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Generalized myasthenia gravis (gMG) is a rare chronic autoimmune disease that can affect eye movement, swallowing, speech, movement, and respiratory function to varying degrees, severely impairing mobility and quality of life1
.
There is no consensus on the ideal regimen for myasthenia gravis (MG), and most patients with MG require induction therapy with high-dose glucocorticoids, but multiple side effects following long-term oral corticosteroids are a major problem2, especially in adolescents who are particularly prone to hormonal side effects1
。 Therefore, how to avoid serious side effects and better treat adolescent gMG has become a problem
.
At the recent 2022 Annual Meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), the newly published conference abstract presented new options
for the treatment of adolescent gMG.
Traditional treatment of adolescents with MG is prone to side effects, and the treatment and prognosis are not optimistic
MG is caused by antibodies that target neuromuscular junctions, most commonly acetylcholine receptors (AChR), which can cause extraocular and/or generalized skeletal muscle weakness and fatigue1 and 2
.
In China, more than half of MG patients initially develop symptoms in childhood3
.
Long-term treatment for MG patients typically includes glucocorticoids and immunosuppressants (IS)4,5, however, about 20-35% of MG patients are insensitive to hormone therapy6
.
。 Adolescent patients with gMG urgently need alternative treatments
with more satisfactory efficacy and fewer adverse effects for long-term use.
Study 6 found that patients with CMG had low improvement rates and high
rates of exacerbations and exacerbations after following up 424 patients with CMG for at least 5 years.
Therefore, treatment should not be stopped prematurely after the patient has achieved a completely stable remission
.
The long-term prognosis of adolescents is a major concern, and more research is needed to better manage symptoms
.
Biologics are becoming an important therapeutic tool, promising to provide better results than standard treatments and even induce symptom relief, while efgartigimod that depletes antibodies has been shown to be effective
in multiple phase studies.
The increased availability of new biologics offers opportunities to target immunotherapies and develop more specific therapies2
.
The ADAPT and ADAPT+ studies have shown that efgartigimod has a good safety and tolerability in adult patients with gMG
Efgartigimod is a human IgG1 antibody Fc fragment that blocks the neonatal Fc receptor (FcRn), thereby reducing pathogenic IgG autoantibody levels
.
The approval of Efgartigimod is based on the results of the global Phase III clinical study ADAPT, which was published in Lancet in July 2021
in
the journal Neurology.
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 current data are from the results
of 145 studies that received at least one treatment cycle efgartigimod as of January 31, 2022.
The results showed that 88.
7% of patients with a median of 88.
7% of AChR-Ab-positive patients received a clinically meaningful improvement in MG-ADL over 10 treatment cycles, and a median of 25.
3% achieved a ≥9 point improvement in MG-ADL score
.
A similar trend was observed in QMG score improvement, with a median of 64.
4% of patients achieving a clinically meaningful improvement in QMG over 7 treatment cycles, and a median of 16.
0% achieving a ≥9 point improvement in QMG score over 7 treatment cycles (Figure 2).
Simultaneous multi-cycle data showed reproducible efficacy (Figure 3).
Figure 1 ADAPT and ADAPT+ study design Figure 2 Interim Results of the ADAPT+ Study Show Clinically Meaningful Improvement with Multiple Cycles of MG-ADL and QMG Figure 3 In the ADAPT+ study, improvements in MG-ADL and QMG were reproducible across multiple treatment cycles
Overall, efgartigimod, as the world's first FcRn antagonist, can safely and rapidly remove pathological IgG antibodies in the body through its unique mechanism of action, thus becoming a novel therapeutic drug for highly targeted IgG antibodies for antibody-mediated autoimmune diseases.
The ADAPT study shows that efgartigimod has good efficacy and safety in the treatment of adult gMG, which provides important evidence-based medical support
for the treatment of adult gMG.
efgartigimod is a novel targeted biologic
suitable for clinical application that is effective, well tolerated overall, and satisfies individualized dosing (selection of treatment cycles based on the patient's response to drugs).
The ADAPT study evaluated the safety and efficacy of efgartigimod in adult gMG patients, but what about the efficacy and safety of efgartigimod for adolescents with gMG?
An efgartigimod study at the AANEM congress is currently being presented in adolescent gMG patients, raising concerns
The AANEM conference also presented the study design
for the use of efgartigimod in the treatment of adolescent gMG patients.
This was an open-label, multicentre, uncontrolled phase II/III study to determine the dose of efgartigimod intravenously given to adolescents of different ages and the evidence
for model prediction of treatment response.
The study will enroll 12 patients aged 2 to 17 years who have been diagnosed with gMG and are in the MGFA
Type II, III, or IVa and are positive for AChR-Ab antibodies and in treatment with a stable background
.
: A and B.
Part A is a dose-confirmation study for a total of 6 weeks
.
Participants were divided into groups aged 2 to 11 years (6) and 12 to 18 years (6).
Follow-up was 5 weeks
after an intravenous infusion of one dose of efgartigimod in the first week of Phase A.
Data from six patients in the 12- to 18-year-old age group will be used to build a PK/PD model to predict the dose
of efgartigimod used in the 2-11 year-old age group.
Subsequently, the 2-11 age group is recruited into Phase
A.
After completing stage A in each group, they will enter the phase B treatment response confirmation stage for a total of 18 weeks
.
Weekly intravenous efgartigimod infusions are given for the first four weeks of Phase B, followed for four weeks
.
After 4 weeks of follow-up, the doctor determines whether the patient needs to undergo the next treatment cycle
.
Stage B patients receive up to 2 cycles
of treatment.
After completing Phase B, the long-term security expansion study AGRX-113-2008 (Figure 4)
was entered.
The primary endpoints of the study are the concentration of efgartigimod for the analysis of clearance and volume of distribution in pharmacokinetics, as well as the analysis of total IgG levels and anti-AChR antibody levels
in pharmacodynamics.
Secondary endpoints were assessment of safety, tolerability, immunogenicity, and efficacy
.
Figure 4 Evaluation of efgartigimod study design in adolescents with gMG
ADAPT is a phase III study of adult gMG, and the results confirm that efgartigimod is effective and well tolerated in adult gMG patients, but further observationis needed on the efficacy and safety of efgartigimod in adolescents with gMG.
The unique design of the study above will provide data to support PK/PD modeling during the study to confirm age-appropriate doses and evaluate the efficacy and safety
of efgartigimod in adolescent gMG patients.
The results of this study will hopefully bring new options for the treatment of adolescent gMG and provide new hope for adolescent patients!
Expert profiles
Professor Zhangyu Zou
Member of the Myogram and Clinical Neurophysiology Group of the Neurology Branch of the Chinese Medical Association
Member of the Peripheral Neuropathy Collaborative Group of the Neurology Branch of the Chinese Medical Association
Secretary of the Amyotrophic Lateral Sclerosis Collaborative Group of the Neurology Branch of the Chinese Medical Association
Vice Chairman of the Neuroscience Professional Committee of the Chinese Research Hospital Association
Member and Secretary of the Nervous System Rare Disease Professional Committee of the China Alliance for Rare Diseases
Member of the Rare Disease Professional Committee of the Chinese Hospital Association
Member of the Standing Committee of the Neurodegenerative Disease Professional Committee of the Chinese Society of Microcirculation, Frontotemporal Dementia and Related Diseases
He is a standing member of the Frontotemporal Dementia and Related Diseases Professional Committee of Beijing Neurodegenerative Disease Professional Committee
Member of the Standing Committee of the Rare Disease Rehabilitation Professional Committee of the China Association for the Rehabilitation of the Disabled
Member of Neurology Branch of Fujian Medical Association, Deputy Head of Peripheral Neuropathy and Neuroelectrophysiology Group
Member of Rare Disease Branch of Fujian Medical Association
Vice Chairman of the Youth Committee of Medical Genetics Branch of Fujian Medical Association
Member of the Standing Committee of the Neurology Branch of Fujian Strait Medical and Health Exchange Association, leader of the Neurodegenerative Group
Expert reviews
Compared with adult MG patients, adolescent systemic MG patients are more likely to develop steroid resistance, are more likely to relapse, and have serious adverse drug reactions in long-term immunotherapy, so there is an urgent need for long-term use of alternative treatments
with more satisfactory efficacy and less adverse effects.
Efgartigimod blocks the neonatal Fc receptor, thereby reducing the level of
pathogenic IgG autoantibodies.
The ADAPT study showed that efgartigimod has good efficacy and safety in the treatment of adult systemic MG, but there is no evidence-based medical evidence
for the efficacy and safety of systemic MG in adolescents.
A study design of efgartigimod in adolescents with systemic MG was presented at the 2022 AANEM Congress to confirm age-appropriate doses and evaluate efficacy and safety
.
The results of the study will lead to new options
for the treatment of systemic MG in adolescents.
ZMCNNP20221123005 Expire Date 2023/11/23
References:
1.
D B Sanders, G I Wolfe, M Benatar, et al.
Neurology.
2016; 87(4):419-25.
2.
M C Dalakas.
Nat Rev Neurol.
2019; 15(2):113-24.
3.
C Liu, M Gui, Y Cao, et al.
Pediatr Neurol.
2017; 77:42-7.
4.
H Yoshikawa, T Kiuchi, T Saida, et al.
J Neurol Neurosurg Psychiatry.
2011; 82(9):970-7.
5.
J Morren, Y Li.
J Neurol Sci.
2022; 410:116648.
6.
M Gui, X Luo, J Lin, et al.
J Neurol.
2015; 262(4):823-30.
7.
J F Howard Jr, V Bril, T Vu, et al.
Lancet Neurol.
2021; 20(7):526-36.
8.
J F Howard Jr, V Bril, T Vu, et al.
Long-Term Safety, Tolerability, and Efficacy of Efgartigimod in Patients With Generalized Myasthenia Gravis: Interim Results of the ADAPT+ Study.
2022 AANEM, Poster #108.
9.
N L Kuntz, A Bogatyreva, A Bogatyreva, et al.
Study Design of Intravenous Efgartigimod in Children With Generalized Myasthenia Gravis.
2022 AANEM, Poster #203.
NCT04833894.
Past Review
☑ Is there also benefit in patients with seronegative myasthenia gravis? One of the 2022 AANEM Essentials Hot Review Series
☑ Expert Comment/Efgartigimod can coexist with the body defense of patients with generalized myasthenia gravis! ——2022 AANEM Essence Hot Review Series No.
2
☑ Patients can use efgartigimod early and seek greater benefits! 2022 AANEM Essence Hot Review No.
3
