Comprehensive Report on VIS-649 (Sibeprenlimab): An Investigational Agent for IgA Nephropathy

1. Executive Summary

Sibeprenlimab (VIS-649) is an investigational humanized IgG2 monoclonal antibody engineered to specifically target and inhibit A PRoliferation-Inducing Ligand (APRIL), a cytokine understood to play a critical role in the immunopathogenesis of IgA Nephropathy (IgAN).[1] Developed by Visterra, Inc., now a wholly-owned subsidiary of Otsuka Pharmaceutical, sibeprenlimab is designed to intervene in the early stages of IgAN by reducing the production of pathogenic galactose-deficient IgA1 (Gd-IgA1) and the subsequent formation of nephritogenic immune complexes.[2]

Clinical development programs, notably the Phase 2 ENVISION trial and the ongoing Phase 3 VISIONARY trial, have demonstrated that treatment with sibeprenlimab leads to statistically significant and clinically meaningful reductions in proteinuria in adult patients with IgAN.[2] Proteinuria is a key surrogate marker for the progression of kidney disease. Furthermore, early data suggest a favorable impact on the stabilization of estimated glomerular filtration rate (eGFR), a direct measure of kidney function.[6] The safety profile of sibeprenlimab observed in these trials has been generally favorable and consistent, without major emergent safety concerns.[2]

Sibeprenlimab is administered via subcutaneous injection every four weeks, a regimen that offers potential convenience for patients requiring long-term management.[8] Recognizing its potential to address a significant unmet medical need in a serious condition, sibeprenlimab has received Breakthrough Therapy Designation and Priority Review for its Biologics License Application (BLA) from the U.S. Food and Drug Administration (FDA), with a Prescription Drug User Fee Act (PDUFA) target action date set for November 28, 2025.[11] Additionally, it has been granted Orphan Drug Designation by the European Medicines Agency (EMA).[14] These regulatory milestones underscore the promising nature of sibeprenlimab as a targeted therapy for IgAN, potentially offering a disease-modifying approach that moves beyond current standards of supportive care or broader immunosuppression.

The development of sibeprenlimab signifies a shift towards precision medicine in nephrology, targeting a specific molecular driver of IgAN. Its progression through rigorous clinical evaluation and expedited regulatory pathways reflects both the urgency for new IgAN treatments and the strength of the clinical data generated to date.

2. Introduction to VIS-649 (Sibeprenlimab)

VIS-649, known by its non-proprietary name sibeprenlimab, is an advanced investigational therapeutic agent. It is classified as a humanized Immunoglobulin G2 (IgG2) kappa monoclonal antibody.[1] The core pharmacological activity of sibeprenlimab lies in its highly selective binding to and inhibition of the cytokine A PRoliferation-Inducing Ligand, commonly referred to as APRIL.[1]

Sibeprenlimab was originally designed and engineered by Visterra, Inc., leveraging the company's proprietary Hierotope® antibody discovery and engineering platform.[2] In a significant strategic move to bolster its presence in nephrology and other challenging therapeutic areas, Otsuka Pharmaceutical Co., Ltd. announced the acquisition of Visterra, Inc. in July 2018 for approximately USD 430 million, with the transaction anticipated to close in the third quarter of that year. Consequently, Visterra now operates as a wholly-owned subsidiary of Otsuka Pharmaceutical.[4] This acquisition underscores Otsuka's commitment to incorporating innovative biologic platforms to address diseases with high unmet medical needs.

The Hierotope® platform, central to Visterra's drug discovery efforts, represents a sophisticated integration of novel computational tools and experimental methodologies. It is specifically designed to facilitate the creation of precision antibody-based therapies.[2] A key strength of this platform is its ability to identify and effectively target unique, often conformational, epitopes on disease-associated proteins that may be intractable to conventional antibody development approaches. The platform employs advanced techniques such as single-cell multiomics, artificial intelligence, and machine learning for comprehensive target validation and epitope mapping, followed by precise antibody design.[17] Furthermore, the Hierotope® platform incorporates capabilities for Fc engineering, including proprietary ViSTAR™ mutations, to optimize antibody half-life, effector functions, and developability, and can be applied to various formats like multi-specific antibodies and antibody-drug conjugates (ADCs).[2] Sibeprenlimab itself is a testament to the platform's capacity to generate novel biologics against complex molecular targets, with Dr. Karthik Viswanathan, a founding scientist at Visterra, being instrumental in the platform's establishment and an inventor of sibeprenlimab.[16] The substantial investment by Otsuka in acquiring Visterra likely reflected a strong confidence not only in specific pipeline candidates like sibeprenlimab but also in the broader potential of the Hierotope® platform as an engine for future drug discovery, particularly for complex immunological and nephrological conditions.

The primary therapeutic indication for which sibeprenlimab is being rigorously investigated is Immunoglobulin A Nephropathy (IgAN), a chronic autoimmune kidney disease also known as Berger's disease.[1]

Table 1: Key Characteristics of Sibeprenlimab (VIS-649)

Attribute	Description
Alternative Name	VIS-649
Drug Class	Humanized Monoclonal Antibody
Isotype	IgG2 kappa 1
Developer	Visterra, Inc. (a wholly owned subsidiary of Otsuka Pharmaceutical Co., Ltd.) 2
Origin of Design	Visterra's Hierotope® Platform 16
Mechanism of Action Target	A PRoliferation-Inducing Ligand (APRIL) 1
Primary Indication	IgA Nephropathy (IgAN) 1
Route of Administration	Intravenous (Phase 2), Subcutaneous (Phase 3) 6
Investigational Dosing Regimen	400 mg subcutaneously every 4 weeks (Phase 3) 8

The advanced capabilities of the Hierotope® platform, particularly its proficiency in identifying and targeting specific, often complex, epitopes that are critical in disease pathways, were directly instrumental in the design and engineering of sibeprenlimab as a highly selective inhibitor of APRIL. This precision is fundamental for effectively targeting a specific cytokine like APRIL while aiming to minimize potential off-target interactions and associated adverse effects.

3. Pathophysiology of IgA Nephropathy and the Rationale for Targeting APRIL

Immunoglobulin A Nephropathy (IgAN) is recognized as the most prevalent form of primary glomerulonephritis worldwide and stands as a significant contributor to chronic kidney disease (CKD) and eventual kidney failure.[18] Pathologically, IgAN is an autoimmune condition characterized by the aberrant deposition of IgA1-containing immune complexes within the glomerular mesangium of the kidneys.[21] Clinically, the disease often manifests with hematuria (blood in urine) and proteinuria (protein in urine), frequently accompanied by hypertension. Despite supportive care measures, a substantial fraction of patients, estimated at 20-40%, progress to end-stage kidney disease (ESKD) within two decades of their initial diagnosis.[2] Notably, IgAN shows a higher prevalence among individuals of East Asian descent, with a particularly high incidence reported in China, where it constitutes a large proportion of glomerular nephritis cases.[24]

The pathogenesis of IgAN is commonly elucidated by the "multi-hit" or "4-hit" hypothesis, which outlines a sequence of interconnected events culminating in kidney damage [2]:

• Hit 1: Elevated Levels of Galactose-Deficient IgA1 (Gd-IgA1): A hallmark of IgAN is the presence of increased circulating levels of IgA1 molecules that feature aberrantly glycosylated O-linked glycans in their hinge region. Specifically, these glycans are deficient in galactose residues.[21] This galactose-deficient IgA1 (Gd-IgA1) is considered the primary autoantigen in the disease. The synthesis of Gd-IgA1 is influenced by genetic predispositions and the activity of specific glycosyltransferases, such as core 1 $ \beta $1,3-galactosyltransferase (C1GalT1), and its molecular chaperone Cosmc (C1GalT1C1).[21] The gut-associated lymphoid tissue (GALT), particularly the Peyer's patches located in the ileum, is increasingly recognized as a significant site for the production of this pathogenic Gd-IgA1.[24]
• Hit 2: Generation of Autoantibodies against Gd-IgA1: The immune system recognizes these abnormally structured Gd-IgA1 molecules as foreign, leading to the production of autoantibodies. These autoantibodies are predominantly of the IgG isotype and specifically target the galactose-deficient hinge-region glycoforms of IgA1.[21]
• Hit 3: Formation of Pathogenic Circulating Immune Complexes (CICs): The binding of these anti-Gd-IgA1 IgG autoantibodies to Gd-IgA1 results in the formation of nephritogenic CICs.[2] These complexes may also incorporate other components, such as complement C3, indicating complement system involvement.[21]
• Hit 4: Mesangial Deposition and Subsequent Kidney Injury: These Gd-IgA1-containing CICs are transported via the circulation to the kidneys, where they deposit within the glomerular mesangium. This deposition initiates a cascade of local inflammatory responses, including mesangial cell activation and proliferation, overproduction of extracellular matrix components, and activation of the complement system (with the alternative pathway often implicated). These processes collectively lead to glomerular damage, resulting in the clinical manifestations of proteinuria and hematuria, and contribute to the progressive decline in kidney function.[2]

A PRoliferation-Inducing Ligand (APRIL) is a cytokine belonging to the tumor necrosis factor (TNF) superfamily and has emerged as a key player in the immunopathology of IgAN.[2] APRIL is crucial for normal B-cell biology, where it promotes B-cell survival, differentiation, and immunoglobulin class-switch recombination, particularly favoring the production of IgA.[2] In the context of IgAN, APRIL is considered a significant pathogenic factor because it appears to drive the production of the aberrant, pathogenic Gd-IgA1, thereby fueling the "4-hit" cascade.[2] Consequently, APRIL is viewed as an important factor in both the initiation and perpetuation of IgAN progression.[2]

The historical therapeutic landscape for IgAN has been limited, primarily relying on supportive care measures such as rigorous blood pressure control with renin-angiotensin system (RAS) inhibitors (ACE inhibitors or ARBs) and optimization of proteinuria.[18] Systemic corticosteroids have been employed in selected high-risk patients, but their use is often associated with significant side effects and their efficacy can be variable. The substantial number of IgAN patients who inexorably progress to ESKD underscores a profound unmet medical need for targeted, disease-modifying therapies that can safely and effectively arrest or retard the progression of this chronic kidney disease.[18]

The "4-hit" hypothesis provides a coherent framework for understanding IgAN pathogenesis, identifying Gd-IgA1 as a central pathogenic molecule. APRIL's established role in promoting B-cell IgA production, and specifically its implicated role in driving the synthesis of pathogenic Gd-IgA1, positions it as a critical upstream mediator in this disease cascade.[2] Therefore, the therapeutic strategy of inhibiting APRIL, as pursued with sibeprenlimab, is based on the rationale of interrupting the disease process at one of its earliest identifiable checkpoints. This approach aims to prevent the downstream consequences of immune complex formation and deposition, thereby averting or mitigating kidney damage. Such an intervention offers the prospect of a more fundamental and targeted modulation of the disease course compared to treatments that primarily address symptoms or downstream inflammatory events. The high prevalence of IgAN in East Asian populations [24] may also reflect underlying genetic or environmental factors that influence Gd-IgA1 production or the immune response to it, making targeted therapies like APRIL inhibitors particularly relevant for these demographic groups. The successful targeting of APRIL in IgAN would not only introduce a novel therapeutic option but also further validate the current understanding of IgAN immunopathogenesis, potentially opening avenues for other therapies targeting this pathway and for the development of biomarkers related to APRIL activity or Gd-IgA1 levels.

4. Mechanism of Action of Sibeprenlimab

Sibeprenlimab exerts its therapeutic effect through a highly specific mechanism of action. As a humanized IgG2 monoclonal antibody, it is engineered to selectively bind to A PRoliferation-Inducing Ligand (APRIL) and neutralize its biological activity.[1] This targeted inhibition is designed to disrupt one of the specific immunopathological drivers contributing to nephron loss in IgA Nephropathy (IgAN) by interfering with APRIL's established roles in B-cell function and the production of pathogenic IgA.[2] The European Medicines Agency (EMA) summary for orphan designation explicitly notes that sibeprenlimab attaches to APRIL, thereby limiting its activity, which is expected to lead to a reduction in the body's production of IgA and consequently prevent its detrimental accumulation in the kidney glomeruli.[15]

The primary consequence of APRIL inhibition by sibeprenlimab is a reduction in the production of immunoglobulins, particularly total IgA and, critically for IgAN pathogenesis, the aberrant galactose-deficient IgA1 (Gd-IgA1).[1] Gd-IgA1 is the autoantigen that initiates the formation of pathogenic immune complexes in IgAN. By lowering the circulating levels of Gd-IgA1, sibeprenlimab reduces the availability of this substrate for complexing with anti-Gd-IgA1 autoantibodies.[2] This reduction in immune complex formation is, in turn, hypothesized to lead to diminished deposition of these nephritogenic complexes within the glomerular mesangium. The anticipated outcome of this reduced deposition is an alleviation of local kidney inflammation and a decrease in proteinuria, which is a cardinal sign of kidney damage in IgAN and a key therapeutic target.[2]

An important and potentially distinguishing feature of sibeprenlimab, highlighted in early research, is its capacity to suppress pathogenic immunoglobulins (such as IgA and possibly IgM involved in the disease process) while potentially preserving protective antibody responses to certain vaccines, for instance, mRNA-based vaccines against SARS-CoV-2.[1] This observation suggests a degree of selectivity in its immunomodulatory effects, potentially sparing crucial components of the host's protective humoral immunity.

The mechanism of sibeprenlimab is thus highly targeted, focusing on an upstream mediator, APRIL, within the pathogenic cascade of IgAN. This contrasts with broader immunosuppressive strategies or therapies that act on downstream consequences such as proteinuria or hypertension. The specificity for APRIL is central to its therapeutic rationale. APRIL is recognized for its role in promoting B-cell survival and facilitating IgA class-switching.[2] By neutralizing APRIL, sibeprenlimab directly interferes with the signals that support the B cells responsible for producing the pathogenic Gd-IgA1. This targeted modulation or functional inhibition of pathogenic IgA-producing plasma cells is expected to be more precise and potentially associated with fewer systemic side effects than general B-cell depletion or broad-spectrum immunosuppression.

The core therapeutic hypothesis underpinning sibeprenlimab's development can be summarized as follows: Sibeprenlimab binds to and inhibits APRIL; this reduction in APRIL activity leads to a decreased production and/or survival of B cells that synthesize Gd-IgA1; consequently, circulating levels of Gd-IgA1 are lowered; this results in reduced formation of Gd-IgA1-containing immune complexes; with fewer immune complexes circulating, their deposition in the kidney glomeruli is diminished; this, in turn, leads to reduced glomerular inflammation and structural damage, manifesting clinically as a reduction in proteinuria and stabilization or improvement in estimated glomerular filtration rate (eGFR). The potential to preserve vaccine responses, if substantiated by further clinical data, would represent a significant advantage for a therapy intended for long-term use in IgAN patients, who remain susceptible to infections. This characteristic also implies that sibeprenlimab may not induce profound, generalized immunosuppression, which is a common concern with other immunomodulatory treatments.

5. Preclinical Evidence

The progression of sibeprenlimab into clinical trials was supported by a body of preclinical evidence demonstrating its ability to engage its target, APRIL, and elicit relevant downstream biological effects.

In Vitro Studies:

Laboratory-based experiments provided initial validation of sibeprenlimab's (then known as VIS649) mechanism. Studies showed that at concentrations of 10 and 50 $ \text{\mu g/mL} $, administered over a 5-day period, sibeprenlimab effectively inhibited the APRIL-mediated proliferation of naïve (CD43-) mouse B cells.1 This finding is significant as it directly demonstrates the antibody's capacity to interfere with a key biological function of APRIL related to B-cell activation and expansion.

Furthermore, sibeprenlimab was shown to inhibit the survival of human myeloma cell lines RPMI 8226 and JJN3.1 These cell lines are often utilized in hematological cancer research and are known to be dependent on APRIL for their survival and proliferation. Their response to sibeprenlimab served as a surrogate indicator of the antibody's ability to block APRIL signaling in human cells, providing further support for its potential to modulate B-cell and plasma cell activity, which is central to IgA production.

In Vivo Studies (Non-human primates):

To assess the effects of sibeprenlimab in a more complex biological system, studies were conducted in Cynomolgus monkeys. Intravenous administration of sibeprenlimab at doses ranging from 0.5 to 25 mg/kg per week, over a period of 4 to 8 weeks, resulted in a selective reduction of serum IgA levels.1 This outcome was crucial as it demonstrated that the antibody could effectively modulate IgA levels in a primate model, which shares greater physiological similarity with humans compared to rodent models, especially concerning antibody therapeutics. The observed reduction in IgA provided a strong preclinical rationale for anticipating a similar effect on pathogenic IgA in patients with IgAN.

Collectively, these preclinical data established an essential proof-of-concept for sibeprenlimab. They confirmed that the antibody could engage its molecular target, APRIL, and exert downstream biological effects consistent with its proposed therapeutic mechanism for IgAN, namely the inhibition of B-cell activity and the reduction of IgA levels. The in vitro studies validated APRIL's role in B-cell biology and sibeprenlimab's ability to block these functions. The in vivo studies in monkeys then translated these findings to a physiological system, demonstrating tangible reductions in serum IgA. These results were fundamental in supporting the decision to advance sibeprenlimab into human clinical trials for IgA Nephropathy, as they established a plausible biological mechanism of action and demonstrated successful target engagement in a relevant animal species.

6. Clinical Development Program for IgA Nephropathy

The clinical evaluation of sibeprenlimab for the treatment of IgA Nephropathy (IgAN) has been primarily driven by two major multicenter, randomized, double-blind, placebo-controlled clinical trials: the Phase 2 ENVISION study and the larger, confirmatory Phase 3 VISIONARY study. These studies were meticulously designed to assess the efficacy and safety of sibeprenlimab in patients with IgAN who are at risk of disease progression.

Table 2: Overview of Key Clinical Trials for Sibeprenlimab in IgA Nephropathy

Trial Name (Identifier)	Phase	Number of Patients (Randomized)	Key Objectives	Primary Endpoint(s)	Key Secondary Endpoint(s)	Treatment Duration (Main)	Route of Administration (Sibeprenlimab)	Key References/Data Sources
ENVISION (NCT04287985)	2	155	Evaluate dose-response, efficacy (proteinuria, eGFR), safety	Change in log-transformed 24-hour uPCR at 12 months	Change in eGFR at 12 months	12 months	Intravenous (2, 4, or 8 mg/kg monthly)	6, NEJM
VISIONARY (NCT05248646)	3	Approx. 510-530	Confirm efficacy (proteinuria, eGFR), safety	Change in 24-hour uPCR at 9 months (interim analysis)	Annualized slope of eGFR over ~24 months (final analysis)	Approx. 24 months	Subcutaneous (400 mg every 4 weeks)	2, Otsuka Press Releases, ERA Presentations

Phase 2 ENVISION Trial (NCT04287985) [6]

The ENVISION trial was a critical dose-finding and proof-of-concept study. It enrolled 155 adult patients with biopsy-confirmed IgAN who were at high risk for disease progression, characterized by an estimated glomerular filtration rate (eGFR) of $ \geq 30 \text{ mL/min/1.73m}^2 $ and significant proteinuria ($ \geq 0.75 \text{ g/g} $ or $ \geq 1 \text{ g/day} $) despite receiving optimized standard-of-care treatment, including a maximally tolerated dose of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) for at least three months.6 Patients with nephrotic syndrome, those receiving systemic immunosuppression, or individuals with advanced kidney fibrosis or extensive crescents in glomeruli were excluded.7 The study population had a median age of 39 years, with 57% being male and a significant representation of Asian patients (74%).7 Participants were randomized in a 1:1:1:1 ratio to receive intravenous (IV) sibeprenlimab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg of body weight, or a placebo, administered as a monthly infusion for a duration of 12 months.6

The primary efficacy endpoint was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio (uPCR) at month 12.[6] Key secondary endpoints included the change from baseline in eGFR at month 12 and an overall assessment of safety and tolerability.[6]

The ENVISION trial successfully met its primary endpoint, demonstrating a statistically significant and dose-dependent reduction in proteinuria at the 12-month mark for all sibeprenlimab treatment groups when compared to the placebo group. The geometric mean ratio reduction from baseline in 24-hour uPCR was reported as 47.2% for the 2 mg/kg dose, 58.8% for the 4 mg/kg dose, and 62.0% for the 8 mg/kg dose, in contrast to a 20.0% reduction in the placebo group.[6] Importantly, sibeprenlimab treatment also showed a beneficial effect on eGFR, indicating a stabilization of kidney function decline relative to placebo. The least-squares mean (±SE) change from baseline in eGFR at 12 months was -2.7±1.8 $ \text{mL/min/1.73m}^2 $ for the 2mg/kg group, +0.2±1.7 $ \text{mL/min/1.73m}^2 $ for the 4mg/kg group, and -1.5±1.8 $ \text{mL/min/1.73m}^2 $ for the 8mg/kg group. This compared favorably to a decline of -7.4±1.8 $ \text{mL/min/1.73m}^2 $ observed in the placebo group.[6] Furthermore, the reductions in proteinuria were noted to be sustained for at least five months after the discontinuation of treatment in the 4mg/kg and 8mg/kg arms, suggesting a durable biological effect.[7]

Regarding safety, the incidence of adverse events occurring after the start of administration was 78.6% in the pooled sibeprenlimab groups, compared to 71.1% in the placebo group.[6] No new or unexpected safety signals were identified, and concerns regarding infections or lymphopenia were not prominent.[7] One report indicated that the risk of infection was slightly lower in the sibeprenlimab group (49.6%) compared to the placebo group (55.3%).[32] The compelling results of the ENVISION trial were published in The New England Journal of Medicine (NEJM), a high-impact peer-reviewed journal, which significantly underscored the potential of sibeprenlimab.[6]

Phase 3 VISIONARY Trial (NCT05248646) [2]

Building on the positive Phase 2 findings, the VISIONARY trial was initiated as the largest clinical study in IgAN to date, designed to confirm the efficacy and safety of sibeprenlimab. This multicenter, randomized, double-blind, placebo-controlled trial enrolled approximately 510 to 530 adult patients with biopsy-confirmed IgAN who were already receiving optimized standard-of-care therapy, defined as a maximally tolerated dose of an ACE inhibitor or ARB, with or without the addition of an SGLT2 inhibitor.2 The trial was designed to include a diverse patient population reflective of the broader IgAN epidemiology.2

A notable change from the Phase 2 study was the route and formulation of sibeprenlimab. In the VISIONARY trial, patients receive sibeprenlimab at a dose of 400 mg administered subcutaneously (SC) every four weeks, or a matching placebo.[2] This SC formulation is supplied in a single-dose prefilled syringe and is intended for self-administration by the patient or administration by a caregiver at home, thereby offering greater convenience for long-term treatment.[2]

The primary efficacy endpoint for a prespecified interim analysis was the change in 24-hour uPCR at 9 months compared with baseline.[2] The key secondary endpoint, which will determine the final efficacy outcome, is the annualized slope of eGFR decline over approximately 24 months.[2]

Interim results from the VISIONARY trial at 9 months, based on an analysis of 320 patients, were highly positive and consistent with the Phase 2 findings. The study met its primary endpoint, with patients treated with sibeprenlimab achieving a statistically significant and clinically meaningful 51.2% reduction in proteinuria (as measured by 24-hour uPCR) compared to those receiving placebo (P<0.0001).[2] This corresponded to a -50.2% change in uPCR from baseline for the sibeprenlimab group, versus a +2.1% change for the placebo group.[9] Notably, spot uPCR measurements indicated that these reductions in proteinuria began as early as 4 weeks into treatment, suggesting a rapid onset of action.[20] The VISIONARY study remains ongoing in a blinded fashion to evaluate the long-term impact on eGFR slope, with completion anticipated in early 2026.[2]

The interim safety profile from the VISIONARY trial was reported as favorable and consistent with previous data.[2] Treatment-Emergent Adverse Events (TEAEs) were experienced by 76.3% of patients in the sibeprenlimab group versus 84.5% in the placebo group. The incidence of serious TEAEs was also lower in the sibeprenlimab arm, at 3.9%, compared to 5.4% in the placebo arm.[2]

The transition from intravenous administration in the Phase 2 ENVISION trial [6] to subcutaneous administration in the Phase 3 VISIONARY trial [8] represents a significant advancement in the development of sibeprenlimab. This change is aimed at enhancing patient convenience and facilitating the potential for self-administration at home, which is particularly beneficial for a chronic condition like IgAN that requires long-term therapy. Such a patient-centric approach can improve treatment adherence and overall quality of life. The consistency of robust proteinuria reduction observed from the IV formulation in Phase 2 to the SC formulation in the Phase 3 interim analysis strengthens the evidence for sibeprenlimab's efficacy. The ability to reproduce positive results in a larger and more diverse Phase 3 population [2] builds substantial confidence in the drug's therapeutic effect beyond the more controlled and often smaller setting of a Phase 2 study. Furthermore, the scale of the VISIONARY trial, being the "largest IgAN trial to date" [2], will yield a very robust and comprehensive dataset. This dataset will be invaluable not only for establishing the efficacy and safety of sibeprenlimab but also for enhancing the broader understanding of the natural history of IgAN and treatment responses within a contemporary population receiving modern standard-of-care therapies.

7. Efficacy of Sibeprenlimab in IgA Nephropathy

The efficacy of sibeprenlimab in treating IgA Nephropathy (IgAN) has been primarily evaluated through its impact on proteinuria and the estimated glomerular filtration rate (eGFR), both critical markers of kidney health and disease progression.

Proteinuria Reduction (Primary Efficacy Measure):

Proteinuria, specifically the urinary protein-to-creatinine ratio (uPCR), has been a central focus of sibeprenlimab's clinical trials, as it is a well-recognized surrogate marker that correlates with the risk of progression to kidney failure in IgAN. Reductions in proteinuria have been accepted by regulatory authorities as an endpoint to support accelerated approvals for IgAN therapies.2

• Phase 2 ENVISION Trial: This study demonstrated a statistically significant and dose-dependent reduction in 24-hour uPCR at 12 months with intravenous sibeprenlimab compared to placebo. The geometric mean ratio reductions from baseline were 47.2% for the 2 mg/kg dose, 58.8% for the 4 mg/kg dose, and 62.0% for the 8 mg/kg dose, whereas the placebo group showed a 20.0% reduction.[6]
• Phase 3 VISIONARY Trial (Interim 9-month data): The larger Phase 3 trial, using a subcutaneous 400mg dose of sibeprenlimab every four weeks, confirmed these promising findings. At the 9-month interim analysis, sibeprenlimab treatment resulted in a statistically significant and clinically meaningful 51.2% reduction in 24-hour uPCR when compared directly to placebo (P<0.0001).[2] This placebo-corrected reduction was derived from a -50.2% change from baseline in uPCR for the sibeprenlimab group versus a +2.1% change from baseline in the placebo group.[9] An early onset of action was also noted, with spot uPCR reductions observed as early as 4 weeks into treatment.[20]

The magnitude of proteinuria reduction observed with sibeprenlimab, consistently around 50-60% in the active treatment arms of both Phase 2 and interim Phase 3 studies, is considered clinically significant. This level of reduction is comparable to, and in some numerical comparisons potentially larger than, effects reported for other emerging therapies for IgAN in their respective clinical trials [9], positioning sibeprenlimab favorably within the developing therapeutic landscape. Given that proteinuria is a strong predictor of IgAN progression, such substantial reductions are highly indicative of a potential long-term benefit on the preservation of kidney function. The consistency of these findings across different doses (in Phase 2) and different routes of administration (intravenous in Phase 2 versus subcutaneous in Phase 3) further bolsters the evidence for sibeprenlimab's robust effect on this key marker.

Impact on Estimated Glomerular Filtration Rate (eGFR):

While proteinuria reduction is a critical early indicator, the ultimate measure of a therapy's success in CKD is its ability to preserve kidney function, typically assessed by changes in eGFR over time.

• Phase 2 ENVISION Trial: The 12-month eGFR data from the ENVISION trial provided encouraging early signals. Patients treated with sibeprenlimab showed a stabilization of eGFR decline compared to those on placebo. The least-squares mean change from baseline in eGFR was -2.7 $ \text{mL/min/1.73m}^2 $ (2mg/kg), +0.2 $ \text{mL/min/1.73m}^2 $ (4mg/kg), and -1.5 $ \text{mL/min/1.73m}^2 $ (8mg/kg) in the sibeprenlimab groups. In contrast, the placebo group experienced a more pronounced decline of -7.4 $ \text{mL/min/1.73m}^2 $.[1] This stabilization, and in one dose group a slight mean improvement, over 12 months was a very positive finding.
• Phase 3 VISIONARY Trial: The VISIONARY study is designed to provide more definitive long-term eGFR data. The trial continues in a blinded manner to evaluate the annualized slope of eGFR change over approximately 24 months, which is a key secondary endpoint.[2] The final results for this endpoint are anticipated in early 2026. While specific interim eGFR data from the VISIONARY trial have not been detailed in the provided information beyond stating it is an ongoing evaluation, the positive eGFR trends from the Phase 2 study set a hopeful precedent.

Other Efficacy Outcomes:

Sibeprenlimab's mechanism of action involves reducing levels of total IgA and, critically, pathogenic Gd-IgA1.1 By lowering Gd-IgA1, sibeprenlimab reduces the substrate available for the formation of nephritogenic immune complexes.2 While direct measurements of these biomarkers in patient cohorts from the trials are not extensively detailed in the provided summaries, this effect is the presumed biological basis for the observed clinical benefits. Outcomes such as clinical remission and time to CKD progression are likely being assessed, particularly in the long-term follow-up of the VISIONARY trial, but specific data on these are not yet publicly available.

Table 3: Summary of Key Efficacy Results from Phase 2 (ENVISION) and Phase 3 (VISIONARY - Interim) Trials

Endpoint	Trial	Sibeprenlimab Arm (Dose)	Placebo Arm	Placebo-Corrected Geometric Mean Ratio Reduction in 24-hr uPCR (95% CI)	p-value	Reference(s)
Geometric Mean Ratio Reduction in 24-hr uPCR from baseline at Month 12	ENVISION	2 mg/kg IV Q4W	IV Q4W	34.0% (vs. placebo baseline change of -20.0%)	<0.05	6
	ENVISION	4 mg/kg IV Q4W	IV Q4W	48.5% (vs. placebo baseline change of -20.0%)	<0.001	6
	ENVISION	8 mg/kg IV Q4W	IV Q4W	52.5% (vs. placebo baseline change of -20.0%)	<0.001	6
% Reduction in 24-hr uPCR from baseline at Month 9	VISIONARY (Interim)	400 mg SC Q4W	SC Q4W	51.2% (Sibeprenlimab: -50.2%; Placebo: +2.1%) (96.5% CI: 42.9%-58.2%)	<0.0001	2
Endpoint	Trial	Sibeprenlimab Arm (Dose)	Placebo Arm	Difference in LS Mean Change in eGFR from baseline (mL/min/1.73m²) (±SE or 95% CI)	-	Reference(s)
LS Mean Change in eGFR from baseline at Month 12 ($ \text{mL/min/1.73m}^2 $)	ENVISION	2 mg/kg IV Q4W (-2.7 ±1.8)	IV Q4W (-7.4 ±1.8)	+4.7	-	6
	ENVISION	4 mg/kg IV Q4W (+0.2 ±1.7)	IV Q4W (-7.4 ±1.8)	+7.6	-	6
	ENVISION	8 mg/kg IV Q4W (-1.5 ±1.8)	IV Q4W (-7.4 ±1.8)	+5.9	-	6

Note: Placebo-corrected reduction for ENVISION uPCR calculated based on reported individual arm reductions. Confidence intervals for ENVISION eGFR differences were not explicitly provided in snippets but differences were noted as significant for 4mg and 8mg doses vs placebo in some summaries.

If the final, long-term eGFR data from the VISIONARY trial confirm a significant slowing of kidney function decline, sibeprenlimab would be strongly positioned as a therapy that can alter the natural history of IgAN for many patients, representing a substantial advancement in the management of this chronic and progressive disease.

8. Safety and Tolerability Profile

The safety and tolerability of sibeprenlimab have been consistently evaluated throughout its clinical development program for IgA Nephropathy (IgAN). Based on the available data from both the Phase 2 ENVISION trial and the interim analysis of the Phase 3 VISIONARY trial, sibeprenlimab has demonstrated a favorable and consistent safety profile.[2]

Overall Incidence of Adverse Events:

In the Phase 2 ENVISION study, the incidence of adverse events occurring after the start of drug administration was 78.6% in the pooled sibeprenlimab groups, compared to 71.1% in the placebo group.6 More recent interim data from the larger Phase 3 VISIONARY trial indicated that 76.3% of patients treated with sibeprenlimab experienced any Treatment Emergent Adverse Event (TEAE), which was notably lower than the 84.5% observed in the placebo group.2 This finding from a larger cohort suggests that sibeprenlimab does not impose a significantly higher overall burden of adverse events compared to placebo.

Common Treatment-Emergent Adverse Events (TEAEs):

Specific TEAEs reported from the VISIONARY trial interim analysis that were more common with sibeprenlimab compared to placebo included 9:

• Upper respiratory tract infection (17.8% with sibeprenlimab)
• Injection-site pain (13.2% with sibeprenlimab)
• COVID-19 infection (12.5% with sibeprenlimab)
• Nasopharyngitis (11.8% with sibeprenlimab)
• Influenza (8.6% with sibeprenlimab)

These events are generally consistent with those expected for an injectable biologic and common infections within the general population.

Serious Treatment-Emergent Adverse Events (TESAEs):

The incidence of serious adverse events has also been reassuring. In the Phase 2 ENVISION trial, TESAEs were reported to be similar between the sibeprenlimab and placebo groups, and importantly, none were considered by investigators to be related to the study drug.32

In the Phase 3 VISIONARY interim analysis, TESAEs were experienced by 3.9% of patients treated with sibeprenlimab, which was lower than the 5.4% reported in the placebo group.2

Discontinuations due to Adverse Events:

While specific rates of discontinuation due to AEs are not consistently detailed across all provided information, the overall favorable safety profile and lower rates of serious AEs in the sibeprenlimab arms imply that discontinuations due to drug-related toxicity are likely not a major concern.

Specific Safety Concerns and Infections:

A critical aspect for an immunomodulatory agent is the risk of infection. The data for sibeprenlimab in this regard appear positive. No major new safety signals have emerged from the reported clinical trial data.7 The risk of infections, in general, did not appear to be substantially elevated with sibeprenlimab compared to placebo. In fact, results from the ENVISION trial published in the NEJM indicated that the risk of infection was slightly less in the sibeprenlimab group (49.6%) than in the placebo group (55.3%).32 While specific types of infections like upper respiratory tract infections and nasopharyngitis were reported as more common in the sibeprenlimab arm in VISIONARY 9, the overall balance of evidence does not suggest a marked increase in susceptibility to severe or opportunistic infections. This is an important consideration, particularly for a therapy that targets a component of the immune system like APRIL. The potential for sibeprenlimab to preserve antibody responses to vaccines, as suggested by early descriptions 1, may contribute to this manageable infection profile. If sibeprenlimab can effectively modulate the pathogenic immune response in IgAN without causing broad immunosuppression, it would be a significant advantage.

Table 4: Incidence of Selected Treatment-Emergent Adverse Events in the Phase 3 VISIONARY Trial (Interim Data) [2]

Adverse Event Category / Specific Event	Sibeprenlimab 400mg SC Q4W (%)	Placebo SC Q4W (%)
Any Treatment-Emergent Adverse Event (TEAE)	76.3	84.5
Any Serious TEAE	3.9	5.4
Upper respiratory tract infection	17.8	Not specified
Injection-site pain	13.2	Not specified
COVID-19 infection	12.5	Not specified
Nasopharyngitis	11.8	Not specified
Influenza	8.6	Not specified
Note: Placebo rates for specific common AEs were not detailed in snippet 9 which listed sibeprenlimab rates.

The safety profile of sibeprenlimab emerging from clinical trials to date appears manageable and generally comparable, if not favorable in some aspects (like overall TEAEs and serious TEAEs in VISIONARY interim data), to placebo. This is a crucial attribute for a medication intended for the long-term management of a chronic condition like IgAN. A favorable safety profile, particularly if maintained throughout the full duration of the VISIONARY trial and in any subsequent long-term extension studies, would significantly enhance sibeprenlimab's clinical utility and attractiveness as a therapeutic option for patients with IgAN.

9. Regulatory Status and Designations

Sibeprenlimab has achieved several important regulatory milestones in both the United States and Europe, reflecting its potential to address a significant unmet medical need in the treatment of IgA Nephropathy (IgAN). These designations are indicative of the promising clinical data generated and facilitate an expedited development and review process.

U.S. Food and Drug Administration (FDA):

• Biologics License Application (BLA): Otsuka Pharmaceutical has submitted a BLA for sibeprenlimab to the FDA.[2] The FDA has accepted this BLA for review.[3]
• Priority Review: The BLA for sibeprenlimab has been granted Priority Review designation by the FDA.[2] This status is conferred to drugs that, if approved, would offer significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions compared to standard applications. Priority Review shortens the FDA's target review period.
• Prescription Drug User Fee Act (PDUFA) Target Action Date: The FDA has set a PDUFA target action date of November 28, 2025, for a decision on the sibeprenlimab BLA.[2]
• Breakthrough Therapy Designation: Sibeprenlimab was granted Breakthrough Therapy Designation by the FDA in 2024 for the treatment of IgAN.[11] This designation is intended to expedite the development and review of drugs that are intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. This designation was based on the favorable results from the Phase 2 ENVISION trial.[11]

European Medicines Agency (EMA):

• Orphan Drug Designation: Sibeprenlimab received Orphan Drug Designation from the EMA for the treatment of primary IgA nephropathy on June 21, 2021 (designation number EU/3/21/2444).[14] Orphan Drug Designation is granted to medicines intended for the diagnosis, prevention, or treatment of life-threatening or chronically debilitating rare conditions (affecting not more than 5 in 10,000 people in the EU) and provides various incentives to the developer, including scientific advice, fee reductions, and potential market exclusivity upon approval.
• The EMA's Committee for Orphan Medicinal Products (COMP) issued a positive opinion for this designation, acknowledging sibeprenlimab's mechanism of action as an antibody targeting APRIL to reduce IgA production and noting the ongoing clinical trials at the time of the application.[15]

The attainment of these multiple expedited regulatory designations from both the FDA and EMA underscores the significant potential that regulatory agencies see in sibeprenlimab to address the serious and unmet medical needs of patients with IgAN. The positive results from the Phase 2 ENVISION trial [6] were instrumental in securing the FDA's Breakthrough Therapy Designation. Subsequently, the robust interim efficacy and safety data from the Phase 3 VISIONARY trial [2] provided the foundation for the BLA submission and its acceptance with Priority Review. Successful navigation of these regulatory pathways and a potential approval by the PDUFA date in November 2025 would position sibeprenlimab as one of the pioneering targeted biologic therapies specifically inhibiting APRIL for IgAN, which would represent a significant advancement in the treatment landscape for this challenging kidney disease.

10. Discussion and Future Perspectives

Sibeprenlimab is emerging as a promising therapeutic agent for IgA Nephropathy (IgAN), distinguished by its targeted mechanism of action and encouraging clinical trial results. Its development signifies a potential paradigm shift in the management of this chronic kidney disease.

Sibeprenlimab's Potential Role in the IgAN Treatment Landscape:

Sibeprenlimab is strategically positioned as a targeted therapy that addresses an upstream pathogenic mechanism in IgAN—the inhibition of A PRoliferation-Inducing Ligand (APRIL).2 This approach differentiates it from other recently approved or emerging therapies for IgAN, which employ varied mechanisms. These include:

• Targeted-Release Formulation of Budesonide (e.g., Tarpeyo/Nefecon): A locally acting corticosteroid designed to modulate B-cell activity within the gut-associated lymphoid tissue (GALT), specifically the Peyer's patches in the ileum, to reduce the production of pathogenic Gd-IgA1.[22]
• Sparsentan (e.g., Filspari): A dual endothelin-1 receptor and angiotensin II receptor blocker (DEARA), offering a non-immunosuppressive approach to reduce proteinuria and slow kidney function decline.[22]
• Iptacopan (e.g., Fabhalta): An oral inhibitor of complement Factor B, targeting the alternative complement pathway, which is implicated in IgAN-related glomerular inflammation.[22]
• Atrasentan (e.g., Vanrafia): A selective endothelin A (ETA) receptor antagonist, also aimed at reducing proteinuria.[22]

Sibeprenlimab's distinct mechanism, focusing on the systemic inhibition of APRIL to reduce pathogenic IgA production, offers a novel angle of attack. Furthermore, the convenience of a once-every-four-weeks subcutaneous injection, with the potential for self-administration at home, presents a significant practical advantage for patients requiring long-term management of a chronic disease.[2]

Strengths of Available Data:

The clinical data for sibeprenlimab gathered to date exhibit several strengths:

• Consistent and Clinically Meaningful Proteinuria Reduction: Both the Phase 2 ENVISION trial and the interim analysis of the Phase 3 VISIONARY trial have demonstrated robust and statistically significant reductions in proteinuria, a key surrogate marker for IgAN progression.[2]
• Positive Early Signals for eGFR Stabilization: The Phase 2 ENVISION study showed encouraging trends towards the stabilization of eGFR decline in patients treated with sibeprenlimab compared to placebo.[1]
• Favorable and Consistent Safety Profile: The safety data accumulated so far suggest that sibeprenlimab is well-tolerated, with an adverse event profile generally comparable to placebo, and no major new safety concerns identified.[2]
• Robust Phase 3 Trial Design: The VISIONARY trial is the largest randomized controlled trial in IgAN to date, enrolling a diverse patient population that is reflective of the real-world disease epidemiology, which will enhance the generalizability of its findings.[2]

Limitations and Unanswered Questions:

Despite the promising data, several aspects require further clarification:

• Long-Term eGFR Data: The definitive impact of sibeprenlimab on long-term kidney function preservation, as measured by the annualized eGFR slope over 24 months in the VISIONARY trial, is crucial and currently pending, with results expected in early 2026.[2] This will be a critical determinant of its disease-modifying potential.
• Patient-Reported Outcomes (PROs): While the provided research snippets allude to PROs in the context of other drugs or general trial considerations [2], specific PRO data for sibeprenlimab from its IgAN trials are not detailed. Understanding the impact of treatment on patients' quality of life, symptoms, and overall well-being will be important.
• Long-Term Safety: Continuous monitoring will be necessary to ascertain the safety profile of sibeprenlimab with prolonged exposure beyond the current trial durations.
• Comparative Efficacy and Safety: Head-to-head clinical trials comparing sibeprenlimab with other emerging or approved targeted therapies for IgAN are not currently available. Such studies would be valuable for guiding treatment choices.
• Optimal Patient Selection: Further research may be needed to identify specific patient subgroups within the broader IgAN population who are most likely to benefit from sibeprenlimab therapy, potentially based on biomarkers or disease characteristics.

The field of IgAN treatment is undergoing a rapid and exciting transformation, moving away from a primary reliance on supportive care towards a multi-targeted therapeutic approach. If approved, sibeprenlimab, with its distinct mechanism targeting APRIL, is poised to become a significant component of this new era. The availability of multiple agents with diverse mechanisms of action—such as budesonide influencing gut mucosal immunity, sparsentan and atrasentan acting on endothelin and angiotensin pathways, iptacopan modulating the complement system, and sibeprenlimab directly impacting APRIL and B-cell activity—will likely enable more personalized treatment strategies. In the future, combination therapies tailored to individual patient profiles and disease drivers may become a reality.

The acceleration in the development of these novel drugs has been substantially aided by the regulatory acceptance of proteinuria reduction as a valid surrogate endpoint for clinical trials in IgAN.[2] However, the ultimate confirmation of their long-term clinical value will rest upon demonstrating a sustained impact on eGFR decline and the prevention of progression to ESKD. The success of sibeprenlimab could also further validate APRIL as a key therapeutic target not only in IgAN but potentially in other immune-mediated diseases where APRIL and B-cell dysregulation are implicated. The subtle but potentially important characteristic of preserving vaccine responses [1], if borne out by further data, could be a meaningful differentiator that influences both physician and patient preference, especially when considering long-term immunomodulatory therapy.

11. Conclusion

Sibeprenlimab (VIS-649) stands out as an investigational, subcutaneously administered humanized monoclonal antibody that specifically targets A PRoliferation-Inducing Ligand (APRIL). Its novel mechanism of action is aimed at the core immunopathogenesis of IgA Nephropathy (IgAN) by reducing the production of pathogenic galactose-deficient IgA1 and subsequent immune complex formation.

Clinical trial data from the Phase 2 ENVISION study and, notably, the interim analysis of the large Phase 3 VISIONARY study, have consistently demonstrated that sibeprenlimab achieves statistically significant and clinically meaningful reductions in proteinuria, a key surrogate marker for disease progression in IgAN. Alongside these robust effects on proteinuria, early signals from the Phase 2 trial suggest a beneficial impact on stabilizing eGFR decline, a critical measure of kidney function. The safety and tolerability profile of sibeprenlimab observed to date has been favorable and generally consistent with placebo, without the emergence of major new safety concerns.

The positive regulatory momentum, including Breakthrough Therapy Designation and Priority Review from the U.S. FDA (with a PDUFA target action date of November 28, 2025) and Orphan Drug Designation from the EMA, reflects the significant potential of sibeprenlimab to address the substantial unmet medical need in IgAN.

In conclusion, sibeprenlimab holds considerable promise as a targeted, potentially disease-modifying therapy for patients with IgA Nephropathy. The forthcoming final results from the Phase 3 VISIONARY trial, particularly the long-term eGFR data, will be pivotal in fully defining its role in the evolving treatment paradigm for this chronic and often progressive kidney disease. Its specific mechanism of action, coupled with a convenient subcutaneous dosing regimen and a reassuring safety profile thus far, positions sibeprenlimab as a potentially valuable and impactful addition to the therapeutic armamentarium for IgAN. The development of sibeprenlimab exemplifies the progress towards more precise and effective interventions in nephrology, offering hope for improved long-term outcomes for individuals living with this challenging condition.

Works cited

1. Sibeprenlimab (VIS649) | Monoclonal Antibody, APRIL Inhibitor | MedChemExpress, accessed June 13, 2025, https://www.medchemexpress.com/sibeprenlimab.html
2. Otsuka Sibeprenlimab Phase 3 Data Show a Statistically Significant and Clinically Meaningful Proteinuria Reduction for the Treatment of Immunoglobulin A Nephropathy (IgAN), accessed June 13, 2025, https://www.otsuka-us.com/news/otsuka-sibeprenlimab-phase-3-data-show-statistically-significant-and-clinically-meaningful
3. Otsuka Announces FDA Acceptance and Priority Review of Biologics License Application (BLA) for Sibeprenlimab in the Treatment of Immunoglobulin A Nephropathy (IgAN) - BioSpace, accessed June 13, 2025, https://www.biospace.com/press-releases/otsuka-announces-fda-acceptance-and-priority-review-of-biologics-license-application-bla-for-sibeprenlimab-in-the-treatment-of-immunoglobulin-a-nephropathy-igan
4. Otsuka Pharmaceutical to Acquire Visterra, accessed June 13, 2025, https://www.otsuka.com/en/group_news/filedownload.php?name=c0ef048ba0fc7b5474d3d8e39b83eb27.pdf
5. Otsuka Pharmaceutical to Acquire Visterra, accessed June 13, 2025, https://www.otsuka-us.com/discover/articles-1206
6. A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy - PubMed, accessed June 13, 2025, https://pubmed.ncbi.nlm.nih.gov/37916620/
7. ENVISION-ing a New Way Forward in IgA Nephropathy A Phase 2 Trial of Sibeprenlimab, accessed June 13, 2025, https://www.theisn.org/blog/2023/12/11/envision-ing-a-new-way-forward-in-iga-nephropathy-a-phase-2-trial-of-sibeprenlimab/
8. Otsuka's Sibeprenlimab Demonstrates Meaningful Outcomes in Phase III Study for Immunoglobulin A Nephropathy - Applied Clinical Trials, accessed June 13, 2025, https://www.appliedclinicaltrialsonline.com/view/otsuka-sibeprenlimab-demonstrates-meaningful-outcomes-study-immunoglobulin-nephropathy
9. Sibeprenlimab is an emerging treatment option for IgA nephropathy - Medical Conferences, accessed June 13, 2025, https://conferences.medicom-publishers.com/specialisation/nephrology/era-2025/sibeprenlimab-is-an-emerging-treatment-option-for-iga-nephropathy/
10. Sibeprenlimab – Application in Therapy and Current Clinical Research, accessed June 13, 2025, https://clinicaltrials.eu/inn/sibeprenlimab/
11. Otsuka Announces FDA Acceptance and Priority Review of Biologics License Application (BLA) for Sibeprenlimab in the Treatment of Immunoglobulin A Nephropathy (IgAN), accessed June 13, 2025, https://www.otsuka-us.com/news/otsuka-announces-fda-acceptance-and-priority-review-biologics-license-application-bla
12. Otsuka Sibeprenlimab Phase 3 Data Show a Statistically Significant and Clinically Meaningful Proteinuria Reduction for the Treatment of Immunoglobulin A Nephropathy (IgAN) - BioSpace, accessed June 13, 2025, https://www.biospace.com/press-releases/otsuka-sibeprenlimab-phase-3-data-show-a-statistically-significant-and-clinically-meaningful-proteinuria-reduction-for-the-treatment-of-immunoglobulin-a-nephropathy-igan
13. FDA Accepts, Grants Priority Review to Sibeprenlimab BLA for IgA Nephropathy - HCPLive, accessed June 13, 2025, https://www.hcplive.com/view/fda-accepts-grants-priority-review-to-sibeprenlimab-bla-for-iga-nephropathy
14. Orphan designation: Overview | European Medicines Agency (EMA), accessed June 13, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/orphan-designation-overview
15. EU/3/21/2444 - orphan designation for treatment of primary IgA nephropathy | European Medicines Agency (EMA), accessed June 13, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-21-2444
16. Karthik Viswanathan, PhD - Visterra, Inc, accessed June 13, 2025, https://visterrainc.com/visterra_people/karthik-viswanathan-phd/
17. Our Approach - Visterra Inc., accessed June 13, 2025, https://visterrainc.com/our-research/our-approach/
18. NEJM: Sibeprenlimab Stabilized Kidney Function Decline in Most Common Glomerular Disease - MedicalResearch.com, accessed June 13, 2025, https://medicalresearch.com/nejm-sibeprenlimab-stabilized-kidney-function-decline-in-most-common-glomerular-disease/
19. Sibeprenlimab (VIS649) | CAS 2382896-07-1 | AbMole BioScience, accessed June 13, 2025, https://www.abmole.com/products/sibeprenlimab.html
20. ERA 2025: Sibeprenlimab Halves Proteinuria in IgAN in Phase 3 VISIONARY Trial, accessed June 13, 2025, https://www.hcplive.com/view/era-2025-sibeprenlimab-halves-proteinuria-in-igan-in-phase-3-visionary-trial
21. Pathogenesis of IgA Nephropathy: Current Understanding and ..., accessed June 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8509647/
22. Treatment Advances in IgA Nephropathy - MedCentral, accessed June 13, 2025, https://www.medcentral.com/nephrology/kidney/treatment-advances-in-iga-nephropathy
23. The road ahead: emerging therapies for primary IgA nephropathy - Frontiers, accessed June 13, 2025, https://www.frontiersin.org/journals/nephrology/articles/10.3389/fneph.2025.1545329/pdf
24. Efficacy and Safety of Nefecon in Patients with IgA Nephropathy from Mainland China: 2-Year NefIgArd Trial Results - PubMed Central, accessed June 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11687989/
25. Efficacy and safety of iptacopan in patients with IgA nephropathy (IgAN): Interim analysis of the Phase 3 - Unitedwebnetwork.com, accessed June 13, 2025, https://storage.unitedwebnetwork.com/files/1099/6bd27c8585d571a1c9229a3cfde887d2.pdf
26. eGFR slope modelling predicts long-term clinical benefit with nefecon in a real-world IgAN population - Oxford Academic, accessed June 13, 2025, https://academic.oup.com/ckj/article/18/2/sfae404/7924246
27. Sibeprenlimab Shows 51% Reduction in Proteinuria in Pivotal IgAN Trial - Xtalks, accessed June 13, 2025, https://xtalks.com/sibeprenlimab-shows-51-reduction-in-proteinuria-in-pivotal-igan-trial-4284/
28. Everest Medicines Announces Positive Results of Complete Chinese Subpopulation Data from the NEFECON® Global Phase 3 NefIgArd Clinical Trial Published in "Kidney 360" Magazine, accessed June 13, 2025, https://www.everestmedicines.com/news/everest-medicines-announces-positive-results/9a45ece6-68e9-43fd-ba27-8ce2c0178691
29. The Pathophysiology of IgA Nephropathy - PMC - PubMed Central, accessed June 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3892742/
30. Iptacopan Results in Significant Proteinuria Reduction in IgAN | Docwire News, accessed June 13, 2025, https://www.docwirenews.com/post/iptacopan-results-in-significant-proteinuria-reduction-in-igan
31. Otsuka Submits BLA for Sibeprenlimab: A Novel Targeted Therapy for IgA Nephropathy, accessed June 13, 2025, https://trial.medpath.com/news/935193ca8e7d505f/otsuka-submits-bla-for-sibeprenlimab-a-novel-targeted-therapy-for-iga-nephropathy
32. Otsuka Reports More Positive Results From Its Phase 3 Trial of Sibeprenlimab, accessed June 13, 2025, https://www.managedhealthcareexecutive.com/view/otsuka-reports-more-positive-results-from-its-phase-3-trial-of-sibeprenlimab
33. Phase 3 Data Show Sibeprenlimab Reduces Proteinuria in IgAN | Docwire News, accessed June 13, 2025, https://www.docwirenews.com/post/phase-3-data-show-sibeprenlimab-reduces-proteinuria-in-igan
34. Atrasentan (Vanrafia) Receives Accelerated Approval in IgA Nephropathy - HCPLive, accessed June 13, 2025, https://www.hcplive.com/view/atrasentan-vanrafia-receives-accelerated-approval-in-igan
35. FDA Grants Priority Review to Sibeprenlimab for the Kidney Disease IgAN, accessed June 13, 2025, https://www.managedhealthcareexecutive.com/view/fda-grants-priority-review-to-sibeprenlimab-for-the-kidney-disease-igan
36. Clinical Trials - Visterra Inc., accessed June 13, 2025, https://visterrainc.com/for-patients/clinical-trials/
37. www.hcplive.com, accessed June 13, 2025, https://www.hcplive.com/view/era-2025-sibeprenlimab-halves-proteinuria-in-igan-in-phase-3-visionary-trial#:~:text=Sibeprenlimab%20achieved%20a%2051.2%25%20reduction,promising%20safety%20data%20for%20sibeprenlimab.
38. www.nejm.org, accessed June 13, 2025, https://www.nejm.org/doi/full/10.1056/NEJMoa2305635
39. One-Year Results of the AFFINITY Study of Atrasentan in Patients ..., accessed June 13, 2025, https://www.docwirenews.com/post/one-year-results-of-the-affinity-study-of-atrasentan-in-patients-with-igan
40. Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy - PubMed, accessed June 13, 2025, https://pubmed.ncbi.nlm.nih.gov/39453772/
41. Effect of Iptacopan on Proteinuria and Complement Biomarkers in IgA Nephropathy (IgAN): Interim Analysis of the Phase 3 APPLAUSE, accessed June 13, 2025, https://medcommshydhosting.com/CRM/Renal//ASN/presentations/2024/oral-presentation/ASN2024_Effect_of_iptacopan_on_proteinuria_OralPresentation.pdf
42. Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy - PubMed, accessed June 13, 2025, https://pubmed.ncbi.nlm.nih.gov/37914086/
43. Atrasentan in Patients with IgA Nephropathy - PubMed, accessed June 13, 2025, https://pubmed.ncbi.nlm.nih.gov/39460694/
44. Atrasentan in Patients with IgA Nephropathy - JournalFeed, accessed June 13, 2025, https://journalfeed.org/article-a-day/2025/atrasentan-in-patients-with-iga-nephropathy/
45. Top Stories in Nephrology 2024 - NephJC, accessed June 13, 2025, http://www.nephjc.com/news/2024/1/15/top-stories-in-nephrology-2024
46. FDA Approves Atrasentan for Proteinuria Reduction in Primary IgA Nephropathy, accessed June 13, 2025, https://www.ajmc.com/view/fda-approves-atrasentan-for-proteinuria-reduction-in-primary-iga-nephropathy
47. Patient-reported improvements in paroxysmal nocturnal hemoglobinuria treated with iptacopan from 2 phase 3 studies - PubMed, accessed June 13, 2025, https://pubmed.ncbi.nlm.nih.gov/39774762/
48. Iptacopan (Fabhalta) - NCBI Bookshelf, accessed June 13, 2025, https://www.ncbi.nlm.nih.gov/books/NBK613794/