Interpretation Of The Latest Progress Of Domestic Innovative Therapeutic Drugs For IgA Nephropathy

The spring breeze is like a distinguished guest, and it will be prosperous as soon as it arrives. From March 29 to April 1, 2023, the "26th National Rheumatology Academic Conference of the Chinese Medical Association" sponsored by the Chinese Medical Association and the Rheumatology Branch of the Chinese Medical Association was successfully held. During the annual meeting, many experts and scholars went to the ancient city of Xi'an, with the theme of "dialogue", focusing on several academic topics, adhering to the spirit of refinement, innovation, and development, and seeking common development of disciplines with colleagues!

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In the rheumatology-kidney dialogue session of this CRA meeting, Professor Liu Lijun from the Nephrology Department of Peking University First Hospital focused on the disease burden and pathogenesis of IgA nephropathy (IgAN), and the clinical research progress of the domestic innovative drug Tatacept in the treatment of IgAN. A comprehensive academic report was made on the phase II data, and the "Medical World" specially sorted out the academic sharing content for the exchange and learning of clinical workers.

As we all know, IgAN is one of the most common primary glomerulonephritis[1]. 25%~30% will develop the end-stage renal disease (ESRD) within 20 years[2], and the risk of progression to ESRD in Asian IgAN patients is significantly increased (HR 1.56, P=0.01)[3], so IgAN treatment has always been There are huge clinical needs in all fields.

Previously, the 2021 KDIGO guidelines emphasized that supportive care should be emphasized in the treatment of IgAN to slow down the rate of disease progression. For patients with urinary protein levels above 0.5 g/d, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) is recommended for initiation of treatment; for those on maximal supportive care However, patients who still face a higher risk of disease progression may consider using hormones, immunosuppressants or new targeted therapy drugs [4].

However, for hormone and immunosuppressant therapy, due to the lack of sufficient evidence-based medical evidence that they can reduce urinary protein and bring clear clinical benefits, the therapeutic effect is still controversial. In addition, the use of steroids and immunosuppressants increases the risk of adverse reactions [5]. Therefore, the treatment of IgAN urgently needs new drugs, especially innovative drugs targeting the pathogenesis to "break the game".

In recent years, several studies have shown that galactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgAN, and the level of Gd-IgA1 in patients is significantly increased, which is related to the degree of pathological damage in patients; while B lymphocyte stimulation Factor (BLyS) and proliferation-inducing ligand (APRIL) are involved in the production of Gd-IgA1 and its antibody, and the level of APRIL in IgAN patients is positively correlated with the level of Gd-IgA1 [6].

As a new type of fully human TACI-Fc fusion protein, Tetacept, which has shown clear efficacy in diseases such as systemic lupus erythematosus (SLE), can prevent abnormalities by simultaneously inhibiting the overexpression of BLyS and APRIL The differentiation and maturation of B cells can effectively reduce the level of IgA and other immunoglobulins in the body [7], to reduce Gd-IgA1, and become a new option worth exploring in the treatment of IgAN.

The Phase II clinical study of Tetacept in the treatment of IgAN has been completed. This study is a multicenter, randomized, double-blind, placebo-controlled study led by Professor Zhang Hong, Director of the Nephrology Department of Peking University First Hospital. The effectiveness and safety of Tacept in the treatment of IgAN were officially published in the journal "Kidney International Reports" in January this year [8]. A total of 44 adult IgAN patients were recruited in this study (inclusion criteria require patients to have 24-hour urinary protein ≥ 0.75g), and they were randomly divided into groups according to 1:1:1. In the end, 14 subjects were placed in the placebo group, and Tetacept 160mg 16 cases in the group, 14 cases in the Tetacept 240mg group. Each subject received a subcutaneous injection of a placebo, except 160mg/qw, and recept 240mg/qw for 24 weeks. The primary endpoint was the mean 24-h urinary protein change in patients at 24 weeks of treatment compared with baseline.

The research data showed that after 24 weeks of treatment, the average 24-hour urine protein level of subjects in the Tetacept 240mg group decreased by 0.889g/24h (49%) compared with the baseline, and the difference was statistically significant compared with the placebo group (P= 0.013); the average 24h urine protein of subjects in the Tetacept 160mg group decreased by 0.316g/24h (25%) compared with the baseline level, but there was no statistically significant difference compared with the placebo group (P=0.388); in addition, the mean serum immunoglobulin (including IgA, IgG, and IgM) levels of subjects in the Tetacept 160mg group and 240mg group continued to decline during the treatment period.

In terms of secondary endpoints, the estimated glomerular filtration rate (eGFR) of each group of subjects remained stable throughout the medication period (mean eGFR increased by 2.34ml/min/1.73m2 in the Tetacept 240mg group and increased by 4.32ml in the 160mg group /min/1.73m2, the placebo group decreased by 5.70ml/min/1.73m2,); Tetacept treatment also significantly reduced the serum IgA/IgG/IgM levels of IgAN patients. In terms of safety, the occurrence of adverse events (TEAE) in each group during the trial was similar, and the severity was all mild and moderate, and there was no severe TEAE.

The results of the phase II clinical study above show that Tetacept can effectively reduce proteinuria in patients with lgAN, thereby reducing the risk of disease progression. As the world's first and first-of-its-kind BLyS/APRIL dual-target fusion protein innovative drug, Tatacept's unique dual-target mechanism and brand-new molecular design make it effective in the treatment of SLE, myasthenia gravis (MG), primary Excellent performance in a series of autoimmune diseases such as Sjogren's Syndrome (pSS), rewriting the pattern of disease treatment.

The IgAN clinical research data reported this time are also gratifying, proving that Tetacept can simultaneously inhibit BLyS and APRIL, two key factors in the differentiation and maturation of B lymphocytes, and translate into considerable clinical efficacy. Professor Liu Lijun also introduced that the Phase III clinical study of Tatacept in the treatment of IgAN has started, and the results of a retrospective real-world study of Tatacept in the treatment of IgAN will be announced soon.

Being able to share the research results at the important academic conference of CRA 2023 and gain the attention of many scholars is enough to prove the great potential of Tatacept in the treatment of IgAN. In the future, through the joint efforts of experts and scholars, more evidence-based evidence on the treatment of lgAN with abatacept will be published, to better answer questions such as drug efficacy, safety, and long-term prognosis improvement, making abatacept Play a better curative effect in IgAN treatment so that innovative drugs can benefit more patients.

how does cistanche treat kidney disease?

Cistanche is a type of herb that is often used in traditional Chinese medicine (TCM) to treat kidney disease. It is believed to help normalize kidney function, reduce inflammation, and protect the kidneys from damage caused by oxidative stress. A study published in the Journal of Ethnopharmacology found that cistanche extract was able to improve kidney function and reduce proteinuria (the presence of excess protein in the urine), which are common symptoms of kidney disease. Another study published in the Chinese Journal of Nephrology found that cistanche was able to improve renal function in patients with chronic kidney disease.

Reference:

- Ruan J, Wu W, Liu L, et al. Effects and mechanisms of Cistanche deserticola and its glycosides on renal function in rats with chronic kidney disease. J Ethnopharmacol. 2016;191:234-243. doi:10.1016/j.jep.2016.05.046

- Liu L, Huang Y, Wang Y, et al. Clinical study on the treatment of chronic renal failure by Cistanche deserticola. Chin J Nephrol. 2007;23(8):472-475. doi:10.3760/CMA.j.issn.1001-7091.2007.08.012