Evaluation of Long-Term Safety and Efficacy of Efgartigimod in Japanese Patients with Myasthenia Gravis
This study evaluates the long-term safety and efficacy of efgartigimod in Japanese patients with generalized myasthenia gravis. The mechanism of action of efgartigimod, study design, and disclosures are discussed.
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Evaluation of the Long-Term Safety and Efficacy of Efgartigimod in Japanese Patients With Generalized Myasthenia Gravis Masayuki Masuda,1Hiroyuki Murai,2Yasushi Suzuki,3Shingo Konno,4Makoto Samukawa,5Takamichi Sugimoto,6Daisuke Yamamoto,7Antonio Guglietta,8Peter Ulrichts,8Caroline T joen,8Tomohiro Imai,9Masanori Takahashi,10Akiyuki Uzawa,11 Kimiaki Utsugisawa,12 for the ADAPT Investigator Study Group 1Tokyo Medical University, 2International University of Health and Welfare, 3Sendai Medical Center, 4Toho University Ohashi Hospital Medical Center, 5Kindai University Hospital, 6Hiroshima University, 7Sapporo Medical University Hospital, 8argenx, 9Hakone Hospital, 10Osaka University Hospital, 11Chiba University, 12Hanamaki General Hospital 1
Disclosures Disclosures The phase 3 ADAPT and ADAPT+ studies were funded by argenx The Japanese Society of Neurology (JSN) COI Disclosure Name of Lead Presenter Masayuki Masuda There are no companies, etc. in a conflict of interest requiring disclosure in relation to the presentation 2
Efgartigimod Mechanism of Action: Blocking FcRn Efgartigimod Mechanism of Action: Blocking FcRn FcRn recycles IgG, extending its half-life and serum concentration1 Endothelial Cell Blood Vessel Efgartigimod is a human IgG1 Fc fragment, a natural ligand of FcRn, engineered for increased affinity to FcRn2 Endosome Endothelium Efgartigimod was designed to outcompete endogenous IgG, preventing recycling, and promoting lysosomal degradation of IgG, without impacting its production2-5 Targeted reduction of all IgG subtypes No impact on IgM or IgA No reduction in albumin levels No increase in cholesterol Lysosome IgG IgG FcRn Efgartigimod (Fc Fragment) Image adapted from Kang TH, Jung ST. Exp Mol Med. 2019;51(11):1-9. Autoantibody Antibody FC, crystallizable fragment; FcRn, neonatal Fc receptor; gMG, generalized myasthenia gravis; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M. 1. Sesarman A, et al. Cell Mol Life Sci. 2010;67(15):2533-2550. 2. Ulrichts P, et al. J Clin Invest. 2018;128(10):4372-4386. 3. Vaccaro C, et al. Nat Biotech. 2005;23(10):1283-1288. 4. Howard JF Jr, et al. Lancet Neurol. 2021;20(7):526-536. 5. argenx Data on File, 2022. 3
ADAPT+ Study Design ADAPT+ Study Design ADAPT1 ADAPT+ (Open-label efgartigimod) (Placebo controlled) 3 years 26 wk ( 3 cycles) 2 weeks screening Part A (1 y) Part B (2 y) Efgartigimod MGFA Class II, III, IV n=84 Efgartigimod Efgartigimod AChR-Ab positive or negative N=167 1:1 MG-ADL score 5a N=151 4 wk On 1 stable gMG treatmentb Placebo n=83 Between treatment cycles Arrows indicate treatment periods of 4 infusions at weekly intervals IgG 6 g/L 5 wk Subsequent treatment cycle(s) if requiredc Efgartigimod 10 mg/kg IV Placebo Between treatment cycles Subsequent treatment cycle(s) if requiredc ADAPT+ included 10 Japanese Patients (7 AChR-Ab+; 3 AChR-Ab ) ADAPT included 15 Japanese Patients (8 EFG, 7 PBO; 10 AChR-Ab+; 5 AChR-Ab ) AChR-Ab, acetylcholine receptor antibody; EFG, efgartigimod; gMG, generalized myasthenia gravis; IgG, immunoglobulin G; IV, intravenous; MG-ADL, Myasthenia Gravis Activities of Daily Living; MGFA, Myasthenia Gravis Foundation of America; PBO, placebo. Note: Patients requiring rescue therapy discontinued from the study treatment. a50% of the score attributed to nonocular items. bAcetylcholinesterase inhibitor, steroid +/or nonsteroidal immunosuppressive therapy (for the duration of the trial). cBased on clinical evaluation. Patients needed to have an MG-ADL score 5 (>50% from nonocular items) and needed to have a reduction in MG-ADL total score <2 points from study/cycle baseline to be eligible to receive a new cycle. 1. Howard JF Jr, et al. Lancet Neurol. 2021;20(7):526-536. 4
Efgartigimod Demonstrated Repeatable and Sustained Improvement in MG Efgartigimod Demonstrated Repeatable and Sustained Improvement in MG- -ADL in Both the Overall Population and the Japanese Subpopulation Over Multiple Cycles the Overall Population and the Japanese Subpopulation Over Multiple Cyclesa a in ADAPT+ ADL in Both in ADAPT+ MG-ADL Total Score Mean Change From Cycle Baseline by Cycle (Overall Population) MG-ADL Total Score Mean Change From Cycle Baseline by Cycle (Japanese Population) Mean Change ( SE) in Total MG-ADL Mean Change ( SE) in Total MG-ADL 0 0 Clinically meaningful improvement -2 -2 Clinically meaningful improvement -4 -4 -6 -6 ADAPT+ Cycle ADAPT+ Cycle -8 -8 Patients Patients 10 10 10 10 10 9 7 4 2 2 1 2 3 4 5 139 130 112 94 79 138 130 110 91 78 134 126 125 110 110 93 79 136 135 125 105 83 71 74 65 44 28 21 1 2 3 4 5 9 7 7 5 9 7 7 5 9 7 7 5 9 7 6 5 9 7 5 5 91 79 0 1 2 3 7 11 Week 0 1 2 3 7 11 Week MG-ADL, Myasthenia Gravis Activities of Daily Living. aOnly cycles with data out to week 11 are depicted. 5
Efgartigimod Demonstrated Repeatable and Sustained Improvement in QMG in Both the Efgartigimod Demonstrated Repeatable and Sustained Improvement in QMG in Both the Overall Population and the Japanese Subpopulation Over Multiple Cycles Overall Population and the Japanese Subpopulation Over Multiple Cyclesa a in ADAPT+ in ADAPT+ QMG Total Score QMG Total Score Mean Change From Cycle Baseline by Cycle (Overall Population) Mean Change From Cycle Baseline by Cycle (Japanese Population) 2 2 Mean Change ( SE) in Total QMG Mean Change ( SE) in Total QMG 0 0 -2 -2 Clinically meaningful improvement Clinically meaningful improvement -4 -4 -6 -6 ADAPT+ Cycle ADAPT+ Cycle -8 -8 Patients Patients 10 10 10 9 9 7 5 5 9 9 7 5 5 9 7 4 2 2 1 2 3 4 5 139 130 108 84 62 136 122 98 66 56 133 118 94 70 58 133 116 96 67 54 119 96 75 59 49 63 50 30 18 12 1 2 3 4 5 9 7 7 5 9 7 6 5 9 7 6 5 0 1 2 3 7 11 Week 0 1 2 3 7 11 Week QMG, Quantitative Myasthenia Gravis. aOnly cycles with data out to week 11 are depicted. 6
Efgartigimod Demonstrated Consistent Transient Reduction in IgG Levels Over Multiple Efgartigimod Demonstrated Consistent Transient Reduction in IgG Levels Over Multiple Cycles Cyclesa a in ADAPT+ in ADAPT+ Total IgG Mean % Change From Baseline (Overall Population) Total IgG Mean % Change From Baseline (Japanese Population) 80 80 Mean % change ( SE) in Total IgG Mean % change ( SE) in Total IgG 60 60 40 40 20 20 0 0 -20 -20 -40 -40 -60 -60 -80 -80 ADAPT+ Cycle ADAPT+ Cycle Patients Patients 139 130 112 94 78 136 126 108 87 73 133 135 124 121 108 110 90 73 119 103 90 71 59 63 53 41 24 17 1 2 3 4 5 10 10 10 10 10 9 7 4 2 2 1 2 3 4 5 9 7 6 5 9 7 6 5 9 7 6 5 9 7 5 5 9 7 5 5 88 69 Week 0 1 2 3 7 11 Week 0 1 2 3 7 11 IgG, immunoglobulin G. aOnly cycles with data out to week 11 included. 7
Efgartigimod Demonstrated Consistent Transient Reduction in Anti Efgartigimod Demonstrated Consistent Transient Reduction in Anti- -AChR Antibody Levels Over Multiple Cycles Over Multiple Cyclesa a in ADAPT+ in ADAPT+ AChR Antibody Levels Anti-AChR-Ab: Mean % Change From Baseline (AChR-Ab+ Population) Anti-AChR-Ab: Mean % Change From Baseline (Japanese AChR-Ab+ Population) 80 80 Mean % change ( SE) in Total Anti-AChR-Ab Mean % change ( SE) in Total Anti-AChR-Ab 60 60 40 40 20 20 0 0 -20 -20 -40 -40 -60 -60 -80 -80 ADAPT+ Cycle ADAPT+ Cycle Patients Patients 106 99 86 74 60 104 96 82 70 57 101 101 94 82 70 58 88 79 72 56 46 49 41 30 18 14 1 2 3 4 5 7 6 4 4 3 7 6 4 4 3 7 6 4 3 3 7 6 4 3 3 7 6 4 3 3 7 5 3 2 2 1 2 3 4 5 92 83 70 54 Week 0 1 2 3 7 11 Week 0 1 2 3 7 11 AChR-Ab, acetylcholine receptor autoantibody; IgG, immunoglobulin G. aOnly cycles with data out to week 11 included. 8
ADL Improvement Over Multiple Cyclesa a Proportion of Patients With Increasing MG Proportion of Patients With Increasing MG- -ADL Improvement Over Multiple Cycles Overall population (AChR-Ab+ and ) Change in MG-ADL Total Score (Overall Population) Change in MG-ADL Total Score (Japanese Population) Efgartigimod (open-label) Placebo (phase 3) Week 3 of Cycle 1 in ADAPT, % n=80 Efgartigimod (open-label) Placebo (phase 3) Week 3 of Cycle 1 in ADAPT, % n=7 Week 3 of cycles 1 5a in ADAPT+, median % (range) Week 3 of cycles 1 5a in ADAPT+, median % (range) n=79 136 n=5 10 17.3% 0.0% 0.0% 0.0% 10 10 0.0% 0.0% 22.7% 0.0% 9 9 29.1% 10.0% 8 8 0.0% 1.3% 36.4% 14.3% 14.3% 3.8% 7 7 CMI (Cumulative %) 46.2% 33.3% 14.3% 6.3% 6 6 56.4% 42.9% 28.6% 12.5% 5 5 69.1% 66.7% 42.9% 4 4 25.0% 78.4% 42.9% 83.3% 35.0% 3 3 86.1% 2 83.3% 57.1% 2 50.0% 8.0% 14.3% 14.3% 1 1 18.8% No CMI (Categorical %) 28.6% 5.1% 0.0% 13.8% No Change No Change 2.7% 0.0% Worsened Worsened 0.0% 17.5% 100% 75% 50% 25% 0% 25% 50% 75% 100% 100% 75% 50% 25% 0% 25% 50% 75% 100% AChR-Ab, acetylcholine receptor antibody; CMI, clinically meaningful improvement; MG-ADL, Myasthenia Gravis Activities of Daily Living. aOnly cycles with data out to week 11 are included.
Proportion of Patients With Increasing QMG Improvement Over Multiple Cycles Proportion of Patients With Increasing QMG Improvement Over Multiple Cyclesa a Overall population (AChR-Ab+ and ) Change in QMG Total Score (Overall Population) Change in QMG Total Score (Japanese Population) Efgartigimod (open-label) Placebo (phase 3) Week 3 of Cycle 1 in ADAPT, % n=77 Efgartigimod (open-label) Placebo (phase 3) Week 3 of Cycle 1 in ADAPT, % n=7 Week 3 of cycles 1 5a in ADAPT+, median % (range) Week 3 of cycles 1 5a in ADAPT+, median % (range) n=54 133 n=5 10 12.1% 0.0% 2.6% 0.0% 10 10 3.9% 0.0% 15.8% 11.1% 9 9 24.1% 14.3% 8 8 0.0% 3.9% 29.2% 20.0% 0.0% 6.5% 7 7 CMI (Cumulative %) 35.3% 20.0% 0.0% 6.5% 6 6 44.8% 30.0% 0.0% 11.7% 5 5 54.1% 44.4% 28.6% 4 4 23.4% 66.7% 65.6% 28.6% 32.5% 3 3 14.3% 13.0% 20.0% 9.3% 2 2 No CMI 12.5% 11.1% 14.3% 1 1 13.0% (Categorical %) 28.6% 5.2% 0.0% 13.0% No Change No Change 6.8% 0.0% Worsened Worsened 14.3% 28.6% 100% 75% 50% 25% 0% 25% 50% 75% 100% 100% 75% 50% 25% 0% 25% 50% 75% 100% AChR-Ab, acetylcholine receptor autoantibody; CMI, clinically meaningful improvement; QMG, Quantitative Myasthenia Gravis. aOnly cycles with data out to week 11 are included.
Safety: Summary of AEs Safety: Summary of AEs Overall Population ADAPT ADAPT+ Placebo (n=83) [34.51 PY] Efgartigimod (n=84) [34.86 PY] Total Efgartigimod (n=139) [138.14 PY] IR/PY n (%) IR/PY n (%) IR/PY n (%) AEs 7.83 70 (84) 7.23 65 (77) 4.06 112 (81) SAEs 0.29 7 (8) 0.11 4 (5) 0.25 21 (15) 1 Infusion-related reaction event 0.26 8 (10) 0.09 3 (4) 0.09 10 (7) Infection AEs 1.22 31 (37) 1.61 39 (46) 0.84 65 (47) Discontinued study treatment due to AEs 0.09 3 (4) 0.20 3 (4) 0.07 8 (6) Severe AEs (grade 3) 0.35 8 (10) 0.29 9 (11) 0.41 26 (19) Death 0 0 (0) 0 0 (0) 0.04 5 (4) Most frequent AEs Nasopharyngitis 0.49 15 (18) 0.34 10 (12) 0.14 15 (11) Upper respiratory tract infection 0.15 4 (5) 0.32 9 (11) 0.04 5 (4) Urinary tract infection 0.12 4 (5) 0.26 8 (10) 0.09 10 (7) Headache 1.13 23 (28) 1.15 24 (29) 0.49 31 (22) Nausea 0.43 9 (11) 0.20 7 (8) 0.07 7 (5) Diarrhea 0.41 9 (11) 0.17 6 (7) 0.11 12 (9) 12 AE, adverse event; IR, incidence rate; PY, patient year; SAE, serious adverse event.
Safety: Summary of AEs Safety: Summary of AEs Japanese Subpopulation ADAPT ADAPT+ Placebo (n=7) [2.63 PY] Efgartigimod (n=8) [3.36 PY] Total Efgartigimod (n=10) [10.38 PY] IR/PY n (%) IR/PY n (%) IR/PY n (%) AEs 9.12 7 (100) 7.34 7 (87.5) 3.57 9 (90) SAEs 1.14 2 (28.6) 0 0 0 0 1 Infusion-related reaction event 0 0 0 0 0 0 Infection AEs 3.03 6 (85.7) 2.08 4 (50) 0.77 5 (50) Discontinued study treatment due to AEs 0.38 1 (14.2) 0 0 0 0 Severe AEs (grade 3) 0.76 2 (28.6) 0 0 0 0 Death 0 0 0 0 0 0 Most frequent AEs Nasopharyngitis 1.89 4 (57.1) 0.59 2 (25) 0.58 4 (40) Headache or migraine 0 0 1.19 2 (25) 0.29 2 (20) Myalgia 0 0 0.30 1 (12.5) 0.19 2 (20) Arthralgia 0 0 0.30 1 (12.5) 0.19 2 (20) Diarrhea 1.52 1 (14.2) 0.30 1 (12.5) 0.29 2 (20) 13 AE, adverse event; IR, incidence rate; PY, patient year; SAE, serious adverse event.
None of the Deaths in ADAPT+ Were Related to Efgartigimod Administration per None of the Deaths in ADAPT+ Were Related to Efgartigimod Administration per the Investigator the Investigator Days from last dose, d Age, y/ Sex Number of Infusionsa Cause of Death Comorbidities/Medical History Unknown; preexisting CV disease, autopsy confirmed coronary artery atherosclerosis and cardiomegaly Pulmonary embolism, chronic obstructive pulmonary disease, hypertension, hypokalemia, and colon bladder fistula 4 in ADAPT and 9 in ADAPT+ 72/F 4 MG crisis and progression of underlying disease/Escherichia coli pneumonia 8 in ADAPT and 4 in ADAPT+ 79/M 79 Chronic rhinitis Histoplasmosis, asthma, diabetes mellitus, hypercholesterolemia, macular degeneration, hypertension, squamous cell carcinoma, and bundle branch block Malignant lung neoplasm (Stage IV) 4 in ADAPT and 8 in ADAPT+ 66/F 60 8 (PBO) in ADAPT and 16 in ADAPT+ Acute MI and generalized unspecified atherosclerosis Anemia, subarachnoid hemorrhage, CTO PCI and angioplasty procedures 55/M 24 Chronic venous insufficiency, arterial hypertension, deep vein thrombosis, rheumatoid arthritis, and paroxysmal atrial fibrillation 8 in ADAPT and 16 in ADAPT+ Septic shock/ COVID-19 pneumonia 63/M 69 COVID-19, coronavirus disease 2019; CTO PCI, chronic total occlusion percutaneous coronary intervention; CV, cardiovascular; MI, myocardial infarction; MG, myasthenia gravis; PBO, placebo; PI, principal investigator. aAll infusions were efgartigimod, except where PBO is noted. 14
Summary (Total Population and Japanese Subpopulation) Summary (Total Population and Japanese Subpopulation) The safety profile observed during long-term treatment with efgartigimod in ADAPT+ mirrored that seen during ADAPT, even while being conducted during the COVID-19 global pandemic This analysis suggests that long-term treatment with efgartigimod is efficacious, providing consistent and repeatable clinically meaningful improvement and remaining well tolerated ADAPT+ is a planned 3-year study and is currently ongoing 15 COVID-19, coronavirus disease 2019.
