Drug Development Helps Improve Long-term Prognosis Of IgA Nephropathy

IgA nephropathy (IgAN) is currently the most common primary glomerulonephritis in China and even the world. Previous studies have shown that more than one-third of Chinese adult IgAN patients will progress to end-stage kidney disease (ESKD) within 20 years[1]. At present, the clinical treatment methods for IgAN are very limited, and there is a huge unmet clinical need. 

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The 2021 Clinical Practice Guidelines for the Management of Glomerular Diseases of the Improving Global Kidney Outcomes Organization (KDIGO) [2] set the target of proteinuria control to <1 g/d, but whether there is still room for optimization of this target value still needs more evidence accumulation. The results of a large cohort study recently published by Professor Jonathan Barratt of the University of Leicester in the United Kingdom show that even patients traditionally considered as "low risk", that is, patients with urine protein-to-creatinine ratio (UPCR) <0.88 g/d (equivalent to proteinuria 1 g/d), their risk of developing renal failure within 10 years is still high. 

How to further reduce proteinuria in IgAN patients, stabilize renal function, and improve the long-term prognosis of the disease has become the focus of common attention of doctors and patients. This article is based on the research of Professor Jonathan Barratt and the research progress of IgAN-related drugs disclosed at the 2023 European Society of Nephrology (ERA) annual meeting. We invite experts in the field to analyze the current status of IgAN treatment in China, look forward to the future, and explore the optimal solution to IgAN.

The latest evidence-based research reveals the truth about the long-term prognosis of IgAN patients[3]

IgAN is the main cause of chronic kidney disease (CKD) and ESKD, and most patients develop it in young adults (<40 years old). However, in the current situation where the average life expectancy is >70 years old, China still lacks long-term assessment data on the prognosis of long-term diseases that last for decades.

To better understand the long-term prognosis of IgAN patients, Professor Jonathan Barratt, a world-renowned nephrologist, analyzed the relationship between proteinuria and estimated glomerular filtration rate (eGFR) slope and the lifetime risk of ESKD based on the clinical data of IgAN patients from the Rare Kidney Disease Registry (RaDaR). The study included 2,439 IgAN patients (IgAN confirmed by renal biopsy, proteinuria > 0.5 g/d or eGFR < 60 ml/min·1.73 ㎡), including 2,299 adults and 140 minors.

The results of the study showed that the long-term prognosis of IgAN patients is not optimistic. After a median follow-up of 5.9 years (3.0-10.5), 50% of patients developed ESKD or died. The median renal survival period was 11.4 (10.5-12.5) years, and the average age of ESKD/death was only 48 years old.

Based on eGFR and age at diagnosis, almost all patients are at risk of disease progression to ESKD within their life expectancy. Specifically, for patients with an eGFR slope ≥3 ml/min/1.73 m2/year and age at diagnosis ≤40 years, the lifetime risk of ESKD is 100%; while for patients with eGFR slope 1 ml/min/1.73 m2/year and age at diagnosis ≤50 years, the lifetime risk of ESKD is about 40%.

The study further revealed the relationship between proteinuria and renal outcomes. Time-average proteinuria analysis showed that the higher the time-average proteinuria, the worse the renal survival and the faster the eGFR decline. Specifically, the IgAN patients with time-average proteinuria of 0.44-0.88 g/d had a 30% risk of ESKD within 10 years; patients with time-average proteinuria <0.44 g/d had a 20% risk of ESKD within 10 years.

In particular, the study noted that for those patients generally considered "low risk," i.e., proteinuria <0.88 g/d (equivalent to proteinuria 1 g/d), the risk of developing ESKD within 10 years was high and the long-term prognosis was poor. This skinny reality reminds us that the effective prevention and treatment of IgAN still have a long way to go. In the future, the collective efforts of all forces are needed to fundamentally improve the long-term prognosis of IgAN patients.

Q1 Professor Jonathan Barratt's cohort study based on the British population showed that most IgAN patients will progress to ESKD within 10-15 years, and the clinical outcome is generally poor. Combined with this data, could you please talk about the current status of the long-term management of IgAN patients in China?

Professor Lu Jicheng:

The data of this study (follow-up up to 30 years) suggest that even the Western population, which is traditionally considered to have a better prognosis for IgAN, has a very different prognosis than imagined. In the past, we generally believed that more than 30% of patients would progress to uremia within 10 to 20 years, but the latest research results of Professor Jonathan Barratt suggest that the prognosis of IgAN patients is worse, and the proportion of patients entering ESKD is as high as 50%, and the enrolled patients (proteinuria>0.5g/d or eGFR<60 ml/min·1.73㎡) almost all will progress to renal failure during their lifetime. Based on this challenge, we must update the existing IgAN treatment measures. In addition, although China currently lacks national and multi-center data on the long-term prognosis of IgAN, an early retrospective study of more than 1,000 patients from the Eastern Theater General Hospital showed that more than 1/3 of IgAN patients (average proteinuria 0.9g/d) would progress to ESKD within 20 years; research results from Peking University First Hospital showed that more than 40% of IgAN patients (average proteinuria> 1.8g/d) would progress to ESKD after 10 years.

These two cohort studies from China suggest that the prognosis of IgAN patients in China may be worse than that of Western patients. This reminds us that we need to work on IgAN in many ways:

1. Optimize the current treatment strategy and promote the standardization of diagnosis and treatment;

2. To improve the prognosis of patients, continue to strengthen the research of new drugs;

3. Advance the timing of renal biopsy to achieve early diagnosis and treatment as much as possible.

Q2 Professor Jonathan Barratt's research results show that for "low-risk" IgAN patients with proteinuria <0.88 g/g, the incidence of ESKD is still high within 10 years. What does this suggest for the current management goals of IgAN in China?

Professor Lu Jicheng:

The management goal of reducing proteinuria to <0.88g/d (equivalent to 24-hour proteinuria <1g) mainly comes from an early Toronto cohort study. The results of this study showed that reducing proteinuria to <1g/d, <0.5g/d, or even <0.3g/d has no significant difference in clinical outcomes. Based on this research, the current 2021 KDIGO guidelines set the goal of proteinuria control and the inclusion criteria for clinical research as proteinuria <1g/d. However, according to previous studies, the prognosis of IgAN in Easterners is often worse than that in Westerners, and the risk of renal failure increases by more than 80%. Therefore, the current research data reminds us to adjust the control standard of proteinuria, a chronic risk factor for renal failure, to a lower level, that is, at least control UPCR below 0.44g/d (equivalent to 24-hour proteinuria<0.5g).

Q3 From the research of Professor Jonathan Barratt, we know that strict control of proteinuria levels is of great significance to improve the long-term prognosis of IgAN patients. To better achieve the goal of improving the long-term prognosis of patients, how should we optimize clinical practice and trial design?

Professor Lu Jicheng: To better control proteinuria in patients, we can work on the following three aspects.

1. Pay attention to the long-term management of patients. The kidney is a "silent organ", and disease progression often occurs imperceptibly, so disease management of patients cannot be carried out purely based on clinical symptoms. During patient management, patients should be fully communicated to make them aware of the importance of self-monitoring of blood pressure, regular monitoring of urinary protein (at least every 3 months under stable control), and the importance of regular monitoring of renal function.

2. Optimizing based on traditional treatment to control the level of proteinuria as much as possible. A cohort study showed that optimizing existing treatment strategies, such as diet and blood pressure control, and adequate RAS blocker (RASi) supportive treatment, can significantly improve proteinuria in patients.

3. Pay attention to the research and development of new drugs. Existing treatment measures are still unable to meet the treatment needs. According to the results of the TESTING study, the risk of renal failure in the future increases by 7.8% every year for patients whose proteinuria is not well controlled after supportive treatment, that is, nearly 80% of patients will develop renal failure within 10 years. After combined hormone therapy, the curative effect is obvious but the adverse reactions increase. Although hormone therapy reduces the risk of renal failure by 40%, the risk of residual renal failure still increases by 4.9% per year, that is, 50% of patients still develop ESKD within 10 years. Therefore, we urgently need more effective drugs on the market to reduce the residual 4.9% annual risk of renal failure to below 1% or lower per year.

Q4 Based on the enlightenment brought by Professor Jonathan's research and the current clinical diagnosis and treatment status, which drug research and development directions do you think can be expected in the future?

Professor Lu Jicheng:

Traditional IgAN treatment is mainly based on non-specific treatments, such as antihypertensive drugs, RASi, hormones, etc. Now it is based on the pathogenesis of IgAN, and the development of new drugs mainly includes three categories.

The first class of drugs plays a therapeutic role by inhibiting the production of upstream IgA, mainly including monoclonal antibodies targeting proliferation-inducing ligand (APRIL), targeting B cell activating factor (BAFF)/APRIL dual inhibitors, and intestinal immunosuppressants.

The second class of drugs targets complement. After the immune complex is formed and deposited in the kidney, it will activate the complement and cause kidney damage. Therefore, a variety of drugs targeting complement have been actively explored, mainly including factor B inhibitor LNP023, antisense nucleotides, and drugs targeting mannan-binding lectin-associated serine protease-2 (MASP-2) inhibitors.

The first two types of drugs are immunomodulators or immunosuppressants, and the risk of adverse reactions of long-term use needs more data accumulation. The third type of drug is a new target drug for non-specific treatment of kidney injury other than RASi, which can be used as a supportive treatment for a long time to exert a long-term protective effect. Such drugs mainly include endothelin receptor blockers such as Atrasentan, Sparsentan, sodium-glucose cotransporter 2 inhibitors (SGLT2i), etc. Both Atrasentan and Sparsentan have carried out clinical phase 2 and phase 3 trials in IgAN patients, and the results have proved that these drugs are more effective than specific drugs in reducing proteinuria, with an average proteinuria reduction of >40%.

We have reason to predict that in the future, the combined use of the above three types of drugs is expected to significantly reduce the risk of residual renal failure in patients with IgAN.

See hope from ERA 2023 IgAN drug progress

Although the status quo of IgAN nephropathy control is still skinny, the dawn of hope is flashing ahead. At the 60th ERA Congress held in 2023, research on new drugs targeting various targets to improve IgAN treatment continues to emerge.

It is used at the source of the "quadruple hit" to target the production of upstream Gd-IgA, and has attracted much attention as a therapeutic drug. Zigakibart (BION-1301), a new humanized monoclonal antibody (mAb) that binds and blocks APRIL, was released [4] The interim analysis results of the latest phase I/II clinical study showed that in all patients in the combined analysis of cohorts 1 and 2, BION-1301 treatment could reduce proteinuria by an average of 20% at 12 weeks, 39% at 24 weeks, and 67% at 52 weeks. At the same time, the study also showed that extended treatment with BION-1301 can bring sustained clinical benefits to patients: at 76 weeks of treatment, the average proteinuria of 7 patients decreased by 67%; at 100 weeks of treatment, the average proteinuria of 5 patients decreased by 72%.

The drug VIS649, which is also an anti-APRIL monoclonal antibody, also showed good efficacy in reducing proteinuria. The interim analysis results of its Phase II study showed that compared with the placebo group, VIS649 treatment for 36 weeks significantly reduced proteinuria by 43%[5].

In addition, the results of the phase 2b clinical study (ORIGIN) of the B cell activating factor (BAFF)/APRIL dual inhibitor Atacicept in the treatment of IgAN patients showed that after 36 weeks of Atacicept treatment, the changes in proteinuria assessed by UPCR were reduced by an average of 35% compared with baseline [6].

The 2-year follow-up results of the phase III NeflgArd study of budesonide delayed-release capsules for intestinal immunity (Nefecon) showed that compared with the placebo group, the Nefecon 16mg group had a significantly lower UPCR from baseline (30.7% vs 1%)[7], and a significantly lower decline in eGFR from baseline (-6.11 vs -12.00 ml/min·1.73 ㎡, P <0.0001).

Atrasentan, which targets and blocks endothelin type A (ETA) receptors, is a research drug that has attracted much attention in the field. At this ERA conference, the design of the ASSIST study exploring the combination therapy of Atrasentan and SGLT2i [8] was announced, which is expected to further enrich the non-immunotherapy strategy for IgAN. Atrasentan is a promising new drug for IgAN. The results of its phase II clinical study (AFFINITY) show that Atrasentan can continuously and significantly reduce proteinuria, with an average reduction of proteinuria by 54.7% after 24 weeks of treatment, and is safe and well tolerated[9].

Professor Jonathan Barratt's cohort study has given us a lot to think about. This study shows that traditionally considered "low-risk" patients with proteinuria <0.88 g/d are still at high risk of developing ESKD within 10 years. This suggests that the current prevention and control status of IgAN patients in my country still has a large gap with the target. To better control proteinuria and improve the long-term prognosis of IgAN patients, we need to diagnose as early as possible, optimize existing treatment strategies, strengthen long-term management of blood pressure, proteinuria, and renal function in patients, and adjust the control target of proteinuria to a lower level. Due to the limited existing treatment measures, traditional treatment can no longer meet the current treatment needs, so we urgently need new drugs to be launched.

At present, a variety of new drugs with different mechanisms bring us hope. These drugs include targeting APRIL monoclonal antibodies, BAFF/APRIL dual inhibitors, and intestinal immunosuppressants that inhibit upstream IgA production; targeting complement drugs-factor B inhibitors and targeting MASP-2 inhibitors; new non-specific drugs that can be used for long-term treatment-endothelin receptor blockers Atrasentan, Sparsentan, and SGLT2i, etc. These drugs have shown good efficacy in reducing proteinuria in the research. It is believed that with the development of more clinical studies, more new drugs will enter clinical application, which is bound to "break" the current treatment dilemma of IgAN and improve the long-term prognosis of IgAN patients.

Reference:

[1]Le W, et al. Nephrol Dial Transplant. 2012 Apr;27(4):1479-1485.

[2] 2021 Improving Kidney Outcomes Global Organization (KDIGO) Clinical Practice Guidelines for IgA Nephropathy.

[3]Pitcher D, et al. Clin J Am Soc Nephrol. 2023 Apr 13.

[4] After the "marriage" with Novartis, Chinook brought two core assets to "explode the field" ERA annual meeting. Medicine Rubik's Cube, 2023.6.21. https://mp.weixin.qq.com/s/82OJsDurjmLk7y0UrfRG3A

[5]Kieran McCafferty, et al. Covid Vaccine Responses During Sibeprenlimab Treatment of IgA Nephropathy (IgAN): An Interim Analysis. Presented at ERA2023.

[6]Richard Lafayette, et al. 36-Week Efficacy & Safety of Atacicept 150 mg in the ORIGIN Randomized, Double-blind, Placebo-controlled Phase 2b Study in IgAN and Persistent Proteinuria. Presented at ERA2023.

[7]Richard Lafayette, et al. The long-term renal benefit over 2 years with Nefecon verified: The NefIgArd Phase III full trial results. Presented at ERA2023.

[8]Hiddo Lambers Heerspink, et al. ASSIST Study Design: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study of Atrasentan in Patients with IgA Nephropathy (IgAN) on SGLT2i. Presented at ERA2023.

[9]2022ASNKW.ABSTRACT:TH-PO497.

[10] WCN'23 venue express 丨 3 important research results are updated, and clinical inspiration continues. Yimaitong. 2023.4.10. https://news.medlive.cn/neph/info-progress/show-198543_161.html