What drugs are in development for Immunoglobulin A nephropathy?

Overview of Immunoglobulin A NephropathyDefinitionon and Pathophysiology
Immunoglobulin A nephropathy (IgAN), also known as Berger’s disease, is the most common primary glomerulonephritis worldwide. The disease is characterized by mesangial deposition of immune complexes containing IgA1 molecules—often with aberrant glycosylation—and frequently elicits an inflammatory cascade that results in mesangial proliferation, glomerular injury, and progressive loss of kidney function over time. The pathophysiologic process involves multiple “hits”: first, the generation of galactose-deficient IgA1; second, the formation of anti‑glycan autoantibodies; and third, the formation and deposition of IgA1‑containing immune complexes in the kidney mesangium. These deposits activate complement mechanisms and inflammatory pathways, eventually leading to fibrosis and irreversible kidney damage. Genetic factors, dysregulation of the mucosal immune system, and environmental triggering events all contribute to the disease’s heterogeneity.

Current Treatment Landscape
At present, IgAN is managed primarily with supportive strategies including blood pressure control, renin–angiotensin system (RAS) blockade, low-sodium diets, and lifestyle modifications. In more severe or progressive cases, corticosteroids and other nonspecific immunosuppressants (e.g., cyclophosphamide or mycophenolate mofetil) have long been used, but controversies remain about efficacy and safety. Recently, a more targeted approach has emerged with the approval of the first disease‐specific agent TARPEYO—a delayed‑release formulation of budesonide (originally developed as Nefecon)—aimed at reducing proteinuria by targeting the gut mucosal B‑cells responsible for producing the abnormal IgA1. Despite these advances, many patients continue to progress and there remains a significant unmet need for therapies that intervene at the pathogenic level rather than solely offering symptomatic or supportive care.

Drug Development Pipeline

In recent years, pharmaceutical research has focused on a diverse set of molecules and modalities aimed at modifying either the production of aberrant IgA1, the formation/deposition of immune complexes, or the downstream inflammatory and complement‑mediated injury. The current pipeline can broadly be divided into early-phase and late-phase clinical candidates.

Early-Stage Clinical Trials
Several agents that target novel mechanisms are under investigation in Phase 1 or Phase 2 studies:

• Cemdisiran (an RNA interference therapeutic)
Cemdisiran is designed to silence the messenger RNA of complement component C5. By reducing C5 levels, cemdisiran targets the terminal complement pathway. The Phase II descriptive trial for cemdisiran in IgAN patients has reported a mean 37% reduction in proteinuria (assessed by the 24‑hour urine protein-to-creatinine ratio) after 32 weeks of subcutaneous administration relative to placebo. Its RNAi mechanism represents an innovative approach compared with traditional small molecules or antibodies. The agent is currently being further investigated to determine the durability of the response and safety profile in IgAN‐specific populations.

• Sibeprenlimab
Sibeprenlimab is a monoclonal antibody that is in early-stage studies for IgAN. In a Phase 2 trial, sibeprenlimab demonstrated a statistically significant and clinically meaningful reduction in 24‑hour urinary protein excretion (uPCR) relative to placebo after nine months of treatment. Although details such as dosing regimen and exact target are still emerging, sibeprenlimab is being evaluated as a precision immunotherapy candidate with the potential to modulate key immune pathways involved in disease progression.

• Additional Novel Modalities
Other early-stage candidates—while not always exclusively developed for IgAN—are being explored in cohorts that include patients with IgAN as part of the broader portfolio for glomerular diseases. For example, there are preclinical efforts aimed at highly selective inhibitors of factors involved in IgA complex formation, or agents that modulate gut immune responses. These programs are in initial phases and therefore less information is publicly available, but they contribute to an overall diversification of the pipeline as investigators search for disease-specific interventions.

Late-Stage Clinical Trials
Several drugs have advanced to later stages of clinical development for IgAN. These candidates have more robust clinical data and are expected to either seek regulatory approval soon or are under pivotal evaluation.

• TARPEYO (Nefecon)
TARPEYO is already approved in some regions on the basis of accelerated approval, but it remains an important part of the current pipeline because confirmatory trials are ongoing to verify its long-term benefit on kidney outcomes. As a targeted-release corticosteroid formulation, TARPEYO releases budesonide in the ileum, thereby locally modulating the mucosal immune system and reducing the production of galactose-deficient IgA1. Its pivotal Phase 3 NefIgArd trial met its primary endpoint of proteinuria reduction, and the confirmatory studies will assess its impact on estimated glomerular filtration rate (eGFR) decline and other long-term renal outcomes.

• Sparsentan
Sparsentan is a dual endothelin receptor and angiotensin receptor blocker that has been advanced into Phase 3 clinical evaluation for its potential to reduce proteinuria and slow the progression of IgAN. Early exploratory clinical data from the SPARTAN trial and related subgroup analyses have shown that sparsentan can produce robust reductions in proteinuria compared with irbesartan. Its dual mechanism allows it to target both hemodynamic factors and inflammatory pathways that contribute to disease progression. Sparsentan represents a novel approach by combining two distinct mechanisms into one molecule, thereby potentially offering increased efficacy over standard RAS inhibitors.

• Atrasentan
Atrasentan, an endothelin receptor antagonist that has been developed for diabetic kidney disease, is now being evaluated in IgAN as well. Clinical trial data suggest that atrasentan can significantly reduce proteinuria in patients with IgAN, although its safety profile—especially regarding fluid retention and potential cardiovascular effects—has been closely scrutinized. The ongoing Phase 3 trial in IgAN aims to demonstrate that atrasentan can improve kidney survival without incurring unacceptable adverse event rates. Its development in IgAN builds on previous evidence in similar proteinuric conditions and suggests a new application for agents that modulate the endothelin system.

• Povetacicept
From a different angle, povetacicept is a dual inhibitor of the BAFF (B‑cell activating factor) and APRIL (a proliferation‑inducing ligand) pathways. These pathways are central to B‑cell maturation and the production of immunoglobulins, including the aberrantly glycosylated IgA1 implicated in IgAN. Vertex Pharmaceuticals and its collaborators are advancing povetacicept into Phase 3 testing for IgAN. The rationale for this approach is that by simultaneously inhibiting BAFF and APRIL, the drug may reduce both the quantity and pathogenic quality of IgA produced by mucosal B‑cells. Late‑stage trials for povetacicept are being carefully designed with surrogate endpoints such as proteinuria reduction and eGFR slope to support its clinical efficacy.

• Narsoplimab
Narsoplimab, a monoclonal antibody that targets the lectin pathway of complement activation, was in clinical development for IgAN. However, interim analysis in a pivotal Phase 3 trial showed that narsoplimab did not meet its primary endpoint for reducing proteinuria compared to placebo. Although this represents a setback, data from such trials often inform the design of future studies and help refine the target patient population. The experience with narsoplimab illustrates how even late-stage candidates may encounter challenges in translating mechanism into clinical benefit in a heterogeneous disease such as IgAN.

Mechanisms of Action

Novel Drug Targets
The development of new drugs for IgAN is partly driven by a more sophisticated understanding of the immunopathogenesis of the disease. Several novel drug targets have emerged:

• Complement System Modulation
Complement activation plays a major role once immune complexes are deposited in the glomeruli. Agents such as cemdisiran work by directly interfering with the synthesis of C5, thereby preventing the formation of the membrane attack complex and subsequent inflammation. Targeting complement components offers a strategy to attenuate the amplification loop of inflammation without broad immunosuppression.

• Dual Inhibition of Endothelin and Angiotensin Receptors
Sparsentan’s unique dual receptor antagonism enables it to address two key pathways implicated in IgAN: the RAS-mediated hemodynamic stress and the endothelin-driven inflammatory and fibrotic responses. This combined approach is a significant departure from conventional monotherapies and is designed to reduce proteinuria more effectively.

• B-Cell Modulation via BAFF and APRIL Inhibition
Povetacicept is targeted against two cytokines essential for B‑cell survival and differentiation. Excessive activity of BAFF and APRIL is thought to drive the overproduction of pathogenic IgA1. By inhibiting these targets, povetacicept aims to reduce the generation of the aberrant IgA and potentially modify the disease course at an earlier stage of immune dysregulation.

• Lectin Pathway Inhibition
Narsoplimab was designed to block MASP-2, a key enzyme in the lectin pathway of complement activation. Although its development in IgAN faced challenges, this mechanism remains of interest because the lectin pathway is activated by immune complex deposition and may contribute to glomerular injury. The failure of narsoplimab to meet endpoints in its Phase 3 trial provides insights into the complexities of complement inhibition in IgAN.

• RNA Interference
Cemdisiran leverages RNAi technology to silence specific mRNAs—in this case, C5 mRNA. This approach underscores the emergence of nucleic acid therapeutics as a new modality in nephrology. The high specificity of RNAi combined with its durability of effect represents an innovative way to modulate disease mechanisms at the genetic level.

• Monoclonal Antibodies Against Cell Surface Antigens
Sibeprenlimab is one example of a monoclonal antibody currently being evaluated in IgAN. While its exact target is under further investigation, bivalent antibodies in early trials are being explored for their ability to specifically neutralize key mediators of immune complex formation or deposition. This category of therapeutics may offer a high degree of specificity compared with broad-spectrum immunosuppressants.

Comparison with Existing Treatments
Existing therapies for IgAN—such as corticosteroids, RAS inhibitors, and nonspecific immunomodulators—primarily provide supportive benefit by reducing proteinuria or blood pressure and slowing progression. However, their mechanisms are not directly aimed at the underlying pathogenic mechanisms that drive IgA production and immune complex formation. In contrast, the drugs in development are designed to target these upstream processes. For instance, whereas TARPEYO uses targeted delivery of budesonide to modulate gut immune function, povetacicept directly disrupts B‑cell cytokine pathways that govern IgA synthesis. Similarly, while standard immunosuppressants can broadly reduce inflammation, targeted therapies like cemdisiran or sparsentan aim to modulate specific pathogenic pathways with potentially fewer systemic side effects. This mechanistic precision may ultimately translate into more effective and safer long-term treatments.

Regulatory and Market Considerations

Regulatory Approval Process
The regulatory path for drugs in IgAN has traditionally been challenging because of the variable and slowly progressive nature of the disease. To overcome these hurdles, agencies like the FDA and EMA have accepted surrogate endpoints—most notably reductions in proteinuria and changes in eGFR slopes—as primary endpoints in pivotal trials. TARPEYO, for example, was granted accelerated approval based on these surrogate outcomes, with confirmatory studies ongoing to validate its long-term benefit. For drugs in the later stages of development such as sparsentan, atrasentan, and povetacicept, regulatory submissions are being planned with careful designs to show statistically significant changes in clinically relevant endpoints. Additionally, novel modalities like cemdisiran require detailed risk–benefit evaluations, and the use of RNA interference therapeutics is an emerging area that regulators are scrutinizing with new guidelines.

It is also important to note that many companies now incorporate biomarker-based stratification in their trials. This approach helps to identify patients more likely to benefit from targeted therapy and may shorten the time needed to achieve endpoints that have previously required long-term follow-up. The regulatory landscape is evolving in tandem with advances in the understanding of IgAN pathogenesis. In the future, combining traditional efficacy endpoints with genetic or proteomic signatures could further enhance the approval process for these new modalities.

Market Potential and Challenges
IgAN has a high prevalence in certain geographic areas, with significant numbers of patients in East Asia, Europe, and North America. However, the heterogeneity of the disease represents a major challenge for market uptake. Drugs that offer a clear benefit in terms of slowing progression to end-stage renal disease and reducing proteinuria are highly attractive, especially because the current standard of care is often based on supportive therapy rather than disease modification.

The market potential for innovative drugs like povetacicept, sparsentan, and cemdisiran is high because these agents promise a mechanistically targeted approach that could change the natural history of the disease. The successful demonstration of efficacy in Phase 3 trials, as is the case for TARPEYO, can set a precedent and open the door to subsequent approvals. Nevertheless, clinical trial recruitment, the inherent slow progression of IgAN, and the need for surrogate endpoints mean that companies must carefully design their programs and commit to long-term evidence generation.

There are also commercial implications from competitive dynamics. For example, the failure of one candidate such as narsoplimab underscores the risks inherent in this competitive field. Companies are therefore also looking at niche positioning, combination therapies, or even repositioning agents that have been approved for other indications (such as atrasentan, previously studied in diabetic kidney disease) for application in IgAN. The strategy of targeting multiple pathways—for example using dual receptor antagonists like sparsentan—is seen as a way to outcompete therapies that act on a single target.

In addition, the pricing and reimbursement environment for kidney diseases is evolving as payers increasingly demand the demonstration of long-term cost effectiveness. Companies developing drugs in IgAN need to not only achieve clinical endpoints but also generate models showing that slowing the progression of kidney failure can potentially reduce expensive dialysis or transplantation costs in the long term. This economic argument is central to the value proposition of innovative drug candidates in a disease with a clear unmet need.

Detailed Conclusion
In summary, there is an exciting and diverse drug development pipeline for Immunoglobulin A nephropathy that represents both a shift toward mechanistically targeted therapies and an effort to overcome traditional limitations of supportive care. Current drugs in development can be broadly divided into those in early clinical stages—such as cemdisiran, which uses RNA interference to silence complement components, and sibeprenlimab, a monoclonal antibody designed to neutralize key pathogenic immune mediators—and those in late-stage trials that are either awaiting confirmatory data or on the cusp of regulatory submission. TARPEYO, already approved in some regions, reflects the success of a targeted gut‑delivered corticosteroid approach, while sparsentan and atrasentan offer promise as dual‑mechanism agents that combine hemodynamic and anti‑inflammatory effects. Moreover, povetacicept—which targets B‑cell cytokines BAFF and APRIL—illustrates the new therapeutic angle of modulating immune dysregulation at its source.

From a mechanistic standpoint, these drugs are developing on several novel targets including complement inhibition, dual receptor antagonism, and cytokine blockade. This targeted approach contrasts sharply with earlier non‑specific immunosuppressive agents and has the potential to improve both efficacy and safety profiles in the long term. Regulatory pathways now accepting surrogate endpoints have greatly eased the process for these emerging therapies, although the heterogeneity, slow progression, and regional differences in IgAN continue to pose clinical trial and market challenges.

Ultimately, while some agents such as narsoplimab have faced hurdles, the overall pipeline is robust and represents a major shift from supportive management to potentially disease‑modifying treatments for IgAN. The success of these drugs could not only improve kidney survival and quality of life for patients but also transform the medical and commercial landscape of nephrology treatment. Clinicians, researchers, and pharmaceutical developers remain focused on providing safer, more effective treatments that address the underlying immunopathogenesis of IgAN rather than merely its symptoms.

In conclusion, drugs in development for Immunoglobulin A nephropathy include both early‐stage candidates like cemdisiran and sibeprenlimab as well as late‐stage candidates such as TARPEYO (Nefecon), sparsentan, atrasentan, and povetacicept. These drugs are targeting distinct mechanistic pathways such as the complement cascade, endothelin and angiotensin receptors, and B‑cell cytokines (BAFF and APRIL), which may provide more effective, targeted, and safer treatment options compared with traditional approaches. While the regulatory and market landscapes present challenges that require innovative trial designs and robust long-term data, the potential impact on patient outcomes is substantial. This multi‑angled development approach, which integrates genetic, immunological, and pharmacological insights, promises a paradigm shift in the treatment of IgAN and could ultimately change the prognosis for millions of patients worldwide.