Myasthenia gravis (MG) is a heterogeneous autoimmune disorder caused by pathogenic antibodies, characterized by muscle weakness and fatigue. It mainly affects the neuromuscular junction, where autoantibodies target proteins essential for muscle contraction, disrupting communication between nerves and muscles. The disease is categorized into subgroups based on the specific autoantibodies involved. About 90% of patients with generalized MG and 72% with ocular MG have IgG antibodies that bind to the muscle nicotinic acetylcholine receptor (AChR). In comparison, 4–8% have IgG antibodies targeting muscle-specific kinase (MuSK) protein (1, 2). Lipoprotein-related protein 4 (LRP4) antibodies directly block AChR function, and agrin antibodies (Agrin-Ab) are found in some patients with coexisting AChR, MuSK, or LRP4 antibodies (1). These autoantibodies influence clinical symptoms, affect prognosis, and guide treatment options. In generalized MG (gMG), their pathogenic effects reduce functional acetylcholine receptor levels and damage the neuromuscular junction, leading to impaired neuromuscular transmission (3).

Current treatments, including corticosteroids and non-steroidal immunosuppressive therapies (NSISTs), generally suppress the immune system without specifically targeting IgG autoantibodies (4). However, long-term use of corticosteroids is linked to serious side effects such as hyperglycemia, hypertension, osteoporosis, myopathy, and lymphocytopenia (5). Most NSISTs take months to become fully effective and may increase the risk of secondary malignancies, liver dysfunction, and bone marrow suppression (6). Additionally, some gMG patients remain resistant to standard treatments. According to international consensus, refractory gMG is defined by an inadequate response to at least two immunosuppressive therapies, relapse during corticosteroid tapering, or dependence on intravenous immunoglobulin (IVIG) or plasma exchange (PE) (7). These patients often experience frequent myasthenic flares and crises, which frequently lead to hospitalization, emphasizing the need for alternative treatment options (7).

Recent advances in biologic therapies, such as B-cell-depleting agents, complement inhibitors, and FcRn antagonists, highlight the importance of targeting specific immune pathways (8). B cells are crucial in MG development because they produce harmful autoantibodies against acetylcholine receptors (9). B lymphocyte stimulator (BLyS/BAFF) and a proliferation-inducing ligand (APRIL) are cytokines vital for B cell survival and differentiation (10). Telitacicept (Remegen Co., Ltd., China), a biologic targeting B cells, is a recombinant fusion protein that links the transmembrane activator and calcium modulator ligand interactor (TACI) receptor with the Fc domain of human IgG (11). By blocking both BLyS and APRIL, telitacicept inhibits B cell activation and differentiation, offering a potential therapeutic advantage over traditional immunosuppressants.

Approved in China for systemic lupus erythematosus (SLE) in 2021, telitacicept has demonstrated efficacy in immunoglobulin A nephropathy (IgAN), neuromyelitis optica spectrum disorders (NMOSD), Sjögren’s syndrome, and rheumatoid arthritis (11–14). A phase 2 clinical trial in gMG patients reported safety, tolerability, and significant clinical improvement (15). A phase 3 clinical trial (NCT05737160) aimed at further confirming telitacicept’s efficacy for gMG in China was completed in December 2024, but the results have not yet been published. A global phase 3 trial (NCT06456580) is currently ongoing across 54 international sites, including the United States, Canada, and Australia. Telitacicept has received Orphan Drug Designation from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of MG.

Critical considerations include the safety and tolerability of new biologics like telitacicept. Clinical trials show that telitacicept may cause fewer side effects than traditional immunosuppressants, which carry significant long-term risks (16). This is particularly important for MG patients, as many are worried about the side effects of long-term immunosuppressive treatment. Given the unmet need in refractory gMG, this retrospective study looks at the real-world effectiveness of telitacicept in Chinese patients with refractory AChR+ gMG.

Managing refractory generalized myasthenia gravis (gMG) remains a significant therapeutic challenge, as demonstrated by the limited responses to standard immunosuppressive treatments in our group. Our real-world study shows that telitacicept provides notable clinical benefits in refractory AChR+ gMG, with strong improvements confirmed through mixed-effects model analysis. The least-squares mean reduction in the QMG total score of -2.24 points (95% CI: -3.34 to -1.15) at month 5 indicates meaningful clinical improvement, consistent with previous evidence from phase 2 trials (15). Our findings are particularly relevant given the strict refractory criteria used, which require failure of at least 2 immunosuppressive therapies or dependence on rescue treatments, thereby identifying a population with exceptionally high unmet needs (7).

The treatment regimen of 160 mg weekly for four weeks, followed by biweekly doses, proved pharmacologically sound, aligning with the drug’s pharmacokinetic profile, which shows an elimination half-life of 10.9-12.5 days and sustained target engagement (18). This dosing strategy led to gradual clinical improvement, with response rates increasing (from 16% to 69.9% for MGFA-PIS and from 20.5% to 73.8% for QMG improvement between months 3 and 6), indicating that a longer treatment duration could provide greater benefits. The significant reductions across multiple QMG domains—especially in ocular (LS mean -0.83, p=0.006) and limb scores (LS mean -0.83, p=0.008) at month 5—demonstrate comprehensive neuromuscular improvement. Although the effect size was slightly smaller than that in phase 2 trials (-7.7-point reduction) (15), this probably reflects key differences between controlled trials and real-world practice, including broader patient selection and varying concomitant therapies in our cohort.

Kaplan-Meier analysis revealed significant response rates: 69.9% of patients reached MGFA-PIS minimal manifestation status, and 73.8% achieved QMG improvement (≥3-point reduction) within 6 months, demonstrating the progressive effects of telitacicept. These meaningful improvements enabled substantial corticosteroid reduction, with LS mean prednisone doses decreasing by -10.17 mg/day (95% CI -12.80 to -7.54, p<0.001) at month 5, approaching the <5 mg target recommended by international guidelines (19, 20). The discontinuation rates of non-steroidal immunosuppressants (30% for tacrolimus, 12.5% for mycophenolate mofetil) further highlight telitacicept’s potential as a steroid-sparing treatment. Our findings align with recent real-world evidence indicating telitacicept’s effectiveness in refractory gMG (21, 22).

The consistent treatment responses across various demographic and clinical subgroups, including age, disease duration, MGFA class, and antibody levels, demonstrate broad applicability in refractory gMG. Interestingly, five of nine patients who previously did not respond to complement inhibitors or FcRn antagonists achieved minimal manifestation status with telitacicept, highlighting the importance of targeting alternative pathways in treatment-resistant cases. This observation supports the emerging paradigm of mechanism-based therapeutic selection in the management of MG (8, 23, 24).

The favorable safety profile of telitacicept aligns with phase 2 trial observations (15), with mostly mild injection-related reactions and infections being the most common TEAEs. The mixed-effects model analysis used in our study, which accounts for within-patient correlations and missing data, provides more reliable estimates of treatment effects than traditional methods, improving the robustness of our findings.

Several limitations should be considered when interpreting these findings. The retrospective, single-center design presents potential selection and information biases, while the modest sample size (n=42) restricts subgroup analyses. The limited number of patients using specific non-steroidal immunosuppressants hampers our ability to perform formal statistical testing for these agents, leading to a mainly descriptive presentation. The declining number of patients at risk (from 38 at month 1 to 3 at month 6) illustrates real-world challenges but warrants caution in interpreting long-term estimates. Financial constraints that lead to treatment discontinuation in some patients may affect the generalizability of the results. Additionally, the average treatment duration of 3.5 months, though reflective of real-world patterns, might underestimate the potential benefits of longer-term therapy.

These results are influenced by the ongoing global development of telitacicept, including its FDA and EMA orphan drug designations for MG and the multinational phase 3 trial (NCT06456580). While our study provides promising real-world evidence, prospective controlled trials with longer follow-up are needed to define telitacicept’s role in the MG treatment algorithm clearly. Future research should also explore biomarkers that predict response and identify the most effective combination strategies with current therapies.

This study provides clinically relevant evidence that telitacicept improves measurable outcomes in refractory AChR+ gMG across different patient subgroups, while also enabling a reduction in concomitant immunosuppression. The consistency of these real-world findings with earlier clinical trial data strengthens the therapeutic rationale for BLyS/APRIL inhibition in MG treatment. While awaiting confirmatory phase 3 results, our experience indicates that telitacicept is a valuable addition to the limited options available for this challenging patient population.