Atacicept Becomes First BAFF/APRIL Inhibitor Approved for IgA Nephropathy: Richard Lafayette, MD

Last month, on July 7, the FDA approved atacicept (Trutakna; Vera Therapeutics) for adults with immunoglobulin A (IgA) nephropathy, making it the first dual inhibitor of patients’ B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) cleared for the progressive kidney disease.

The approval was based on data from a prespecified interim analysis from the phase 3 ORIGIN 3 trial (NCT04716231), which found that treatment with atacicept resulted in a significantly greater reduction in proteinuria than placebo at week 36 in patients with IgA nephropathy.

In an interview with The American Journal of Managed Care^® (AJMC^®), Richard Lafayette, MD, lead investigator of the ORIGIN 3 trial and director of the Stanford Glomerular Disease Center, discussed how the trial’s findings supported the FDA approval of atacicept. He also highlighted what distinguishes the treatment from other approaches for IgA nephropathy and how it may shape clinical decision-making for this population.

This transcript has been lightly edited for clarity.

AJMC: Can you summarize how findings from the ORIGIN 3 trial supported the FDA's approval of atacicept for the treatment of IgA nephropathy?

Lafayette: ORIGIN 3 carried on from ORIGIN 2 as a randomized controlled global trial of atacicept vs placebo in patients who were on background, maximally tolerated renin-angiotensin system (RAS) inhibitors. They were allowed to be on sodium-glucose cotransporter-2 (SGLT2) inhibitors, as well. The patients had to have evidence of salvageable kidney function with more than 30 mL per minute kidney function and had to be at significant risk of progression of their chronic kidney disease with proteinuria of 1 g or more per day. The patients fulfilled that, and they were followed in this trial.

It's a 2-year randomized trial but had a pre-specified interim analysis at 36 weeks to look at proteinuria, because we found that proteinuria is a very powerful surrogate of the long-term outcome of kidney disease. The study was subject to the interim analysis at 36 weeks, and the data supported benefit in a really major way. There was a very substantial proteinuria reduction, by more than 46% compared with baseline with atacicept, and more than 42% when compared with placebo at just 36 weeks, suggesting it met its primary goal, and that likely surrogate is suggesting that patients are truly benefiting.

At the same time, the mechanism of these drugs is a B-cell modulator agent that blocks BAFF and APRIL, utilizing a TACI-based fusion protein, TACI being the natural receptor on B cells that BAFF and APRIL normally bind, to capture both cytokines very efficiently. Associated with that, we know that one of the early factors that propagates IgA nephropathy itself is this antibody called galactose-deficient IgA, so that's been measured in these trials.

Atacicept very promptly and substantially reduced galactose-deficient IgA1 levels by about 70% from baseline throughout the study. Along the same time point, another supporting feature was that it resulted in a reduction of hematuria, another cardinal sign of IgA nephropathy and a prognostic factor as well. It really did all the things we would expect an anti-APRIL and BAFF drug to do: effectively reduce galactose-deficient IgA, reduce hematuria, and reduce proteinuria, this very powerful surrogate of kidney outcomes.

AJMC: Overall, what sets atacicept apart from other treatment approaches for IgA nephropathy?

Lafayette: The mechanism is very, very important. This is the first approved agent that seeks to modify B-cell activity, particularly the production of pathogenic antibodies in terms of galactose-deficient IgA and very likely anti-glycan antibodies, as well, which are very important in the pathogenesis of this disease. By blocking 2 of the major mediators of development and sustenance of B cells and antibody-producing plasma cells, this is really the first evidence and first approved drug blocking both of those cytokines, resulting in this reduction in galactose-deficient IgA hematuria and proteinuria.

We have to wait; this is a fully 2-year study that will be looking at glomerular filtration rate (GFR) outcomes. Vera Therapeutics publicly announced that they'll probably look at that outcome before the 2-year end point by doing another earlier interim analysis. Again, proteinuria is a very nice surrogate, so we've already achieved evidence that the proteinuria is reduced. But the kind of GFR stabilization that was seen in phase 2, with similar reductions in galactose-deficient IgA, hematuria, and proteinuria, was really much superior to what's been experienced with other therapies for IgA nephropathy, including supportive therapies like RAS inhibitors, SGLT2 inhibitors, and endothelin antagonists.

Very recently, we've seen data for finerenone (Kerendia; Bayer), a mineral corticoid receptor agonist, but we’ve also seen data with steroids, targeted budesonide, and iptacopan (Fabhalta; Novartis), other therapies for IgA nephropathy, and the predicted stability of GFR with atacicept looks to be superior.

AJMC: Building on that, how do you see this approval shaping clinical decision-making and the management of IgA nephropathy going forward? Which patients are most appropriate candidates for atacicept?

Lafayette: One of the critical things about the study was that it was relatively permissive. It accepted anybody with biopsy-proven IgA nephropathy within a decade who met those proteinuria and GFR criteria. In a pre-planned analysis of subgroups, the use of atacicept was effective regardless of age, gender, race, country of origin, severity of proteinuria, or severity of kidney function change.

It looked to work broadly across all of these subgroups of patients with IgA nephropathy. Anybody who's suspected to have ongoing IgA nephropathy is likely to benefit, and it doesn't have to be narrowed into any particular subgroup.