Tarpeyo budesonide 4 mg Capsule, Delayed Release, 120-count — NDC 81749-004-01 (Billing 81749-0004-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Budesonide is a corticosteroid with potent glucocorticoid activity and weak mineralocorticoid activity that undergoes substantial first pass metabolism. Mucosal B-cells present in the ileum, including the Peyer's patches, express glucocorticoid receptors and are responsible for the production of galactose-deficient IgA1 antibodies (Gd-Ag1) causing IgA nephropathy. Through their anti-inflammatory and immunosuppressive effects at the glucocorticoid receptor, corticosteroids can modulate B-cell numbers and activity.

It has not been established to what extent TARPEYO's efficacy is mediated via local effects in the ileum vs systemic effects.

12.2Pharmacodynamics Treatment with corticosteroids, including TARPEYO, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function.

12.3Pharmacokinetics Absorption Following single oral administration of TARPEYO 16 mg to healthy subjects, the average geometric mean C max (CV%) was 4.4 ng/mL (58.3), and AUC 0-24 was 24.1 h*ng/mL (49.7). Median T lag (min, max) was 3.1 h (0, 6) while median T max (min, max) was 5.1 h (4.5, 10). Food Effect There was no clinically relevant food effect observed on the overall systemic exposure of budesonide when either a moderate or high fat meal was consumed 1 hour after administration of TARPEYO.

Distribution Approximately 85 to 90% of budesonide binds to plasma proteins in blood over the concentration range of 0.43 to 99 ng/mL. The volume of distribution at steady state reported in the literature is 3 to 4 L/kg. Metabolism Budesonide is metabolized by the liver (and to lesser extent the gut), primarily by oxidative pathways via CYP3A4 to two main metabolites, 16α-hydroxyprednisolone and 6β-hydroxybudesonide, which have less than 1% of the corticosteroid activity of budesonide.

Elimination Budesonide had a high plasma clearance, 0.9 to

1.8L/min in healthy adults, which is close to the estimated liver blood flow, and, accordingly, suggests that budesonide is a high hepatic clearance drug. Following single oral administration of TARPEYO 16 mg to healthy subjects, the elimination half-life (t½) for TARPEYO ranged from 5.0 to 6.8 hours. Excretion Budesonide was excreted in urine and feces in the form of metabolites.

After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 16α-hydroxyprednisolone and 6β-hydroxybudesonide, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine.

Specific Populations Age, race, and body weight The effect of age, race, and body weight on the pharmacokinetics of TARPEYO has not been established. Sex Of the 143 healthy volunteers included in the Phase 1 studies, 29% were female. Pharmacokinetics of budesonide was similar between males and females.

Hepatic Impairment Subjects with moderate hepatic impairment (Child-Pugh class B) had 3.5 times the budesonide AUC compared with healthy volunteers while subjects with mild hepatic impairment (Child-Pugh class A) had approximately 1.4 times the budesonide AUC compared with healthy volunteers. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. Renal Impairment Intact budesonide is not excreted renally.

The main metabolites of budesonide, which have negligible corticosteroid activity, are largely (60%) excreted in urine. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase plasma levels of budesonide.

Thus, clinically relevant drug interactions with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, and grapefruit juice, are to be expected. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Budesonide is a corticosteroid with potent glucocorticoid activity and weak mineralocorticoid activity that undergoes substantial first pass metabolism. Mucosal B-cells present in the ileum, including the Peyer's patches, express glucocorticoid receptors and are responsible for the production of galactose-deficient IgA1 antibodies (Gd-Ag1) causing IgA nephropathy. Through their anti-inflammatory and immunosuppressive effects at the glucocorticoid receptor, corticosteroids can modulate B-cell numbers and activity.

It has not been established to what extent TARPEYO's efficacy is mediated via local effects in the ileum vs systemic effects.

12.3Pharmacokinetics Absorption Following single oral administration of TARPEYO 16 mg to healthy subjects, the average geometric mean C max (CV%) was 4.4 ng/mL (58.3), and AUC 0-24 was 24.1 h*ng/mL (49.7). Median T lag (min, max) was 3.1 h (0, 6) while median T max (min, max) was 5.1 h (4.5, 10). Food Effect There was no clinically relevant food effect observed on the overall systemic exposure of budesonide when either a moderate or high fat meal was consumed 1 hour after administration of TARPEYO.

Distribution Approximately 85 to 90% of budesonide binds to plasma proteins in blood over the concentration range of 0.43 to 99 ng/mL. The volume of distribution at steady state reported in the literature is 3 to 4 L/kg. Metabolism Budesonide is metabolized by the liver (and to lesser extent the gut), primarily by oxidative pathways via CYP3A4 to two main metabolites, 16α-hydroxyprednisolone and 6β-hydroxybudesonide, which have less than 1% of the corticosteroid activity of budesonide.

Elimination Budesonide had a high plasma clearance, 0.9 to

1.8L/min in healthy adults, which is close to the estimated liver blood flow, and, accordingly, suggests that budesonide is a high hepatic clearance drug. Following single oral administration of TARPEYO 16 mg to healthy subjects, the elimination half-life (t½) for TARPEYO ranged from 5.0 to 6.8 hours. Excretion Budesonide was excreted in urine and feces in the form of metabolites.

After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 16α-hydroxyprednisolone and 6β-hydroxybudesonide, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine.

Specific Populations Age, race, and body weight The effect of age, race, and body weight on the pharmacokinetics of TARPEYO has not been established. Sex Of the 143 healthy volunteers included in the Phase 1 studies, 29% were female. Pharmacokinetics of budesonide was similar between males and females.

Hepatic Impairment Subjects with moderate hepatic impairment (Child-Pugh class B) had 3.5 times the budesonide AUC compared with healthy volunteers while subjects with mild hepatic impairment (Child-Pugh class A) had approximately 1.4 times the budesonide AUC compared with healthy volunteers. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. Renal Impairment Intact budesonide is not excreted renally.

The main metabolites of budesonide, which have negligible corticosteroid activity, are largely (60%) excreted in urine. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase plasma levels of budesonide.

Thus, clinically relevant drug interactions with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, and grapefruit juice, are to be expected. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations. Effects of Other Drugs on Budesonide Ketoconazole In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily.

Co-administration of ketoconazole resulted in 8-fold the AUC of budesonide, compared to budesonide alone. In an open, randomized, cross-over study 8 healthy subjects were given Entocort EC 3 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 4 days treatment with ketoconazole 200 mg once daily. Co-administration of ketoconazole resulted in 6.5-fold the AUC of budesonide, compared to budesonide alone.

Grapefruit Juice In an open, randomized, cross-over study, 8 healthy subjects were given Entocort EC 3 mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Treatment with corticosteroids, including TARPEYO, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function.

14 CLINICAL STUDIES

14.1Treatment of IgAN TARPEYO was shown to reduce the loss of kidney function in adults with primary IgAN at risk of disease progression in the NefIgArd trial. While the effect on kidney function that was seen during the 9-month treatment period persisted following completion of treatment, TARPEYO did not change the long-term rate of decline in kidney function. NefIgArd Study: A Phase 3, Double-Blind Placebo-Controlled, Randomized Trial in Adults with Primary IgAN The effect of TARPEYO on proteinuria and kidney function (estimated glomerular filtration rate, eGFR) was assessed in a randomized, double-blind, phase 3, 2-part, multicenter study (NefIgArd, NCT: 03643965) in adults with biopsy-proven IgAN, eGFR ≥35 mL/min/1.73 m 2 , and proteinuria (defined as either ≥1 g/day or urine protein to creatinine ratio (UPCR) ≥0.8 g/g) who were on a stable dose of maximally-tolerated RAS inhibitor therapy.

Patients with other glomerulopathies, nephrotic syndrome, or those who had been treated with systemic immunosuppressive medications were excluded. Patients were randomized 1:1 to either TARPEYO 16 mg once daily or placebo and treated for nine months followed by a 2-week taper of either TARPEYO 8 mg once daily or placebo. Patients were then followed off-treatment for 15 months.

The primary endpoint for Part A of the study (interim analysis) was the ratio of UPCR (based on 24-hour urine collections) at 9 months compared to baseline based on the first 199 randomized patients who completed the Month 9 visit. The primary endpoint for Part B of the study (final analysis) was a time-weighted average of the log ratio of eGFR at each time point over 2 years relative to baseline. Of the 364 randomized patients evaluated for efficacy, 66% were male, 76% were Caucasian, 23% were Asian, and 20% were from North America.

The median age was 43 years (range 20 to 73 years). At baseline, the mean eGFR was approximately 58 mL/min/1.73 m 2 , with 60% of patients having an eGFR <60 mL/min/1.73 m 2 . The mean baseline UPCR was 1.5 g/g and 21% of patients had proteinuria >3.5 g/24 hours.

Approximately 70% of patients had a history of hypertension and 7% had a history of type 2 diabetes mellitus. At baseline, 98% were treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and <1% of patients were on a sodium-glucose cotransporter 2 (SGLT2) inhibitor. At study entry, the median systolic/diastolic blood pressure was 125/79 mmHg.

The trial met the prespecified Part A primary endpoint based on an interim analysis of 199 randomized patients who had completed the Month 9 visit. The interim analysis showed a 31% reduction in UPCR in patients treated with TARPEYO 16 mg once daily compared to placebo (95% CI: 16% to 42% reduction; p=0.0001). In the final analysis of 364 patients, the percentage change in UPCR observed at 9 months was consistent with the results in the subset of 199 patients included in the interim analysis.

The final analysis of the percentage change in UPCR during the treatment and follow-up phase is shown in Figure 1 . Figure 1: LS Mean (95% CI) Percentage Change from Baseline in UPCR (g/g) in NefIgArd Study (Full Analysis Set) Estimated mean percentage change from baseline in UPCR with 95% confidence intervals estimated from a mixed model repeated measures analysis of log-transformed post-baseline to baseline ratios at 3, 6, 9, 12, 18, and 24 months. Analysis included all UPCR data regardless of use of prohibited medication at any point during the study.

Values reported under the figure are converted to percent reduction from baseline. Relative percent reductions comparing TARPEYO and placebo are estimated from the regression model. Abbreviations: UPCR, urine protein to creatinine ratio; CI, confidence interval; LS, least squares.

In the final analysis of 364 patients, the trial met the prespecified Part B primary endpoint (p<0.0001). The mean change from baseline in eGFR and respecti… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.03 times the maximum recommended human dose (MRHD) on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.015 times the MRHD on a body surface area basis) and above.

No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.03 times the MRHD on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.03 times the MRHD on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.03 times the MRHD of a body surface area basis).

The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.06 times the MRHD on a body surface area basis). Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK +/- ) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethal test, the rat hepatocyte UDS test and the mouse micronucleus test.

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.05 times the MRHD on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal food consumption and body weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.012 times the MRHD on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.003 times the MRHD on a body surface area basis).