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Clinical Trial
. 2024 Sep;21(5):e00378.
doi: 10.1016/j.neurot.2024.e00378. Epub 2024 Sep 2.

Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: A phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+)

James F Howard Jr  1 , Tuan Vu  2 , George Li  3 , Denis Korobko  4 , Marek Smilowski  5 , Li Liu  6 , Fien Gistelinck  6 , Sophie Steeland  6 , Jan Noukens  7 , Benjamin Van Hoorick  6 , Jana Podhorna  6 , Filip Borgions  6 , Yuebing Li  8 , Kimiaki Utsugisawa  9 , Heinz Wiendl  10 , Jan L De Bleecker  11 , Renato Mantegazza  12 ; ADAPT-SC and ADAPT-SC+ Study Groups
Affiliations
Clinical Trial

Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: A phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+)

James F Howard Jr et al. Neurotherapeutics. 2024 Sep.

Abstract

ADAPT-SC (NCT04735432) was designed to evaluate noninferiority of subcutaneous (SC) efgartigimod PH20 to intravenous (IV) efgartigimod in participants with generalized myasthenia gravis (gMG). ADAPT-SC+ (NCT04818671) is an open-label extension study designed to assess long-term safety, tolerability, and efficacy of efgartigimod PH20 SC. Adult participants in ADAPT-SC were randomly assigned to receive a treatment cycle of 4 once-weekly administrations of efgartigimod PH20 SC 1000 ​mg or efgartigimod IV 10 ​mg/kg, followed by 7 weeks of follow-up. Primary endpoint was percentage change from baseline in total immunoglobulin G (IgG) level at week 4 (1 week after the fourth administration). Secondary efficacy endpoints assessed number and percentage of Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) responders and mean change from baseline in total score for each measure. The primary endpoint was met, demonstrating noninferiority in total IgG reduction between efgartigimod PH20 SC 1000 ​mg and efgartigimod IV 10 ​mg/kg. Clinically meaningful improvements were seen as early as 1 week following the first administration in both treatment arms, with maximal improvements at week 4. Continued treatment cycles of efgartigimod PH20 SC in ADAPT-SC+ have demonstrated long-term safety and consistent improvements in MG-ADL total score. Findings from ADAPT-SC and ADAPT-SC+ demonstrate similar safety and efficacy as observed in the placebo-controlled ADAPT study. Collectively, these findings support noninferiority between efgartigimod PH20 SC 1000 ​mg and efgartigimod IV 10 ​mg/kg, as well as long-term safety, tolerability, and efficacy of efgartigimod PH20 SC for treatment of a broad population of patients with gMG.

Keywords: Efgartigimod; FcRn; IgG recycling; Myasthenia gravis; Neonatal Fc receptor antagonist.

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Conflict of interest statement

Declaration of competing interest This study was sponsored by argenx (Ghent, Belgium), the manufacturer of efgartigimod IV and efgartigimod PH20 SC. Efgartigimod IV has received regulatory approval for the treatment of gMG in multiple countries. Efgartigimod PH20 SC was approved for use in gMG by the US Food and Drug Administration. Medical writing and editorial support were funded by argenx. Li Liu, Fien Gistelinck, Sophie Steeland, Benjamin Van Hoorick, Jana Podhorna, and Filip Borgions are employees of argenx. Jan Noukens is partner at Curare Consulting and is a paid consultant for argenx. James F. Howard, Jr has received research support (paid to his institution) from Alexion Pharmaceuticals, argenx, Cartesian Therapeutics, the US Centers for Disease Control and Prevention, the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the US National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), Patient-Centered Outcomes Research Institute, Ra Pharmaceuticals (now UCB Biosciences), and Millennium Pharmaceuticals/Takeda Pharmaceuticals; honoraria from AcademicCME, Alexion Pharmaceuticals, argenx BV, Biologix Pharma, F. Hoffman-LaRoche Ltd, Horizon Therapeutics plc, Merck EMD Serono, NMD Pharma, Novartis Pharmaceuticals, PeerView CME, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, and Sanofi US; and non-financial support from Alexion Pharmaceuticals, argenx BV, Ra Pharmaceuticals (now UCB Biosciences), Toleranzia AB, and ZaiLab. Tuan Vu serves as site principal investigator for MG clinical trials sponsored by argenx, Alexion, UCB/Ra, Cartesian, Horizon/Viela Bio, Janssen/Momenta, Regeneron, Immunovant, and Sanofi and has served as consultant and/or speaker for argenx, Alexion, and UCB/Ra. George Li has nothing to disclose. Denis Korobko has received speaker honoraria from Roche-Moscow, Novartis Russia, Sanofi, Merck, Janssen (Johnson & Johnson company), BIOCAD; research grants from Novartis Russia, UCB, argenx, Viela Bio Inc. (now Horizon Therapeutics), Sanofi, Bristol Myers Squibb, Hoffman-LaRoche Ltd.; and has served on scientific advisory boards for Novartis Russia, Merck, Janssen (Johnson & Johnson company), and BIOCAD. Marek Smilowski has nothing to report. Yuebing Li has served on advisory boards for argenx, Catalyst, Immunovant, and UCB Pharma and has received grant support from argenx. Kimiaki Utsugisawa 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. Heinz Wiendl receives honoraria for acting as a member of scientific advisory boards for AbbVie, Alexion, argenx, Bristol Myers Squibb, Janssen, Merck, Novartis, and Sandoz; has received speaker honoraria and travel support from Alexion, Biogen, Bristol Myers Squibb, Genzyme, Merck, Neurodiem, Novartis, Ology, Roche, Teva, and WebMD Global; has received research funding from Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., European Union, Alexion, Amicus Therapeutics, argenx, Biogen, CSL Behring, F. Hoffmann-La Roche, Genzyme, Merck KgaA, Novartis, Roche Pharma, and UCB Biopharma; and is a paid consultant for AbbVie, Actelion, argenx, BD, Bristol Myers Squibb, EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, INmune Bio, Syneos Health, Janssen, Merck, NexGen, Novartis, Roche, Sanofi, Swiss Multiple Sclerosis Society, UCB, and Worldwide Clinical Trials. Jan L. De Bleecker has served as a paid consultant for or received speaker honoraria from argenx, UCB Pharma, Alexion Pharmaceuticals, Sanofi, CSL Behring, and Roche. Renato Mantegazza has received funding for travel, meeting attendance, or advisory board participation from Alexion, argenx, Biomarin, Catalyst, Sanofi, Regeneron, and UCB.

Figures

Fig. 1
Fig. 1
Study Design Schema for ADAPT-SC and ADAPT-SC+. AChE, acetylcholinesterase; gMG, generalized myasthenia gravis; IgG, immunoglobulin G; IV, intravenous; IVIg, intravenous immunoglobulin; MG, myasthenia gravis; MG-ADL, Myasthenia Gravis Activities of Daily Living; MGFA, Myasthenia Gravis Foundation of America; NSIST, nonsteroidal immunosuppressive therapy; OLE, open-label extension; PLEX, plasma exchange; rHuPH20, recombinant human hyaluronidase PH20; SC, subcutaneous. Fig. 1 footnote: The ADAPT-SC study evaluated whether the pharmacodynamic effect of efgartigimod PH20 SC 1000 ​mg was noninferior to that of efgartigimod IV 10 ​mg/kg in terms of percentage change from baseline in total IgG level at week 4, using a noninferiority margin of 10%. All participants received 1 treatment cycle (1 injection or infusion per week for 4 weeks, denoted by black arrows) concomitant with their current gMG therapy. The primary endpoint of the ADAPT-SC study was the percentage change from baseline in total IgG levels at week 4 (ie, 1 week after the fourth IV or SC administration). After a participant completed the ADAPT-SC study, the participant was allowed, if eligibility criteria were met, to roll over into ADAPT-SC+ to receive efgartigimod PH20 SC 1000 ​mg. Participants in ADAPT+ (efgartigimod IV OLE) also had the option to roll over into ADAPT-SC+. a >50% due to nonocular symptoms. b AChE inhibitors, steroids, and/or NSISTs. c Efgartigimod PH20 SC 1000 ​mg coformulated with 2000 ​U/mL rHuPH20. d Participants did not receive treatment, except rescue therapy (corticosteroids, IVIg, and PLEX) and permitted concomitant stable MG therapy, in the 7-week follow-up period.
Fig. 2
Fig. 2
Participant Disposition (ADAPT-SC and ADAPT-SC+). AE, adverse event; EFG, efgartigimod; IV, intravenous; MG, myasthenia gravis; SC, subcutaneous. Fig. 2 footnote: Of the 153 participants screened for ADAPT-SC, 111 were enrolled and randomly assigned to receive efgartigimod PH20 SC (n ​= ​55) or efgartigimod IV (n ​= ​55). A total of 110 participants were treated, 107 completed treatment, and 108 completed the study (54 from each treatment arm). In the efgartigimod PH20 SC arm, 3 participants did not complete treatment, and 1 of the 3 also discontinued from the study. In the efgartigimod IV arm, no participant discontinued treatment, but 1 participant discontinued from the study. Of the 178 participants enrolled in ADAPT-SC+, 105 rolled over from the ADAPT-SC study and 73 rolled over from the ADAPT+ study, an open-label extension study of efgartigimod IV. a 1 participant assigned to the efgartigimod IV arm withdrew due to an AE of pyrexia prior to administration of efgartigimod. b Treatment discontinuation due to COVID-19 infection occurred on day 3 and MG worsening on day 1.
Fig. 3
Fig. 3
Mean Percentage Change From Baseline in Total IgG and AChR-Ab Levels—Overall and AChR-Ab+ Populationsa—in ADAPT-SC and ADAPT-SC+. AChR-Ab, acetylcholine receptor antibody; IgG, immunoglobulin G; IMP, investigational medicinal product; IV, intravenous; mITT, modified intent to treat; SC, subcutaneous. Fig. 3 footnote: A: Mean percentage change from baseline in total IgG in overall populations in ADAPT-SC and ADAPT-SC+; B: Mean percentage change from baseline in total IgG in AChR-Ab–positive subgroups in ADAPT-SC and ADAPT-SC+; C: Mean percentage change from baseline in AChR-Ab levels in ADAPT-SC and ADAPT-SC+ (in AChR-Ab–positive participants). The mITT analysis set included all randomly assigned participants with a value for total IgG level at baseline and at least 1 postbaseline time point. Each cycle consisted of 4 once-weekly administrations, occurring at baseline and weeks 1, 2, and 3 (denoted by yellow triangles on the x-axis). a Data for AChR-Ab–negative participants are in Supplemental Table 2 and Supplemental Fig. 1.
Fig. 4
Fig. 4
Mean Change From Baseline in MG-ADL and QMGaTotal Scores—Overall and AChR-Ab+ Populationsb—in ADAPT-SC and ADAPT-SC+. AChR-Ab, acetylcholine receptor antibody; IgG, immunoglobulin G; IMP, investigational medicinal product; ITT, intent to treat; IV, intravenous; MG-ADL, Myasthenia Gravis Activities of Daily Living; QMG, Quantitative Myasthenia Gravis; SC, subcutaneous. Fig. 4 footnote: A: Mean change from baseline in MG-ADL total score (overall) in ADAPT-SC and ADAPT-SC+; B: mean change from baseline in MG-ADL total score (AChR-Ab–positive) in ADAPT-SC and ADAPT-SC+; C: mean change from baseline in QMG total score (overall, left and AChR-Ab–positive, right) in ADAPT-SC. The ITT analysis set included all randomly assigned participants who were exposed to the IMP. Each cycle consisted of 4 once-weekly administrations, occurring at baseline and weeks 1, 2, and 3 (denoted by yellow triangles on the x-axis). a QMG was measured in ADAPT-SC study only, not in ADAPT-SC+. b Data for AChR-Ab–negative participants are in Supplemental Table 2 and Supplemental Fig. 1. c Differential scaling of y-axis on AChR-Ab–positive QMG graph to accommodate error bars.
Fig. 5
Fig. 5
Proportion of Participants With Increasing MG-ADL or QMG Improvement in ADAPT-SC Study (Overall and AChR-Ab+Populations, Week 4; ITT Population). AChR-Ab, acetylcholine receptor antibody; AChR-Ab+, acetylcholine receptor antibody–positive; IMP, investigational medicinal product; ITT, intent to treat; IV, intravenous; MG-ADL, Myasthenia Gravis Activities of Daily Living; QMG, Quantitative Myasthenia Gravis; SC, subcutaneous. Fig. 5 footnote: Scores above dashed line indicate clinically meaningful improvement. Values below the dashed lines are actual, not cumulative, percentages. ITT analysis set included all randomly assigned participants who were exposed to the IMP.
Fig. S1
Fig. S1
Mean Percentage Change From Baseline in Total IgG (mITT Population) and Mean Change From Baseline in MG-ADL and QMG Total Scores (ITT Population)—AChR-Ab–Negative Population (ADAPT-SC and ADAPT-SC+) AChR-Ab, acetylcholine receptor antibody; IgG, immunoglobulin G; ITT, intent to treat; IV, intravenous; MG-ADL, Myasthenia Gravis Activities of Daily Living; mITT, modified intent to treat; QMG, Quantitative Myasthenia Gravis; SC, subcutaneous. Supplemental Figure 1 footnote: A: Mean percentage change from study baseline in total IgG in AChR-Ab–negative population in ADAPT-SC (left) and ADAPT-SC+ (right); B: mean change from study baseline in MG-ADL total score in AChR-Ab–negative population in ADAPT-SC (left) and ADAPT-SC+ (right); C: mean change from study baseline in QMG total score in AChR-Ab–negative population in ADAPT-SC. The ITT analysis set included all randomly assigned participants who were exposed to the IMP. The mITT analysis set included all randomly assigned participants with a value for total IgG level at baseline and at least 1 postbaseline time point. Each cycle consisted of 4 once-weekly administrations, occurring at baseline and weeks 1, 2, and 3 (denoted by yellow triangles on x-axis).
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