MG is an antibody-mediated autoimmune disease, and the acetylcholine receptor antibody is the most common pathogenic antibody, with AChR antibodies present in about 85% of patients, MuSK antibodies present in about 5% and LRP4 antibodies present in about 1-5% of patients.

Introduction

MG (Mysas Griculous) is an antibody-mediated autoimmune disease . The acetylcholine receptor (AChR) antibody is the most common pathogenic antibody. AChR antibody is present in about 85% of patients, MuSK (muscle-specific receptor tyrosine kinase) antibody is present in about 5% of patients, and LRP4 (low-density lipoprotein receptor-associated protein 4) antibody is present in about 1-5% of patients. In addition, some patients have not detected the above antibodies in the serum, which are called serum negative MG^{1, 2}. The clinical manifestations of MG are extremely heterogeneous. The subgroup classification based on serum antibody and clinical characteristics is of great guiding significance for individualized treatment and prognostic evaluation of MG ².

Expert Profile

号人博日本司

• Chief Physician, Professor, Doctoral Supervisor

• Capital Medical University Xuanwu Hospital Director of Neurology Neurosarcotics Specialty

• Current member of the Neurology Branch of the Chinese Medical Association

• Member of the National Peripheral Neurology Standard Diagnosis and Treatment Training Center of the Chinese Medical Association Neurology Branch and Director of the Branch

• Member of the Amyotrophic lateral sclerosis Collaborative Group of the Neurology Branch of the Chinese Medical Association

• Member of the Neuroimmunology Branch of the Chinese Society of Neuroscience

• Member of the Nervous System Rare Diseases Professional Committee of the China Rare Disease Alliance

• successively undertakes one key research and development project of "precision medicine" in the 13th Five-Year Plan, 2 projects on the National Natural Surface, published SCI papers nearly 50 articles

Expert comments

Comments by Professor Yuwei Comprehensive analysis and interpretation of data on efgartigimod's treatment of serum AChR-ab-negative systemic MG in the ADAPT/ADAPT+ study:

is the first and only FDA-approved antagonist of FcRn (negative Fc receptor) in the global phase III clinical study of systemic MG. The positive results of ADAPT in Efgartigimod's treatment of systemic MG are impressive, including 38 AChR-ab-negative patients. Given the poor efficacy of currently recognized antibody double-negative MG patients, the efficacy of efgartigimod in such patients has attracted particular attention. ADAPT/ADAPT+ comprehensive interim analysis data showed that 18 AChR-Ab- patients who received placebo in the ADAPT study entered the ADAPT+ study, with 87.9%-35.1% of patients improving MG-ADL scores ≥2 to 7 points, and 86.5%-27.0% of patients improving QMG scores ≥3 to 9 points, and this trend of improvement persisted for at least 7 treatment cycles. Another report showed that all AChR-Ab- patients who entered the ADAPT+ study continued to benefit in multiple repeated treatment cycles after using efgartigimod and more patients received improved scores. The above research results laid the foundation for the efficacy and status of efgartigimod in the treatment of AChR-ab-negative GMG.

At present, the treatment options for patients with AChR-Ab-systemic myasthenia gravis are still limited

Patients with different MG subtypes have different effects on immunotherapy responses. T Akaishi et al. ³ divided 923 MG patients into 5 subtypes through two-step clustering analysis: ocular muscle type MG (OMG), thymoma -related MG, MG with thymic hyperplasia, AChR-Ab-negative MG and AChR-Ab-positive MG without thymic abnormality. The results showed that OMG patients had the best early response and improved status stability to immunotherapy, followed by thymoma-associated MG and athymic abnormalities AChR-Ab-positive MG; in comparison, patients with AChR-Ab-negative MG had the worst stability to early response and improved status, and patients with MuSK antibody-positive MG had better results despite more severe symptoms and systemic weakness, which indicated that patients with AChR-Ab-negative MG (excluding MuSK antibody-positive MG) were different from patients with other systemic MG subtypes from the perspective of treatment response. In addition, studies have confirmed that MuSK antibody positive and antibody double-negative MG are related to poor efficacy ⁴. And some research data analysis showed that about 80% of sero-negative patients did not respond to existing immunotherapy drugs ⁵. It can be seen that the current treatment options for for patients with AChR-Ab-systemic myasthenia gravis (gMG) are still limited.

ADAPT study shows that Efgartigimod has good safety and tolerance in treating gMG patients

Efgartigimod as a targeted biological agent that directly hits the pathogenic core of MG, becoming the first and currently the only FDA-approved FcRn (neonatal Fc receptor) antagonist. Efgartigimod is a human IgG1-derived Fc fragment that binds to FcRn at near neutral and acidic pH, and its affinity to FcRn is higher than that of endogenous IgG and FcRn, thereby competing with IgG to bind FcRn, so that more IgG is degraded by lysosomes ⁶. The approval of

Efgartigimod is based on the results of ADAPT, a global phase III clinical study. The results were published in the journal Lancet Neurology in July 2021. ADAPT study ⁷ is a multicenter, double-blind , randomized, placebo-controlled, 26-week phase III clinical study , aiming to evaluate the efficacy and safety of efgartigimod in patients with gMG. The study included 167 adult patients with (some AChR-Ab negative) , and patients were randomly assigned to receive 10 mg/kg intravenous infusion of efgartigimod or placebo in a 1:1 ratio for a total of 26 weeks of treatment. The main endpoint of the study was the proportion of patients who achieved MG-ADL response (at least 2 points from baseline improvement in 4 consecutive weeks or more) in AChR-ab+ patients in the first treatment cycle. The results of the study show that efgartigimod treats AChR antibody-positive gMG patients with gMG can bring significant and rapid clinical benefits, with good safety and tolerance.

2022 AANEM Conference came to a successful conclusion, and efgartigimod once again attracted high attention

On September 21, 2022, the 2022 American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting (AANEM AM) was held as scheduled in Nashville, Tennessee, USA and ended successfully on September 24. Many valuable and guiding academic research results were published at the meeting. As the world's first and currently the only FcRn antagonist approved for the treatment of gMG, efgartigimod once again attracted high attention. Following the first "unveiling" of the ADAPT+ research results in April this year, this conference released ADAPT/ADAPT+ comprehensive interim analysis data. So, what are the research results and what kind of inspiration will it bring to us? 91% of patients (n=151) in the

ADAPT study entered the open label extension study of ADAPT+, which lasted for 3 years and was designed to evaluate the long-term safety, tolerability and effectiveness of efgartigimod in patients with gMG. The patient received 10 mg/kg intravenous efgartigimod (EFG) once a week for 4 weeks, with subsequent cycles initiated according to predefined criteria. The efficacy of each cycle was evaluated using MG-ADL and myasthenia gravis quantitative score sheet (QMG) (Figure 1).

Figure 1

A total of two comprehensive interim analysis summary of ADAPT/ADAPT+ were published at this conference.

The first abstract analyzed data from 37 AChR-Ab- patients (including 5 MuSK-Ab+ patients) who received ≥1 dose of efgartigimod as of October 2020 (median follow-up of 453 days) ⁸.

Previously, 38 patients were AChR-Ab-patients (19 in the efgartigimod group and 19 in the placebo group). During the first treatment cycle, 68.4% and 63.2% responders who received efgartigimod and placebo were employed in 68.4% and 63.2% responders who reached MG-ADL (improvement ≥2 points) and 52.6% and 36.8% responders who reached QMG (improvement ≥3 points from baseline for 4 consecutive weeks or more) were employed in 52.6% and 36.8% responders, respectively. Some of the above patients were admitted to the ADAPT+ study and all of them received efgartigimod treatment.

Among these patients, whether in the efgartigimod group or the placebo group in the ADAPT study, only 18 AChR-Ab- patients who received placebo in the ADAPT study were included in the 37 patients who received placebo in the ADAPT study. The results showed that during the first treatment cycle, these patients continued to benefit from efgartigimod treatment. 35.1%-87.9% of patients had improved MG-ADL scores of ≥7 to 2 points, and 27.0%-86.5% of patients had improved QMG scores of ≥9 to 3 points. And the improvement of similar trends in the two scores continued to exist for at least 7 treatment cycles, demonstrating that the efficacy of efgartigimod treatment was good.In the ADAPT+ study released at the AAN meeting in April 2022, the interim results of the AChR-Ab+ population were ⁹. During the 1-5th treatment cycle, 38.9%-85.9% of patients improved MG-ADL scores from baseline to 2 points, and 16.0%-63.6% of patients improved QMG scores from ≥9 to 3 points. It can be seen that the MG-ADL score and QMG score improve in multiple cycles after AChR-Ab+ and Ab- patients treated with efgartigimod.

and the second abstract describes the data of the continuing ADAPT+ study from the deadline for the previous abstract data, after October 2020 and until February 2022, 34 AChR-Ab- patients (including 4 MuSK-Ab+ patients) who received at least one dose of efgartigimod, ¹⁰.

mentioned earlier that in the ADAPT study, there was no significant difference in the proportion of patients with MG-ADL response during the first treatment cycle between the efgartigimod group and the placebo group. In addition, the MG-ADL scores of 0%-63.2% of patients treated with placebo improved from baseline to 9 points to 2 points in week 3 of the first treatment cycle, and the QMG scores of 15.8%-47.4% of patients improved from baseline to 8 points to 3 points. However, these patients still benefited by starting treatment with efgartigimod after entering the ADAPT+ study. At week 3 of the 1st treatment cycle in the ADAPT+ study, AChR-Ab- patients (including 18 patients who received placebo in the ADAPT study) had mean changes in baseline scores (± standard error ) to –5.3 (0.74, MG-ADL) and –5.2 (0.74, QMG). Compared with ADAPT+ baseline, more patients received improvement in scores. The MG-ADL score in 23.5%-79.4% of patients improved by ≥9 points to ≥2 points from baseline; the QMG score in 27.3%-63.6% of patients improved by ≥8 points to 3 points from baseline.

showed similar improvements in the 10 repeated treatment cycles experienced, especially in AChR-Ab- patients who used placebo in the ADAPT study and efgartigimod in the ADAPT+ study, which had clinically meaningful improvements in multiple treatment cycles. During the 10 treatment cycles experienced, the proportion of patients who achieved meaningful improvement in MG-ADL in this part of the patients was 86.1%, and the median 16.7% of patients achieved MG-ADL improvement of more than 10 points (Figure 2).

Figure 2

simultaneous efgartigimod long-term treatment is well tolerated, which is similar to the incidence of adverse events in the ADAPT study, and there are no new safety problems (Figure 3).

Figure 3

The above research results confirm that in a long-term clinical research environment, Efgartigimod treatment is related to clinically meaningful improvement of AChR-Ab-patient efficacy evaluation score.

is constantly breaking through innovation, and Efgartigimod may open the "other window" of AChR-Ab-systemic myasthenia gravis patients

Most myasthenia gravis patients are AChR-ab+, MuSK-ab+ or LRP4-ab+, and the pathogenic mechanism of this type of patients is now clear. However, the pathological mechanism of MG in sero-negative patients is not yet clear. Some literature believes that these sero-negative patients may still be caused by antibodies. However, the affinity or concentration of the antibody is too low to detect, or the relevant antigen has not been defined ¹¹. Existing detection methods may affect the detection effect. Moreover, due to the diffusion of epitope or the increased sensitivity of detection methods, repeated tests may also be diagnosed and corrected ¹². Moreover, the new serological diagnostic methods also improve detection sensitivity. For example, the research results published at this year's MGFA (Myasthenia Gravis Foundation of American) International Conference showed that among the 44 negative serums, L-CBA (living cell CBA) can detect 14 of the serum antibodies positive, and F-CBA (fixed cell CBA) can detect 9 of the serum antibodies positive. Therefore, the cause of MG in sero-negative patients with 13 may still be related to antibodies.

can also reflect the outcome of drug treatment. Serum-negative patients are mainly mediated by antibodies. A study analyzed data from 58 patients with MG who had been continuously treated with PE (plasma replacement) to evaluate the responses to PE in MG patients with or without AChR or MuSK autoantibodies . Results showed that sero-negative patients accounted for 12% of the patients in the study. All MG patients responded to PE at 96%, however, only patients with gender and late-onset MG were significantly associated with treatment response.In addition, all sero-negative patients in the study responded to PE. There was no significant difference in the responses of seropositive and serone negative patients to treatment with PE clearance antibodies ¹⁴.

On the other hand, the results of the recent secondary analysis of efgartigimod in the treatment of pemphigus revealed that efgartigimod not only blocks the binding of FcRn to pathogenic IgG and promotes its dissolution; it also has other immune regulatory functions, which is conducive to restoring immune homeostasis ¹⁵. This also increases confidence in the future research on the effects of efgartigimod's other immune .

MG seriously affects patients' life, health and quality of life. Finding better treatment drugs and solutions and improving the quality of life of MG patients has always been the direction of exploration that experts and scholars in the field of MG have been striving to explore. Efgartigimod directly blocks the binding of pathogenic antibodies to FcRn. Although the evidence for efficacy in AChR-Ab-patients is still limited, we believe that with the continuous emergence of high-quality clinical research and evidence-based medical evidence, efgartigimod will bring greater breakthroughs, and the "spring" for patients with AChR-Ab-systemic myasthenia gravis will eventually arrive.

ZMCNNP20221117006 Expire Date 2023/11/17

References:

.T Akaishi, Y Suzuki, T Imai, et al. BMC Neurol. 2016;16(1):225.

9.J F Howard Jr, V Bril, T Vu, et al. Neurology. 2022;98(18_suppl):S25.004.