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. 2024 Jan 17:14:1284444.
doi: 10.3389/fneur.2023.1284444. eCollection 2023.

Long-term safety, tolerability, and efficacy of efgartigimod (ADAPT+): interim results from a phase 3 open-label extension study in participants with generalized myasthenia gravis

James F Howard Jr  1 , Vera Bril  2 , Tuan Vu  3 , Chafic Karam  4 , Stojan Peric  5 , Jan L De Bleecker  6 , Hiroyuki Murai  7 , Andreas Meisel  8 , Said R Beydoun  9 , Mamatha Pasnoor  10 , Antonio Guglietta  11 , Benjamin Van Hoorick  11 , Sophie Steeland  11 , Caroline T'joen  11 , Kimiaki Utsugisawa  12 , Jan Verschuuren  13 , Renato Mantegazza  14 ; ADAPT+ Study Group
Affiliations

Long-term safety, tolerability, and efficacy of efgartigimod (ADAPT+): interim results from a phase 3 open-label extension study in participants with generalized myasthenia gravis

James F Howard Jr et al. Front Neurol. .

Abstract

Objective: ADAPT+ assessed the long-term safety, tolerability, and efficacy of efgartigimod in adult participants with generalized myasthenia gravis (gMG).

Methods: ADAPT+ was an open-label, single-arm, multicenter, up to 3-year extension of the pivotal phase 3 ADAPT study. Efgartigimod was administered in treatment cycles of 4 intravenous infusions (one 10 mg/kg infusion per week). Initiation of subsequent treatment cycles was individualized based on clinical evaluation. Safety endpoints included incidence and severity of adverse events. Efficacy endpoints assessed disease severity using Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores.

Results: As of January 2022, 151 participants had rolled over to ADAPT+ and 145 had received ≥1 dose of efgartigimod, of whom, 111 (76.6%) were AChR-Ab+ and 34 (23.4%) were AChR-Ab-. Mean study duration (treatment plus follow-up) was 548 days, and participants received up to 17 treatment cycles, corresponding to 217.6 participant-years of exposure. In the overall population, 123 (84.8%) participants reported ≥1 treatment-emergent adverse event; most frequent were headache (36 [24.8%]), COVID-19 (22 [15.2%]), and nasopharyngitis (20 [13.8%]). Clinically meaningful improvement (CMI) in mean MG-ADL and QMG scores was seen as early as 1 week following the first infusion across multiple cycles in AChR-Ab+ and AChR-Ab- participants. Maximal MG-ADL and QMG improvements aligned with onset and magnitude of total IgG and AChR-Ab reductions. For AChR-Ab+ participants at any time point in each of the first 10 treatment cycles, more than 90% had a maximum reduction of ≥2 points (CMI) in MG-ADL total score; across the 7 cycles in which QMG was measured, 69.4% to 91.3% of participants demonstrated a maximum reduction of ≥3 points (CMI) in QMG total score. Many participants demonstrated improvements well beyond CMI thresholds. In AChR-Ab+ participants with ≥1 year of combined follow-up between ADAPT and ADAPT+, mean number of annualized cycles was 4.7 per year (median [range] 5.0 [0.5-7.6]).

Conclusion: Results of ADAPT+ corroborate the substantial clinical improvements seen with efgartigimod in ADAPT and support its long-term safety, tolerability, and efficacy, as well as an individualized dosing regimen for treatment of gMG.

Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT03770403, NCT03770403.

Keywords: FcRn; IgG recycling; antibody fragment; autoantibody reduction; efgartigimod; myasthenia gravis; neonatal Fc receptor; neonatal Fc receptor antagonist.

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Conflict of interest statement

SS, CT’j, and BH are employees of argenx, Ghent, Belgium. AG was an employee of argenx during study execution and at the initiation of this manuscript; he is currently an independent consultant for the biotechnology and pharmaceutical industry. JH has received research support (paid to his institution) from Alexion Pharmaceuticals, argenx, Cartesian Therapeutics, the Centers for Disease Control and Prevention (Atlanta, GA, USA), the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), PCORI, Ra Pharmaceuticals (now UCB Biosciences), and Millennium Pharmaceuticals/Takeda Pharmaceuticals; honoraria from AcademicCME, Alexion Pharmaceuticals, argenx, Biologix Pharma, F. Hoffman-LaRoche Ltd., Horizon Therapeutics, Immunovant Inc., Medscape CME, Merck EMB Serono, Novartis Pharmaceuticals, PeerView CME, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, Sanofi US, and Zai Laboratories; and non-financial support from Alexion Pharmaceuticals, argenx BVBA, Ra Pharmaceuticals (now UCB Biosciences), and Toleranzia AB. VB has participated in scientific advisory boards for CSL Behring, Baxalta, Grifols, argenx, Octapharma, Alpha Technologies, Powell Mansfield Inc., Shire, Akcea, UCB, and Alnylam. She has received funding for travel or speaker honoraria from CSL Behring and has consultancies with CSL Behring, Grifols, BioNevia, Octapharma, Powell Mansfield Inc., argenx, Alpha Technologies, Baxalta, Akcea, UCB, Alnylam, and Pfizer. TV served as site principal investigator for MG clinical trials sponsored by Alexion, argenx, Ra/UCB, Horizon/Viela Bio, Janssen/Momenta, Regeneron, and Cartesian Therapeutics and is a consultant for UCB, Alexion, Dianthus, and argenx. CK has participated in scientific advisory boards for CSL Behring, Takeda, argenx, AstraZeneca, Alexion, Alpine, Corino, Ionis, Sanofi, UCB, and Alnylam. He has received research funding from Ionis. JV has been involved in MG research sponsored by the Prinses Beatrix Spierfonds, Health Holland, and consultancies for argenx, Alexion, and NMD Pharma. Reimbursements were received by the LUMC. He is coinventor on patent applications based on MuSK-related research. He is a member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). SP has served as site principal investigator for MG clinical trials sponsored by argenx, Ra/UCB, Takeda/Millennium, and Alexion and is a consultant for argenx and Dianthus. JB has served as a paid consultant for or received speaker honoraria from argenx, UCB Pharma, Alexion Pharmaceuticals, Sanofi, and Biogen. HM has served as a paid consultant for Alexion, AstraZeneca Rare Disease, argenx, UCB Pharma, and Roche and has received speaker honoraria from the Japan Blood Products Organization and Chugai Pharmaceutical and research support from the Ministry of Health, Labour and Welfare, Japan. AM has served as advisor, consultant, principal investigator, or speaker and has received research grants (paid to his employer) and honoraria from Alexion, argenx, Axunio, Grifols, Hormosan, Janssen, Merck, Octapharma, and UCB. He serves as chair of the medical advisory board of the German Myasthenia Gravis Society. SB has participated in research studies sponsored by argenx, Sanofi, UCB, Regeneron, Genentech, Janssen, Amylyx, and Healey ALS. He is a paid consultant and speaker for Takeda, Alnylam, Alexion, Grifols, Amylyx, argenx, and CSL. MP has served as a consultant or medical advisor to Terumo BCT, Alexion, CSL Behring, Momenta, Catalyst, UCB, Immunovant, and Janssen. KU has served as a paid consultant for argenx, UCB Pharma, Janssen Pharma, Viela Bio, Chugai Pharma, Merck, and Mitsubishi Tanabe Pharma and has received speaker honoraria from argenx, Alexion Pharmaceuticals, UCB Pharma, and the Japan Blood Products Organization. RM has received funding for travel, meeting attendance, and advisory board participation from Alexion, argenx, Biomarin, Catalyst, Sanofi, Regeneron, and UCB.

Figures

Figure 1
Figure 1
Study design. AChEI, acetylcholinesterase inhibitor; AChR, acetylcholine receptor; gMG, generalized myasthenia gravis; HCP, healthcare provider; IgG, immunoglobulin G; IV, intravenous; MG-ADL, Myasthenia Gravis-Activities of Daily Living; MGFA, Myasthenia Gravis Foundation of America; NSIST, nonsteroidal immunosuppressive therapy. In ADAPT+ efgartigimod was administered in treatment cycles comprising 4 once-weekly IV infusions (10 mg/kg over 1 h) per cycle on days 1, 8, 15, and 22 of each cycle, with follow-up of at least 4 weeks. a Participants who required retreatment but were unable to complete a treatment cycle within the time frame of ADAPT were eligible to be rolled over to ADAPT+. b Subsequent cycles initiated if ≥5 weeks from last infusion, MG-ADL score improvement <2 points from baseline, and MG-ADL total score ≥5 (>50% due to nonocular items). c Participants requiring rescue therapy in ADAPT and in year 1 of ADAPT+ were discontinued from the study. Participants requiring rescue in years 2 and 3 of ADAPT+ were not discontinued. d Subsequent cycles initiated in the first year of ADAPT+ if ≥4 weeks from last infusion of previous cycle, MG-ADL score improvement <2 points from cycle baseline, and MG-ADL total score ≥5 (>50% due to nonocular items). e Subsequent cycles were initiated in years 2 and 3 of ADAPT+ if ≥4 weeks from last infusion of previous cycle, at the discretion of the investigator. f AChEI, corticosteroid, and/or NSIST. HCPs could not change concomitant therapies in ADAPT; HCPs could change concomitant therapies in ADAPT+.
Figure 2
Figure 2
Study participant disposition. AChR-Ab, acetylcholine receptor antibody. a 6 participants who rolled over to ADAPT+ did not require subsequent treatment cycles based on the defined clinical evaluation criteria. b 1 of the 2 participants who had been discontinued due to using prohibited medications later died; therefore, this participant was not considered as having discontinued treatment due to death. c Eligibility for ADAPT-SC+ study was based on completion of at least 1 cycle of treatment and at least 1 year of ADAPT+ study and had started year 2.
Figure 3
Figure 3
Treatment-emergent adverse events, by cycle (safety analysis set). TEAE, treatment-emergent adverse event. Numbers above bars indicate exact percentage value.
Figure 4
Figure 4
Mean percentage change from cycle baseline in total IgG (overall and AChR-Ab+ populations) and AChR-Ab level. Data for week 11 were not graphed for cycles 6 and 7 because they were unavailable. AChR-Ab, acetylcholine receptor antibody; IgG, immunoglobulin G. (A) Mean percentage change from cycle baseline in total IgG (overall). (B) Mean percentage change from cycle baseline in total IgG (AChR-Ab+). (C) Mean percentage change from cycle baseline in AChR-Ab (AChR-Ab+).
Figure 5
Figure 5
Mean change from cycle baseline in MG-ADL total score, by cycle (AChR-Ab+, AChR-Ab−, and overall populations; safety analysis set). Only time points with ≥3 participants are included. AChR-Ab+, acetylcholine receptor antibody–positive; AChR-Ab−, acetylcholine receptor antibody–negative; CMI, clinically meaningful improvement; MG-ADL, Myasthenia Gravis-Activities of Daily Living. (A) Mean (SE) change from cycle baseline in MG-ADL total score (AChR-Ab+). (B) Mean (SE) change from cycle baseline in MG-ADL total score (AChR-Ab−). (C) Mean (SE) change from cycle baseline in MG-ADL total score (overall population). Dashed line indicates CMI.
Figure 6
Figure 6
Mean change from cycle baseline in QMG total score, by cycle (AChR-Ab+, AChR-Ab−, and overall populations; safety analysis set). Only time points with ≥3 participants are included. Data for week 11 were not graphed for cycles 6 and 7 because they were unavailable. AChR-Ab+, acetylcholine receptor antibody–positive; AChR-Ab−, acetylcholine receptor antibody–negative; CMI, clinically meaningful improvement; QMG, Quantitative Myasthenia Gravis. (A) Mean (SE) change from cycle baseline in QMG total score (AChR-Ab+). (B) Mean (SE) change from cycle baseline in QMG total score (AChR-Ab−). (C) Mean (SE) change from cycle baseline in QMG total score (overall population). Dashed line indicates CMI.
Figure 7
Figure 7
Median cycle proportion of participants with increasing threshold of MG-ADL or QMG improvement, over multiple cycles in ADAPT+ (AChR-Ab+ participants). AChR-Ab+, acetylcholine receptor antibody–positive; CMI, clinically meaningful improvement; MG-ADL, Myasthenia Gravis-Activities of Daily Living; QMG, Quantitative Myasthenia Gravis. Median proportion of AChR-Ab+ participants with increasing thresholds of improvement in MG-ADL (cycle 1 through cycle 10), QMG (cycle 1 through cycle 7), and QMG total score at week 3. Placebo data depicted are from the phase 3 ADAPT study which included 1 cycle (30). Dashed line indicates CMI.
Figure 8
Figure 8
Mean time between cycles in AChR-Ab+ population with ≥1 year of follow-up in ADAPT/ADAPT+ (n = 95). AChR-Ab+, acetylcholine receptor antibody–positive. Post hoc analysis of mean time between cycles in AChR-Ab+ participants with ≥1 year of follow-up in ADAPT/ADAPT+. For each individual participant, time between the last infusion of preceding cycle and the first infusion of the following cycle was calculated, and average duration was calculated for each participant for all completed cycles.
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