New Possibilities For The Treatment Of IgA Nephropathy, Tetacept IgA Nephropathy Research Data Presented At CNA 2023

IgA nephropathy (IgAN) is the most common primary glomerular disease with a poor prognosis and is the leading cause of end-stage renal disease (ESRD) in East Asian countries. Among Chinese patients with primary glomerulonephritis, IgAN accounts for nearly half of the cases [1]. At present, hormones and traditional immunosuppressants are still used clinically, but their effects are limited and cannot meet the treatment needs of patients.

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On July 20-23, 2023, the "2023 Academic Annual Meeting of the Nephrology Branch of the Chinese Medical Doctor Association (CNA)" was grandly held in Qingdao. Experts from all over the country are invited to communicate, share clinical experiences, and explore new concepts of the discipline.

On July 21, 2023, CNA2023 held a Tatacept satellite meeting. The meeting discussed the current difficulties faced by IgAN treatment at home and abroad, shared the results of Phase II clinical study of Tatacept, and provided a new treatment for IgAN patients. direction.

Interpretation of Phase II Study Data of Tatacept in IgAN

The meeting was held under the auspices of Prof. Shao Fengmin from Henan Provincial People's Hospital and Prof. Xu Yan from the Affiliated Hospital of Qingdao University. Prof. Zhang Hong from Peking University First Hospital interpreted and shared the "Phase II Study Data of Tatacept in the Treatment of IgAN".

IgAN is a disease characterized by the deposition of primary IgA in the glomerulus, and the long-term clinical prognosis is poor. Some articles suggest that [2] almost all IgAN patients will face the outcome of renal failure in their lifetime, even if Patients who are traditionally considered low-risk (time-average proteinuria <0.44g/g) still have a 20% chance of progressing to ESRD within 10 years.

At present, IgAN still lacks specific treatment. The "2021 KDIGO Guidelines for Glomerulonephritis" [3] pointed out that the treatment of IgAN should be mainly supportive, that is, the use of sufficient or tolerated doses of renin-angiotensin system inhibitors (RASi), control Blood pressure, minimize cardiovascular risk, and adjust lifestyle. If the patient’s urine protein is still > 0.75-1g/d after 90 days of treatment, it indicates that the patient has a risk of progressive renal function loss. When the patient’s glomerular filtration rate (eGFR) > 30ml /min/1.73m2, consider starting glucocorticoid therapy for 6-8 months. The guidelines do not recommend the use of other immunosuppressive therapies for general patients, and the biological agents or targeted drugs currently under development are still in phase II and III clinical research stages, and no clinical evidence has been formed.

A 10-year international multi-center study TESTING study[4] modified the guideline-recommended dose of methylprednisolone combined with sulfonamides. Compared with a placebo, treatment for 6-9 months can significantly reduce kidney damage by 40%. The composite outcome risk provides an available and economical treatment plan for the clinic. But even so, nearly one-third of patients still have disease progression, and the current treatment methods cannot meet the needs of patients, and the development of new drugs is urgently needed.

Genome-wide association analysis (GWAS) has found more than 30 IgAN susceptibility genes, and some studies [5] pointed out that intestinal mucosal immunity plays a key role in the pathogenesis and progression of IgAN. Changes in the local intestinal microenvironment may lead to intestinal immune imbalance, and then transform intestinal B cells into plasma cells, excessively secrete galactose-deficient IgA1 antibody (Gd-IgA1), and lead to IgAN. B lymphocyte stimulating factor (BLyS) and a proliferation-inducing ligand (APRIL) are important cytokines leading to IgAN, which undertake the maturation, proliferation, and differentiation of B cells, and the transformation and survival of plasma cells, and are important in IgAN. Intervention target. Several studies have also demonstrated that overexpression of BLyS can promote abnormal glycosylation of IgA and deposition of immune complexes in the kidney, and the expression of APRIL can induce the production of Gd-IgA1.

At present, many studies [6-7] use APRIL monoclonal antibody or BLyS+APRIL double antibody to treat IgAN, and the results show that by inhibiting BLyS and APRIL, IgAN patients can reduce immunoglobulin and improve proteinuria. Provide new ideas for the treatment of IgAN.

Tetacept, as a dual-target receptor-antibody fusion protein, can simultaneously target BLyS and APRIL, achieve multi-stage inhibition of B cell maturation and differentiation, and block the development of the disease from the upstream of IgAN pathogenesis.

The Phase II clinical study of Tetacept [8] included 44 patients with IgAN in 25 domestic hospitals. The inclusion criteria were confirmed by renal biopsy, urine protein ≥ 0.75g/d, and eGFR > 35ml/min/1.73 m2 Patients with a high risk of progression IgAN. The study was randomly divided into three groups. The two treatment groups received subcutaneous injections of Tetacept 240 mg and 160 mg weekly, respectively, for a total of 24 weeks.

The results showed that Tetacept could significantly improve the urinary protein in IgAN patients, and the urinary protein in the 240mg treatment group decreased by 0.89g/d compared with the baseline, reaching a reduction ratio of nearly 50%. At the same time, eGFR in the treatment group remained stable during Tetacept treatment. In addition, in terms of drug safety, the study found that by monitoring the serum IgA, IgM, and IgG of patients, Tetacept can bring about a large decrease in IgA and a slight decrease in IgG and IgM, avoiding adverse reactions caused by excessive reduction of IgG and IgM. The main adverse reactions during the treatment period were pain at the injection site, infection, and other adverse reactions, and the incidence rate was not different from the placebo group.

In general, the results of the Phase II study of Tetacept showed a good therapeutic effect and safety in IgAN. At present, the clinical research of Tetacept has started phase III research, and we look forward to the release of further research results to prove the feasibility of its clinical treatment of IgAN.

Efficacy and safety of Tetacept

At the same time, the results of three other real-world studies of Tetacept were also presented in the posters of the conference, explaining the efficacy, safety, and possibility of treatment of Tetacept in other diseases through clinical data.

Efficacy and safety of Tetacept in the short-term treatment of IgA nephropathy

Professor Jin Meng and other experts from the First Affiliated Hospital of Zhengzhou University shared a poster. The study included 15 patients who were diagnosed with IgAN in the First Affiliated Hospital of Zhengzhou University. Litmus, Tataercept + mycophenolate mofetil for treatment. At the 1st, 2nd, and 3rd month of treatment, the indicators of the patients were measured and adverse events were recorded. During the 3-month treatment period, 60% of patients achieved clinical remission, 20% of them achieved complete remission, and 40% achieved partial remission. The results of the study showed that the short-term application of Tetacept in the treatment of IgAN can reduce urinary protein, increase albumin, and delay the decline of renal function.

Efficacy and safety analysis of small sample application of abatacept combined with the standard regimen in the treatment of active LN

Professor Guo Qi and other experts from the Bethune First Hospital of Jilin University applied Tatacept in the clinical treatment of patients with active lupus nephritis (LN). The study included 6 patients with active LN in the hospital and completed Tatacept for more than 12 weeks. Cipro combined with standard treatment (glucocorticoids combined with hydroxychloroquine and immunosuppressants) for treatment. The results showed that the patient's clinical symptoms improved significantly, the dosage of glucocorticoids was reduced, the systemic lupus erythematosus disease activity score (SLEDAI score) continued to decline, and various serological indicators improved significantly. This suggests that the use of abatacept combined with standard regimens in the treatment of active LN has good efficacy and safety, good prognosis, can reduce the dosage of glucocorticoids, and has excellent clinical therapeutic effects.

A retrospective study on the safety and efficacy of Tetacept in patients with IgA nephropathy

Professor Pan Yuting and other experts from Renmin Hospital of Wuhan University shared a retrospective study that included 27 patients with IgAN treated with Tatacept in Renmin Hospital of Wuhan University. The 24-hour proteinuria of the patients decreased significantly after 4 weeks of treatment, and decreased by 69% compared with the baseline after 24 weeks of treatment; after 24 weeks of treatment, a total of 10 patients achieved complete remission of IgAN, 8 achieved partial remission, and the overall remission rate was 67%. The study pointed out that Tetacept can significantly reduce the level of proteinuria in patients without affecting eGFR, and has a high safety.

Summary

Professor Zhang Hong's wonderful sharing brought the participating experts to think about the new goal of IgAN treatment. The meeting introduced the pathogenesis of IgAN, the dilemma of clinical treatment, and the mechanism of action of tatacept, and interpreted the meaning of the phase II clinical study data of the drug. The clinical use questions that can be answered enrich the evidence-based evidence. As a new dual-targeted drug, Tetacept has demonstrated its clinical value in the treatment of IgAN in many studies, and previous studies have also proved its safety. It is believed that with the further deepening of clinical research, Tetacept will become a powerful weapon for the treatment of IgAN in the future!

references:

[1] Yu Xueqing. Current status and prospect of IgA nephropathy treatment [C]//Compilation of special lectures at the 2010 Academic Annual Meeting of Nephrology Branch of Chinese Medical Association. 2010.

[2]Pitcher D, Braddon F, Hendry B, et al. Long-Term Outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023;18(6):727-738.

[3] Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100(4S):S1-S276.

[4]Lv J, Wong MG, Hladunewich MA, et al. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2022;327(19):1888- 1898.

[5]Liu L, Khan A, Sanchez-Rodriguez E, et al. Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits [published correction appears in Nat Commun. 2023 Feb 6; 14(1):655]. Nat Commun. 2022;13(1):6859. Published 2022 Nov 11.

[6]Barratt J, Tumlin J, Suzuki Y, et al. Randomized Phase II JANUS Study of Atacicept in Patients With IgA Nephropathy and Persistent Proteinuria. Kidney Int Rep. 2022;7(8):1831-1841. Published 2022 May 26.

[7]Myette JR, Kano T, Suzuki H, et al. A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy. Kidney Int. 2019;96(1):104-116.

[8]Lv J, Liu L, Hao C, et al. Randomized Phase 2 Trial of Telitacicept in Patients With IgA Nephropathy With Persistent Proteinuria. Kidney Int Rep. 2022;8(3):499-506. Published 2022 Dec 29.