TARPEYO Reduces Loss of Kidney Function in IgA Nephropathy

The US Food and Drug Administration (FDA) announced full approval of TARPEYO (budesonide), a delayed-release capsule to reduce the loss of kidney function in adults with primary IgA nephropathy (IgAN), in December 2023. Full FDA approval of TARPEYO was a significant milestone for the IgAN community. It was based on the 2-year results of the global, phase 3 NefIgArd study, the first and only phase 3 IgAN trial to show a confirmed, statistically significant benefit over placebo in estimated glomerular filtration rate sustained over a 2-year period.

Richard Lafayette, MD, FACP, the primary investigator of the NefIgArd trial, shared his thoughts with Nephrology Times about the study and the clinical impact of TARPEYO.

Diagnosis and Prognosis

IgAN, also known as Berger’s disease, is the most common primary glomerular disease in the world. It is a leading cause of chronic kidney disease and end-stage renal disease. 

An individual with IgAN might have high blood pressure and slightly abnormal kidney function, but often there are no symptoms for years. IgAN is usually identified when blood and protein are detected in a routine urine test. Upon suspicion of IgAN, the patient generally is referred to a kidney specialist. IgAN can only be diagnosed by kidney biopsy. 

A diagnosis of IgAN almost invariably leads to kidney failure during a patient’s lifetime. The disease progresses relatively slowly over 10 to 20 years, but most people with IgAN are at high risk of losing their kidney function and ultimately needing dialysis or kidney transplantation. 

Challenges Around IgA Nephropathy Treatment

The primary challenge in diagnosing IgAN is early identification of patients. In other parts of the world, such as Japan, there is a higher prevalence of the disease and it is routine to conduct yearly urine testing of adults and children to identify subtle changes and further evaluate them. Because this is not standard in the United States, we are confronted with the challenge of trying to identify patients early, when the disease is most likely to be treated successfully. We have only recently started to better understand the natural history of the disease and get more nephrologists to acknowledge that it is a serious disease that requires attention and therapy. 

Another limitation is that our therapies thus far have not been highly effective. We treat IgAN like all other chronic kidney diseases, through diet and exercise, blood pressure control, and medications that interfere with antigens and those that limit proteinuria and slow progression. We have not offered disease-specific interventions. 

This issue has been complicated by the fact that we recognize the presence of inflammation in the kidney and immune activation. We have used general immunosuppressants over the last 30 to 40 years with varying degrees of success and invariable side effects and risks of complications from the immunosuppression.

TARPEYO as Treatment for Primary IgA Nephropathy

TARPEYO (investigational name Nefecon), which is a targeted form of budesonide, was conceived about a decade ago as an opportunity to try to reduce the increased IgA that is observed in at-risk patients and those who develop IgAN because we know that IgA is an antibody that protects our mucosal surfaces. The largest at-risk mucosal surface is our bowels, and the largest production center of IgA is in the terminal ileum. In the terminal ileum, we have Peyer’s patches. 

The idea was to target that area specifically with a corticosteroid, which does not get absorbed into the body well or, in the case of budesonide, is absorbed but gets strongly degraded by the liver upon absorption. The systemic side effects of steroids should be limited, but the local effect on the bowels should be to suppress IgA production. In IgAN, a galactose-deficient form of IgA is associated with the disease and subsequent development of anti-IgA antibodies, which form immune complexes that then can deposit in the kidney and initiate kidney inflammation and injury. So, the drug was designed to work in the bowel to reduce IgA production with the hopes that it would ultimately stop inflammation in the kidney.

The NefIgArd Phase 3 Trial

A well-sized phase 2 study showed an ability to reduce proteinuria in IgAN, which is a cardinal sign of the risk for kidney function loss. It also demonstrated stabilization of kidney function over the 9 months of treatment with Nefecon, which is an oral therapy. 

The phase 3 NefIgArd study was launched globally in an attempt to obtain a mixture of patients with various severities of IgAN all with high risk of progression, defined by reduced kidney function between 30 and 90 mL/min, with high risk also defined as more than 1 g per day of urinary protein losses. The patients were treated for 9 months with Nefecon in addition to their best optimized conservative care, which is their maximally tolerated use of either angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors. The study was designed to follow the patients for an additional 15 months after the drug was stopped to see if there were lasting effects on proteinuria and on kidney function.

As is reported, more than 350 patients participated in the study. This was a typical, representative population of IgAN patients with reduced kidney function and significant proteinuria averaging more than 2 g per day. Patients included men and women representative of Europe, the United States, and Asia. 

The drug was successful within 9 months of reducing proteinuria by about 30%. Even after the drug was stopped for 3 months, proteinuria on average was down about 50% from baseline. This resulted in stabilization of kidney function through the 9-month treatment period, such that there was really no change in kidney function, and then slower progression over the remaining 15 months. At the end of 2 years there was a substantial, clinically important reduction in kidney disease progression, where it was about half the rate as in those patients who were treated with placebo in the study.

TARPEYO looked to be well tolerated with few safety issues. There were some signs of steroid exposure, as one might expect, in the 9 months of treatment. This resolved in the patients after the drug was removed, but patients continued to have significantly reduced proteinuria and significantly stabilized kidney function throughout the 2 years of observation.

Clinical Implications of the TARPEYO FDA Approval

The FDA reviewed the data both in terms of early approval at the 9-month time point, where there was evidence of clinically important reductions in proteinuria in a well-tolerated fashion, and with the 2-year data, when the FDA was again able to give full approval for patients at risk of progression with IgAN. 

TARPEYO is now available in clinics as a medication targeted specifically for IgAN. It gets to the mechanism of the disease, so we think it is truly disease-modifying.

There is additional evidence that it can reduce hematuria and that it reduces galactose-deficient IgA in patients. Therefore, we have for the first time a well-tolerated, safe medication that can change the natural history of this disease and benefit patients. It is an attractive alternative to systemic immunosuppression and a much better choice than no therapy for the vast majority of patients.