Role of telitacicept in the treatment of IgA nephropathy

Although the underlying pathophysiology of IgAN has been extensively investigated, we still lack precise therapies for the condition. Currently, IgAN is treated through therapeutically supportive measures to lower blood pressure, lessen proteinuria, reduce lifestyle risk factors, and lessen other non-specific kidney damage. The main approach to intervention is the use of ACEI or ARB, which lower intraglomerular pressure by inhibiting the RAAS, to some extent lowering the patient's proteinuria levels, and delaying the progression of renal failure [32].

If IgAN patients have concurrent hypertension and the patient’s proteinuria is greater than 1.5 g/day, 2021 KDIGO advises stratified management with RAAS blockade therapy; if the patient’s urine protein remains between 0.75 and 1 g/day after 3 months of optimised supportive therapy, 6 months of glucocorticoid therapy is recommended [33].

However, the effectiveness of glucocorticoids and immunosuppressants in patients with IgAN is still debatable. According to research by the supportive versus immunosuppressive therapy for the treatment of progressive IgA nephropathy (STOP-IgAN) [34], immunosuppressive regimens do not significantly enhance prognosis in relation to that by supportive therapy. Additionally, they have increased negative side effects, such as the development of infection and cancer.

Use of traditional Chinese medicine has also shown results in IgAN [35]. The dialectical treatment of traditional Chinese medicine is effective for IgAN patients with primary chronic lesions (tubular atrophy and renal small blood vessel lesions), whereas IgAN patients with active lesions and chronic kidney lesions require integration of traditional Chinese and Western medicine.

In recent years, several innovative biologics have started to be employed in the treatment of IgAN as a result of advances in our understanding of the disease's aetiology. Sparsentan is a non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist (DEARA), with a double effect as a highly selective antagonist of endothelin type A (ETA) receptor and angiotensin II type-1 receptors (AT1R). An ongoing phase III clinical trial (NCT03762850), one of the largest intervention experiments to study the efficacy and safety of new IgAN drugs, is studying the efficacy and safety of Sparsentan (400 mg once daily) compared with the current standard therapy irbesartan (300 mg once daily) in the treatment of IgAN. A pre-specified interim analysis of the primary efficacy endpoint of 24-h urine proteinuria change in subjects is performed at week 36. And the study met this efficacy endpoint, and the results were statistically significant: after 36 weeks of treatment, the proteinuria level of patients in the sparsentan group was reduced by an average of 49.8% from baseline. This decrease was more than three times higher than that of the irbesartan-treated group, i.e. the positive drug control group (49.8% vs 15.1%; p < 0.0001), and the safety profile was similar between the two groups [36‐38]. Drugs that target the B cell receptor, like CD20 monoclonal antibodies, work in a number of ways, including cytotoxicity-dependent, complement-dependent, and apoptosis-inducing pathways [39]. Rituximab is a CD20 monoclonal antibody. However, according to a randomised controlled trial by Richard A et al [40], it did not lower serum levels of Gd-IgA1 and glycan-specific IgG antibodies, enhance renal function, or reduce proteinuria. Rituximab is a mild anti-CD20 monoclonal antibody that causes B lymphocyte failure by binding to CD20 receptors on the membrane of pre-B lymphocytes and mature B lymphocytes [41]. However, because plasma cell membranes lack CD20 receptors, rituximab cannot bind to plasma cells or clear plasma cells, and may therefore ineffectively inhibit plasma cell formation and the secretion of Gd-IgA1 antibodies. This could be the cause of rituximab's inability to significantly alter the course of treatment or prognosis for IgAN. In a single-arm trial, 24 patients with primary glomerulonephritis—five of whom had IgAN—were treated with a single dose of rituximab at 375 mg/m². In patients with IgAN, proteinuria did not significantly alter after 6 months of rituximab treatment (1.0 ± 0.8 g/day at baseline vs 0.9 ± 0.8 g/day at 6 months). The short follow-up of just 6 months and the potential need for many doses of rituximab to produce a response in a slow-progressing condition like IgAN made it difficult to interpret the trial's findings [42, 43]. A fully human monoclonal antibody to BLyS(BAFF), belimumab reduces immature and mature B lymphocytes directly and indirectly by inhibiting the function of plasma cells [44], which may explain why it is ineffective at preventing the production of Gd-IgA1 antibodies in plasma cells. It also may explain why belimumab is ineffective at improving the effectiveness and prognosis of IgAN. Narsoplimab (OMS721) is a human monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway of the complement system [45]. OMS721 is being developed for treatment of diseases thought to be mediated by the complement lectin pathway, including IgAN [46]. Research is ongoing in a phase III, double-blind, randomised, placebo-controlled experiment (NCT03608033) in which 450 patients have been randomly divided into 2 groups, treated with OMS721 at 185 mg/mL, and controlled with 5% glucose (D5W) or normal saline in the placebo group. Observations include changes from the baseline in a 24-h urine protein excretion (UPE) in g/day at 36 weeks from the beginning of the treatment. Results of this experiment are expected to open up new options for IgAN treatments. There are many studies on IgAN treatments conducted globally [46], and the list summarises the treatments for IgAN mentioned in this article (Table 1) [44, 46].

As a result, new therapeutic targets need to be considered when designing pharmacological treatments. New therapeutic targets must successfully combat re-B lymphocytes, mature B lymphocytes, plasma cells, and the formation of Gd-IgA1 antibodies. This objective can now be accomplished by a novel biologic, which offers fresh start for the treatment, prognosis, and long-term outcome of IgAN.

Telitacicept is an innovative medicine that was independently developed in China and has the qualities of “a new target, a new structure, and a new mechanism” for the treatment of autoimmune diseases [9]. The dual-target action of telitacicept can more successfully lower B lymphocyte activation, limit the body’s immune response, and treat autoimmune illnesses than belimumab, an inhibitor of BLyS/BAFF [11]. Additionally, telitacicept has a slightly higher molecular weight than the identical BLyS/BAFF and APRIL dual-target inhibitor, atacicept (NCT04716231) (TACI-Ig) (73.4 kD vs. 80.24 kD). This helps it to maintain the N-terminal portion of extracellular TACI and enhances its capacity to bind to TACI [47]. Previous studies have indicated that atacicept can, in a dose-dependent manner, lower serum levels of Gd-IgA1 and anti-Gd-IgA1 antibodies in IgAN patients [48, 49]. Since telitacicept targets both BLyS/BAFF and APRIL, it has potential use in the treatment of many autoimmune illnesses linked to B cells such as IgAN, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) [25, 50]. Blocking the binding of BLyS/BAFF to TACI and BAFF-R effectively slows down the maturation and differentiation of B lymphocytes. In addition to this, by blocking the binding of APRIL to BCMA or TACI, telitacicept can lower IgA1 secretion, lower the production of Gd-IgA1, and inhibit the production of anti-Gd-IgA1 autoantibodies. This slows the progression of IgAN by reducing immune complex deposition in the mesangial region of the glomeruli (Fig. 1) [23, 51‐56].

Based on a recent phase II clinical trial (NCT04291781), after 24 weeks of continuous administration of telitacicept at 240 mg/week, patients’ average 24-h proteinuria levels decreased by 49% from baseline 24-h proteinuria. After 24 weeks of continuous administration at 160 mg/week or 240 mg/week, the estimated glomerular filtration rate (eGFR) increased significantly in relation to that of the placebo group, and the patients' serum levels of IgA, IgG, and IgM dramatically dropped [12]. Larger, high-quality clinical investigations are required to further confirm the effectiveness of telitacicept against IgAN.

In our country, telitacicept is currently approved for the treatment of SLE [11], and clinical research is being conducted on its potential use against multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and primary Sjogren's syndrome (pSS) [10, 57]. Thus far, telitacicept has shown substantial promise in the treatment of B lymphocyte-associated immunological disorders as numerous clinical trials have progressed.

Despite the lack of defined indicators for IgAN clinical monitoring, immune variables, inflammatory factors, and indicators related to renal function are frequently utilised to assess clinical efficacy.

In recent years, the serum IgA/C4 ratio, serum soluble IL-2 receptors (IL-2R) level [58], urine type IV collagen content [59], Monocyte chemoattractant protein 1(MCP-1) level [60], and urinary IL-6 levels [61] have all been found to be relevant to IgAN progression and can serve as potential new indicators in the clinical monitoring of IgAN.

Xie et al. [62] discovered that the intensity of glomerular CD206 + and CD68 + macrophage infiltration in IgAN patients predicted the patient's response to immunosuppression; When the level of glomerular CD206 + macrophage infiltration was increased, the body's response to immunosuppression increased by a factor of 40; and when the level of glomerular CD68 + macrophages infiltration was increased, the body’s response rate to immunosuppression increased by a factor of 13. Therefore, clinicians can develop individualised IgAN treatment regimens based on the degree of glomerular CD206 + and CD68 + macrophage infiltration.

In addition to understanding the mechanism of therapeutic intervention, evaluation of the clinical efficacy of IgA therapy requires examination of both the illness characteristics and the function of the injured organs. Telitacicept is a two-target immunosuppressant, and for patients treated with telitacicept, we may be able to monitor treatment and prognosis with CD206 and CD68.

Telitacicept has fewer side effects than conventional medications since it is processed by cells rather than the liver and kidneys [9]. The side effects seen in the placebo group were similar to those experienced by the telitacicept group. Importantly, in phase II randomised, double-blind, placebo-controlled clinical trials of telitacicept in 44 patients with IgAN and persistent proteinuria, all observed side effects were considered mild to moderate [12]. Additionally, there was no increase in the frequency of adverse reactions in patients when the dose was increased from 160 mg/week to 240 mg/week.

Telitacicept has also shown good tolerance and safety in the treatment of patients with SLE [63] and RA [64]. In this 52-week phase III, placebo-controlled, multicenter, randomised, double-blind clinical trial (NCT04082416), the efficacy and safety of telitacicept (160 mg subcutaneously once weekly) were compared with those of a placebo (subcutaneously once weekly) in the treatment of SLE. The SLE Response Index 4 (SRI-4) response rates in the telitacicept and placebo groups were evaluated at week 52 as the primary endpoint. The SRI-4 response was defined as the SELENA-SLEDAI score being reduced by ≥ 4 points from baseline, no new BILAG assessment class A organs or ≤ 2 new BILAG assessment B organs compared to baseline, and the physician's overall assessment (PGA) not deteriorating (< 0.3 points increase from baseline) at 52 weeks. The SRI-4 response rate in the telitacicept group (160 mg subcutaneously once weekly) reached 82.6%, significantly higher than that in the placebo group of 38.1%, (82.6% vs 38.1%; p < 0.001). In addition, the overall infection rate was similar between the telitacicept and placebo groups, with no significant difference, suggesting the good tolerability and safety profile of telitacicept. In a recently published case series, telitacicept was used to treat refractory childhood SLE; The course of treatment lasted 5–26 weeks, and 4 out of 15 patients experienced mild-to-moderate side effects [65]. According to the studies mentioned above, telitacicept is safe and effective for use in the treatment of a range of autoimmune diseases, including IgAN.

IgAN is the most prevalent form of primary glomerulonephritis in the world, including in China [55]. Between 20% and 40% of patients develop ESRD within 20 years of IgAN, putting both patients and their families under significant physical and financial strain. The development of telitacicept provides new possibilities for the treatment and long-term prognosis of IgAN, and for other autoimmune diseases where B cells play a primary role in pathogenesis. The safety and efficacy of telitacicept remain to be further confirmed as clinical trials progress.