory-related mortality was 62% lower in the Jascayd 9 mg group compared with matching placebo (HR 0.38 (95% CI: 0.22, 0.65) and the risk for adjudicated respiratory-related mortality was 57% lower in the Jascayd 18 mg group compared with matching placebo (HR 0.43 (95% CI: 0.25, 0.72).

Figure 13. Cumulative incidence of death over the duration of the FIBRONEER-ILD study (nerandomilast 9 mg vs placebo)

Figure 14. Cumulative incidence of death over the duration of the FIBRONEER-ILD study (nerandomilast 18 mg vs placebo)

bid = twice daily

Absolute Decline from Baseline in FVC Percent Predicted >10% or Death

Over the duration of the trial, at the time of end-of trial analysis, the risk of deterioration in absolute FVC % predicted by >10% or death was reduced in patients treated with Jascayd 18 mg versus placebo (32% vs 43%) (HR 0.71 (95% CI: 0.56, 0.89)).

Pooled analysis for IPF and PPF

Survival

In the prespecified pooled analysis of survival in patients with IPF and PPF from the FIBRONEER-IPF and FIBRONEER-ILD trials, the risk for all-cause mortality over the duration of the trial was reduced by 43% in the Jascayd 18 mg group compared with matching placebo at the time of end-of trial analysis (HR 0.57 (95% CI: 0.41, 0.78)). Across treatment groups, the majority of deaths were adjudicated as respiratory related (150 of 237 adjudicated deaths, 63%) were respiratory-related.

The pharmacokinetics of nerandomilast have been characterised in healthy volunteers, patients with IPF and patients with PPF. No clinically relevant differences in pharmacokinetics of nerandomilast were noted between these populations.

Absorption

Nerandomilast reached peak plasma concentrations (C_max) at a median time (T_max) of 1.00- 1.25 h (range between 0.5-4 hours) after oral administration of 9 mg and 18 mg doses. The absolute oral bioavailability of nerandomilast was 73% (90% CI:67-79%).

Administration of 18 mg nerandomilast with a high-fat and high caloric meal did not change nerandomilast exposure to a clinically relevant extent (AUC increased by approximately 15% while C_max decreased by approximately 14%).

Distribution

After single intravenous administration of nerandomilast, the geometric mean volume of distribution V_ss was approximately 94 L (gCV 32.0%). In vitro, nerandomilast was a substrate of the transporter protein P-gp, but not of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2.

In-vitro human plasma protein binding of nerandomilast was 77% with no concentration dependence.

In healthy volunteers, nerandomilast was preferentially distributed in plasma with a blood-to-plasma ratio of 0.6-0.8.

Biotransformation

Nerandomilast is mainly metabolised via oxidation by CYP3A and glucuronidation by multiple UGT enzymes.

Following single oral administration, nerandomilast was the primary circulating component representing approximately 50% of circulating radioactivity.

After multiple oral administrations of 12 mg nerandomilast twice daily, the only major metabolite identified in plasma at steady state was the di-oxidative metabolite BI 764333/M480(4). This pharmacologically inactive metabolite represented 12% of the total plasma material at steady state consisting of both parent compound and all its metabolites.

Nerandomilast has a chiral sulfur atom and Jascayd predominantly contains chirally pure nerandomilast (R-enantiomer). After oral administration of nerandomilast, chiral inversion from R-enantiomer to S-enantiomer occurs via metabolism. The S-enantiomer was identified as a minor (3% of total circulating radioactivity) metabolite of nerandomilast and is pharmacologically inactive. The pharmacologically active R-enantiomer remained as the predominant circulating enantiomer.

Elimination

Following multiple oral doses of 18 mg nerandomilast twice daily, the terminal half-life was approximately 10 to 17 h and the geometric mean apparent plasma clearance at steady state was 274 mL/min with inter-individual variability (gCV%) of 23.6%. After oral administration of a single 18 mg dose of radiolabelled nerandomilast, approximately 95% of the dose was recovered within 9 days after dosing, with 58% recovered in faeces (13% unchanged) and 36% recovered in urine (12% unchanged).

Linearity/non-linearity

Nerandomilast exhibited dose proportional pharmacokinetics following oral administration of both, single doses (0.06 to 48 mg) and multiple doses (1 to 18 mg twice daily).

Following oral administration of 18 mg nerandomilast twice daily, steady state was achieved within 4 days with an accumulation ratio of up to 1.38 based on AUC and Cmax.

PK in specific populations

Age, sex, ethnicity, renal or hepatic impairment

No clinically significant differences in the pharmacokinetics of nerandomilast were observed based on age (18-90 years), sex, ethnicity (Hispanic/Latino or not Hispanic/Latino), mild, moderate, and severe renal impairment (eGFR ≥15 and <90 ml/min/1.73 m², based on CKD-EPI formula), or mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Subjects with end stage renal disease and subjects with severe hepatic impairment (Child Pugh C) have not been studied.

Race

Asian patients have up to 47% higher nerandomilast trough concentration compared to White patients. This effect is not expected to be clinically meaningful.

Body weight

A population PK analysis indicated higher nerandomilast exposure in patients with lower body weight and lower exposure in patients with higher body weight. The impact of body weight on nerandomilast plasma concentrations is not expected to be clinically meaningful.

General toxicology

Safety pharmacology studies revealed no safety concerns following measurements of cardiovascular, CNS, and respiratory effects and there was no evidence of immunotoxic or phototoxic potential.

Repeat-dose toxicity studies were conducted in rats, minipigs, and monkeys. Vasculopathy (inflammation, haemorrhage, and blood vessel necrosis) was the primary finding observed in the rat and minipig. No adverse vascular effects were observed in monkeys administered up to 30 mg/kg/day (10-times human exposure based on AUC at the maximum recommended human dose (MRHD) (see section 4.2)). Adverse vascular effects observed in rats and in minipigs affected various tissues (i.e., mesentery and GI tract in rats, heart and lung in minipigs). In long-term studies, no adverse vascular changes were observed in rats at 2 mg/kg/day, and vascular changes were observed in one minipig at 3 mg/kg/day (both equivalent to human exposure, based on AUC at the MRHD). The exposure margin in monkeys, considered the most relevant species to humans, suggests that primates are less sensitive to vascular effects than other species.

In toxicology studies in monkeys at exposures higher than 10-times human exposure based on AUC at the MRHD, emesis and heart findings (focal degeneration or necrosis not accompanied by vascular changes) were observed.

Carcinogenicity

Nerandomilast showed no evidence of carcinogenic potential in rats and transgenic mice. This was based on results of a 104-week study in rats at 2 mg/kg/day and a 26-week study in male/female transgenic (Tg.rasH2) mice at 60/100 mg/kg/day (approximately 2- and 47/57-times human exposure based on AUC at the MRHD).

Genotoxicity

Nerandomilast was not mutagenic in the in-vitro bacterial reverse mutation assay. It showed no potential to induce chromosome aberrations in human peripheral blood lymphocytes or in the in-vivo rat micronucleus assay.

Reproductive and developmental toxicology

Fertility and early embryonic development

In a fertility study in male rats, nerandomilast administration at a dose of 6 mg/kg/day (approximately 4-times human exposure based on AUC at the MRHD) showed no effect on mating, fertility, or sperm indices.

In female rats, decreased indices for mating, pregnancy, and fertility were observed at the highest tested dose of 9 mg/kg/day (approximately 9-times human exposure based on AUC at the MRHD) and were related to general toxicity. No such effects were observed at the No Observed Adverse Effects Level (NOAEL) dose of 6 mg/kg/day (approximately 4-times human exposure at the MRHD).

In repeat-dose toxicity studies in rats, minipigs and monkeys, no nerandomilast-related effects on male and female reproductive organs were observed that were considered adverse.

Sexually mature female monkeys administered nerandomilast for 39 weeks showed sporadic menstrual cycle prolongation at dose levels of 10 mg/kg/day and 30 mg/kg/day (approximately 3- or 10-times human exposure based on AUC at the MRHD). Menstrual cycles were not affected in monkeys at 3 mg/kg/day (equivalent to human exposure based on AUC at the MRHD).

No changes in oestrous cycles were observed in rats.

Embryo-foetal development

Embryo-foetal development studies in rats and rabbits showed no teratogenicity, no skeletal variations and no fetotoxicity up to the highest tested dose levels of 9 mg/kg/day and 15 mg/kg/day, equivalent to 7- and 4-times human exposure based on AUC at the MRHD, respectively. Embryo-foetal lethality due to post-implantation loss related to an increase in early resorptions was observed in rats at the dose of 6 mg/kg/day (5-times human exposure based on AUC at the MRHD) administered from gestation day 6 to 17. No embryo-foetal lethality was observed in rats and rabbits at the NOAEL dose of 3 mg/kg/day and 15 mg/kg/day (approximately 3- and 4-times human exposure based on AUC at the MRHD, respectively).

Pre- and postnatal development

In a dose range-finding pre- and postnatal development study in rats, a maternal dose of 6 mg/kg/day (approximately 5- to 6-times human exposure at the MRHD) from gestation day 6 to lactation day 6 resulted in lower pup weights. In the pivotal pre- and postnatal development study, nerandomilast administered to pregnant female rats from gestation day 6 to lactation day 20, had no adverse effects on maternal performance or toxicity or on F1 generation (offspring) development, behaviour, and reproductive performance up to the highest tested dose of 3mg/kg/day (approximately 2-times human exposure based on AUC at the MRHD). In this study, nerandomilast was present in the plasma of rat pups during the lactation period. In a single dose milk secretion study in lactating rats dosed with radio labelled nerandomilast by the oral route, similar concentrations of total radioactivity were observed in the milk and plasma of lactating females, with the maximum radioactive concentration observed at 1 hour post dose that was significantly reduced by 24 hours post dose. The concentration of total radioactivity in animal milk does not necessarily predict the concentration of drug in human milk.

Lactose monohydrate

Microcrystalline cellulose

Hydroxypropylcellulose

Croscarmellose sodium

Magnesium stearate

Hypromellose 2910

Talc

Mannitol

Macrogol 8000

Iron oxide yellow (E172)

Not applicable.

2 years

Store in the original package in order to protect from light.

This medicinal product does not require any special temperature storage conditions.

PVC/aluminium perforated unit dose blisters.

Pack sizes of 10 x 1, 30 x 1, or 60 x 1 film-coated tablets.

HDPE bottle with a child-resistant closure.

Pack sizes of 60 or 180 film-coated tablets.

Not all pack sizes may be marketed.

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