APRIL Inhibition, Dual Blockade, and Proteinuria Endpoints in IgAN, With Edward Lerma, MD

On IgA Nephropathy (IgAN) Awareness Day, HCPLive spoke with Edgar Lerma, MD, Clinical Professor of Medicine with the Section of Nephrology at the University of Illinois at Chicago, about the rapidly evolving treatment landscape, including the rise of targeted therapies, the emerging role of APRIL inhibition, and ongoing debates surrounding proteinuria as a surrogate endpoint in clinical trials.

Once considered a disease with limited therapeutic options beyond supportive care and immunosuppression, IgA nephropathy treatment has entered what Lerma described as a “mechanism-first era,” with multiple newly approved and investigational agents now targeting distinct pathways across the pathogenic cascade. From sparsentan and targeted-release budesonide to complement inhibitors and APRIL-targeting biologics, clinicians are increasingly tasked with determining how to sequence therapy, identify high-risk patients, and communicate prognosis in a more individualized way.

Despite these advances, real-world uptake of newly approved IgAN therapies has remained relatively low through 2025, with barriers including REMS requirements, safety monitoring burdens, prior authorization hurdles, and continued uncertainty surrounding long-term renal outcomes. At the same time, ongoing development of APRIL and dual APRIL-BAFF inhibitors has intensified discussion around upstream immune modulation and whether newer biologics may eventually become foundational therapies in IgAN management.

HCPLive sat down with Lerma for a Q&A on treatment sequencing, proteinuria endpoints, APRIL inhibition, and how clinicians should approach prognosis discussions in the modern IgAN era.

HCPLive: With 5 approved agents now targeting distinct points on the pathogenic cascade, how do you approach treatment selection and sequencing in patients with IgAN?

Lerma: Even though we now have 5 or more targeted options emerging, most guideline-consistent practice still begins with risk stratification. Clinicians are not routinely “stacking” disease-modifying agents at this point. More commonly, treatment involves substituting agents or intensifying therapy within a pathway based on patient response and tolerability. Combination approaches, such as endothelin receptor antagonists plus complement inhibitors, remain more in the trial territory than standard practice.

In my own practice, I still take a stepwise approach. First, patients are started on optimized supportive therapy. That includes maximizing renin-angiotensin system (RAS) blockade as tolerated, adding an SGLT2 inhibitor—which is now essentially standard across CKD, including IgAN—and targeting blood pressure below 130/80 mmHg. We also aim for proteinuria reduction, ideally below .5 g/day if feasible, although older guidelines used <1 g/day as the benchmark.

Once supportive care is optimized, the next step is defining the patient’s risk trajectory. If proteinuria persists above .5 g/day despite optimal care, if eGFR is declining, or if histopathology suggests higher-risk disease—such as crescents or concerning MEST-C scores—then we begin considering the newer pathway-targeted therapies. These include agents targeting IgA production, endothelin pathway therapies with hemodynamic and antifibrotic effects, and complement inhibitors targeting downstream injury modulation.

Recent real-world data suggest fewer than 5% of eligible IgAN patients received newly approved therapies through 2025, with REMS requirements and black box warnings cited as barriers. What do you think is driving that gap?

Lerma: The gap is real, but it’s also not unexpected when new therapies enter practice. The reasons tend to fall into about 5 major categories.

First is regulatory and safety friction. Some agents require REMS programs, frequent laboratory monitoring, or carry black box warnings, all of which create administrative burdens. Those challenges can be particularly difficult in community nephrology settings.

Second is skepticism surrounding proteinuria as a surrogate endpoint. Most clinicians view proteinuria reduction positively, but many still question whether it truly translates into long-term prevention of end-stage kidney disease. As a result, uptake of therapies approved on surrogate endpoints tends to lag behind approvals themselves.

Third are infrastructure barriers, including specialty pharmacy routing, prior authorizations, and documentation requirements proving failure of optimized supportive care. Monitoring demands can also exceed what some practices can realistically support.

Fourth is the inherent heterogeneity of IgAN. The disease is often slowly progressive and highly variable at the individual level, so clinicians may defer immunomodulatory or pathway-targeted therapies unless the patient appears clearly high risk.

Finally, there is the physician familiarity curve. Many nephrologists trained before the era of targeted therapies in IgAN. Historically, adoption of new CKD therapies can lag evidence by several years, so some delay is expected.

HCPLive: For patients who have been on sparsentan or budesonide for a year or more, what role do APRIL inhibitors play? Are you using them as add-on therapy, replacement therapy, or something else entirely?

Lerma: When we talk about APRIL inhibitors—such as sibeprenlimab and other APRIL biologics currently in development—we’re discussing agents that target a different, upstream mechanism. These therapies decrease mucosal B-cell activation and reduce production of galactose-deficient IgA1, which is central to IgAN pathogenesis.

Mechanistically, APRIL inhibitors act earlier in the disease cascade than either budesonide or sparsentan. In practice, there are currently 3 conceptual roles being explored.

One is replacement therapy. If APRIL inhibition demonstrates strong and durable proteinuria reduction with a favorable safety profile, it could potentially replace steroid-based approaches.

The second is sequential escalation. In that model, clinicians would begin with optimized supportive care and hemodynamic modulation, then escalate to APRIL inhibition if progression persists despite treatment.

The third possibility is combination therapy. Biologically, combining upstream and downstream approaches makes sense, but concerns remain regarding overlapping immunosuppression and whether combination therapy provides meaningful additional benefit.

At this point in 2026, APRIL inhibition is not yet standard add-on therapy in routine practice. It’s better viewed as a potentially foundational future therapy whose role is still being defined.

HCPLive: Several pipeline agents target both APRIL and BAFF simultaneously. How do you assess the rationale for dual blockade compared with the more selective approaches already approved?

Lerma: Dual APRIL-BAFF blockade is mechanistically appealing, but it also represents a more aggressive immunosuppressive strategy. Some would argue that selective APRIL inhibition may ultimately fit better within a precision nephrology framework unless dual blockade clearly demonstrates superior efficacy.

The rationale behind dual inhibition is broader suppression of the pathogenic B-cell axis. BAFF inhibition suppresses B-cell survival, while APRIL inhibition reduces plasma cell differentiation and IgA production. In theory, this could produce greater reductions in pathogenic IgA.

However, there are trade-offs. BAFF plays an important role in long-term B-cell homeostasis, so suppressing it may increase infection risk, contribute to hypogammaglobulinemia, or blunt vaccine responses.

Because of that, some clinicians favor APRIL-only inhibition, which may more selectively target pathogenic IgA production while preserving broader immune competence. That creates a potentially cleaner safety profile in patients with CKD.

Right now, the jury is still out, and many practicing clinicians are closely watching how those risk-benefit questions evolve.

HCPLive: Proteinuria as a surrogate endpoint continues to generate debate in IgAN drug development. What are your thoughts on that discussion?

Lerma: Proteinuria remains the central methodological tension in IgAN drug development. For FDA approval, the earliest signal therapies can realistically demonstrate is proteinuria reduction, which is why so many trials use it as a surrogate endpoint.

The challenge is that reducing proteinuria does not automatically prove preservation of long-term kidney outcomes. What clinicians ultimately want to see is stabilization of eGFR over time.

The difficulty is that meaningful eGFR preservation takes years to demonstrate. You may not see those differences within 6 months or even the first year of treatment. Sometimes even 2 years may still be too short.

Ultimately, the field will likely judge these therapies based on whether they meaningfully preserve kidney function long term.

HCPLive: As the treatment landscape expands, what is the most important shift in how clinicians should communicate prognosis to patients?

Lerma: This is probably where practice is changing the most. The older model was largely passive monitoring of kidney function over time. The newer model is much more evidence-driven and trajectory-based.

Risk is no longer viewed as binary. Instead, clinicians are increasingly focusing on proteinuria trajectory, eGFR slope, histologic risk—including MEST-C scoring—and response to therapy within the first 6 to 12 months.

Treatment response itself is now becoming part of prognosis. We know CKD progression is modifiable, even if the disease is not universally curable. The goal is increasingly about altering the slope of progression rather than promising cure.

At the same time, clinicians need to communicate uncertainty carefully. We should avoid overpromising kidney preservation based solely on surrogate endpoints while also acknowledging that individual responses can vary considerably.

Compared with several years ago, our understanding of IgAN pathogenesis has improved substantially, particularly with the development of the 4-hit hypothesis framework. There is still uncertainty, but it is narrower than it once was.

HCPLive: Is there anything else you’d like to highlight?

Lerma: I think the key point is that we are now in a mechanism-first era of IgAN, but not yet in a sequencing-consensus era. Uptake of therapies is being shaped not only by efficacy, but also by system-level barriers, monitoring requirements, and lingering skepticism around surrogate endpoints.

APRIL inhibition may ultimately become a foundational upstream therapy rather than simply an add-on option, while dual APRIL-BAFF blockade raises important questions about balancing broader efficacy with potential safety risks.

Proteinuria remains a necessary—but insufficient—surrogate for long-term renal survival. And importantly, communication with patients is shifting toward dynamic, response-based risk modeling rather than static CKD staging alone.