Targeted-release budesonide formulation makes good in IgAN regardless of baseline eGFR

Treatment with targeted-release budesonide formulation preserves kidney function and reduces proteinuria in patients with IgA nephropathy (IgAN) independent of baseline eGFR, and this benefit is seen both after 9 months of treatment and throughout the remaining 15-month off-treatment period, according to a subanalysis of the phase III NeflgArd study presented at the ERA annual meeting.

The relative benefit of targeted-release-formulation budesonide vs placebo in terms of reducing eGFR decline was seen in patients across most decile boundaries of baseline eGFR (≤ and > 38, 43, 47, 51, 55, 60, 66, 72, and 82 mL/min/1.73 m²) and across timepoints (at the end of the 9-month treatment and at off-treatment observation period of 12 and 24 months), with a generally greater benefit in higher baseline eGFR groups (>72 mL/min/1.73 m²), reported lead researcher Prof Jonathan Barratt from the University of Leicester in Leicester, UK. [ERA 2025, abstract 3345]

“That’s important because what we’re trying to promote in the KDIGO guidelines is an early diagnosis and early intervention,” Barratt said. “Treat patients when they have good eGFRs to stop them from losing nephrons.”

With regard to the relative urine protein-creatinine ratio (UPCR) benefit with targeted-release-formulation budesonide vs placebo, substantial reductions were seen from 9 months regardless of baseline eGFR. These reductions further increased at the 12-month off-treatment observation period and sustained through 24 months independent of the starting eGFR, as Barratt pointed out.

When patients within the two lowest eGFR deciles (≤43 mL/min/1.73 m²) and those within the two highest deciles (>72 mL/min/1.73 m²) were combined, targeted-release-formulation budesonide maintained a sustained effect on eGFR, irrespective of whether baseline eGFR was at the lowest or highest levels. Barratt noted a pronounced on-treatment benefit, with eGFR levels either increasing of remaining stable, and a delay in eGFR decline in the off-treatment observation period relative to placebo.

A similar pattern was observed for UPCR, with a greater reduction in the targeted-release-formulation budesonide group than in the placebo group regardless of whether the starting eGFR was at the lowest or the highest levels, he added.

“These data show that … we are getting as good a response in [IgAN patients with] lower baseline eGFRs or maintained eGFRs. And we should be confident about treating people with [targeted-release-formulation budesonide] across the full range of eGFR,” in terms of kidney function preservation and proteinuria reduction, Barratt said in conclusion.

Targeted release

Asked during a question-and-answer session about whether it was possible for alternative budesonide formulations to simulate or imitate a similar clinical outcome in IgAN patients, Barratt pointed out that the key to the drug’s efficacy lies in its ability to deliver a high, localized concentration of budesonide to a highly selective part of the gastrointestinal tract. “And that concentration of budesonide that is delivered has to be sufficient to interfere with the mucosal immune system and the generation of mucosal IgA.”

Barratt explained that other budesonide formulations, such as those for ulcerative colitis or Crohn’s disease, are designed for release specifically in the large bowel or across the entire small intestine, respectively. If used in the treatment of IgAN patients, these formulations might not be able to achieve the effective local concentration required for the desired pharmacodynamic effect, he added.

Individualized treatment approach

As to whether targeted-release-formulation budesonide can be given to IgAN patients with an eGFR of below 30 mL/min/1.73 m², Barratt advocated for individualizing treatment decisions. He noted that while patients with heavily scarred kidneys might show less dramatic eGFR changes, this should not be a reason not to try the drug in patients with eGFR <30 mL/min/1.73 m².

“Anecdotally, we’ve had a number of instances where we have seen benefit. Now, of course, at that eGFR level, you’re not expecting miracles, but if you’re able … to delay the time to dialysis to allow for planning, for transplantation, or for [the patient] to get their head around developing end-stage kidney disease, then that’s worth its weight in gold,” he said. “We have to manage expectations of what we’re going to achieve with this treatment at those lower eGFRs, but there’s no reason to suspect we couldn’t gain some benefit.”

NeflgArd study

Conducted at 132 hospital-based clinical sites across 20 countries worldwide, the NeflgArd study included 364 adult patients (34 percent women, 76 percent White) with primary IgA nephropathy, eGFR of 35–90 mL/min per 1.73 m², and persistent proteinuria (UPCR ≥0.8 g/g or proteinuria ≥1 g/24 h) despite optimized renin-angiotensin system blockade therapy.

Patients were randomly assigned to receive either 16 mg/day of targeted-release-formulation budesonide (n=182; median age 43 years) or placebo (n=182; median age 42 years) for 9 months, alongside supportive care (RAS inhibition). Following this, all patients underwent a 15-month off-drug observational period with continued supportive care.

The time-weighted average of eGFR over 24 months demonstrated a significant treatment benefit with targeted-release budesonide formulation vs placebo, with a time-weighted average change of –2.47 mL/min per 1·73 m² as opposed to –7·52 mL/min per 1·73 m² with placebo (difference, 5.05 mL/min per 1.73 m²; p<0.0001). The most common treatment-emergent adverse events were peripheral oedema, hypertension, muscle spasms, acne, and headache—all of which occurred more frequently with budesonide. There were no reports of treatment-related deaths. [Lancet 2023;402:859-870]