Nefecon Mechanism of Action

Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents, corticosteroids acting locally. ATC code: A07EA06.
Pharmacology: Pharmacodynamics: Mechanism of action: The intended action of Nefecon is the suppression of mucosal B-cells, located in the Peyer's patches in the ileum, and inhibition of their proliferation and differentiation into plasma cells that produce mucosal galactose-deficient IgA1 antibodies (Gd-IgA1). Consequently, it is expected that the occurrence of Gd-IgA1 antibodies and formation of immune complexes in the systemic circulation will be suppressed, therefore preventing the downstream effects of glomerular mesangial deposition of immune complexes containing Gd-IgA1, manifesting as glomerulonephritis and loss of renal function.
Pharmacodynamic effects: Nefecon is an oral, modified-release hard capsule formulation of budesonide which combines a delayed capsule disintegration with a prolonged release of the active substance budesonide in the ileum. By directing the release of budesonide to the ileum, where Peyer's patches reside in high density, a local pharmacological effect is anticipated.
Clinical efficacy: Primary IgA nephropathy: The efficacy of Nefecon has been evaluated in 2 randomised, double-blind, placebo-controlled studies of patients with primary IgAN, who were receiving Renin-Angiotensin System (RAS) inhibitor therapy. In both studies the primary endpoint evaluated proteinuria reduction by urine protein creatinine ratio (UPCR) at 9 months compared to baseline, with key secondary endpoint analyses of renal function based on estimated glomerular filtration rate (eGFR) at 9 and 12 months.
In 199 of the first 201 patients randomised who have completed part A of a phase 3 study, patients treated with Nefecon 16 mg once daily showed a statistically significant and clinically relevant 27% reduction in UPCR compared to placebo in the overall study population (p=0.0003) after 9 months of treatment. UPCR at 9 months was reduced from baseline by 31% in patients treated with Nefecon 16 mg once-daily compared with 5% in placebo-treated patients. After 3 months of observational follow up without treatment, the reduction in UPCR improved to 48% compared to placebo at 1 year (p<0.0001).
Consistent with the assessment of proteinuria reduction by UPCR, a 31% reduction in urine albumin creatinine ratio (UACR) compared to placebo was observed at 9 months (p=0.0005), and a 54% reduction in UACR at 12 months (p<0.0001).
After 9 months of treatment, Nefecon 16 mg once daily provided a statistically significant and clinically relevant 7% treatment benefit on eGFR CKD-EPI (serum creatinine) compared to placebo (p=0.0014). This 3.87 mL/min/1.73 m² treatment benefit at 9 months corresponded to a slight reduction from baseline of 0.17 mL/min/1.73 m² in patients who received Nefecon 16 mg once daily and a deterioration from baseline of 4.04 mL/min/1.73 m² in patients who received placebo.
The improvement in 1-year eGFR slope was 3.37 mL/min/1.73 m² per year with Nefecon 16 mg once daily compared to placebo (p=0.0111).
The effect of Nefecon treatment on stabilisation of the rate of loss of renal function was greater in patients with higher baseline proteinuria compared to the overall population. In patients with baseline UPCR ≥1.5 g/gram, the improvement in 1-year eGFR chronic slope (from 3 months onwards) was 7.62 mL/min/1.73 m² per year with Nefecon 16 mg once daily compared to placebo (p=0.0068), and the corresponding improvement in 1-year eGFR total slope was 9.31 mL/min/1.73 m² per year (p=0.0005).
A supportive phase 2b study with a similar study design was conducted in a total of 153 randomised patients who received Nefecon 16 mg, Nefecon 8 mg, or placebo, once daily for 9 months, while continuing to receive RAS inhibitor therapy.
The primary objective was met at an interim analysis that compared Nefecon to placebo, and showed a statistically significant reduction in UPCR at 9 months for the combined Nefecon 16 mg/day and 8 mg/day dose groups compared to placebo (p=0.0066).
Using the same statistical methodology as in the phase 3 study, a statistically significant 26% reduction in the primary endpoint UPCR was shown at 9 months for the 16 mg dose of Nefecon versus placebo (p=0.0100) and a 29% reduction at 12 months (p=0.0027).
The difference in eGFR CKD-EPI (serum creatinine) for the 16 mg dose of Nefecon versus placebo was 3.57 mL/min/1.73 m² at 9 months (p=0.0271), and 4.46 mL/min/1.73 m² at 12 months (p=0.0256). The improvement in 1-year eGFR slope was estimated to be 5.69 mL/min/1.73 m² per year with Nefecon 16 mg once daily compared to placebo (p=0.0007).
Paediatric population: Nefecon has not been studied in the paediatric population.
Pharmacokinetics: Absorption: The Nefecon formulation is designed to deliver budesonide topically in the ileum. Oral absorption of budesonide seems to be complete and is rapid, whereas systemic bioavailability due to high first-pass metabolism is low (approximately 10%).
Following single oral administration of Nefecon 16 mg to healthy subjects, the geometric mean C_max ranged between 3.2 and 4.4 ng/mL, and AUC_(0-24) ranged between 24.1 and 24.8 ng/mL×h.
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 dosing.
Distribution: Budesonide is rapidly and extensively distributed into tissues and organs. Approximately 85 to 90% of budesonide binds to plasma proteins in blood over the concentration range of 1 to 100 nmol/L. The volume of distribution at steady state is 3 to 4 L/kg.
Biotransformation: Budesonide is rapidly metabolised 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 glucocorticosteroid receptor affinity and anti-inflammatory activity of budesonide.
The metabolism of budesonide is 2- to 5-fold faster than that of hydrocortisone and 8- to 15-fold faster than that of prednisolone.
Elimination: Budesonide has a high clearance rate of approximately 72 to 80 L/h, which is close to the estimated liver blood flow, and, accordingly, suggests that budesonide is a high hepatic clearance medicinal product.
T_½ for budesonide after dosing with Nefecon ranged from 5 to 6.8 hours in healthy volunteer studies.
Budesonide is excreted in urine and feces in the form of metabolites. 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.
Hepatic impairment: Budesonide is predominantly metabolised by hepatic biotransformation.
In subjects with moderate hepatic impairment (Child-Pugh class B), systemic availability of orally administered budesonide was 3.5-fold higher (27%) compared with healthy volunteers (systemic availability 7.4%); there was no clinically relevant increase in systemic availability in patients with mild hepatic impairment (Child-Pugh class A).
Patients with severe hepatic impairment have not been studied.
Renal impairment: Intact budesonide is not excreted renally. The main metabolites of budesonide, which have negligible glucocorticosteroid activity, are largely (60%) excreted in urine.
Paediatric population: Nefecon was not studied in the paediatric population.
Toxicology: Preclinical safety data: The preclinical safety of budesonide has been documented in studies during the development of other formulations of this compound. No preclinical studies have been conducted with the Nefecon formulation itself.
Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex, are less severe or similar to those observed after administration of other glucocorticosteroids.
Budesonide, evaluated in six different test systems, did not show any signs of mutagenic or clastogenic effects.
An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control group.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect in this species.
Available clinical experience shows that there are no indications that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in humans.
Budesonide had no effect on fertility in rats. In pregnant animals, budesonide, like other glucocorticoids, has been shown to cause foetal death and abnormalities of foetal development (smaller litter size, intrauterine growth retardation of foetuses and skeletal abnormalities). The clinical relevance of these findings to human has not been established (see Use in Pregnancy & Lactation).
The toxicity of budesonide modified-release hard capsules, with focus on the gastro-intestinal tract, has been studied in cynomolgus monkeys at doses of up to 5 mg/kg (approximately 15 times the recommended daily dose of Nefecon in humans on a dose per body weight basis) after repeated oral administration for up to 6 months. No effects were observed in the gastrointestinal tract, either from gross pathology or histopathological examination.