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Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis

Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis
Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis
Objective: To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.

Methods: A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.

Results: Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.

Conclusions: Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.

Classification of evidence: This study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.
Glossary

AChR= acetylcholine receptor;
ADA= antidrug antibody;
AE= adverse event;
CI= confidence interval;
Cmax= maximum observed plasma concentration;
FcRn= neonatal Fc receptor;
gMG= generalized myasthenia gravis;
IgG= immunoglobulin G;
IVIg= IV immunoglobulin;
IWRS= Interactive Web Response System;
MedDRA= Medical Dictionary for Regulatory Authorities;
MG= myasthenia gravis;
MG-ADL= Myasthenia Gravis Activities of Daily Living;
MG-QoL15r= revised 15-item Myasthenia Gravis Quality of Life scale;
MGC= Myasthenia Gravis Composite;
MGFA= Myasthenia Gravis Foundation of America;
MMRM= mixed-model repeated measures;
QMG= Quantitative Myasthenia Gravis;
Rac= accumulation ratio;
SAE= serious adverse event;
TEAE= treatment-emergent adverse event;
tmax= time at maximum observed plasma concentration
0028-3878
2661-2673
Howard, James F.
4cbe10c2-e6bf-42ec-9fa5-7e35b71ac2e6
Bril, Vera
d5669de1-59a1-4c26-8ebe-2402eb57573c
Burns, Ted M.
a9ed9356-c1c7-466a-8caa-ca25ccd138fe
Mantegazza, Renato
899eec6a-8339-47d7-8b48-86a387ca6a9c
Bilinska, Malgorzata
682b1465-d876-4a52-9ed9-be13d7205ca6
Szczudlik, Andrzej
f4f2ca11-f61b-4864-b167-2585103db14e
Beydoun, Said
76f94a13-697b-44bb-a7e7-09f5022b4529
Rodriguez De Rivera Garrido, Francisco Javier
3eb9809b-b3c4-4500-8a1b-647f0b10694b
Piehl, Fredrick
a7979fbd-5b3c-4ad3-9a09-962200d2c5cd
Rottoli, Mariarosa
bfe52ded-5ac7-439c-a84a-58576b084941
Van Damme, Phillip
10010134-4a1b-4d45-9585-51c596115985
Vu, Tuan
02eefc75-2523-4d44-b34b-eeeb2a0b679b
Evoli, Amelia
5ddf03a0-7790-4f92-9865-72480ef4d54b
Freimer, Miriam
d769c711-d66d-49bf-8933-2ac63921756a
Mozaffar, Tahseen
62f862d1-0a15-4b1b-a4ab-2b663717151f
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Dreier, Torsten
2fcf8470-91e6-48c7-975c-2142980fb3ff
Ulrichts, Peter
c255fbf5-bc5c-439a-b95c-096310cb3f14
Verschueren, Katrien
cab79b4c-0a49-4bab-99e6-16aa0972c852
Guglietta, Antonio
01d44162-bdde-4c4c-ab95-066cf724d590
de Haard, Hans
8f6dc3d7-f74e-4091-8495-77fb4c4121e0
Leupin, Nicolas
69af1e1d-247b-4d1c-80c5-929c8f5cfb3c
Verschuuren, Jan J.G.M.
5c2abada-0c54-4cdc-8ce4-18a95b69499a
Efgartigimod MG Study Group
Howard, James F.
4cbe10c2-e6bf-42ec-9fa5-7e35b71ac2e6
Bril, Vera
d5669de1-59a1-4c26-8ebe-2402eb57573c
Burns, Ted M.
a9ed9356-c1c7-466a-8caa-ca25ccd138fe
Mantegazza, Renato
899eec6a-8339-47d7-8b48-86a387ca6a9c
Bilinska, Malgorzata
682b1465-d876-4a52-9ed9-be13d7205ca6
Szczudlik, Andrzej
f4f2ca11-f61b-4864-b167-2585103db14e
Beydoun, Said
76f94a13-697b-44bb-a7e7-09f5022b4529
Rodriguez De Rivera Garrido, Francisco Javier
3eb9809b-b3c4-4500-8a1b-647f0b10694b
Piehl, Fredrick
a7979fbd-5b3c-4ad3-9a09-962200d2c5cd
Rottoli, Mariarosa
bfe52ded-5ac7-439c-a84a-58576b084941
Van Damme, Phillip
10010134-4a1b-4d45-9585-51c596115985
Vu, Tuan
02eefc75-2523-4d44-b34b-eeeb2a0b679b
Evoli, Amelia
5ddf03a0-7790-4f92-9865-72480ef4d54b
Freimer, Miriam
d769c711-d66d-49bf-8933-2ac63921756a
Mozaffar, Tahseen
62f862d1-0a15-4b1b-a4ab-2b663717151f
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Dreier, Torsten
2fcf8470-91e6-48c7-975c-2142980fb3ff
Ulrichts, Peter
c255fbf5-bc5c-439a-b95c-096310cb3f14
Verschueren, Katrien
cab79b4c-0a49-4bab-99e6-16aa0972c852
Guglietta, Antonio
01d44162-bdde-4c4c-ab95-066cf724d590
de Haard, Hans
8f6dc3d7-f74e-4091-8495-77fb4c4121e0
Leupin, Nicolas
69af1e1d-247b-4d1c-80c5-929c8f5cfb3c
Verschuuren, Jan J.G.M.
5c2abada-0c54-4cdc-8ce4-18a95b69499a

Howard, James F., Bril, Vera, Burns, Ted M., Mantegazza, Renato, Bilinska, Malgorzata, Szczudlik, Andrzej, Beydoun, Said, Rodriguez De Rivera Garrido, Francisco Javier, Piehl, Fredrick, Rottoli, Mariarosa, Van Damme, Phillip, Vu, Tuan, Evoli, Amelia, Freimer, Miriam, Mozaffar, Tahseen, Ward, E. Sally, Dreier, Torsten, Ulrichts, Peter, Verschueren, Katrien, Guglietta, Antonio, de Haard, Hans, Leupin, Nicolas and Verschuuren, Jan J.G.M. , Efgartigimod MG Study Group (2019) Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology, 92 (23), 2661-2673, [92 (23)]. (doi:10.1212/WNL.0000000000007600).

Record type: Article

Abstract

Objective: To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.

Methods: A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.

Results: Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.

Conclusions: Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.

Classification of evidence: This study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.
Glossary

AChR= acetylcholine receptor;
ADA= antidrug antibody;
AE= adverse event;
CI= confidence interval;
Cmax= maximum observed plasma concentration;
FcRn= neonatal Fc receptor;
gMG= generalized myasthenia gravis;
IgG= immunoglobulin G;
IVIg= IV immunoglobulin;
IWRS= Interactive Web Response System;
MedDRA= Medical Dictionary for Regulatory Authorities;
MG= myasthenia gravis;
MG-ADL= Myasthenia Gravis Activities of Daily Living;
MG-QoL15r= revised 15-item Myasthenia Gravis Quality of Life scale;
MGC= Myasthenia Gravis Composite;
MGFA= Myasthenia Gravis Foundation of America;
MMRM= mixed-model repeated measures;
QMG= Quantitative Myasthenia Gravis;
Rac= accumulation ratio;
SAE= serious adverse event;
TEAE= treatment-emergent adverse event;
tmax= time at maximum observed plasma concentration

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More information

Accepted/In Press date: 31 January 2019
e-pub ahead of print date: 22 May 2019
Published date: 4 June 2019
Additional Information: This output will be accessible through PMC after a 12-month embargo

Identifiers

Local EPrints ID: 433474
URI: http://eprints.soton.ac.uk/id/eprint/433474
ISSN: 0028-3878
PURE UUID: 770d2acb-fb8c-470b-83da-f13c20bdbcbc
ORCID for E. Sally Ward: ORCID iD orcid.org/0000-0003-3232-7238

Catalogue record

Date deposited: 23 Aug 2019 16:30
Last modified: 16 Mar 2024 04:37

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Contributors

Author: James F. Howard
Author: Vera Bril
Author: Ted M. Burns
Author: Renato Mantegazza
Author: Malgorzata Bilinska
Author: Andrzej Szczudlik
Author: Said Beydoun
Author: Francisco Javier Rodriguez De Rivera Garrido
Author: Fredrick Piehl
Author: Mariarosa Rottoli
Author: Phillip Van Damme
Author: Tuan Vu
Author: Amelia Evoli
Author: Miriam Freimer
Author: Tahseen Mozaffar
Author: E. Sally Ward ORCID iD
Author: Torsten Dreier
Author: Peter Ulrichts
Author: Katrien Verschueren
Author: Antonio Guglietta
Author: Hans de Haard
Author: Nicolas Leupin
Author: Jan J.G.M. Verschuuren
Corporate Author: Efgartigimod MG Study Group

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