Though Specific Therapies Are Few, Clinical Trials Promise Progress for IgA Nephropathy

Although it currently only has 2 FDA-approved therapies in addition to supportive care, several new clinical trials are pushing treatments forward for immunoglobulin A (IgA) nephropathy, according to presenters at a session during the 2023 Asembia Specialty Pharmacy Summit.

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IgA nephropathy is the most common primary glomerular disease in the world, with a global incidence of 2.5 cases per 100,000 person-years. Men are affected more often than women and it is more common in those with Asian descent and Caucasians, rather than Black individuals.

“Typically, the people that we will see in the clinic are patients who are young adults that have had a recent infection…and that precipitating event seems to trigger this disease and this multi-hit hypothesis,” explained presenter Darren W. Grabe, BS, PharmD.

The condition is an autoimmune disease in which glomeruli are damaged by accumulation of IgA deposits in the glomerular mesangium. Grabe noted that it has a multi-hit pathogenesis hypothesis. Hit 1 involves increased circulating galactose-deficient IgA1; hit 2 is the creation of antibodies directed against that galactose-deficient IgA1; hit 3 is the formation of pathogenic IgA1-containing immune complexes; and finally, hit 4 is mesangial deposition of immune complexes, resulting in inflammation and glomerular injury.

Because these patients are often young, ranging from their teens to 30s, Grabe said the disease has a significant impact. Many patients will require dialysis within 20 to 30 years of their diagnosis, when they will be in their 50s or 60s.

“As you might imagine, young adults getting a disease that significant has an impact on quality of life,” Grabe said. “Pain and fatigue are common; the anxiety, depression, and fear associated with [end-stage renal disease] contribute to that quality of life.”

The gold standard for diagnosis of IgA nephropathy is kidney biopsy to determine whether there are IgA deposits present. Grabe emphasized, however, that this is a risky procedure that should ideally only be performed once.

“In essence, depending on the disease and where it is in the kidney and the tissue that’s procured, you’ll see changes in the tissue,” Grabe said. “And depending how severe it is and whether it’s present or not, it will determine what [MEST-C] score it is.”

After diagnosis, management strategies are largely dominated by supportive care. Renin-angiotensin-aldosterone system (RAAS) blockers are particularly common and used in an estimated 80% to 90.5% of patients. Similarly, angiotensin-converting enzyme inhibitors (ACEi) are utilized in approximately 67.7% of patients and angiotensin receptor blockers (ARBs) are utilized in an estimated 37.9% of patients. Doses should be titrated up to the maximally tolerated dose, with a target blood pressure of 120 mm Hg or less.

Lifestyle modifications are also particularly important. Grabe noted, however, that it can be challenging to try to tackle all potential modifications at once, so he encouraged attendees to select one lifestyle modification with their patient and celebrate small wins.

“I think it’s often overlooked how important lifestyle modifications are, but also how difficult,” Grabe said. “If it was easy, we would all do it.”

Corticosteroid therapy may also be a potential option, but it has significant risks that must be carefully considered. Research in 2012 found that there is a lower risk of kidney failure and decreased proteinuria in patients receiving corticosteroids, but, importantly, there was a 55% higher risk of adverse effects, which was confirmed by later research.

Two agents have been FDA-approved for use in IgA nephropathy. Targeted-release budesonide is a corticosteroid FDA-approved in December 2021, although Grabe noted that its dosage form is designed to release the drug to mucosal B cells present in the ileum, including the Peyer’s patches. This area, in particular, is where drugs for IgA nephropathy must act in order to reduce generation of de-regulated IgA1 molecules.

The NeflgArd study of patients with biopsy-confirmed IgA found that it had a beneficial effect on estimated glomerular filtration rate (eGFR) and a single treatment course of 9 months slowed loss of kidney function by 50% compared with placebo at 24 months. It also had durable urine protein creatinine ratio reduction of greater than 30% during the 15-month study period, with peak effect at 12 months.

Treatment-emergent adverse effects (TEAEs) occurred in 86.6% of patients in the budesonide arm compared with 73% of those in the placebo arm. Of those, 50.5% were mild, 32% were moderate, and 4.1% were deemed severe. Nine patients in the budesonide arm (9.3%) discontinued treatment due to TEAEs.

Sparsentan is another FDA-approved option, as a once-daily oral dual endothelin (ET)-1 angiotensin 2 receptor antagonist. Preclinical data demonstrated that blockade of both ET type A and angiotensin 2 type 1 pathways reduces proteinuria and prevents glomerulonephritis and mesangial cell proliferation.

The PROTECT study was a randomized, multicenter, double-blind, parallel-group, active-control trial of adult patients with persistent proteinuria despite ACEi or ARB treatment. The primary outcome was change in proteinuria from baseline to week 36, and treatment with sparsentan achieved a mean reduction of 49.8%. Post-hoc sensitivity analysis of the first 281 randomized patients showed that treatment with sparsentan achieved a mean reduction in proteinuria from baseline of 45%, and results from the confirmatory endpoint analysis are expected in late 2023.

In addition to these FDA-approved options, several clinical trials are investigating other potential treatments for IgA nephropathy, according to presenter Catherine E. Cooke, PharmD, MS, BCPS, PAHM.

“The agents I’m going to talk about are in the pipeline; they are not approved,” Cooke said. “But there’s a lot of interest in this disease space.”

Investigational approaches target different processes in IgA nephropathy as well as new approaches to manage and optimize supportive care. Cooke emphasized that slowing the trajectory of progression is the key goal.

Five investigational agents are in phase 3 trials. Atrasentan is an endothelin receptor type A receptor inhibitor, with the ALIGN trial expected to be completed in December 2025. Iptacopan is a factor B inhibitor with 2 studies: the APPLAUSE-IgAN trial has a planned completion date in January 2025, whereas a long-term safety trial is expected to be completed in January 2029.

Narsoplimab is a mannan-binding lectin serine protease 2 (MASP2) inhibitor. The ARTEMIS-IgAN study was expected to be completed in April 2023, although Cooke said she has not seen any updates yet.

Sibeprenlimab is a monoclonal antibody with action against a proliferation inducing ligand (APRIL) and has a phase 3 trial with planned completion in December 2026 as well as an open-label extension trial. Finally, telitacicept is a B-cell activating factor and APRIL blocker, with a trial expected to be completed in September 2026.

Amid all of the FDA-approved options and the advancing research, Cooke said pharmacists can play a key role in educating patients and helping them access care. One key issue is that patients and clinicians can often have a disconnect. Although Cooke said clinicians may naturally prefer to discuss objective issues and parameters, patients often need to feel supported in more subjective issues, such as sleep issues or other quality of life concerns.

Helping patients access care is also crucial. With a rare disease such as IgA nephropathy, Grabe said membership in disease registries can be a vital source of support and information. Cooke added that research has been done to establish the specific access challenges that patients encounter.

“One of the key components is that they have difficulty accessing disease-specific care. Depending on where you’re located and access to the centers with experts that deal with this disorder, it’s very challenging,” Cooke explained. “And the other aspect is, when you find specialty care, being able to access timely appointments, as well.”

To overcome these barriers, pharmacists can help patients navigate the complicated process of referrals and can sometimes operate as the glue between members of the entire integrated team. Increasing awareness and knowledge among patients, caretakers, and clinicians is also crucial. Finally, as the medication experts, Cooke said pharmacists can always use their expertise to help obtain medications, assess adherence, and monitor outcomes.

REFERENCE

Cooke C, Grabes D. Reducing the Clinical and Economic Burden of Managing IgA Nephropathy With Emerging Therapies: A Review for Specialty Pharmacists. Presented at: Asembia 2023 Specialty Pharmacy Summit. May 3, 2023. Accessed May 3, 2023.