Nonimmunosuppressive Therapy Bests ARB for Cutting Proteinuira in IgA Nephropathy

AUSTIN, Texas -- Once-daily sparsentan (Filspari) was better at reducing proteinuria than standard treatment in IgA nephropathy, according to a prespecified interim analysis of the PROTECT trial.

By week 36 of treatment in the phase III study, patients on sparsentan saw a 49.8% reduction from baseline in urine protein-creatinine (UP/C) ratio compared with only a 15.1% drop in patients on the angiotensin receptor blocker (ARB) irbesartan, reported Jai Radhakrishnan, MD, MS, of Columbia University in New York City, and colleagues.

This translated to a between-group relative reduction of 41% (least squares mean ratio 0.59, 95% CI 0.51-0.69, P<0.0001) based on 24-hour urine samples. The sharpest drop in UP/C was seen in the first 4 weeks on treatment.

"Within the first 4 and maybe up to 6 weeks, most of the drop in the urine protein has occurred," Radhakrishnan said during a presentation of the findings at the National Kidney Foundation Spring Clinical Meeting. The results were published earlier this month in The Lancet.

"From then on, it stays at the same level," he stated.

Radhakrishnan added that "a higher proportion of sparsentan-treated patients achieved complete and partial [proteinuria] remission compared with irbesartan." Sparsentan-treated patients had a 3.1-times and 4.5-times higher odds of achieving complete or partial proteinuria remission than those on irbesartan, respectively:

• Complete remission: 21% vs 8% (P=0.0005)
• Partial remission: 70% vs 44% (P<0.0001)

When asked how this drug will compare with other drugs on the market, such as steroids or budesonide (Tarpeyo, FDA approved December 2021), Radhakrishnan noted that the "most important part of this drug is that it's not an immunosuppressive agent."

"That's the key message from this study, it's that over and above an ARB -- which is standard of care -- there is clearly a further reduction of proteinuria, which...[is] a very important surrogate marker in how patients do. It might be that before you consider immunosuppression, you might escalate this...or it could be part of a multi-targeted therapy paradigm."

These findings from the PROTECT trial sealed the deal for the accelerated FDA approval for the agent in February 2023, making sparsentan the first nonimmunosuppressive therapy for proteinuria in IgA nephropathy. The oral drug works by selectively targeting two critical pathways -- endothelin-1 and angiotensin II -- in the disease progression of IgA nephropathy.

When stratified across certain patient subgroups, sparsentan still performed significantly better at proteinuria reduction than irbesartan in PROTECT: age (over 45 and under), sex, race (Asian and white), urine protein (over 1.75 g/day and under), time since kidney biopsy (over 5 years and under), and age at IgA nephropathy diagnosis (over 40 and under).

When stratified by baseline eGFR, sparsentan was significantly more effective in those with a value under 60 mL/min/1.73 m², as well as between 60 to less than 90. However, there was no significant difference in patients with a baseline eGFR of 90 or higher. "This is most likely from the fact that the number were quite low, this group of [90 or higher] GFR" said Radhakrishnan.

Changes in body weight also didn't differ between the treatment groups (+0.33 kg in sparsentan vs +0.69 kg in irbesartan).

By week 36, those on sparsentan saw an average 1.8 mmHg drop in systolic blood pressure while irbesartan had a 2.9 mmHg drop. Sparsentan and irbesartan groups saw average 2.5 mmHg and 0.4 mmHg drops in diastolic blood pressures, respectively.

Very few patients on either treatment had to be down-titrated or couldn't go up in dose, added Radhakrishnan. Treatment-emergent adverse events (TEAE) were similar between the groups, with no cases of severe edema, heart failure, hepatotoxicity, or edema-related discontinuation. The most common TEAEs with sparsentan were mild peripheral edema, hypotension, dizziness, hyperkalemia, anemia, acute kidney injury, and liver enzyme elevations over three times the upper limit of normal.

Study Details

The ongoing, 134-site global trial enrolled 404 adult patients with biopsy-proven IgA nephropathy and proteinuria of 1.0 g/day or higher despite maxing out renin-angiotensin system inhibitor treatment for a minimum of 12 weeks. A total of 202 participants were randomized to receive 400 mg once daily of sparsentan of 300 mg once daily of irbesartan.

Patients had to come into the study on a stable dose of an ACE inhibitor and/or ARB therapy for at least 12 weeks and also had to have an eGFR of 30 or higher.

At baseline, there was an average of 6 years from time to initial kidney biopsy to the study. Around two-thirds of participants were white and another third were Asian. Baseline urinary protein excretion was 1.8 g/day and UP/C was a median of 1.3 g/g.

Limitations of the current interim analysis meant that the researchers were not able to "draw conclusions about the longer-term efficacy and safety of sparsentan in patients with IgA nephropathy," they stated. Also, the results cannot be generalized to patients with proteinuria levels below 1 g/day.

Future Findings

The trial is slated to wrap-up after 110-weeks with topline results from the confirmatory endpoint analysis expected in the second half of 2023, according to developer Travere Therapeutics. After the 110-week double-blind treatment period, there is a planned 4-week no-treatment period, followed by another 156-week open-label extension period where all participants will receive the study drug.

"The final analysis [will] hopefully be appearing ... shortly where the 2-year, double-blind period will be adjudicated to see if there's a difference in the GFR slopes, which will be the final results of the study," added Radhakrishnan.

In an accompanying The Lancet comment, Sigrid Lundberg, MD, PhD, and Karin Bergen, both of the Karolinska Institutet in Sweden, said that if "the final analysis of the PROTECT trial confirms an attenuation of eGFR decline, future clinical trials in IgA nephropathy will probably have to include RAS-blockade, SGLT2 inhibitors, and ETA receptor antagonists as baseline treatment."

But they said they'd like to see how sparsentan performs in patients with IgA nephropathy with more advanced-stage chronic kidney disease (eGFR under 30).