Richard Lafayette, MD, is a professor of medicine and director of the Glomerular Disease Center at Stanford University Medical Center.

Richard Lafayette, MD

US Food and Drug Administration’s (FDA) 

accelerated approval of atacicept (Trutakna) for adults with primary

at risk for disease progression, Richard Lafayette, MD, FACP, discusses how BAFF/APRIL inhibition may reshape the treatment landscape for IgAN.

The approval was supported by data from the phase 3 ORIGIN 3 trial, in which atacicept reduced proteinuria by 42% compared with placebo at 36 weeks (

<.0001) and lowered galactose-deficient IgA1 (Gd-IgA1) levels by 68%. 

Q&A: Atacicept and Upstream Immune Targeting in IgAN With Richard Lafayette, MD

: Atacicept’s approval represents a major milestone in IgAN care. How do you see this therapy shaping the next era of disease management?

 I think this is really an amazing event. Patients now have access to a medication that can completely retarget their disease course and can actually give them the promise of not slowing, but completely preserving, their kidney function.

Of course, that data is yet to be seen from the phase 3 study, but the phase 3 study results showing very dramatic improvements in proteinuria, hematuria, and control of galactose-deficient IgA to a similar, if not better, degree than what we saw in the phase 2 trial gives us great optimism that this will really control their disease in a meaningful way and give them that chance of true preservation of kidney function.

: Atacicept targets both BAFF and APRIL, addressing key pathways involved in B-cell activation and IgAN pathogenesis. What does this approach reveal about our evolving understanding of the biology driving this disease?

 I think there is a lot of potential pushback about the four-hit hypothesis and the underlying tenets of that, including the role of mucosal immune dysregulation and genetic predisposition.

I think the fact that a BAFF plus APRIL inhibitor is being so effective at managing these biomarkers of IgA nephropathy really lends credence to this being a disease of B-cell misregulation or dysregulation, and that both BAFF and APRIL have key elements in controlling the disease.

Atacicept itself can be successful at managing BAFF and APRIL and, in turn, reducing the aberrant immune response that underlies IgA nephropathy.

: With the rapid expansion of disease-modifying therapies in IgAN, how should clinicians think about where atacicept fits within the broader treatment landscape?

 I think we have very clear goals from KDIGO and other treatment guidelines to get the patient’s disease activity under control rapidly and effectively.

So if patients are not already near goal where they can be simply managed with supportive therapy, atacicept really represents a true way forward that is targeted, effective, well tolerated, and really should be a tool that we reach for in the vast majority of patients who have the need for intervention.

 As clinicians begin incorporating atacicept into practice, which patients do you believe are most likely to derive the greatest benefit from this therapy?

I think any patient who is deemed at risk for progression. Again, those patients with more moderate disease can be stabilized with conservative therapy.

But any patient who fails reaching KDIGO guidelines of completely controlled proteinuria and no progression would be a fantastic candidate for atacicept, and hopefully will be treated in the near term.

: The ongoing ORIGIN 3 trial will eventually provide important insight into long-term kidney outcomes. What questions do you hope these data will answer about atacicept’s potential to alter the trajectory of IgAN?

 As I mentioned, we certainly have to wait for the GFR data for ORIGIN 3. Again, I’m confident that it will look similar to the phase 2b study, but seeing it is believing, and actually getting to that data will be really important.

We also hope it will shine light on the more long-term safety and tolerability of a once-weekly simple injection of atacicept, and that we’ll see, similar to the 9-month report, that the drug is well tolerated, that it’s safe, that it’s not associated with any excess infection, and most importantly, that the GFR truly is stable from baseline in patients who are experiencing these biomarker changes of improved proteinuria and hematuria.

: Is there anything else you would like to highlight about atacicept and its role in IgAN?

 Just to again go even deeper with the fact that this is the first real release of a drug that blocks both BAFF and APRIL, and that both cytokines have been legitimately linked to IgA nephropathy.

This really gives us the first opportunity to really control the source of the galactose-deficient IgA production and do it effectively.

Editor’s Note: Relevant disclosures for Lafayette include Aurinia, Callidatas, Complexa, Mallinckrodt, Omeros, Pfizer, Vera Therapeutics, and others.

Vera Therapeutics Receives FDA Accelerated Approval for TRUTAKNA™ for Adult Patients with Primary IgA Nephropathy.

Lafayette R, Barbour SJ, Brenner RM, et al. 

A Phase 3 Trial of Atacicept in Patients with IgA Nephropathy.

 N Engl J Med. Published online November 6, 2025. doi:10.1056/nejmoa2510198

Articles

FDA accelerated approval of atacicept for adults with primary IgA nephropathy at risk for progression introduces upstream BAFF/APRIL blockade as a disease-modifying strategy. In ORIGIN 3, atacicept achieved a 42% proteinuria reduction versus placebo at 36 weeks and a 68% decrease in galactose-deficient IgA1, with accompanying improvements in hematuria. Dual-cytokine inhibition supports a B-cell dysregulation model and offers a targeted, once-weekly injectable option. Definitive impact on eGFR preservation, long-term safety, and infection risk awaits mature phase 3 outcomes.

Richard Lafayette, MD, discusses how atacicept's FDA approval advances BAFF/APRIL targeting in IgA nephropathy.

Atacicept and Upstream Immune Targeting in IgAN With Richard Lafayette, MD

Atacicept Approval Brings BAFF/APRIL Targeting to IgAN With Richard Lafayette, MD

 has granted accelerated approval to atacicept (Trutakna) for adults with primary

 at risk for disease progression, introducing the first BAFF and APRIL inhibitor designed to target upstream immune pathways driving disease.

The FDA based the approval on data from the phase 3 ORIGIN 3 trial, an ongoing randomized study evaluating atacicept in adults with IgAN. Richard Lafayette, MD, FACP, professor of medicine in nephrology and director of the Glomerular Disease Center at Stanford University Medical Center and a principal investigator in the ORIGIN clinical program, said the findings reinforce the role of B-cell dysregulation in IgAN and highlight the potential of targeting disease biology earlier in the disease process.

FDA Approves Atacicept (Trutakna) for IgA Nephropathy

Atacicept inhibits B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), 2 cytokines involved in B-cell survival, activation, and antibody production. By targeting these pathways, the therapy reduces production of galactose-deficient IgA1 (Gd-IgA1), a key component of IgAN pathogenesis.

“I think this is really an amazing event,” Lafayette told 

. “Patients really now have access to medication that can completely retarget their disease course and can actually give them the promise of not slowing but completely preserving their kidney function.”

Although long-term kidney outcomes remain under evaluation, Lafayette said the improvements observed with atacicept in proteinuria, hematuria, and Gd-IgA1 provide optimism that the therapy may meaningfully alter disease progression.

ORIGIN 3 Demonstrates Significant Proteinuria Reduction With Atacicept

The phase 3 ORIGIN 3 trial is a global, multicenter, randomized, double-blind, placebo-controlled study evaluating atacicept in adults with primary IgAN.

The trial enrolled 431 adults with IgAN who were randomized in a 1:1 ratio to receive atacicept 150 mg once weekly through subcutaneous injection or placebo.

Among the first 203 participants included in the prespecified interim analysis, atacicept reduced 24-hour urine protein-to-creatinine ratio (UPCR) by 46% from baseline, with a statistically significant 42% reduction compared with placebo at 36 weeks (

The proteinuria reduction was consistent across prespecified subgroups, including age, sex, race, geographic region, baseline proteinuria, baseline estimated glomerular filtration rate (eGFR), and baseline sodium-glucose cotransporter-2 inhibitor use.

Participants treated with atacicept also experienced a 68% reduction in Gd-IgA1, although this secondary endpoint was considered observational because it was not adjusted for multiplicity.

The safety profile of atacicept was comparable with placebo, with adverse events occurring in 59.3% of patients receiving atacicept compared with 50.0% of patients receiving placebo.

BAFF/APRIL Inhibition Highlights Role of B-Cell Dysregulation in IgAN

The approval of atacicept provides clinical evidence supporting a growing understanding of IgAN as a disease driven by abnormal immune regulation.

IgAN develops through a multistep process in which immune dysregulation leads to production of Gd-IgA1, formation of pathogenic immune complexes, and subsequent kidney injury.

For years, treatment strategies have focused primarily on reducing downstream consequences of disease, including proteinuria and kidney function decline. However, recent advances have shifted attention toward therapies that target the immune pathways responsible for generating pathogenic IgA.

“The fact that a BAFF plus APRIL inhibitor is being so effective at managing these biomarkers of IgA nephropathy really lends credence to this being a disease of B-cell misregulation or dysregulation, and that both BAFF and APRIL have key elements in controlling the disease,” Lafayette said.

He added that atacicept provides an opportunity to directly address the source of abnormal IgA production.

“This really gives us the first opportunity to really control the source of the galactose-deficient IgA production and do it effectively,” Lafayette said.

Where Atacicept Fits in the Expanding IgAN Treatment Landscape

Atacicept enters an increasingly expanding IgAN treatment landscape, with therapies now targeting multiple components of disease progression, including immune activation, complement pathways, and downstream kidney injury.

For clinicians incorporating new therapies into practice, Lafayette emphasized the importance of achieving rapid and effective disease control among patients who remain at risk for progression.

“We have very clear goals from KDIGO and other treatment guidelines to get the patient’s disease activity under control rapidly and effectively,” Lafayette said.

Patients who fail to achieve adequate disease control with supportive therapy may represent those most likely to benefit from targeted immune intervention.

“If patients are not already near goal where they can be simply modified with supportive therapy, atacicept really represents a true way forward that’s targeted, effective, well tolerated, and really should be a tool that we reach for in the vast majority of patients who have the need for intervention,” Lafayette said.

ORIGIN 3 Will Determine Long-Term Kidney Impact

Although proteinuria reduction and biomarker improvements demonstrate atacicept’s biological activity, investigators must still determine whether these changes translate into long-term preservation of kidney function.

The ongoing ORIGIN 3 trial will continue evaluating kidney outcomes, including changes in eGFR over 2 years, as part of the confirmatory requirements following accelerated approval.

Lafayette said those data will ultimately determine whether atacicept can alter the trajectory of kidney decline in IgAN.

“We certainly have to wait for the GFR data for ORIGIN 3,” Lafayette said. “Again, I’m confident that it will look similar to the phase 2b study, but seeing it is believing, and actually getting to that data will be really important.”

Beyond efficacy, continued follow-up will provide additional information regarding the long-term safety and tolerability of once-weekly BAFF/APRIL inhibition, including whether the therapy maintains its safety profile without increased infection risk.

 Published online November 6, 2025. doi:10.1056/nejmoa2510198

Videos

ORIGIN 3 investigator brings atacicept approval to BAFF/APRIL targeting to IgAN 

Welcome to Kidney Compass: Navigating Clinical Trials!

Kidney Compass: Lafayette and ORIGIN 3 at Kidney Week 2025

Kidney Compass: Navigating Clinical Trials

, hosts Brendon Neuen, MBBS, PHD, and Shikha Wadhwani, MD, MS, are joined by Ricahrd Lafayette, MD, from the floor at the 

American Society of Nephrology (ASN) Kidney Week 2025

 evaluating atacicept and how it adds to the totality of evidence supporting the use of the dual BAFF/APRIL inhibitor in IgA nephropathy (IgAN). 

Lafayette describes the moment as “predictably exciting,” noting that the phase 3 findings strongly mirror the promising signals seen previously in the ORIGIN phase 2 program.

The phase 2 trial, which evaluated weekly atacicept dosing, demonstrated a robust biologic impact with approximate reductions of 75% in galactose-deficient IgA1 and 50% in proteinuria at 96 weeks, hematuria resolution in most affected patients, and an annual eGFR decline of only ~0.6 mL/min/1.73 m², which Lafayette noted was far below the expected trajectory in this population. These data guided the design of ORIGIN 3, which enrolled biopsy-proven IgA nephropathy with >1 g/day of proteinuria, eGFR >30 mL/min/1.73 m², and maximally tolerated background therapy. More than half of the participants were also taking an SGLT2 inhibitor. 

Lafayette reports the 9-month primary outcome results aligned closely with phase 2. Atacicept achieved >45% reductions in proteinuria, compared with approximately 7% in the placebo group. Gd-IgA1 fell by approximately 75–80%, and hematuria resolved in most atacicept-treated patients with minimal change on placebo. Lafayette highlighted these effects were consistent across prespecified subgroups, including those on SGLT2 inhibitors.

Safety findings demonstrated there was no increase in infections or serious adverse events relative to placebo, aside from mild injection-site reactions. Lafayette pointed out, numerically, severe adverse events occurred more often in the placebo arm.

While regulatory restrictions prevent release of 9-month eGFR data, Lafayette notes the close resemblance to the phase 2 trajectory supports optimism for the upcoming 2-year readout. However, he emphasizes that atacicept-related biomarker improvements reverse when treatment stops, indicating that ongoing therapy may be necessary for sustained benefit.

The discussion concludes by situating atacicept within a rapidly expanding therapeutic landscape, including other B-cell–directed agents targeting APRIL alone. Head-to-head differences remain unknown, but atacicept’s dual BAFF/APRIL inhibition and consistent efficacy across optimized background therapy make it a compelling potential addition.

 include Aurinia, Callidatas, Complexa, Mallinckrodt, Omeros, Pfizer, Vera Therapeutics, and others. Relevant disclosures for 

 include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for

include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others.

ORIGIN 3: A Phase 3 Trial of Atacicept in IgAN

. Presented at the American Society of Nephrology (ASN) Kidney Week. Houston, Texas. November 05-09, 2025.

Vera Therapeutics Announces Atacicept Achieved 46% Proteinuria Reduction in ORIGIN Phase 3 Trial in Adults with IgA Nephropathy. Vera Therapeutics, Inc. June 2, 2025. Accessed June 2, 2025. 

https://ir.veratx.com/news-releases/news-release-details/vera-therapeutics-announces-atacicept-achieved-46-proteinuria

Podcasts

Discover groundbreaking insights from the ORIGIN 3 study on IgA nephropathy, showcasing promising results and future treatment possibilities.

Kidney Compass: Atacicept and ORIGIN 3 at Kidney Week 2025, with Richard Lafayette, MD

Counting down the biggest news from major medical meetings, it's the HCPLive Five!

HCPLive Five at European Renal Association (ERA) Congress 2025

European Renal Association (ERA) Congress

 is a medical conference bringing together world-renowned experts, researchers, and practitioners in nephrology. ERA Congress 2025 was hosted in Vienna, Austria, and saw more than 10,000 participants from  91 countries around the world, with a record 2835 abstract submissions. This year’s conference was centered around the theme “Game Changers in Nephrology” with the slogan “Beyond Nephrology,” boasting a comprehensive and innovative program exploring the latest advancements and transformative ideas in nephrology.

As part of HCPLive’s on-site coverage, the editorial team conducted expert interviews and reported on timely topics across therapeutic advances, pipeline updates, new renal clinical trial data, and more. In this edition of the HCPLive Five, the team highlights key conversations on pegcetacoplan in 

 and idiopathic immune-complex membranoproliferative glomerulonephritis (IC-MPGN), a trio of 

 drugs in clinical development, and the potential benefits of simultaneous initiation of finerenone (Kerendia) and empagliflozin (Jardiance) in patients with 

Pegcetacoplan Sustains Proteinuria Reductions in C3G, IC-MPGN at 52 Weeks

Extended data from the phase 3 VALIANT trial were presented at ERA 2025 and support the sustained efficacy and safety of pegcetacoplan (Empaveli) in patients with C3G or IC-MPGN, including adolescents and adults with native or transplanted kidneys. The 52-week results show continued proteinuria reduction and eGFR stabilization in both treatment-naïve and crossover groups, reinforcing 26-week data presented at the American Society of Nephrology’s 2024 Scientific Sessions.

In this on-site interview at the meeting, Fadi Fakhouri, MD, PhD, co-lead principal investigator for the VALIANT study and a professor of nephrology at CHUV Lausanne, Switzerland, describes pegcetacoplan’s long-term potential in C3G and IC-MPGN and how the data presented at ERA could shift treatment strategies.

Understanding Zigakibart's Potential in IgA Nephropathy, with Jonathan Barratt, MD, PhD

100-week data from the phase 1/2 ADU-CL-19 trial presented at ERA suggest zigakibart, an APRIL inhibitor under development by Novartis, offers durable reductions in proteinuria and maintains a favorable safety profile in patients with IgAN. In the study, patients experienced a mean 60% reduction in proteinuria from baseline, with 55% achieving proteinuria below 500 mg and 31% below 300 mg, as described by Jonathan Barratt, MD, PhD, the Mayer Professor of Renal Medicine at the University of Leicester, in this interview. Additionally, serum IgA and pathogenic Gd-IgA1 levels dropped by 74%, building on earlier 52-week data showing reductions in IgA, IgM, and IgG of 67%, 78%, and 35%, respectively.

Kidney Compass: CONFIDENCE Trial at ERA 2025, with Rajiv Agarwal, MD, MS

Simultaneous initiation of finerenone (Kerendia) and empagliflozin (Jardiance) in patients with CKD and type 2 diabetes was well-tolerated and resulted in significantly greater reductions in urinary albumin-to-creatinine ratio (UACR) than either agent alone, according to results from the CONFIDENCE trial. During ERA, Kidney Compass host Brendon Neuen, MBBS, PhD, a senior research fellow with the George Institute for Global Health and the director of the Kidney Trials Unit with Royal North Shore Hospital, held a discussion with trial investigators Rajiv Agarwal, MD, Professor Emeritus at Indiana University School of Medicine, about the study results and what they mean for CKD management landscape in real-world settings.

Phase 3 ORIGIN Sets Stage for Atacicept in IgA Nephropathy, with Richard Lafayette, MD

Just days before the ERA 2025, the nephrology community welcomed and celebrated new positive data for atacicept in IgAN in the form of topline results from the phase 3 ORIGIN trial. Announced by Vera Therapeutics on June 02, 2025, the data indicate the trial met its primary endpoint of reduction in proteinuria at week 36, with the atacicept group achieving a 46% reduction from baseline and a statistically significant 42% reduction compared to placebo at week 36.

’s coverage of ERA, we sat down with Lafayette to discuss how this latest data adds to our understanding of atacicept and its potential role in the management of IgAN if it were to receive FDA approval.

Kidney Compass: Sibeprenlimab and the VISIONARY Trial, with Vlado Perkovic, MBBS, PhD, at ERA 2025

, hosts Brendon Neuen, MBBS, PHD, and Shikha Wadhwani, MD, MS, are joined by Vlado Perkovic, MBBS, PhD, dean and scientia professor of Medicine at UNSW Sydney, as he dives into one of the meeting’s most anticipated releases—

. Less than 2 weeks prior to the presentation, Otsuka Pharmaceutical Co. announced the US Food and Drug Administration had granted priority review for their BLA and the application has been given a target action date of November 28, 2025.

These 5 represent only some of the data the 

 team covered at this year's meeting! Check out more KOL insight and our full conference coverage on our 

From new data for potential IgAN treatments to the use of combination initiation therapy for type 2 diabetes and CKD, here are 5 key updates from the annual meeting.