The US Food and Drug Administration (FDA) announced accelerated approval for budesonide delayed release capsules (Tarpeyo) to reduce proteinuria in adults with primary immunoglobulin A (IgA) nephropathy at risk of rapid disease progression.

This is the first time the FDA has approved an agent for this indication — reducing proteinuria in patients with a possibly rapidly progressing form of IgA nephropathy. Tarpeyo received orphan drug designation for this indication, given that IgA nephropathy is a rare disease.

The company that will market this agent, Calliditas, announced that it expects to launch the product in the US in early 2022.

The FDA notes “it has not been established whether Tarpeyo slows kidney function decline in patients with IgA nephropathy,” so instead, the agency based this accelerated approval on a surrogate marker for clinical benefit ― reduction of proteinuria in patients who were also taking a stable dose of maximally tolerated renin-angiotensin system (RAS) inhibitor therapy.

The FDA’s statement added that “as a condition of the accelerated approval, an ongoing study of Tarpeyo must be completed to confirm that the medication slows kidney function decline in patients with IgA nephropathy.”

Approval Rests on Early Pivotal Trial Results

The first phase of this ongoing study, Nefigard, included 199 patients with primary IgA nephropathy who received either 16 mg/day budesonide delayed-release or placebo for 9 months of treatment.

There was a 31% mean reduction in the primary endpoint ― urine protein creatinine ratio (UPCR), or proteinuria ― in the budesonide arm vs baseline, with placebo showing a 5% mean reduction vs baseline.

This netted a 27% average reduction in proteinuria at 9 months (P = .0005) of the 16-mg arm vs placebo, the company reported in a press release in November 2020.

The Nefigard trial enrolled patients for this phase of the trial from November 2018 to December 2019 at about 146 sites in 19 countries. As of late 2021, the results cited in the company’s press release have not appeared in a published report.

The key secondary endpoint, change in estimated glomerular filtration rate (eGFR), showed a treatment benefit of budesonide vs placebo at 9 months, reflecting stabilization in the treatment arm and a 7% decline of eGFR in the placebo arm (P = .0029).

On an absolute basis, patients showed an eGFR decline of 4.04 mL/min/1.73 m² in the placebo group over 9 months compared to just a 0.17 ml/min/1.73 m² decline in the treatment group.

The company also reported that the newly approved formulation of budesonide delayed release was generally well-tolerated and produced adverse effects that were “consistent with the known safety profile of budesonide.” The number of withdrawals in the trial was “significantly less” than what was seen in the a phase 2b study of the formulation.

In its approval statement, the FDA also highlighted several other safety considerations for this formulation, including the following:

• Tarpeyo is a corticosteroid and can cause side effects similar to other corticosteroids, which include hypercortisolism and adrenal suppression. Patients with moderate to severe liver impairment may be at increased risk of these side effects.

• Tarpeyo is an immunosuppressant. As such, patients should not take Tarpeyo if they have tuberculosis; untreated fungal, bacterial, systemic viral, or parasitic infections; or ocular herpes simplex. Patients taking Tarpeyo should avoid being exposed to active, easily transmitted infections. Corticosteroids, such as Tarpeyo, may decrease the immune response to some vaccines.

• The most common side effects of Tarpeyo are high blood pressure; swelling in the lower legs and hands; muscle spasms; acne; skin irritation; weight increase; difficulty breathing; face swelling; indigestion; fatigue; and excess hair, often around the nose and mouth.

The 199 patients with evaluated results in the Nefigard trial represent just a part of the study’s complete enrollment, expected to include a total of about 360 patients, that is addressing whether the treatment succeeds against placebo in reducing clinical endpoints such as decreased renal function and kidney failure.

Results from another study, named TESTING, also recently showed the efficacy of treatment with an oral glucocorticoid, methylprednisolone, for slowing progression of renal failure in patients with primary IgA nephropathy. Findings from the 503 patients showed that treatment with either of two different doses of oral methylprednisolone slowed a combined measure of progressive renal disease by almost 50% compared with placebo in an analysis that combined the two different dose subgroups.

The study’s interm results, in 262 patients, also showed that the higher dose tested of this oral glucocorticoid led to an unacceptably high level of infections secondary to immunosuppression. This led to premature discontinuation of use of the higher dose in this study.

Use Steroids With Extreme Caution in IgA Nephropathy

The prevailing, 2021 treatment guideline for primary IgA nephropathy from the Kidney Disease: Improving Global Outcomes (KDIGO) organization says that “the primary focus” of management “should be multifaceted, optimized supportive care.”

The recommendation continues that if the patient’s proteinuria persists at high level despite at least 90 days of optimized supportive care, “the patient has a high risk of progressive loss of kidney function and may be considered for a 6-month course of glucocorticoid therapy (Grade 2B), or preferably, the opportunity to take part in a therapeutic clinical trial.” The guideline adds that “the clinical benefit of glucocorticoids in IgA nephropathy is not established,” and hence these agents “should be given with extreme caution or avoided entirely” in selected patients.

Budesonide is a locally acting agent with limited systemic effects. Formulations of oral budesonide have had FDA marketing approval for several years for treating inflammatory bowel diseases as well as certain other diseases.

Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler

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