- Approval Id
- edf0aaa45e7a936a
- Drug Approval Emc Name
- Kinpeygo 4 mg modified release hard capsules
- Drug Name
- Kinpeygo 4 mg modified release hard capsules
- Company Name
- Genus Pharmaceuticals
- Company Address
- Linthwaite, Huddersfield, West Yorkshire, HD7 5QH, UK
- Company Telephone
- +44 (0)1484842217
- Company Medical Info Direct Line
- +44 (0)1484 848164
- Company Medical Info Email
- thorntonross@medinformation.co.uk
- Company Customer Care Direct Line
- +44 (0)1484 848200
- Company Medical Info Fax
- +44 (0)1484 848164
- Atc Code
- A07EA06
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Genus Pharmaceuticals Holdings Ltd. (trading as 'STADA'),
Linthwaite, Huddersfield,
HD7 5QH, UK
- Authorisation Number
- PLGB 17225/0027
- Authorisation Date
- 01/02/2023
- Instruction Authorisation Holder
- Genus Pharmaceuticals Holdings Ltd. (trading as 'STADA'),
Linthwaite, Huddersfield,
HD7 5QH, UK
- Instruction Authorisation Number
- PLGB 17225/0027
- Instruction Authorisation Date
- 01/02/2023
- Instruction Composition
- Each modified-release hard capsule contains budesonide 4 mg.
Excipient(s) with known effect
Each capsule contains 230 mg of sucrose.
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Modified-release hard capsule.
19 mm white coated opaque capsules printed with “CAL10 4MG” in black ink.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Kinpeygo is indicated for the treatment of adults with primary immunoglobulin A nephropathy (IgAN) with a urine protein excretion ≥1.0 g/day (or urine protein-to-creatinine ratio ≥0.8 g/g).4.2 Posology and method of administration
Posology
The recommended dose is 16 mg once daily in the morning, at least one hour before a meal, for an initial duration of 9 months. When treatment is to be discontinued, the dose should be reduced to 8 mg once daily for 2 weeks of therapy; the dose may be reduced to 4 mg once daily for an additional 2 weeks, at the discretion of the treating physician.
Re-treatment may be considered at the discretion of the treating physician. Safety and efficacy of treatment with subsequent courses of Kinpeygo have not been established.
If the patient forgets to take Kinpeygo, the patient should take Kinpeygo the next day, in the morning as usual. The patient should not double the daily dose to make up for a missed dose.
\*Special populations\*
\*Elderly\*
Experience of the use of Kinpeygo in the elderly is limited. However, from the clinical data available, the efficacy and safety of Kinpeygo are expected to be similar to that of other age groups studied.
\*Hepatic impairment\*
The safety and efficacy of Kinpeygo capsules in patients with hepatic impairment have not been studied.
Kinpeygo is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). See section 4.3, 4.4 and 5.2.
\*Renal impairment\*
The pharmacokinetics of budesonide are not expected to be altered in patients with renal impairment.
\*Paediatric population\*
The safety and efficacy of Kinpeygo capsules in children and adolescents below 18 years of age have not yet been established. No data are available.
Method of administration
Kinpeygo is for oral use. The modified-release hard capsules should be swallowed whole with water in the morning, at least 1 hour before a meal (see section 5.2). The capsules must not be opened, crushed or chewed, as it could affect the release profile.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with severe hepatic impairment (Child-Pugh Class C).4.4 Special warnings and precautions for use
Hypercorticism and adrenal axis suppression
When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended.
Since Kinpeygo contains a glucocorticosteroid, general warnings concerning glucocorticosteroids, as given below, should be followed.
Hepatic impairment
Patients with moderate or severe hepatic impairment (Child-Pugh Class B or C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Patients with moderate hepatic impairment (Child-Pugh Class B) should be monitored for increased signs and/or symptoms of hypercorticism.
Symptoms of steroid withdrawal in patients transferred from systemic corticosteroids
Patients who are transferred from glucocorticosteroid treatment with high systemic availability to glucocorticosteroids with lower systemic availability, such as budesonide, should be monitored since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.
Replacement of systemic glucocorticosteroids with budesonide may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic medicinal product.
Infections
Patients who are on medicinal products that suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.
How the dose, route, and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed to chickenpox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See Summaries of Product Characteristics for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered.
Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.
Caution with special diseases
Patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where use of glucocorticosteroids may be associated with an increased risk of adverse effects, should be monitored.
Visual disturbance
Visual disturbance may be reported with systemic and topical glucocorticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical glucocorticosteroids.
Concomitant treatment with potent CYP3A4 inhibitors
Concomitant treatment with potent CYP3A4 inhibitors, including ketoconazole and cobicistat-containing products, is expected to increase the risk of systemic side effects attributable to budesonide. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticosteroid side effects. If this is not possible, the period between treatments should be as long as possible and a reduction of the budesonide dose to 8 mg budesonide daily could also be considered (see section 4.5).
After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure to budesonide after oral administration increased approximately two-fold. As with other medicinal products primarily metabolised through CYP3A4, regular ingestion of grapefruit or its juice should be avoided in connection with Kinpeygo administration (other juices such as orange juice or apple juice do not inhibit CYP3A4). See also section 4.5.
ACTH stimulation test
Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).
Sucrose
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicinal product.4.5 Interaction with other medicinal products and other forms of interaction
Medicinal products/substances inhibiting CYP3A4
Budesonide is metabolised via CYP3A4. Potent inhibitors of CYP3A4 can increase plasma levels of budesonide. Co-administration of the potent CYP3A4 inhibitor ketoconazole or intake of grapefruit juice resulted in a 6.5-fold and 2-fold increase, respectively in the bioavailability of budesonide, compared to budesonide alone.
Thus, clinically relevant interactions with potent CYP3A inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, and grapefruit juice, are to be expected, and may increase systemic budesonide concentrations (see sections 4.4 and 5.2).
Medicinal products/substances inducing CYP3A4
Concomitant treatment with CYP3A4 inducers such as carbamazepine may reduce budesonide systemic exposure.
Medicinal products/substances metabolised by CYP3A4
Given its low affinity for CYP3A4 and P-gp, as well as the formulation, pharmacokinetic (PK) characteristics and low systemic exposure, Kinpeygo is unlikely to affect the systemic exposure of other medicinal products.
Oral contraceptives
Oral contraceptives containing ethinyl estradiol, which are also metabolised by CYP3A4, do not affect the pharmacokinetics of budesonide.
Proton pump inhibitors
The pharmacokinetics of budesonide have not been evaluated in combination with proton pump inhibitors (PPIs). In a study assessing intragastric and intraduodenal pH in healthy volunteers after repeated dosing with the PPI omeprazole 40 mg once daily, intragastric and intraduodenal pH did not exceed that required for disintegration of Kinpeygo. Beyond the duodenum, PPIs such as omeprazole are unlikely to affect pH.
Other interactions to be considered
Budesonide treatment may reduce serum potassium, which should be considered when Kinpeygo is co-administered with a medicinal product where the pharmacological effects may be potentiated by low serum potassium, such as cardiac glucosides, or when co-administered with diuretics that lower serum potassium.4.6 Fertility, pregnancy and lactation
Pregnancy
Administration during pregnancy should be avoided unless there are compelling reasons for therapy with Kinpeygo. There are only few data of pregnancy outcomes after oral administration of budesonide in humans. Although data on the use of inhaled budesonide in a large number of exposed pregnancies indicate no adverse effect, the maximal concentration of budesonide in plasma is expected to be higher in association with treatment with Kinpeygo compared to inhaled budesonide. In pregnant animals budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of fetal development (see section 5.3). The relevance of this to man has not been established.
Therefore, Kinpeygo should not be used during pregnancy unless the clinical condition of the woman requires treatment with budesonide. The expected benefits for the pregnant woman have to be weighed against the potential risk for the fetus.
Budesonide was found to cross the placental barrier. The relevance of this observation to humans has not been established.
Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in utero; carefully observe neonates for signs and symptoms of hypoadrenalism.
Breast-feeding
Budesonide is excreted in breast milk.
Lactation studies have not been conducted with oral budesonide, including Kinpeygo, and no information is available on the effects of the medicinal product on the breast-fed infant or the effects of the medicinal product on milk production. A risk to the breast-fed infant cannot be excluded.
If Kinpeygo is used when a mother is breast-feeding, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from budesonide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
There are no data on the effect of budesonide on human fertility. There were no effects on fertility in rats after treatment with budesonide.4.7 Effects on ability to drive and use machines
No studies on the effects of Kinpeygo on the ability to drive and use machines have been performed. It is expected that Kinpeygo has no or negligible influence on the ability to drive or use machinery.4.8 Undesirable effects
Summary of the safety profile
In the Kinpeygo phase 3 clinical study the most commonly reported adverse drug reactions were acne reported in approximately 10% of patients, peripheral oedema, face oedema, weight increased and white blood cell count increased, each occurring in approximately 5% of patients; these were mainly of mild or moderate severity and reversible, reflecting the low systemic exposure to budesonide after oral administration.
Tabulated list of adverse reactions
Adverse drug reactions reported in the pivotal phase 3 clinical study and from post-marketing data with Kinpeygo are presented in Table 1.
Adverse reactions reported are listed according to the following frequency: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
\*\*Table 1: Adverse drug reactions by frequency and system organ class\*\*
| | | |
| --- | --- | --- |
| \*\*MedDRA system organ classification\*\* | \*\*Frequency\*\* | \*\*Reaction\*\* |
| Blood and lymphatic system disorders | Common | White blood cell count increased |
| Common | Neutrophil count increased |
| Endocrine disorders | Common | Cushingoid |
| Metabolism and nutrition disorders | Very common | Hypokalaemia |
| Common | Diabetes mellitus\\* |
| Eye disorders | Rare | Vision blurred (see also section 4.4) |
| Vascular disorders | Common | Hypertension |
| Gastrointestinal disorders | Common | Dyspepsia |
| Skin and subcutaneous tissue disorders | Very common | Skin reactions (acne, dermatitis) |
| Musculoskeletal and connective tissue disorders | Common | Muscle spasms |
| General disorders and administration site conditions | Common | Oedema peripheral |
| Common | Face oedema |
| Common | Weight increased |
\\* All patients with new onset of diabetes diagnosed during or following Kinpeygo treatment had levels of FBG and HbA1c prior to the start of treatment that were indicative of pre-diabetes (HbA1c ≥ 5.7% or FBG≥100 mg/dL).
Description of selected adverse reactions
\*Potential class effects\*
Adverse drug reactions typical of systemic glucocorticosteroids may occur (e.g., cushingoid features, increased blood pressure, increased risk of infection, delayed wound healing, reduced glucose tolerance, sodium retention with oedema formation, muscle weakness, osteoporosis, glaucoma, mental disorders, peptic ulcer, increased risk of thrombosis). These adverse drug reactions are dependent on dose, treatment time, concomitant and previous glucocorticosteroid intake, and individual sensitivity. Not all of these adverse reactions were observed in the clinical study program of Kinpeygo.
Paediatric population
No data available.
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
Reports of acute toxicity or death following overdose of glucocorticosteroids are rare. Acute overdose, even in excessive doses, is not expected to lead to clinically significant consequences. In the event of acute overdose, no specific antidote is available. Treatment consists supportive and symptomatic therapy.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents, corticosteroids acting locally, ATC code: A07EA06
Mechanism of action
The intended action of Kinpeygo is the suppression of mucosal B-cells, located in the Peyer's patches in the ileum where the majority of galactose-deficient IgA1 antibodies (Gd-IgA1) are produced. The inhibition of their proliferation and differentiation into plasma cells is expected to lower the occurrence of Gd-IgA1 antibodies and hence the formation of immune complexes in the systemic circulation, 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
Kinpeygo 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 Kinpeygo has been evaluated in 2 randomised, double-blind, placebo-controlled studies of patients with primary IgAN, who were receiving optimised dose (maximum allowed dose or maximum tolerated dose) of Renin-Angiotensin System (RAS) inhibitor therapy as a standard of care (SOC). The effect of Kinpeygo on kidney function decline based on estimated glomerular filtration rate (eGFR) and proteinuria reduction based on urine protein creatinine ratio (UPCR) was assessed in a randomised, double-blind, multicentre phase 3 study in patients with biopsy proven IgAN. 364 patients in the Full Analysis Set were randomised 1:1 to either Kinpeygo 16 mg once daily or placebo and treated for 9 months followed by a 2-week taper phase of 8 mg and 15 months of observational follow-up.
The final analysis of the study demonstrated that over the 2-year period, a 9-month treatment course of Kinpeygo (Nefecon) 16 mg/day reduced the loss of kidney function at 2 years in patients with primary IgAN in a statistically significant manner. The eGFR benefit accrued by the end of 9 months of treatment was maintained during 15 months of observational follow-up (Figure 1).
\*\*Figure 1: Mean absolute change in eGFR from baseline in Phase 3 NefIgArd Study\*\*
The treatment effect eGFR difference at 2 years was 6.00 mL/min/1.73 m2 using the MMRM analysis without explicit missing data assumptions (MAR assumption) and was statistically significant. The change from baseline in eGFR at 24 months was -7.50 mL/min/1.73 m2 in the Kinpeygo group compared to -13.50 mL/min/1.73 m2 in the placebo group; there was a treatment benefit of 6.00 mL/min/1.73 m2 (95% CI: 2.76 to 10.08) with Kinpeygo treatment compared to placebo (Table 2).
A supplementary analysis of 2-year eGFR total slope using a linear spline mixed effects analysis method to account for the acute (baseline to 3 months) and chronic (from 3 months onwards) phases estimated an overall treatment benefit of 2.62 mL/min/1.73 m2 per year (95% CI 1.23 to 4.00) in favour of Kinpeygo (Table 2).
\*\*Table 2: Analysis of eGFR at 24 months in Phase 3 NefIgArd Study\*\*
| | | |
| --- | --- | --- |
| \*\*eGFR (CKD-EPI) (mL/min/1.73 m2) a\*\* | \*\*Kinpeygo\*\* \*\*16 mg\*\* \*\*(N=182)\*\* | \*\*Placebo\*\* \*\*(N=182)\*\* |
| \*\*Mean change from baseline (mL/min/1.73 m2)\*\* at 24 months (15 months after Kinpeygo treatment ended) b | -7.50 | -13.50 |
| \*Kinpeygo 16 mg versus Placebo:\* (95% CI) Change from baseline in eGFR at 24 months (mL/min/1.73 m2) b 2-year eGFR total slope (mL/min/1.73 m2 per year) c | 6.00 (2.76 to 10.08) 2.62 (1.23 to 4.00) | |
a Including all observed eGFR data recorded after use of prohibited medication.
b Adjusted geometric least squares mean ratio of eGFR relative to baseline analysed using mixed model repeated measures analysis. Mean changes derived directly from the analysis performed on a log scale.
c Linear-spline mixed effects model in which eGFR was modelled simultaneously and separately over the acute (baseline to 3 months) and chronic (from 3 months onwards) phases and then combined to estimate the overall total slope. Data not log-transformed and including all observed eGFR data regardless of the use of prohibited medications or starting dialysis or having a renal transplant.
CI: confidence interval; eGFR (CKD-EPI): estimated glomerular filtration rate based on Chronic Kidney Disease Epidemiology Collaboration calculation
The 2-year eGFR treatment effect was consistent across all key subgroups, including key demographic (such as age, sex, race) and baseline disease (such as baseline proteinuria) characteristics.
The time to a confirmed 30% reduction in eGFR or end-stage renal disease (defined as renal-related death, renal transplantation, dialysis, or sustained eGFR <15 mL/min/1.73 m2) was delayed in patients who received Kinpeygo compared with those who received placebo (HR 0.45; 95% CI 0.26 to 0.75). The proportion of patients with a confirmed event over the 2-year study period was 11.5% in the Kinpeygo group versus 21.4% of patients in the placebo group.
The final analysis of treatment effect on proteinuria at 2 years was consistent with that observed at the end of the 9 months course of Kinpeygo treatment. However, in the Kinpeygo treatment arm proteinuria increased after a peak reduction at 12 months (Table 3). The UPCR treatment effect at 9 months was highly consistent across subgroups, including key demographic (such as age, sex, race) and baseline disease (such as baseline proteinuria) characteristics. A similarly consistent pattern in UPCR across subgroups was observed at 2 years.
\*\*Table 3: Proteinuria reduction at 9, 12, and 24 months and averaged over 12 to 24 months in Phase 3 NefIgArd Study\*\*
| | | |
| --- | --- | --- |
| \*\*Percentage reduction from baseline in UPCR g/g a, b\*\* | \*\*Kinpeygo\*\* \*\*16 mg\*\* \*\*(N=182)\*\* | \*\*Placebo\*\* \*\*(N=182)\*\* |
| At 9 months c | 34% | 5% |
| At 12 months (3 months after Kinpeygo treatment ended) | 51% | 3% |
| At 24 months (15 months after Kinpeygo treatment ended) | 31% | 1% |
| \*Kinpeygo 16 mg versus placebo\*: Average UPCR percentage reduction over 12 to 24 months compared to baseline d (95% CI) | 41% (32% to 49%) | |
a Excluding UPCR data recorded after use of prohibited medication.
b Adjusted geometric least squares mean ratio of UPCR relative to baseline were based on a longitudinal repeated measures model.
c Percent reduction in UPCR was previously evaluated in the first 199 patients randomised (p=0.0003). The final analysis in all 364 patients confirmed a 30% reduction in UPCR at 9 months with Kinpeygo compared with placebo (95% CI 20% to 39%).
d Average UPCR percentage reduction during follow-up (over 12 to 24 months) based on longitudinal repeated measures model.
CI: confidence interval; UPCR: urine protein creatinine ratio.
A supportive phase 2b study with a similar study design was conducted in a total of 153 randomised patients who received Kinpeygo 16 mg, Kinpeygo 8 mg, or placebo, once daily for 9 months followed by a 2-week taper phase and 3 months of observational follow-up, while continuing to receive RAS inhibitor therapy.
The primary objective was met at an interim analysis that compared Kinpeygo to placebo and showed a statistically significant reduction in UPCR at 9 months for the combined Kinpeygo 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 Kinpeygo 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 Kinpeygo versus placebo was 3.57 mL/min/1.73m2 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 Kinpeygo 16 mg once daily compared to placebo (p=0.0007).
Paediatric population
Kinpeygo has not been studied in the paediatric population.5.2 Pharmacokinetic properties
Absorption
The Kinpeygo 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 Kinpeygo 16 mg to healthy subjects, the geometric mean Cmax 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.
T½ for budesonide after dosing with Kinpeygo 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
Kinpeygo was not studied in the paediatric population.5.3 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 Kinpeygo 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 caues 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 section 4.6).
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 Kinpeygo 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.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Capsule content
Sugar spheres (sucrose and corn starch)
Hypromellose
Macrogol
Citric acid monohydrate
Ethylcellulose
Medium chain triglycerides
Oleic acid
Capsule shell
Hypromellose
Macrogol
Titanium dioxide (E171)
Methacrylic acid - methyl methacrylate co-polymers
Talc
Dibutylsebacate
Printing ink
Shellac
Black iron oxide (E172)6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years6.4 Special precautions for storage
Do not store above 25°C.6.5 Nature and contents of container
White high density polyethylene (HDPE) bottle with a white polypropylene (PP) child-resistant closure with an induction seal.
Or
Polyamide/Aluminium/Polyvinyl chloride//Aluminium (oPA/Al/PVC//Al) blisters.
Pack size: 1 bottle containing 28, 120 modified-release hard capsules.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
Each modified-release hard capsule contains budesonide 4 mg.
Excipient(s) with known effect
Each capsule contains 230 mg of sucrose.
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Modified-release hard capsule.
19 mm white coated opaque capsules printed with “CAL10 4MG” in black ink.
## Clinical Particulars
4.1 Therapeutic indications
Kinpeygo is indicated for the treatment of adults with primary immunoglobulin A nephropathy (IgAN) with a urine protein excretion ≥1.0 g/day (or urine protein-to-creatinine ratio ≥0.8 g/g).4.2 Posology and method of administration
Posology
The recommended dose is 16 mg once daily in the morning, at least one hour before a meal, for an initial duration of 9 months. When treatment is to be discontinued, the dose should be reduced to 8 mg once daily for 2 weeks of therapy; the dose may be reduced to 4 mg once daily for an additional 2 weeks, at the discretion of the treating physician.
Re-treatment may be considered at the discretion of the treating physician. Safety and efficacy of treatment with subsequent courses of Kinpeygo have not been established.
If the patient forgets to take Kinpeygo, the patient should take Kinpeygo the next day, in the morning as usual. The patient should not double the daily dose to make up for a missed dose.
\*Special populations\*
\*Elderly\*
Experience of the use of Kinpeygo in the elderly is limited. However, from the clinical data available, the efficacy and safety of Kinpeygo are expected to be similar to that of other age groups studied.
\*Hepatic impairment\*
The safety and efficacy of Kinpeygo capsules in patients with hepatic impairment have not been studied.
Kinpeygo is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). See section 4.3, 4.4 and 5.2.
\*Renal impairment\*
The pharmacokinetics of budesonide are not expected to be altered in patients with renal impairment.
\*Paediatric population\*
The safety and efficacy of Kinpeygo capsules in children and adolescents below 18 years of age have not yet been established. No data are available.
Method of administration
Kinpeygo is for oral use. The modified-release hard capsules should be swallowed whole with water in the morning, at least 1 hour before a meal (see section 5.2). The capsules must not be opened, crushed or chewed, as it could affect the release profile.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with severe hepatic impairment (Child-Pugh Class C).4.4 Special warnings and precautions for use
Hypercorticism and adrenal axis suppression
When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended.
Since Kinpeygo contains a glucocorticosteroid, general warnings concerning glucocorticosteroids, as given below, should be followed.
Hepatic impairment
Patients with moderate or severe hepatic impairment (Child-Pugh Class B or C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Patients with moderate hepatic impairment (Child-Pugh Class B) should be monitored for increased signs and/or symptoms of hypercorticism.
Symptoms of steroid withdrawal in patients transferred from systemic corticosteroids
Patients who are transferred from glucocorticosteroid treatment with high systemic availability to glucocorticosteroids with lower systemic availability, such as budesonide, should be monitored since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.
Replacement of systemic glucocorticosteroids with budesonide may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic medicinal product.
Infections
Patients who are on medicinal products that suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.
How the dose, route, and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed to chickenpox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See Summaries of Product Characteristics for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered.
Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.
Caution with special diseases
Patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where use of glucocorticosteroids may be associated with an increased risk of adverse effects, should be monitored.
Visual disturbance
Visual disturbance may be reported with systemic and topical glucocorticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical glucocorticosteroids.
Concomitant treatment with potent CYP3A4 inhibitors
Concomitant treatment with potent CYP3A4 inhibitors, including ketoconazole and cobicistat-containing products, is expected to increase the risk of systemic side effects attributable to budesonide. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticosteroid side effects. If this is not possible, the period between treatments should be as long as possible and a reduction of the budesonide dose to 8 mg budesonide daily could also be considered (see section 4.5).
After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure to budesonide after oral administration increased approximately two-fold. As with other medicinal products primarily metabolised through CYP3A4, regular ingestion of grapefruit or its juice should be avoided in connection with Kinpeygo administration (other juices such as orange juice or apple juice do not inhibit CYP3A4). See also section 4.5.
ACTH stimulation test
Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).
Sucrose
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicinal product.4.5 Interaction with other medicinal products and other forms of interaction
Medicinal products/substances inhibiting CYP3A4
Budesonide is metabolised via CYP3A4. Potent inhibitors of CYP3A4 can increase plasma levels of budesonide. Co-administration of the potent CYP3A4 inhibitor ketoconazole or intake of grapefruit juice resulted in a 6.5-fold and 2-fold increase, respectively in the bioavailability of budesonide, compared to budesonide alone.
Thus, clinically relevant interactions with potent CYP3A inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, and grapefruit juice, are to be expected, and may increase systemic budesonide concentrations (see sections 4.4 and 5.2).
Medicinal products/substances inducing CYP3A4
Concomitant treatment with CYP3A4 inducers such as carbamazepine may reduce budesonide systemic exposure.
Medicinal products/substances metabolised by CYP3A4
Given its low affinity for CYP3A4 and P-gp, as well as the formulation, pharmacokinetic (PK) characteristics and low systemic exposure, Kinpeygo is unlikely to affect the systemic exposure of other medicinal products.
Oral contraceptives
Oral contraceptives containing ethinyl estradiol, which are also metabolised by CYP3A4, do not affect the pharmacokinetics of budesonide.
Proton pump inhibitors
The pharmacokinetics of budesonide have not been evaluated in combination with proton pump inhibitors (PPIs). In a study assessing intragastric and intraduodenal pH in healthy volunteers after repeated dosing with the PPI omeprazole 40 mg once daily, intragastric and intraduodenal pH did not exceed that required for disintegration of Kinpeygo. Beyond the duodenum, PPIs such as omeprazole are unlikely to affect pH.
Other interactions to be considered
Budesonide treatment may reduce serum potassium, which should be considered when Kinpeygo is co-administered with a medicinal product where the pharmacological effects may be potentiated by low serum potassium, such as cardiac glucosides, or when co-administered with diuretics that lower serum potassium.4.6 Fertility, pregnancy and lactation
Pregnancy
Administration during pregnancy should be avoided unless there are compelling reasons for therapy with Kinpeygo. There are only few data of pregnancy outcomes after oral administration of budesonide in humans. Although data on the use of inhaled budesonide in a large number of exposed pregnancies indicate no adverse effect, the maximal concentration of budesonide in plasma is expected to be higher in association with treatment with Kinpeygo compared to inhaled budesonide. In pregnant animals budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of fetal development (see section 5.3). The relevance of this to man has not been established.
Therefore, Kinpeygo should not be used during pregnancy unless the clinical condition of the woman requires treatment with budesonide. The expected benefits for the pregnant woman have to be weighed against the potential risk for the fetus.
Budesonide was found to cross the placental barrier. The relevance of this observation to humans has not been established.
Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in utero; carefully observe neonates for signs and symptoms of hypoadrenalism.
Breast-feeding
Budesonide is excreted in breast milk.
Lactation studies have not been conducted with oral budesonide, including Kinpeygo, and no information is available on the effects of the medicinal product on the breast-fed infant or the effects of the medicinal product on milk production. A risk to the breast-fed infant cannot be excluded.
If Kinpeygo is used when a mother is breast-feeding, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from budesonide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
There are no data on the effect of budesonide on human fertility. There were no effects on fertility in rats after treatment with budesonide.4.7 Effects on ability to drive and use machines
No studies on the effects of Kinpeygo on the ability to drive and use machines have been performed. It is expected that Kinpeygo has no or negligible influence on the ability to drive or use machinery.4.8 Undesirable effects
Summary of the safety profile
In the Kinpeygo phase 3 clinical study the most commonly reported adverse drug reactions were acne reported in approximately 10% of patients, peripheral oedema, face oedema, weight increased and white blood cell count increased, each occurring in approximately 5% of patients; these were mainly of mild or moderate severity and reversible, reflecting the low systemic exposure to budesonide after oral administration.
Tabulated list of adverse reactions
Adverse drug reactions reported in the pivotal phase 3 clinical study and from post-marketing data with Kinpeygo are presented in Table 1.
Adverse reactions reported are listed according to the following frequency: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
\*\*Table 1: Adverse drug reactions by frequency and system organ class\*\*
| | | |
| --- | --- | --- |
| \*\*MedDRA system organ classification\*\* | \*\*Frequency\*\* | \*\*Reaction\*\* |
| Blood and lymphatic system disorders | Common | White blood cell count increased |
| Common | Neutrophil count increased |
| Endocrine disorders | Common | Cushingoid |
| Metabolism and nutrition disorders | Very common | Hypokalaemia |
| Common | Diabetes mellitus\\* |
| Eye disorders | Rare | Vision blurred (see also section 4.4) |
| Vascular disorders | Common | Hypertension |
| Gastrointestinal disorders | Common | Dyspepsia |
| Skin and subcutaneous tissue disorders | Very common | Skin reactions (acne, dermatitis) |
| Musculoskeletal and connective tissue disorders | Common | Muscle spasms |
| General disorders and administration site conditions | Common | Oedema peripheral |
| Common | Face oedema |
| Common | Weight increased |
\\* All patients with new onset of diabetes diagnosed during or following Kinpeygo treatment had levels of FBG and HbA1c prior to the start of treatment that were indicative of pre-diabetes (HbA1c ≥ 5.7% or FBG≥100 mg/dL).
Description of selected adverse reactions
\*Potential class effects\*
Adverse drug reactions typical of systemic glucocorticosteroids may occur (e.g., cushingoid features, increased blood pressure, increased risk of infection, delayed wound healing, reduced glucose tolerance, sodium retention with oedema formation, muscle weakness, osteoporosis, glaucoma, mental disorders, peptic ulcer, increased risk of thrombosis). These adverse drug reactions are dependent on dose, treatment time, concomitant and previous glucocorticosteroid intake, and individual sensitivity. Not all of these adverse reactions were observed in the clinical study program of Kinpeygo.
Paediatric population
No data available.
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
Reports of acute toxicity or death following overdose of glucocorticosteroids are rare. Acute overdose, even in excessive doses, is not expected to lead to clinically significant consequences. In the event of acute overdose, no specific antidote is available. Treatment consists supportive and symptomatic therapy.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents, corticosteroids acting locally, ATC code: A07EA06
Mechanism of action
The intended action of Kinpeygo is the suppression of mucosal B-cells, located in the Peyer's patches in the ileum where the majority of galactose-deficient IgA1 antibodies (Gd-IgA1) are produced. The inhibition of their proliferation and differentiation into plasma cells is expected to lower the occurrence of Gd-IgA1 antibodies and hence the formation of immune complexes in the systemic circulation, 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
Kinpeygo 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 Kinpeygo has been evaluated in 2 randomised, double-blind, placebo-controlled studies of patients with primary IgAN, who were receiving optimised dose (maximum allowed dose or maximum tolerated dose) of Renin-Angiotensin System (RAS) inhibitor therapy as a standard of care (SOC). The effect of Kinpeygo on kidney function decline based on estimated glomerular filtration rate (eGFR) and proteinuria reduction based on urine protein creatinine ratio (UPCR) was assessed in a randomised, double-blind, multicentre phase 3 study in patients with biopsy proven IgAN. 364 patients in the Full Analysis Set were randomised 1:1 to either Kinpeygo 16 mg once daily or placebo and treated for 9 months followed by a 2-week taper phase of 8 mg and 15 months of observational follow-up.
The final analysis of the study demonstrated that over the 2-year period, a 9-month treatment course of Kinpeygo (Nefecon) 16 mg/day reduced the loss of kidney function at 2 years in patients with primary IgAN in a statistically significant manner. The eGFR benefit accrued by the end of 9 months of treatment was maintained during 15 months of observational follow-up (Figure 1).
\*\*Figure 1: Mean absolute change in eGFR from baseline in Phase 3 NefIgArd Study\*\*
The treatment effect eGFR difference at 2 years was 6.00 mL/min/1.73 m2 using the MMRM analysis without explicit missing data assumptions (MAR assumption) and was statistically significant. The change from baseline in eGFR at 24 months was -7.50 mL/min/1.73 m2 in the Kinpeygo group compared to -13.50 mL/min/1.73 m2 in the placebo group; there was a treatment benefit of 6.00 mL/min/1.73 m2 (95% CI: 2.76 to 10.08) with Kinpeygo treatment compared to placebo (Table 2).
A supplementary analysis of 2-year eGFR total slope using a linear spline mixed effects analysis method to account for the acute (baseline to 3 months) and chronic (from 3 months onwards) phases estimated an overall treatment benefit of 2.62 mL/min/1.73 m2 per year (95% CI 1.23 to 4.00) in favour of Kinpeygo (Table 2).
\*\*Table 2: Analysis of eGFR at 24 months in Phase 3 NefIgArd Study\*\*
| | | |
| --- | --- | --- |
| \*\*eGFR (CKD-EPI) (mL/min/1.73 m2) a\*\* | \*\*Kinpeygo\*\* \*\*16 mg\*\* \*\*(N=182)\*\* | \*\*Placebo\*\* \*\*(N=182)\*\* |
| \*\*Mean change from baseline (mL/min/1.73 m2)\*\* at 24 months (15 months after Kinpeygo treatment ended) b | -7.50 | -13.50 |
| \*Kinpeygo 16 mg versus Placebo:\* (95% CI) Change from baseline in eGFR at 24 months (mL/min/1.73 m2) b 2-year eGFR total slope (mL/min/1.73 m2 per year) c | 6.00 (2.76 to 10.08) 2.62 (1.23 to 4.00) | |
a Including all observed eGFR data recorded after use of prohibited medication.
b Adjusted geometric least squares mean ratio of eGFR relative to baseline analysed using mixed model repeated measures analysis. Mean changes derived directly from the analysis performed on a log scale.
c Linear-spline mixed effects model in which eGFR was modelled simultaneously and separately over the acute (baseline to 3 months) and chronic (from 3 months onwards) phases and then combined to estimate the overall total slope. Data not log-transformed and including all observed eGFR data regardless of the use of prohibited medications or starting dialysis or having a renal transplant.
CI: confidence interval; eGFR (CKD-EPI): estimated glomerular filtration rate based on Chronic Kidney Disease Epidemiology Collaboration calculation
The 2-year eGFR treatment effect was consistent across all key subgroups, including key demographic (such as age, sex, race) and baseline disease (such as baseline proteinuria) characteristics.
The time to a confirmed 30% reduction in eGFR or end-stage renal disease (defined as renal-related death, renal transplantation, dialysis, or sustained eGFR <15 mL/min/1.73 m2) was delayed in patients who received Kinpeygo compared with those who received placebo (HR 0.45; 95% CI 0.26 to 0.75). The proportion of patients with a confirmed event over the 2-year study period was 11.5% in the Kinpeygo group versus 21.4% of patients in the placebo group.
The final analysis of treatment effect on proteinuria at 2 years was consistent with that observed at the end of the 9 months course of Kinpeygo treatment. However, in the Kinpeygo treatment arm proteinuria increased after a peak reduction at 12 months (Table 3). The UPCR treatment effect at 9 months was highly consistent across subgroups, including key demographic (such as age, sex, race) and baseline disease (such as baseline proteinuria) characteristics. A similarly consistent pattern in UPCR across subgroups was observed at 2 years.
\*\*Table 3: Proteinuria reduction at 9, 12, and 24 months and averaged over 12 to 24 months in Phase 3 NefIgArd Study\*\*
| | | |
| --- | --- | --- |
| \*\*Percentage reduction from baseline in UPCR g/g a, b\*\* | \*\*Kinpeygo\*\* \*\*16 mg\*\* \*\*(N=182)\*\* | \*\*Placebo\*\* \*\*(N=182)\*\* |
| At 9 months c | 34% | 5% |
| At 12 months (3 months after Kinpeygo treatment ended) | 51% | 3% |
| At 24 months (15 months after Kinpeygo treatment ended) | 31% | 1% |
| \*Kinpeygo 16 mg versus placebo\*: Average UPCR percentage reduction over 12 to 24 months compared to baseline d (95% CI) | 41% (32% to 49%) | |
a Excluding UPCR data recorded after use of prohibited medication.
b Adjusted geometric least squares mean ratio of UPCR relative to baseline were based on a longitudinal repeated measures model.
c Percent reduction in UPCR was previously evaluated in the first 199 patients randomised (p=0.0003). The final analysis in all 364 patients confirmed a 30% reduction in UPCR at 9 months with Kinpeygo compared with placebo (95% CI 20% to 39%).
d Average UPCR percentage reduction during follow-up (over 12 to 24 months) based on longitudinal repeated measures model.
CI: confidence interval; UPCR: urine protein creatinine ratio.
A supportive phase 2b study with a similar study design was conducted in a total of 153 randomised patients who received Kinpeygo 16 mg, Kinpeygo 8 mg, or placebo, once daily for 9 months followed by a 2-week taper phase and 3 months of observational follow-up, while continuing to receive RAS inhibitor therapy.
The primary objective was met at an interim analysis that compared Kinpeygo to placebo and showed a statistically significant reduction in UPCR at 9 months for the combined Kinpeygo 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 Kinpeygo 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 Kinpeygo versus placebo was 3.57 mL/min/1.73m2 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 Kinpeygo 16 mg once daily compared to placebo (p=0.0007).
Paediatric population
Kinpeygo has not been studied in the paediatric population.5.2 Pharmacokinetic properties
Absorption
The Kinpeygo 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 Kinpeygo 16 mg to healthy subjects, the geometric mean Cmax 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.
T½ for budesonide after dosing with Kinpeygo 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
Kinpeygo was not studied in the paediatric population.5.3 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 Kinpeygo 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 caues 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 section 4.6).
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 Kinpeygo 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.
## Pharmaceutical Particulars
6.1 List of excipients
Capsule content
Sugar spheres (sucrose and corn starch)
Hypromellose
Macrogol
Citric acid monohydrate
Ethylcellulose
Medium chain triglycerides
Oleic acid
Capsule shell
Hypromellose
Macrogol
Titanium dioxide (E171)
Methacrylic acid - methyl methacrylate co-polymers
Talc
Dibutylsebacate
Printing ink
Shellac
Black iron oxide (E172)6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years6.4 Special precautions for storage
Do not store above 25°C.6.5 Nature and contents of container
White high density polyethylene (HDPE) bottle with a white polypropylene (PP) child-resistant closure with an induction seal.
Or
Polyamide/Aluminium/Polyvinyl chloride//Aluminium (oPA/Al/PVC//Al) blisters.
Pack size: 1 bottle containing 28, 120 modified-release hard capsules.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
