Atacicept Shows Encouraging Safety Profile in IgA Nephropathy: Richard Lafayette, MD

Richard Lafayette, MD, lead investigator of the ORIGIN 3 trial (NCT04716231) and director of the Stanford Glomerular Disease Center, continued his conversation with The American Journal of Managed Care^® (AJMC^®) by highlighting the encouraging safety and tolerability profile of atacicept (Trutakna; Vera Therapeutics) in adults with immunoglobulin A (IgA) nephropathy enrolled in the ORIGIN trials.

Aside from mild to moderate injection-site reactions, he noted that atacicept has not demonstrated an increased risk of infections or other complications to date, which may distinguish it from treatments such as corticosteroids. However, Lafayette emphasized that additional follow-up will be needed to fully understand the therapy’s impact on kidney outcomes, including kidney function decline, progression to dialysis or transplant, and other clinical end points.

Looking ahead, he said key questions in IgA nephropathy research include defining the long-term safety and effectiveness of emerging therapies, determining how best to sequence or combine treatments, and ensuring patients have access to individualized treatment strategies that can prevent progression to kidney failure.

This transcript has been lightly edited for clarity.

AJMC: What should clinicians know about the safety and tolerability profile of atacicept, and how do you expect it to be managed in practice?

Lafayette: This is one of the really beautiful parts of the ORIGIN trial that’s extremely exciting. As I mentioned, the drug is specifically designed to modulate B-cell activity and reduce antibody production by mature B cells and plasma cells. Therefore, there's always a concern that with reductions in IgA, immunoglobulin G, and immunoglobulin M, we leave our patients more vulnerable to adverse effects.

What’s remarkable about ORIGIN 2 and now the ORIGIN 3 data is that the adverse event profile looks to be no different than placebo. So far, we are not seeing any increased risk of adverse effects or infections, other than mild to moderate injection-site reactions. The drug is looking really, really well tolerated. In fact, those infections and complications we deem as severe adverse events were actually numerically a little bit lower.

We'll have to see if that holds up with further data, but that's really remarkable compared with things like corticosteroids, where we know there are rates of infection that can be concerning. This is really incredible that we can come to our patients with a drug that's showing great efficacy and not have to be overly concerned about adverse events.

AJMC: Looking ahead, what additional evidence will be needed to better understand atacicept's long-term impact on kidney outcomes?

Lafayette: This week 36 interim analysis was preplanned, part of the accelerated approval plan, but it's only a subset of patients out to 36 weeks. The original plan was for a 2-year trial to demonstrate benefit on kidney function through the estimated GFR [glomerular filtration rate], but now we await an earlier interim analysis to see about safety and then efficacy by both proteinuria and kidney function to look for full approval, so we definitely have to wait for that.

It'll be much more full-throated to look at safety with more exposure to the drug and compare it to more exposure with placebo. Then, to look at the actual kidney function impact and impact on other secondary end points, like reduction of GFR to 30%, patients coming to dialysis or transplant, is going to be really, really important in having us fully understand this drug and how beneficial it might actually be.

AJMC: More broadly, what do you consider the most pressing unanswered questions in IgA nephropathy research?

Lafayette: It's really amazing that we have so many approved agents looking effective, looking safe. I'd say atacicept is now an amazing exemplar of that and may well be a firstline agent, but longer experience with these agents for efficacy and safety is going to be essential.

How to make sure that every patient has access to therapy that works for them as an individual, and learning how to use this new, really lovely group of medications in series or in combination, is going to be really essential to give every patient the best treatment and the best opportunity of a healthy life without a future threat of kidney failure.