 Home > Active Ingredient News > Study of Nervous System > Is there also benefit in patients with seronegative myasthenia gravis? One of the 2022 AANEM Essentials Hot Review Series

Is there also benefit in patients with seronegative myasthenia gravis? One of the 2022 AANEM Essentials Hot Review Series

 Last Update: 2023-01-06
 Source: Internet
 Author: User

Tags

11 year old workout plan

otc definition medical

Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

Guide

MG (myasthenia gravis) is an antibody-mediated autoimmune disease, acetylcholine receptor (AChR) antibodies are the most common pathogenic antibodies, AChR antibodies are present in about 85% of patients, MuSK (muscle-specific receptor tyrosine kinase) antibodies are present in about 5% of patients, and LRP4 (low-density lipoprotein receptor-associated protein 4) antibodies
are present in about 1-5% of patients.
In addition, there are patients in whom these antibodies are not detected in the serum and are called seronegative MG^1,2
.
The clinical manifestations of MG are extremely heterogeneous, and the subgroup classification based on serum antibodies and clinical features has important guiding significance for the individualized treatment and prognosis assessment of ^MG2
.

Expert profiles

Professor Yuwei Di

Chief physician, professor, doctoral supervisor
Director of the Department of Neurology, Xuanwu Hospital, Capital Medical University
He is currently a member of the Neuromuscular Disease Group of the Neurology Branch of the Chinese Medical Association
Member of the National Peripheral Neurology Standardized Diagnosis and Treatment Training Center and director of the sub-center of the Neurology Branch of the Chinese Medical Association
Member of the Collaborative Group of Amyotrophic Lateral Sclerosis of the Neurology Branch of the Chinese Medical Association
Member of Neuroimmunology Branch of Chinese Society of Neuroscience
Member of the Nervous System Rare Disease Professional Committee of the China Alliance for Rare Diseases
He has undertaken 1 key R&D project of "precision medicine" in the 13th Five-Year Plan, 2 projects of national nature, and published nearly 50 SCI papers

Expert reviews

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

As the first and currently the only FDA-approved FcRn (Neonatal Fc Receptor) antagonist, Efgartigimod has yielded impressive positive results in the global phase III clinical study ADAPT, including 38 AChR-ab-negative patients
.
Given the currently recognized poor efficacy in patients with antibody double-negative MG, the efficacy of efgartigimod in these patients is of particular concern
.
The data from the ADAPT/ADAPT+ comprehensive interim analysis showed that 18 AChR-Ab- patients who received placebo in the ADAPT study entered the ADAPT+ study, 87.
9% to 35.
1% of patients improved their MG-ADL scores by ≥ 2 to 7 points, and 86.
5% to 27.
0% of patients improved their QMG scores by ≥ 3 to 9 points, and this improvement trend continued
for at least 7 treatment cycles 。 Another report showed that AChR-Ab- patients, all enrolled in the ADAPT+ study, continued to benefit from efgartigimod over multiple repeat treatment cycles, and more patients experienced improved
scores.
The above results have established the efficacy and status
of efgartigimod in the treatment of AChR-ab-negative GMG.

Currently, treatment options for patients with AChR-Ab-generalized myasthenia gravis remain limited

Patients with different MG subtypes have different responses to immunotherapy
.
T Akaishi et ^{al.
3} divided 923 MG patients into five subtypes through two-step cluster analysis: ophthalmomyotype MG (OMG), thymoma-associated MG, MG with thymic hyperplasia, AChR-Ab-negative MG and AChR-Ab-positive MG
without thymic abnormalities 。 The results showed that patients with OMG had the best stability in early response to immunotherapy and improved status, followed by thymoma-associated MG and AChR-Ab-positive MG without thymic abnormalities; In contrast, patients with AChR-Ab-negative MG had the worst stability in early response to treatment and improved status, and MuSK antibody-positive MG patients had better outcomes despite more severe symptoms and general weakness, suggesting that AChR-Ab-negative MG (excluding MuSK antibody-positive MG) patients differed
from other systemic MG subtypes from a treatment response perspective.
In addition, MuSK antibody positive and antibody double-negative MG have been shown to be associated with poor ^efficacy4
.
Data analysis has shown that about 80% of seronegative patients do not respond to existing immunotherapy ^drugs5
.
It can be seen that the current treatment options for patients with AChR-Ab-generalized myasthenia gravis (gMG) are still limited
.

The ADAPT study showed that Efgartigimod was both safe and tolerated in patients with gMG

Efgartigimod emerged as a targeted biologic that directly targets 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 with FcRn is higher than that of endogenous IgG and FcRn, thereby competitively binding to FcRn with IgG, so that more IgG is degraded by lysosomes6
.
The approval of Efgartigimod is based on the results of the global phase III clinical study ADAPT, which was 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 to evaluate the efficacy and safety
of efgartigimod in patients with gMG 。 The study included 167 adult patients (some AChR-Ab negative) who were randomized 1:1 to receive 10 mg/kg intravenous efgartigimod or placebo for 26 weeks, with the primary endpoint being the proportion of
patients who achieved MG-ADL response (at least 2 points improvement from baseline for 4 or more consecutive weeks) in patients with AChR-ab+ in the first treatment cycle 。 The results showed that efgartigimod treatment of AChR antibody-positive gMG patients brought significant and rapid clinical benefit, with good safety and tolerability
.

The 2022 AANEM Conference ended successfully, and efgartigimod once again attracted high attention

September 21, 2022: The American Association of Neuromuscular & Electrodiagnostic Medicine Annual Meeting (AANEM AM) was held in Nashville, Tennessee, as scheduled and concluded
successfully on September 24 。 Many valuable and guiding academic research results were published at the conference, and efgartigimod, as the world's first and currently the only approved FcRn antagonist for the treatment of gMG, once again attracted high attention
.
Following the first "unveiling" of the results of the ADAPT+ study in April this year, the conference released the ADAPT/ADAPT+ comprehensive interim analysis data
.
So, what are the results of the study and what will they tell us? 91% of patients (n=151) in the ADAPT study were enrolled in the ADAPT+ open-label extension study, which was conducted over a 3-year period to evaluate the long-term safety, tolerability, and efficacy
of efgartigimod in patients with gMG.
Patients received 10 mg/kg intravenous efgartigimod (EFG) once a week for 4 weeks, and subsequent cycles were initiated
according to predefined criteria.
The efficacy of each cycle was evaluated using MG-ADL and a quantitative scale for myasthenia gravis (QMG) (Figure 1).

Figure 1

A total of two comprehensive
interim analysis abstracts of ADAPT/ADAPT+ were published.
The first abstract analyzes data (median follow-up 453 days) from 37 AChR-Ab- patients (including 5 MuSK-Ab+ patients) who received ≥ 1 dose of efgartigimod in the ADAPT/ADAPT+ study as of October 20208
.
A total of 38 patients in previous ADAPT studies were AChR-Ab- patients (19 in the efgartigimod group and 19 in the placebo group).

In the first treatment cycle, 68.
4% and 63.
2% of patients treated with efgartigimod and placebo achieved MG-ADL (improvement ≥2 points) and 52.
6% and 36.
8%
of those who achieved QMG (at least ≥3 points from baseline) for 4 or more consecutive weeks.
Some of these patients entered the ADAPT+ study and all received efgartigimod
.
Of these patients, whether in the efgartigimod or placebo groups in the ADAPT study, only 18 AChR-Ab- patients who received placebo in the ADAPT study were included out of the 37 patients
in this comprehensive analysis.
The results showed that these patients continued to benefit
from efgartigimod treatment during the first treatment cycle.
MG-ADL scores improved by ≥ 7 to 2 points in 35.
1% to 87.
9% of patients, and QMG scores improved by ≥ 9 to 3 points in 27.
0% to 86.
5
% of patients.
Similar trends in both scores persisted over at least 7 treatment cycles, demonstrating good reproducibility of treatment with efgartigimod
.
In the ADAPT+ study presented at the AAN meeting in April 2022, the interim results of the AChR-Ab+ ^population9, in the 1st to 5th treatment cycles, 38.
9%-85.
9% of patients improved their MG-ADL scores by ≥ 7 points to 2 points from baseline, and 16.
0%-63.
6% of patients improved their QMG scores by ≥9 to 3 points
。 It can be seen that the MG-ADL score and QMG score improvement trend in multiple cycles after treatment with efgartigimod in AChR-Ab+ and Ab- patients
.
The second abstract describes data from the ongoing ADAPT+ study on 34 AChR-Ab- patients (including 4 MuSK-Ab+ patients) who received at least one dose of efgartigimod from the previous abstract data cut-off date of October 2020 until February 202210
。 As mentioned earlier, in the ADAPT study, there was no significant difference
in the proportion of patients responding to MG-ADL in the first treatment cycle between the efgartigimod group and the placebo group in the AChR-Ab- patient.
AChR-Ab- patients treated with placebo had MG-ADL scores of 0% to 63.
2% from baseline improvement of ≥ 9 to 2 points from baseline in week 3 of the first treatment cycle, and QMG scores of 15.
8% to 47.
4% from baseline improved by ≥8 to 3 points from baseline
.
However, these patients who entered the ADAPT+ study were still able to benefit
from treatment with efgartigimod.
At week 3 of cycle 1 in the ADAPT+ study, AChR-Ab- patients (including 18 patients who received placebo in the ADAPT study) changed from baseline score mean (± standard error) to –5.
3 (0.
74, MG-ADL) and –5.
2 (0.
74, QMG).

Compared with the ADAPT+ baseline, more patients had improved scores, and 23.
5%-79.
4% of patients had MG-ADL scores improved by ≥9 to ≥2 points from baseline.
QMG scores improved ≥ 8 to 3 points from baseline in 27.
3% to 63.
6
% of patients.
Similar improvements were seen over 10 repeat treatment cycles, particularly in AChR-Ab- patients who used placebo in the ADAPT study and efgartigimod in the ADAPT+ study, with clinically meaningful improvements
across multiple treatment cycles.
Over the 10 treatment cycles experienced, the median proportion of patients who achieved meaningful improvement in MG-ADL was 86.
1%, and the median 16.
7% achieved MG-ADL improvement of more than 10 points (Figure 2).

Figure 2

At the same time, efgartigimod was well tolerated with long-term treatment, similar to the adverse event rate in the ADAPT study, and there were no new safety issues (Figure 3).

Figure 3

The above results confirm that Efgartigimod therapy is associated with
clinically meaningful improvement in AChR-Ab-patient efficacy assessment scores in long-term clinical study settings.

Continuous breakthrough and innovation, Efgartigimod may open another window for patients with AChR-Ab-generalized myasthenia gravis

Most patients with myasthenia gravis are AChR-ab+, MuSK-ab+, or LRP4-ab+, and the pathogenesis in these patients is well understood
.
However, the pathological mechanism of MG in seronegative patients is not well understood
.
It has been suggested that these seronegative patients may still be mediated by antibodies
.
However, the affinity or concentration of the antibody is too low to detect, or the relevant antigen has not been ^defined11
.
Existing detection methods may affect the effectiveness
of the test.
Furthermore, in some patients, repeat testing may be diagnosed due to epitope diffusion or increased sensitivity of detection ^methods12
.
New serological diagnostic methods have also improved detection sensitivity
.
For example, the results presented at this year's MGFA (Myasthenia Gravis Foundation of America) international conference showed that live-cell and fixed-cell-based testing (CBA) In 44 negative serums, L-CBA (live-cell CBA) can detect 14 of them as positive for serum antibodies, and F-CBA (fixed cell CBA) can detect 9 of them as positive for serum antibodies ¹³
。 Therefore, the cause of MG in seronegative patients may still be related to
antibodies.
The outcome of pharmacotherapy also reflects that seronegative patients are still mainly mediated
by antibodies.
Data from 58 MG patients who received continuous PE (plasmapheresis) therapy were analyzed to assess response to PE in MG patients with or without AChR or MuSK autoantibodies
.
The results showed that seronegative patients accounted for 12% of the study's
patients.
The response rate to PE was 96% in all patients with MG, however, only patient sex and late-onset MG were significantly associated
with treatment response.
In addition, all seronegative patients in the study responded
to PE.
There was no significant difference in response to treatment with PE-clearing antibodies between seropositive and seronegative ^patients14
.
On the other hand, the results of the recent secondary analysis of efgartigimod in the treatment of pemphigus in the phase II study revealed that efgartigimod can not only block the binding of FcRn to pathogenic IgG, but also promote its dissolution; It also has other immunomodulatory functions, which are conducive to restoring immune homeostasis15
.
This also gives confidence
to future research into efgartigimod's other immune effects.
MG seriously affects the life and health and quality of life of patients, and finding better therapeutic drugs and programs to improve the quality of life of MG patients has always been the direction
of exploration of experts and scholars in the field of MG.
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 emergence of high-quality clinical studies and evidence-based medical evidence, efgartigimod will bring more breakthroughs, and the "spring" of AChR-Ab-generalized myasthenia gravis patients will finally arrive
.
ZMCNNP20221117006 Expire Date 2023/11/17

References:

1.
A Behin, R L Panse.
J Neuromuscul Dis.
2018; 5(3):265-77.

2.
Neuroimmunology Branch of Chinese Society of Immunology.
Chinese Journal of Neuroimmunology and Neurology.
2021; 28(1):1-12.
3.
T Akaishi, Y Suzuki, T Imai, et al.
BMC Neurol.
2016; 16(1):225.
4.
J Suh, J M Goldstein, R J Nowak, et al.
Yale J Biol Med.
2013; 86(2):255-60.
5.
E Cortés-Vicente, R Álvarez-Velasco, S Segovia, et al.
Neurology.
2020; 94(11):e1171-80.
6.
J D Lünemann.
Nat Rev Neurol.
2021; 17(10):597-8.
7.
J F Howard Jr, V Bril, T Vu, et al.
Lancet Neurol.
2021; 20(7): 526-36.
8.
T Vu, V Bril, C Karam, et al.
AANEM Abstract Guide.
2022; 56:105.
9.
J F Howard Jr, V Bril, T Vu, et al.
Neurology.
2022; 98(18_suppl):S25.
004.
10.
T Papsdorf, J Durrani, D Gelinas, et al.
AANEM Abstract Guide.
2022; 143:MGFA-33.
11.
G I Wolfe, E S Ward, H Haard, et al.
J Neurol Sci.
2021; 430:118074.
12.
N E Gilhus, G O Skeie, F Romi, et al.
Nat Rev Neurol.
2016; 12(5):259-68.
13.
G Spagni, G Monte, Z Chemkhi, et al.
Muscle & Nerve.
2022; 65(S1):S21.
14.
A Usmani, L Kwan, D Wahib-Khalil, et al.
J Clin Apher.
2019; 34(4):416-22.
15.
M Goebeler, Z Bata-Csörgő, C D Simone, et al.
Br J Dermatol.
2022; 186(3):429-39.

This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.