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IMPORTANT SAFETY INFORMATION & INDICATION

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

TARPEYO is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of TARPEYO. Serious hypersensitivity reactions, including anaphylaxis, have occurred with other budesonide formulations.

WARNINGS AND PRECAUTIONS

Hypercorticism and adrenal axis suppression:

When corticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Corticosteroids 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 corticosteroid is recommended. When discontinuing therapy or switching between corticosteroids, monitor for signs of adrenal axis suppression.

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism in patients with moderate hepatic impairment (Child-Pugh Class B).

Immunosuppression and increased risk of infection:

Corticosteroids, including TARPEYO, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: reduce resistance to new infections, exacerbate existing infections, increase the risk of disseminated infections, increase the risk of reactivation or exacerbation of latent infections, and mask some signs of infection. Corticosteroid-associated infections can sometimes be serious. Monitor for infection and consider TARPEYO withdrawal as needed.

Avoid corticosteroid therapy, including TARPEYO, in patients with active or quiescent tuberculosis or hepatitis B infection; untreated fungal, bacterial, systemic viral, or parasitic infections; ocular herpes simplex; or Kaposi’s sarcoma. Avoid exposure to active, easily transmitted infections (e.g., chickenpox, measles). Corticosteroid therapy may decrease the immune response to some vaccines.

Other corticosteroid effects:

TARPEYO is a systemically available corticosteroid and is expected to cause related adverse reactions. Monitor patients with hypertension, prediabetes, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.

ADVERSE REACTIONS

In clinical studies, the most common adverse reactions with TARPEYO (occurring in ≥5% of TARPEYO-treated patients, and ≥2% higher than placebo) were peripheral edema (17%), hypertension (12%), muscle spasms (12%), acne (11%), headache (10%), upper respiratory tract infection (8%), face edema (8%), weight increased (7%), dyspepsia (7%), dermatitis (6%), arthralgia (6%), and white blood cell count increased (6%).

DRUG INTERACTIONS

Budesonide is a substrate for CYP3A4. Avoid use with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine. Avoid ingestion of grapefruit juice with TARPEYO. Intake of grapefruit juice, which inhibits CYP3A4 activity, can increase the systemic exposure to budesonide.

USE IN SPECIFIC POPULATIONS

Pregnancy:

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 IgAN. Infants exposed to in utero corticosteroids, including budesonide, are at risk for hypoadrenalism.

INDICATION

TARPEYO is indicated to reduce the loss of kidney function in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression.

Please see Full Prescribing Information.

MOD

IgA nephropathy (IgAN) is a progressive autoimmune disease that warrants immunomodulating therapy1,2

The 4-HIT hypothesis is a widely accepted model for understanding the pathogenesis of IgAN1

The 4-HIT hypothesis consists of 4 sequential processes:

A graphic illustrating TARPEYO’s mechanism of action in four key steps (HITs): HIT 1: Mucosal B cells present in the ileum, including the Peyer's patches, are depicted. Increased IgA1 production leads to intestinal injury. HIT 2: Elevated levels of Gd-IgA1 antibodies enter systemic circulation. B cells are primed to produce Gd-IgA1. HIT 3: Production of IgA or IgG autoantibodies specific for Gd-IgA1 leads to the formation of immune complexes. HIT 4: Immune complexes deposit in the kidneys, resulting in kidney damage. Each HIT is highlighted with detailed visuals and annotations, showing the progression from mucosal B cells to kidney damage through the formation and deposition of immune complexes. A graphic illustrating TARPEYO’s mechanism of action in four key steps (HITs): HIT 1: Mucosal B cells present in the ileum, including the Peyer's patches, are depicted. Increased IgA1 production leads to intestinal injury. HIT 2: Elevated levels of Gd-IgA1 antibodies enter systemic circulation. B cells are primed to produce Gd-IgA1. HIT 3: Production of IgA or IgG autoantibodies specific for Gd-IgA1 leads to the formation of immune complexes. HIT 4: Immune complexes deposit in the kidneys, resulting in kidney damage. Each HIT is highlighted with detailed visuals and annotations, showing the progression from mucosal B cells to kidney damage through the formation and deposition of immune complexes.

Increased levels of circulating Gd-IgA1 lead to immune complex formation and mesangial deposition5:

  • Although IgAN manifests in the kidney, evidence supports the pivotal role of the gut, specifically the GALT, in production of Gd-IgA1 similar to those found in circulation, immune complexes, and mesangium deposits2
  • Peyerʼs patches are lymphoid follicles within the GALT that are in greatest concentrations in the distal ileum2
    • Nearly 50% of Peyerʼs patch tissue has been shown to be found in the human distal ileum6,7
  • Gd-IgA1 is an emerging biomarker that has been correlated with predicting progression8,9

GALT=gut-associated lymphoid tissue; Gd-IgA1=galactose-deficient IgA1; IgA1=immunoglobulin A1; IgG=immunoglobulin G.

Reductions in Gd-IgA1 were seen with TARPEYO11*

The majority of Gd-IgA1 production is thought to be concentrated in an area of the ileum2,5

In the NefIgArd study, Gd-IgA1 serum samples were collected at screening and after 3, 6, and 9 months of treatment from a subset of subjects (TARPEYO + RASi; RASi alone).11 NefIgArd is a randomized, double-blind, placebo-controlled, 2-year, Phase 3 trial.4

Change in Gd-IgA1 with TARPEYO + RASi vs RASi alone11

Graph showing the difference in percentage change from baseline in Gd-IgA1 for TARPEYO plus optimized RASi versus RASi alone while on treatment. TARPEYO plus RASi line decreases to -11.8% at 9 months, while RASi alone increases to 22.0%. Graph showing the difference in percentage change from baseline in Gd-IgA1 for TARPEYO plus optimized RASi versus RASi alone while on treatment. TARPEYO plus RASi line decreases to -11.8% at 9 months, while RASi alone increases to 22.0%.

TARPEYO is the only approved treatment to date shown to reduce the levels of pathogenic forms of IgA and IgA immune complexes

It has not been established to what extent the efficacy of TARPEYO is mediated via local effects in the ileum vs systemic effects. Small sample sizes of a specific patient group are limitations of these analyses. Additional longitudinal studies of more diverse patient cohorts are needed to validate findings.

  • Through anti-inflammatory and immunosuppressive effects at the glucocorticoid receptor, TARPEYO can modulate B-cell numbers and activity2,3
  • In the NefIgArd trial, TARPEYO + RASi significantly reduced levels of circulating Gd-IgA1 and IgA immune complexes from baseline at 3, 6, and 9 months vs RASi alone11,12

*Data from Part A of the Phase 3 NefIgArd trial.
RASi=renin-angiotensin system inhibitor.

MOA

TARPEYO is a targeted-release capsule designed to deliver budesonide directly to a key site of Gd-IgA1 production13

TARPEYO uses a unique 2-step process to deliver budesonide to an area of the ileum.13 The capsule has a pH-sensitive enteric coating and contains sustained-release, triple-coated beads with budesonide.13

Once the capsule disintegrates, triple-coated beads provide sustained release of budesonide, dissolving the drug over a broader area of the ileum.13

Designed to deliver an immunomodulating agent to where IgAN is thought to originate13

A graphic illustrating the proprietary TARPEYO technology and its components: On the left, it shows the immunomodulating active ingredient, Budesonide, with its molecular structure depicted. In the center, it highlights the triple-coated beads designed to help control the rate of release. On the right, it shows the enteric coat for delayed release, with an illustration of a capsule containing these beads (4 mg per capsule). A graphic illustrating the proprietary TARPEYO technology and its components: On the left, it shows the immunomodulating active ingredient, Budesonide, with its molecular structure depicted. In the center, it highlights the triple-coated beads designed to help control the rate of release. On the right, it shows the enteric coat for delayed release, with an illustration of a capsule containing these beads (4 mg per capsule).

Budesonide was selected to limit systemic exposure.

  • Budesonide is a locally acting glucocorticoid that has not been developed for systemic treatment due to its rapid first-pass liver metabolism, limiting systemic exposure13
  • Budesonide was developed for topical use on mucosal surfaces, showing evidence of deep penetration and high retention in mucosal tissues13
  • In pharmacokinetic studies comparing TARPEYO and Entocort, TARPEYO exhibited higher maximum plasma concentrations of budesonide while having a shorter terminal half-life, indicating a shorter duration of systemic exposure to budesonide14
    • Clinical significance is unknown

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

TARPEYO has a unique dissolution profile from other budesonide formulations15

An in vitro study compared the release patterns of commercially available oral budesonide products. Its aim was to determine if the products are interchangeable regarding their delivery of budesonide to the GI tract.15*

Findings suggest that the release pattern of TARPEYO is consistent with the intended design of the product, to deliver budesonide to the Peyerʼs patch-rich area of the ileum.15

Dissolution profiles of 3 delayed-release budesonide oral formulations15

Graph showing dissolution rates of TARPEYO, Entocort, and Uceris over 180 minutes. TARPEYO shows delayed release, reaching ~80% at 180 minutes, compared to faster release in Entocort and Uceris. Graph showing dissolution rates of TARPEYO, Entocort, and Uceris over 180 minutes. TARPEYO shows delayed release, reaching ~80% at 180 minutes, compared to faster release in Entocort and Uceris.

Approximate GI tract transit time (highly variable; illustrative only and not intended to compare efficacy and safety). TARPEYO was studied under the name Nefecon.

  • TARPEYO demonstrated a unique dissolution profile compared to other budesonide formulations, including Entocort15
  • The release pattern of TARPEYO indicates that the delivery of budesonide would occur in the ileum15

*Dissolution test conditions were conducted based on USP, FDA, and EMA guidelines.15

EMA=European Medicines Agency; FDA=Food and Drug Administration; GI=gastrointestinal; USP=United States Pharmacopeia.

DISCOVER DOSING

REFERENCES: 1. Chang S, Li X-K. The role of immune modulation in pathogenesis of IgA nephropathy. Front Med (Lausanne). 2020;7:92. doi:10.3389/fmed.2020.00092 2. Barratt J, Rovin BH, Cattran D, et al. Why target the gut to treat IgA nephropathy? Kidney Int Rep. 2020;5(10):1620-1624. doi:10.1016/ j.ekir.2020.08.009 3. TARPEYO. Prescribing Information. Calliditas Therapeutics AB; June 2024. 4. Lafayette R, Kristensen J, Stone A, et al. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet. 2023. https://doi.org/10.1016/S0140-6736(23)01554-4 5. Lim RS, Yeo SC, Barratt J, et al. An update on current therapeutic options in IgA nephropathy. J Clin Med. 2024;13(4):947. doi: 10.3390/jcm13040947 6. Jung C, Hugot J-P, Barreau F. Peyerʼs patches: the immune sensors of the intestine. Int Journal Inflammation. 2010;1-12. https://doi.org/10.4061/2010/823710 7. Van Kruiningen, H, West AB, Freda BJ, et al. Distribution of Peyerʼs patches in the distal ileum. Inflammatory Bowel Dis. 2002;8(3):180-185. https://doi.org/10.1097/00054725-200205000-00004 8. Kim JS, Hwang HS, Sang HL, et al. Clinical relevance of serum galactose deficient IgA1 in patients with IgA nephropathy. J Clin Med. 2020;9:3549. 9. Zeng Q, Wang WR, Li YH, et al. Diagnostic and prognostic value of galactose-deficient IgA1 in patients with IgA nephropathy: an updated systematic review with meta-analysis. Front Immunol. 2023;14:1209394. doi:10.3389/fimmu.2023.1209394 10. Canetta PA, Kiryluk K, Appel GB. Glomerular diseases: emerging tests and therapies for IgA nephropathy. Clin J Am Soc Nephrol. 2014;9(3):617-625. 11. Data on file. Gd-IgA1 data. Calliditas Therapeutics AB. 12. Cotton V, Nawaz N, Molyneux K, et al. Analysis of the NefIgArd Part A study population confirms Nefecon suppresses circulating levels of IgA-containing immune complexes in IgA nephropathy. Leicester IgAN research group. Poster presented at IIgANN Congress; September 28-30, 2023. 13. Data on file. Part B. Calliditas Therapeutics AB. 14. Barratt J, Kristensen J, Pedersen C, Jerling M. Insights on Nefecon®, a targeted-release formulation of budesonide and its selective immunomodulatory effects in patients with IgA nephropathy. Drug Des Devel Ther. 2024;18:3415-3428. doi:10.2147/DDDT.S383138 15. Dressman, J. Comparative dissolution of budesonide from four commercially available products for oral administration: implications for interchangeablity. Dissolution Technol. 2023;30(4):224-229.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

TARPEYO is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of TARPEYO. Serious hypersensitivity reactions, including anaphylaxis, have occurred with other budesonide formulations.

WARNINGS AND PRECAUTIONS

Hypercorticism and adrenal axis suppression:

When corticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Corticosteroids 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 corticosteroid is recommended. When discontinuing therapy or switching between corticosteroids, monitor for signs of adrenal axis suppression.

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism in patients with moderate hepatic impairment (Child-Pugh Class B).

Immunosuppression and increased risk of infection:

Corticosteroids, including TARPEYO, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: reduce resistance to new infections, exacerbate existing infections, increase the risk of disseminated infections, increase the risk of reactivation or exacerbation of latent infections, and mask some signs of infection. Corticosteroid-associated infections can sometimes be serious. Monitor for infection and consider TARPEYO withdrawal as needed.

Avoid corticosteroid therapy, including TARPEYO, in patients with active or quiescent tuberculosis or hepatitis B infection; untreated fungal, bacterial, systemic viral, or parasitic infections; ocular herpes simplex; or Kaposi’s sarcoma. Avoid exposure to active, easily transmitted infections (e.g., chickenpox, measles). Corticosteroid therapy may decrease the immune response to some vaccines.

Other corticosteroid effects:

TARPEYO is a systemically available corticosteroid and is expected to cause related adverse reactions. Monitor patients with hypertension, prediabetes, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.

ADVERSE REACTIONS

In clinical studies, the most common adverse reactions with TARPEYO (occurring in ≥5% of TARPEYO-treated patients, and ≥2% higher than placebo) were peripheral edema (17%), hypertension (12%), muscle spasms (12%), acne (11%), headache (10%), upper respiratory tract infection (8%), face edema (8%), weight increased (7%), dyspepsia (7%), dermatitis (6%), arthralgia (6%), and white blood cell count increased (6%).

DRUG INTERACTIONS

Budesonide is a substrate for CYP3A4. Avoid use with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine. Avoid ingestion of grapefruit juice with TARPEYO. Intake of grapefruit juice, which inhibits CYP3A4 activity, can increase the systemic exposure to budesonide.

USE IN SPECIFIC POPULATIONS

Pregnancy:

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 IgAN. Infants exposed to in utero corticosteroids, including budesonide, are at risk for hypoadrenalism.

INDICATION

TARPEYO is indicated to reduce the loss of kidney function in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression.

Please see Full Prescribing Information.

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TARPEYO is a registered trademark of Calliditas Therapeutics AB, or its affiliates.

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