PROTECT Drugs Tied to Slower eGFR Decline vs Standard Care in IgA Nephropathy

LONG BEACH, Calif. — Both sparsentan (Filspari) and irbesartan were associated with significantly slower estimated glomerular filtration rate (eGFR) decline compared with standard of care in patients with immunoglobulin A nephropathy (IgAN), according to a comparison of trial data.

Compared with the U.K. National Registry of Rare Kidney Diseases (RaDaR) IgAN subpopulation representing standard of care delivered in a real-world setting, patients treated with maximally titrated sparsentan or irbesartan in the PROTECT trial had a slower decline in kidney function as measured by 2-year eGFR total slopes, reported Chee Kay Cheung, MBChB, PhD, of Leicester General Hospital in England, at the National Kidney Foundation Spring Clinical meeting:

• Sparsentan: -3.4 mL/min/1.73m²
• Irbesartan: -4.2 mL/min/1.73 m²
• Real-world standard of care: -5.3 mL/min/1.73 m²

This equated to a difference of 1.89 mL/min/1.73m² per year with sparsentan (P=0.0004) and 1.12 mL/min/1.73m² per year with irbesartan (P=0.0239) compared with standard of care, which involved renin-angiotensin system (RAS) inhibition, blood pressure control, and lifestyle management.

“These results highlight the importance of considering the 2-year eGFR total slope difference between arms of the PROTECT trial in the context of what is achieved in current clinical practice,” Cheung said during a presentation of the late-breaking findings.

“Unfortunately, in the U.K. — and it’s similar in the U.S. — we are diagnosing patients with a median eGFR around the 50s, so by the time that happens, we’ve already experienced significant nephron loss,” he said. “We’re going to need therapies that can protect against further nephron loss — SGLT2 inhibitors, angiotensin receptor blockers [ARBs], anti-inflammatories, and other drugs — that can target galactose-deficient IgA reduction.”

“I think it’s great that we’re developing lots of tools in the toolbox for autoimmune disease and I see a role for multi-targeted therapy,” he added. “But I think we’ll be more aggressive in our approach, certainly in select patients in the future. We want to be tackling things rather than waiting for that damage to occur and then starting therapies later.”

Similar findings were observed when the two PROTECT trial arms were compared with the control arm of the NefIgArd trial of optimized standard of care with RAS inhibitor therapy in a clinical trial setting, with a difference of 2.26 mL/min/1.73m² per year with sparsentan (P=0.0004) and 1.30 mL/min/1.73m² per year with irbesartan (P=0.0395).

The phase III NefIgArd trial was designed to test targeted-release-formulation budesonide (Tarpeyo), which was the first drug specifically indicated to reduce proteinuria in IgAN and was approved in December 2021 based on this trial, plus RAS inhibitor therapy versus RAS inhibitor therapy plus placebo.

The main findings from the PROTECT trial underpinned sparsentan’s February 2023 approval, which made it the first non-immunosuppressive therapy for this rare kidney disorder, also known as Berger’s disease.

In the trial, patients on sparsentan had an average proteinuria reduction of 50% from baseline versus a drop of 15% among irbesartan-treated patients after 36 weeks, meeting the trial’s primary endpoint (P<0.0001).

One member of the audience questioned why sparsentan was compared with standard of care and not budesonide, to which Cheung responded, “That analysis is coming.”

In PROTECT, 202 participants were randomized to sparsentan and another 202 to irbesartan. All discontinued angiotensin-converting enzyme (ACE) inhibitors/ARBs prior to treatment. Those on sparsentan were started on 200 mg and titrated up to 400 mg, and those on irbesartan were started on 150 mg and titrated up to 300 mg. Both groups then stopped study medication for 1 month, and then all started sparsentan through the end of the 156-week open-label extension period.

All participants had biopsy-proven IgAN and had an eGFR ≥30 mL/min/1.73m². Other inclusion criteria included blood pressure ≤150/100 mm Hg, urine protein ≥1 g/day, and treatment with a stable ACE inhibitor and/or ARB therapy for at least 12 weeks at the patient’s maximum tolerated dose and at least half of the maximum labeled dose.

The RaDaR IgAN subpopulation included 535 adults (mean age 43) with biopsy-proven IgAN, an eGFR ≥30 mL/min/1.73m², and a urine protein-creatinine ratio ≥0.88 g/g at least 6 months from IgAN diagnosis.

The control arm of the NefIgArd trial included 182 patients (median age 42) with biopsy-proven IgAN, an eGFR of 35-90 mL/min/1.73m², blood pressure <140/90 mm Hg, a urine protein-creatinine ratio ≥0.8 g/g or urine protein ≥1 g/day, and stable and optimized RAS inhibitor therapy with an ACE inhibitor and/or an ARB for ≥3 months.

Cheung noted that one limitation of the study was a lack of data on which patients in the RaDaR group received immunosuppressant therapy, though he pointed out that steroid use in the U.K. tends to be less common than in the U.S.

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