Risk Summary

The available data from published case series, epidemiological studies and reviews with oral budesonide use in pregnant women have not identified 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 IgA Nephropathy. Infants exposed to in-utero corticosteroids, including budesonide, are at risk for hypoadrenalism (see Clinical Considerations). In animal reproduction studies with pregnant rats and rabbits, administration of subcutaneous budesonide during organogenesis at doses approximately 0.3 times or 0.03 times, respectively, the maximum recommended human dose (MRHD), resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels (see Data).

The estimated background risk of major birth defects and miscarriage of 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 and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Data

Risk Summary

Breastfeeding is not expected to result in significant exposure of the infant to TARPEYO. Lactation studies have not been conducted with oral budesonide, including TARPEYO, and no information is available on the effects of the drug on the breastfed infant or the effects on the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide (see Data). Routine monitoring of linear growth in infants is recommended with chronic use of budesonide in the nursing mother. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TARPEYO and any potential adverse effects on the breastfed infant from TARPEYO, or from the underlying maternal condition.

Data

One published study reports that budesonide is present in human milk following maternal inhalation of budesonide, which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk to plasma ratio was approximately 0.5. Budesonide was not detected in plasma, and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide.

Assuming a daily average milk intake of about 150 mL/kg/day and a milk to plasma ratio of 0.5, the estimated oral dose of budesonide for a 5 kg infant is expected to be less than 2 mcg/day for a maternal dose of 16 mg TARPEYO. Assuming 100% bio-availability in the infant this is about 0.1% of the maternal dose and about 3% of the highest inhaled dose used clinically for asthma in infants.

Absorption

Following single oral administration of TARPEYO 16 mg to healthy subjects, the average geometric mean Cmax (CV%) was 4.4 ng/mL (58.3), and AUC0-24 was 24.1 h*ng/mL (49.7). Median Tlag (min, max) was 3.1 h (0, 6) while median Tmax (min, max) was 5.1 h (4.5, 10).

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 1.8 L/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 [3H]-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

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 CYP3A 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.

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 m2, and proteinuria (defined as either ≥1 g/day or 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 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 m2, with 60% of patients having an eGFR <60 mL/min/1.73 m2. 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 intervals; 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 respective 95% CI for each arm at each scheduled visit during the treatment and follow-up phase is shown in Figure 2. The favorable effect of TARPEYO on eGFR was seen by Month 3 (the earliest assessment) and did not appear to increase in magnitude over two years. At Year 2, there was a 5.9 mL/min/1.73 m2 difference in the mean change from baseline in eGFR between TARPEYO and placebo (95% CI: 3.3 to 8.5 mL/min/1.73 m2; p<0.0001).

Figure 2: LS Mean (95% CI) Change from Baseline in eGFR (mL/min/1.73 m2) in NefIgArd Study (Full Analysis Set)

   Estimated least squares mean change from baseline in eGFR (mL/min/1.73 m2) with 95% confidence intervals estimated from a mixed model repeated measures analysis of post-baseline to baseline differences at 3, 6, 9, 12, 18, and 24 months. Analysis was based on untransformed data and includes all eGFR data regardless of use of prohibited medication at any point during the study. A total of 15 patients in the TARPEYO arm and 20 patients in the placebo arm received rescue medication during the 2-year study.

   Abbreviations: eGFR, estimated glomerular filtration rate; CI, confidence interval; LS least squares

The treatment effect based on the change from baseline in eGFR at 2 years was consistent across key subgroups, including key demographic (such as age, sex, race) and baseline disease (such as baseline proteinuria) characteristics.