It is estimated that 20–40% of people with IgA nephropathy will develop end-stage kidney disease (ESKD), which means they will need dialysis or kidney transplantation to survive. The diagnosed prevalent cases of IgA nephropathy in the US are expected to be around 135,000 in 2030, which are further expected to increase by 2034, according to the latest IgAN Market and Epidem Forecast Report by DelveInsight.
Conventional major treatments for IgA nephropathy include ACE inhibitors (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) to manage symptoms like high blood pressure. Other treatments include corticosteroids to slow the progression of the disease and other immunosuppressants like MMF (mycophenolate mofetil), cyclophosphamide, etc.
The only three FDA-approved treatments for managing IgA nephropathy are TARPEYO/KINPEYGO (budesonide), FILSPARI (sparsentan), and FABHALTA (iptacopan). TARPEYO became the first therapy to receive regulatory approval for the treatment of IgA nephropathy. Initially, TARPEYO’s pricing was a potential concern before its launch. However, it successfully entered the market at a premium price, with price increases in early 2023 and again in early 2024. In 2023, TARPEYO earned around USD 102 million in the United States, while FILSPARI made USD 29.2 million following its commercial introduction in late February 2023.
Travere’s FILSPARI received conditional approval in February 2023, but early interest appears moderate based on initial sales data, potentially due to its black box warning and interest in TARPEYO. Also, the 2-year eGFR data of FILSPARI was insignificant/insufficient. This March, the company requested to convert the accelerated approval status to full approval, and the PDUFA (Prescription Drug User Fee Act) was set for September 2024. Now, FILSPARI has received full FDA approval. FILSPARI is expected to “replace” ARBs in the IgA nephropathy therapy paradigm.
Key companies advancing IgA nephropathy therapies include Novartis, Visterra (a subsidiary of Otsuka Pharmaceutical), Ionis Pharmaceuticals, Roche, Vertex Pharmaceuticals, Alpine Immune Sciences, AstraZeneca, Vera Therapeutics, Biogen, NovelMed Therapeutics, Q32 Bio, Alexion Pharmaceuticals, Kira Pharmaceuticals, Walden Biosciences, Arrowhead Pharmaceuticals, and Takeda, among others. Omeros’s Narsoplimab failed at the interim stage, whereas Novartis is continuing to build its renal portfolio with therapies like FABHALTA (approved), Atrasentan, and Zigakibart in IgA nephropathy.
The IgA nephropathy treatment landscape is projected to undergo major changes between 2024 and 2034, driven by the introduction of these novel therapies. Until recently, no specific treatment options were available for IgA nephropathy, and there is an urgent need for therapies that can slow the progression to ESKD, a critical unmet need. Any substantial progress in this area is anticipated to have a transformative effect on the market during this period.
By 2034, the total market size of IgA nephropathy is expected to reach ~USD 4.1 billion in the US, as per the latest report titled IgA Nephropathy Market Insight, Epidemiology And Market Forecast - 2034. Now, let’s take a look at the 10 most promising therapies poised to reshape the IgA nephropathy treatment landscape.
Novartis’ Atrasentan
Phase III
Atrasentan is an investigational, highly potent, and selective oral antagonist of the ETA receptor, currently advancing through Phase III clinical trials for IgA nephropathy and in early-stage trials for additional rare kidney diseases. Activation of the ETA receptor is linked to increased proteinuria, which contributes to kidney damage, fibrosis, and impaired kidney function in IgA nephropathy.
Atrasentan holds promise as an addition to existing supportive treatments to help lower persistent proteinuria and preserve kidney function across a wide range of patients. Preclinical studies also indicate that atrasentan may reduce inflammation and fibrosis in IgA nephropathy. At the 61st European Renal Association Congress, Novartis shared findings from a pre-specified interim analysis of the Phase III ALIGN study on atrasentan during a late-breaking clinical trials session. According to an interim analysis from baseline to Week 36, administering 0.75 mg/day of atrasentan resulted in a 38.1% decrease in UPCR from baseline, while administering a placebo caused a 3.1% decrease. The mean percentage change for atrasentan was -36.1% lower than that of a placebo. At the initial evaluation at six weeks, atrasentan was shown to reduce proteinuria. The study also suggested that atrasentan has a favorable safety profile, consistent with prior data.
Novartis is continuing to build its renal portfolio with therapies like FABHALTA, Atrasentan, and Zigakibart. Following the recent approval of FABHALTA, Atrasentan is anticipated to be the next Novartis drug (formerly Chinook Therapeutics) entering the IgA nephropathy market. Atrasentan, an endothelin A receptor antagonist, shares characteristics with Travere’s FILSPARI, which acts as a dual endothelin angiotensin receptor antagonist.
Upon approval, Atrasentan is expected to directly compete with FILSPARI and is projected to launch in the US by 2025, as Novartis received FDA filing acceptance for it in the second quarter of 2024. When comparing the two drugs, FILSPARI seems to hold a competitive advantage.
● FILSPARI has already received full approval and has a two-year advantage on Atrasentan.
● Second, FILSPARI’s dual action may lessen the pill load for patients.
● In the ALIGN study, Atrasentan showed a 38.1% decrease in proteinuria as evaluated by the UPCR, but FILSPARI exhibited a 49.8% reduction in proteinuria in its phase III PROTECT trial.
However, as previously stated, FILSPARI did not achieve statistical significance in its confirmatory trial for kidney function improvement, leaving room for Atrasentan to potentially distinguish itself (if positive results are obtained in its ongoing ALIGN study). In addition, unlike dual action, separate pills may allow for a more tailored dose, which is crucial in doctor-patient decision-making. Given the similarities between Atrasentan and FILSPARI, it is uncertain if Atrasentan will be subject to the same black box warning. No black box warning could provide an edge to Atrasentan. Based on above mentioned parameters, Atrasentan could differentiate itself from FILSPARI.
Otsuka/Visterra’s Sibeprenlimab
Phase III
Sibeprenlimab (formerly VIS649) is an investigational humanized IgG2 monoclonal antibody designed to decrease the production of Gd-IgA1 by targeting APRIL (a proliferation-inducing ligand), a key signaling molecule involved in IgA and Gd-IgA1 production. By binding and neutralizing APRIL, sibeprenlimab may lower levels of IgA and Gd-IgA1, potentially leading to reduced auto-antibody formation, fewer immune complexes, less immune complex deposition in the kidney, and decreased kidney inflammation. By inhibiting Gd-IgA1 production, sibeprenlimab is thought to help protect kidney function and prevent progression to ESKD. In February 2024, Otsuka Pharmaceutical and its US group company Visterra’s Sibeprenlimab (first-in-class and easy-to-use drug) became the first APRIL inhibitor therapy to receive the US FDA’s Breakthrough Therapy designation for the IgA nephropathy treatment.
As a first-in-class, user-friendly treatment, sibeprenlimab is also being explored for conditions beyond IgA nephropathy within its lifecycle management (LCM) program. Its subcutaneous administration, with a four-week dosing interval, is anticipated to provide a safer, more tolerable profile without significant immunosuppressive effects.
Vertex Pharmaceuticals/Alpine Immune Sciences’ Povetacicept
Phase III
Vertex is committed to furthering the “pipeline-in-a-pill” potential of povetacicept by aiming for approval for “several conditions”. Vertex announced on April 10, 2024, that it will buy Alpine Immune Sciences for USD 4.9 billion in cash. Through the agreement, Vertex acquired the rights to Povetacicept, a medication for IgA nephropathy that is in late-stage research (global Phase III RAINIER trial is ongoing).
Povetacicept (ALPN-303) acts as a dual antagonist to the cytokines BAFF and APRIL, which are crucial in the development of various autoimmune diseases due to their influence on the activation, differentiation, and survival of B-cells, T-cells, and innate immune cells. Developed from an engineered TACI domain, povetacicept exhibits higher binding affinity and enhanced potency in preclinical studies compared to other BAFF and/or APRIL inhibitors.
Since 2021, povetacicept’s preclinical data has attracted experts' attention. Based on its early-stage data, povetacicept is exhibiting best-in-class potential, but this argument was based on small cohort data. Vertex's povetacicept "has maintained its potential to be a best-in-class drug", according to data presented at the American Society of Nephrology (ASN) 2024 conference. Vertex reported results on 54 IgA nephropathy patients who were administered 80 mg or 240 mg of povetacicept subcutaneously every 4 weeks (SC Q4W). As measured by estimated glomerular filtration rate (eGFR), treatment with povetacicept 80 mg SC Q4W resulted in a clinically significant reduction in proteinuria, with a mean 66% decrease from baseline in the urine protein to creatinine ratio at 48 weeks (UPCR; n=8). By 48 weeks, 63% (5 out of 8) of trial participants had reached clinical remission, which is characterized by stable renal function (less than 25% decrease in eGFR from baseline), negative hematuria, and UPCR <0.5 g/g.
After successful interactions with regulators at the end of Phase II, Vertex has commenced the Phase III clinical trial of povetacicept in IgA nephropathy (the RAINIER study). RAINIER is a global pivotal trial comparing 80 mg of povetacicept to a placebo alongside standard care in around 480 participants with IgA nephropathy. The study includes a pre-scheduled interim analysis to assess the UPCR for the povetacicept group versus placebo once a specified number of patients have completed 36 weeks of treatment. If the results are favorable, this interim analysis could support Vertex’s application for accelerated approval in the US. The final analysis will be conducted after two years of treatment, focusing on the total eGFR slope through Week 104. Vertex hopes to receive accelerated approval in the US for IgA nephropathy by the end of 2027.
While FDA-approved IgAN drugs such as TARPEYO and FILSPARI have more convenient oral dosage schedules, Povetacicept is an injectable. However, Povetacicept’s once-monthly dosing frequency and small-volume subcutaneous method of administration offer the potential to be a revolutionary treatment for IgA nephropathy patients. In addition to IgA nephropathy, povetacicept is being explored for the treatment of several serious conditions, including other autoimmune kidney diseases and autoimmune cytopenias.
Novartis’ Zigakibart
Phase III
Zigakibart is Novartis’ third candidate in the development of IgA nephropathy, and it lags behind its rivals. This treatment belongs to the same class as povetacicept and atacicept. Zigakibart is a novel monoclonal antibody targeting APRIL, offering a potentially disease-modifying strategy for treating IgA nephropathy by depleting Gd-IgA1, the pathogenic form of IgA, and lowering proteinuria levels. It specifically binds to a defined epitope on APRIL, effectively blocking APRIL-induced receptor activation.
At the 2024 World Congress of Nephrology, Novartis unveiled the BEYOND trial design—a Phase III, randomized, double-blind, placebo-controlled study assessing zigakibart in adults with IgA nephropathy. Currently, zigakibart is under evaluation in a Phase III clinical trial for this condition, with results expected in 2026. Novartis plans to submit the Biologics License Application (BLA) for zigakibart for IgA nephropathy in 2027 or later.
This class of drugs appears to be very promising, and in the future, the IgA nephropathy standard of care (SoC) will shift toward BAFF/APRIL antagonists since they appear to have a stronger therapeutic impact than FDA approved TARPEYO and FILSPARI. This promise and optimism are underpinned and represented in Vertex and Novartis’ high-value deals. Vertex purchased Alpine for around USD 4.6 billion, whereas Novartis acquired Chinook for approximately USD 3.5 billion (with a cash payment of USD 3.2 billion, which included two IgA nephropathy assets). The competition in this class is getting intense, since Atacicept and Povetacicept along with Zigakibart are in line to get regulatory nod for the treatment of IgA nephropathy.
Ionis Pharmaceuticals/Roche’s IONIS-FB-LRx/RG6299
Phase III
IONIS-FB-LRx, also referred to as RG6299/RO7434656, is an experimental Ligand-Conjugated Antisense (LICA) therapy aimed at decreasing the production of complement factor B (FB) and inhibiting the alternative complement pathway. In the second quarter of 2023, Roche progressed IONIS-FB-LRx to Phase III clinical trials for patients with IgA nephropathy.
In October 2023, Ionis announced encouraging interim results from the ongoing Phase II trial of IONIS-FB-LRx in IgA nephropathy patients. Roche plans to submit the Biologics License Application (BLA) for RG6299 in or after 2027 for this indication. Based on encouraging Phase II findings, Roche/Ionis moved forward with the IONIS-FB-LRx IgA nephropathy Phase III study last year. In addition, for the treatment of IgA nephropathy, ULTOMIRIS—another medication that targets the complement pathway—is also under investigation in Phase III. However, among complement inhibitors, FABHALTA has the first-mover advantage (accelerated approval on August 8, 2024).
AstraZeneca’s ULTOMIRIS
Phase III
Understanding the pathophysiology of IgA nephropathy, and in particular, the role of complement activation has advanced significantly in recent years. The development of novel complement-targeted therapeutics for IgA nephropathy has been made possible by all the advancements in understanding of complement’s function in IgA nephropathy. There is currently one authorized complement inhibitor, FABHALTA, and apart from this, other active trials are assessing its effectiveness.
ULTOMIRIS (ravulizumab) is a long-acting C5 complement inhibitor that offers immediate, complete, and sustained inhibition of the complement system. This medication functions by blocking the C5 protein in the terminal complement pathway, which is part of the immune system. When activated excessively, the complement cascade can cause the body to mistakenly attack its own healthy cells.
ULTOMIRIS is given intravenously every eight weeks to adult patients following an initial loading dose. It is currently undergoing the Phase III ICAN trial, which started in Q1 2024 and has a projected Primary Completion Date (PCD) in February 2026. In IgA nephropathy, ULTOMIRIS is anticipated to compete with IONIS-FB-LRx and FABHALTA.
Vera Therapeutics’ Atacicept
Phase II/III
Atacicept is an experimental recombinant fusion protein that features the soluble Transmembrane Activator and Calcium-modulating Cyclophilin Ligand Interactor (TACI) receptor, which binds to the cytokines B-cell Activating Factor (BAFF) and A Proliferation-inducing Ligand (APRIL). These cytokines belong to the tumor necrosis factor family and are involved in promoting B-cell survival and the production of autoantibodies linked to certain autoimmune disorders, such as IgA nephropathy and lupus nephritis.
The Phase IIb ORIGIN clinical trial of atacicept in IgA nephropathy achieved its primary endpoint, demonstrating a statistically significant reduction in mean proteinuria compared to baseline at Weeks 24 and 36. Vera Therapeutics considers atacicept to have best-in-class potential, as it targets B-cells and plasma cells to lower autoantibody levels, with over 1,500 patients having received the drug in various clinical studies.
In May 2024, the FDA awarded Breakthrough Therapy Designation to atacicept for treating IgA nephropathy. Vera plans to submit its Biologics License Application (BLA) to the FDA in the latter half of 2025, aiming for a product launch in 2026.
In September 2024, Vera Therapeutics announced that it had successfully completed enrollment ahead of schedule for the primary endpoint in the pivotal Phase III ORIGIN 3 trial of atacicept for patients with IgA nephropathy. The trial’s initial cohort of 200 participants will provide data for the 36-week UPCR primary efficacy endpoint, facilitating the next steps for regulatory approval.
It is worth mentioning that Vera Therapeutics is not the only company investigating a BAFF and APRIL antagonist. Several other companies like Vertex Pharmaceuticals (Povetacicept), and Otsuka/Visterra’s (Sibeprenlimab) are also trying to get into the IgA nephropathy market with BAFF and APRIL antagonists. In November 2023, Otsuka Pharma released results from their IgA nephropathy candidate, sibeprenlimab, as follows: geometric mean ratio decrease in 24-h UPCR from baseline was 47.2%, 58.8%, 62.0%, and 20.0% with sibeprenlimab 2mg/kg, 4mg/kg, and 8 mg/kg, and placebo, respectively. This data looks to be as competitive, if not more outstanding, than Vertex’s evidence derived from a limited number of patients. Vertex’s Povetacicept reduced proteinuria by roughly twice as much as Vera Therapeutics’ atacicept and more than doubled the reduction shown by Calliditas Therapeutics’ TARPEYO.
Biogen’s Felzartamab
Phase II
An alternative depletion approach currently being evaluated in IgA nephropathy adapted from treating the plasma cell malignancy multiple myeloma is CD38 depletion. CD38+ plasma cells are likely the main source of pathogenic Gd-IgA1 and the related autoantibodies in IgA nephropathy. Anti-CD38 has the potential to be a non-chronic treatment option in IgA nephropathy.
Felzartamab is an experimental human monoclonal antibody targeting CD38, a protein found in mature plasma cells. Clinical studies have demonstrated that Felzartamab can selectively reduce CD38+ plasma cells, potentially leading to improved clinical outcomes in various diseases associated with pathogenic antibodies. Originally developed by MorphoSys AG for multiple myeloma, the rights to develop and market Felzartamab for all indications worldwide, except in China, were exclusively licensed to HI-Bio.
Biogen intends to advance Felzartamab to Phase III clinical trials for three rare kidney diseases. In July 2024, Biogen finalized its acquisition of Human Immunology Biosciences (HI-Bio), following a definitive agreement in May 2024 in which Biogen agreed to purchase HI-Bio for an upfront payment of USD 1.15 billion, along with up to USD 650 million in potential milestone payments.
During the ASN 2024 conference, Biogen provided full results from their Phase II IGNAZ study, which showed that felzartamab could help patients with IgA nephropathy maintain kidney function and lower proteinuria. Additionally, the effects of felzartamab persisted for almost 18 months following its last dosage. With 24 months of follow-up, Felzartamab could sustain an approximately 50% reduction in patients' UPCR.
Q32 Bio’s ADX-097
Phase II
Q32 Bio has developed an innovative discovery platform that supports the development of tissue-targeted complement inhibitors, which could be therapeutically beneficial for various diseases where C3 complement fragments accumulate in affected tissues. This platform has enabled the progression of ADX-097, Q32 Bio’s primary clinical candidate, into Phase II clinical trials. Initially, Q32 Bio focused on ADX-097 for treating renal and other complement-mediated diseases with significant unmet needs, such as lupus nephritis, IgA nephropathy, C3 glomerulopathy, and ANCA-associated vasculitis (AAV).
In preclinical research, ADX-097 effectively targeted the relevant tissues and organs, showing sustained pharmacokinetics and pharmacodynamics. Furthermore, in a Phase I clinical trial with healthy participants, Q32 Bio observed circulating pharmacokinetics and pharmacodynamics that aligned with preclinical findings, confirming the integrity of ADX-097 in vivo and informing the dosing strategy for subsequent clinical tests. The treatment was also found to be well tolerated.
Given the strong evidence from these studies, Q32 believes that ADX-097 could overcome the challenges associated with existing systemic complement inhibition methods, such as infection risk and the requirement for high doses and frequent administration to achieve therapeutic inhibition levels. Currently, Q32 Bio is conducting an open-label Phase II renal basket clinical trial (IgA Nephropathy, Lupus Nephritis, C3 Glomerulopathy) for ADX-097 and plans to assess its effectiveness in a Phase II trial for AAV. For its Renal Basket trial, the topline data is expected in the second half of 2025, with initial open-label data by year-end 2024.
Kira Pharmaceuticals’ KP104
Phase II
Kira Pharmaceuticals’ leading program, KP104, marks a major advancement in complement therapy. This innovative, first-in-class bifunctional biologic is designed to selectively and effectively inhibit both the alternative and terminal complement pathways, offering a robust and synergistic approach to target key factors in complement-related diseases.
KP104 features a formulation suitable for both intravenous and subcutaneous administration. Early manufacturing results indicate high yields and excellent purity. KP104 is progressing to Phase II proof-of-concept trials for various indications with significant unmet needs, such as IgA nephropathy, C3 glomerulopathy, thrombotic microangiopathies linked to systemic lupus erythematosus, and Paroxysmal nocturnal hemoglobinuria.
The landscape of therapy for IgA nephropathy is evolving as more medicines are being licensed for the condition and several others are currently being investigated in phase III studies. With consecutive projected approvals, it is expected that the IgA nephropathy market will become competitive. Several new classes of drugs have been shown to have promising effects in the clinical trial and may play a pivotal role in treating IgA nephropathy in the future.
Currently, over 30 therapies are in the IgA nephropathy pipeline landscape, as per DelveInsight’s IgAN Pipeline Report. New classes of drug include endothelin A receptor antagonist (atrasentan), APRIL inhibitors (sibeprenlimab, zigakibart), BAFF and APRIL antagonist (povetacicept), Complement inhibitors (ULTOMIRIS, IONIS-FBLRx/RG6299, ARO-C3, KP104, Vemircopan, ADX-097, Ruxoprubart, etc.), BLyS inhibitor and APRIL inhibitor (atacicept), Anti-CD38 (felzartamab, Mezagitamab), and others.
Companies such as Arrowhead Pharmaceuticals, Takeda, Walden Biosciences, Alexion Pharmaceuticals, and NovelMed Therapeutics are also investigating their products in patients with IgA nephropathy in addition to the major players listed above. The recent FDA approval, growing robust pipeline, and the study of several therapeutic classes for IgA nephropathy indicate that this field is expected to undergo major changes in the years to come.
Even though some of these potential new IgAN drugs are anticipated to hit the market in the next few years, there are still several unmet needs, particularly among groups that have not yet been the subject of clinical studies. For example, how should children with IgA nephropathy be treated? How should individuals with low kidney function who have not yet been included in clinical trials be treated? And how should IgA nephropathy following kidney transplantation be treated?
Even with this rapid clinical development and consecutive regulatory approvals, the issues of drug price, reimbursement, and drug-associated side effects (boxed warning and REMS program) of approved medications still exist and are expected to affect how well the emerging IgAN therapies do on the market. The FDA-approved IgA nephropathy treatments are expensive. A 30-day supply of TARPEYO costs USD 14,160, or almost USD 170,000 a year, according to Calliditas. Additionally, Travere has set a USD 9,900 monthly list price for FILSPARI, or around USD 118,800 annually. Presently, FABHALTA (the only approved complement inhibitor in IgA nephropathy) is one of the most expensive licensed therapies for IgA nephropathy, costing a whopping USD 550,000 annually. For therapies, expected to be priced at a premium range like FABHALTA —a complement inhibitor—reimbursement may be a major hurdle. Securing positive reimbursement and recommendation is only possible if the drug demonstrates long-term clinical benefits.
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