IgA Nephropathy (IgAN) is a global leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). It is an autoimmune disorder characterized by the deposition of IgA antibodies in the kidney, leading to inflammation and gradual loss of kidney functions. Despite its prevalence, the therapeutic options for IgA Nephropathy have been relatively limited, focusing primarily on controlling blood pressure, reducing proteinuria, and slowing the progression of the disease. However, recent advances in our understanding of the disease's pathogenesis have paved the way for the development of more targeted and potentially effective treatments. This article explores the landscape of upcoming therapeutic options for IgA Nephropathy, delving into novel pharmacological interventions, emerging biological therapies, and the future directions of treatment strategies.
Therapeutic Target: APRIL
APRIL, A Proliferation-Inducing Ligand, stands at the forefront of therapeutic exploration for the treatment of IgA Nephropathy (IgAN), with two notable monoclonal antibodies, Sibeprenlimab and BION-1301, leading the charge. Sibeprenlimab, formerly recognized as VIS649, serves as a pivotal solution by neutralizing APRIL. Its efficacy, safety, and tolerability are currently being scrutinized in a global phase 2 randomized controlled trial (RCT) aimed at patients with IgAN. This study not only assesses the optimal dosing by monitoring changes in proteinuria but also sets the stage for Sibeprenlimab's subsequent clinical trajectory. Remarkably, no serious adverse events (AEs) leading to discontinuation were reported in both the experimental and sham groups, underlining its potential as a safe treatment avenue. On a parallel track, BION-1301 emerges as a promising contender against APRIL by targeting a specific epitope to block APRIL-mediated receptor activity effectively. This antibody seeks to mitigate the disease's impact by eliminating Gd-IgA1, a pathogenic IgA variant, and reducing proteinuria levels. BION-1301's journey through a phase 1/2 clinical trial among IgAN patients has showcased its good tolerability, with early feedback indicating no serious adverse events or treatment cessation due to side effects.
Fig 1. Safety, tolerability, pharmacokinetics, and pharmacodynamics of Sibeprenlimab in healthy volunteers.1
Therapeutic Target: Plasma Cells
In the realm of IgAN treatment, the focus on plasma cells has led to the exploration of several therapeutic agents, among which Bortezomib, Felzartamab, and Mezagitamab are noteworthy for their innovative approaches. Bortezomib, a proteasome inhibitor, has shown potential in a pilot trial (NCT01103778) involving eight IgAN patients with significant proteinuria. The trial's findings, particularly the achievement of complete remission in three subjects by the one-year mark, underscore the effectiveness of proteasome inhibition in reducing proteinuria in a subset of IgAN patients.
Parallelly, Felzartamab, sourced from the MorphoSys HuCAL antibody library and targeting CD38, is under investigation for its ability to improve renal function by eliminating CD38-positive plasma cells. The commencement of the phase 2 IGNAZ clinical trial for IgAN, aiming to recruit around 48 patients, highlights the anticipation surrounding Felzartamab's potential benefits.
Mezagitamab (TAK-079), initially developed for multiple myeloma, is another promising agent in this arena. As a fully human monoclonal antibody targeting CD38, Mezagitamab's role extends beyond tumor cell depletion, exploring its utility in treating IgAN patients. By focusing on adults with primary IgAN on stable background therapy, the clinical trial for Mezagitamab aims to shed light on its short-term and long-term side effects, potentially offering a new therapeutic pathway.
Therapeutic Target: Complement Systems
In the quest for innovative treatments for IgAN, the complement system, specifically the alternative and lectin pathways, has emerged as a crucial therapeutic target. The initiation of the alternative pathway through the cleavage of Factor B by Factor D, and the lectin pathway activated by pattern-recognition molecules binding to MASP-3, are key processes implicated in the progression of IgAN. Evidence of this involvement is seen in the alterations of plasma MASP-3 levels and the deposition of Factor H and related proteins in the glomeruli. These insights have catalyzed research into developing treatments that can modulate these pathways to combat IgAN.
Among the therapeutic agents under scrutiny, Eculizumab (Soliris®), a humanized recombinant monoclonal IgG antibody against human complement C5, stands out. Eculizumab acts by inhibiting the terminal part of the complement activation pathway, specifically preventing the cleavage of C5 into C5a and the membrane attack complex (MAC), thereby averting the cascade's pro-inflammatory and cell-lytic effects. Originally developed for conditions like paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), Eculizumab's application in IgAN was highlighted in a case where it was used to halt renal function decline in a rapidly progressing patient, despite the risk of increasing susceptibility to bacterial infections such as meningitis. However, the high cost associated with Eculizumab limits its widespread use as a treatment option for IgAN.
Parallel to Eculizumab, IONIS-FB-LRx, an antisense oligonucleotide targeting factor B to curb its expression, represents another innovative approach. Currently under evaluation in two phase 2 clinical studies involving IgAN patients, IONIS-FB-LRx has shown promising preliminary results, including a significant reduction in urinary protein excretion. This reduction is pivotal, as proteinuria is a key marker of IgAN severity and progression. Despite the overall positive outcome, the studies underscore the importance of monitoring for potential adverse effects, such as reversible ALT elevation in one case.
Therapeutic Target: Endothelin
Endothelin (ET), a key vasoconstrictor in the human body, consists of three isoforms, with ET1 being the most potent and the primary form found in the kidneys. Its role in inducing prolonged vasoconstriction highlights its involvement in the development of renal diseases, including early diabetic nephropathy and obesity-related nephropathy. This prolonged action leads to glomerular hyperfiltration, damaging glomerular epithelial cells, which in turn causes proteinuria and decreases the glomerular filtration rate, signaling its potential as a therapeutic target in renal pathologies such as IgAN.
In exploring treatments targeting the endothelin pathway, Atrasentan emerges as a promising candidate due to its potent and selective antagonism of the endothelin A receptor. This mechanism suggests a beneficial effect in reducing proteinuria across various proteinuric glomerular diseases, including IgAN. The AFFINITY study, a phase 2 international trial, sought to evaluate the efficacy and safety of Atrasentan in a cohort that included IgA patients, revealing significant reductions in proteinuria in a majority of participants. Concurrently, the ALIGN study, a phase 3 trial, further investigates Atrasentan in IgAN patients at risk of progressive renal function loss, with early findings indicating a tolerable side effect profile without severe adverse events halting the study.
Parallel to Atrasentan, Sparsentan represents another innovative approach, functioning as a dual antagonist of both endothelin and angiotensin receptors. Its exploration in the PROTECT phase 3 clinical trial targets adults with IgAN, showcasing a significant reduction in proteinuria compared to traditional treatments and displaying a safety profile on par with established therapies. Notably, no serious cases of edema or heart failure were recorded, underscoring Sparsentan's potential as a safe and effective treatment option.
Conclusion
While challenges remain, the therapeutic landscape for IgAN is active and evolving, with several new targets and strategies in the pipeline. Still, more robust, large-scale studies are needed to verify the safety and efficacy of these novel therapies. Through interdisciplinary and global efforts, we can advance our understanding of IgAN, and develop effective diagnostic tools and therapies to control the disease and improve patients' quality of life.
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Reference
- Mathur, Mohit, et al. "Safety, tolerability, pharmacokinetics, and pharmacodynamics of VIS649 (sibeprenlimab), an APRIL-neutralizing IgG2 monoclonal antibody, in healthy volunteers." Kidney International Reports 7.5 (2022): 993-1003.
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