Novel Immunotherapies for Myasthenia Gravis

Figures & data

Table 1 Summary of the Newer Molecules for Myasthenia Gravis Therapy

Molecule	Mechanism of Action	Target Group	Route and Dose of Administration (if Available)	Current Evidence
Complement inhibitors
Eculizumab	C5 complement inhibitor	AChR+ MG	IV induction of 900 mg weekly for 4 weeks followed by 1200 mg maintenance every 2 weeks	Approved for treatment of adults with AChR+ gMG
Ravulizumab	C5 complement inhibitor (long acting)	AChR+ MG	IV weight-based dose. Single loading dose of 2400–3000 mg and maintenance doses of 3000–3600 mg every 8 weeks	Approved for treatment of adults with AChR+ gMG
Zilucoplan	C5 and C5b complement inhibitor	AChR+ MG	SC, once daily dose of 0.3 mg/kg	Phase 3 study is completed (NCT04115293)
Pozelimab	C5 complement inhibitor	AChR+ or LRP4+ MG	IV loading dose followed by SC (usually in combination with cemdisiran)	Phase 3 study is ongoing (NCT05070858)
Cemdisiran	siRNA suppressing hepatic C5 synthesis	AChR+ or LRP4+ MG	200 mg SC 4-weekly (usually in combination with pozelimab)	Phase 3 study is ongoing (NCT05070858)
Gefurulimab (ALXN1720)	Anti-C5 antibody	AChR+ MG	SC weight-based dose once weekly	Phase 3 study is underway (NCT05556096)
Vemircopan (ALXN2050)	Complement pathway factor D inhibitor	AChR + MG	Oral, multiple dosages in trial	Phase 2 study is ongoing (NCT05218096)
FcRn blockers
Efgartigimod	FcRn antagonist	All antibody subtypes of MG	IV, first cycle of 10 mg/kg/dose weekly for 4 weeks and repeat cycles at variable intervals based on symptom recurrence	Approved for treatment of AChR+ gMG in adults
Rozanolixizumab	Anti-FcRn monoclonal antibody	All antibody subtypes of MG	SC, in phase 2 study 7 mg/kg was given weekly for 3 weeks followed by weekly 7 mg/kg or 4 mg/kg injections for 3 more doses	Phase 3 study is completed (NCT03971422)
Nipocalimab (M281)	Anti-FcRn monoclonal antibody	All antibody subtypes of MG	IV infusion of 60 mg/kg every 2 weeks, multiple doses experimented in phase 2 trial	Phase 3 study is ongoing (NCT04951622)
Batoclimab (RVT 1401)	Anti-FcRn monoclonal antibody	All antibody subtypes of MG	SC 340 or 680 mg every week induction followed by maintenance of 340 mg every 1 or 2 weeks	Phase 3 study is ongoing (NCT05403541)
ABY-039	Bivalent antibody-mimetic against FcRn	-	-	Phase 1 study was prematurely terminated
B cell and plasma cell targeting therapies
Rituximab	Anti CD20 monoclonal antibody	All antibody subtypes of MG	IV infusion. Various regimens are used, commonly two doses of 1 g 2 weeks apart or 375 mg/m^2 infusions repeated weekly for 4 weeks	One phase 2 study was completed, extensive class IV data
Inebilizumab	Anti CD19 monoclonal antibody	AChR+ or MuSK+ MG	IV infusion, 300 mg 2 doses 2 weeks apart and maintenance after 6 months	Phase 3 study is underway (NCT04524273)
Obinutuzumab	Anti CD20 monoclonal antibody	-	IV infusion as 6 treatment cycles, Dose of 100 mg in day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of the first cycle followed by 1000 mg on the first day of the subsequent cycles	No ongoing study, anecdotal evidence emanates from a single case report
Bortezomib	26S proteasome inhibitor	All antibody subtypes of MG	SC, administered in 2 treatment cycles, each with 4 injections of 1.3 mg/m^2 body surface per cycle	Phase 2 study was terminated due to recruitment difficulties
Tolebrutinib	Bruton’s tyrosine kinase inhibitor	All antibody subtypes of MG	Oral once daily dose	Phase 3 study is underway (NCT05132569)
TAK-079	Anti CD38 monoclonal antibody	AChR+ or MuSK+ MG	SC injection weekly with one of 2 doses for 8 weeks	Recruitment has been completed for phase 2 study (NCT04159805)
Chemokine and cytokine pathway targeting therapies
Belimumab	Monoclonal antibody against BAFF	AChR+ or MuSK+ MG	IV 10 mg/kg every 2 weeks for 4 weeks and then once every 4 weeks	Phase 2 study has been completed
Telitacicept (RC18)	Inhibition of BAFF and APRIL	AChR+ or MuSK+ MG	SC 160 mg or 240 mg weekly	Phase 2 study is ongoing (NCT04302103)
Iscalimab (CFZ533)	Anti CD40 monoclonal antibody	All antibody subtypes of MG	IV infusion 10 mg/kg, 2 to 4 weekly doses	Phase 2 study has been completed
Tocilizumab	IL-6 receptor antibody	AChR+ MG	IV infusion every 4 weeks	Phase 2 study is ongoing (NCT05067348)
Satralizumab	IL-6 receptor antibody	All antibody subtypes of MG	SC, 120 mg every 2 weeks for 4 weeks and every 4-weeks maintenance thereafter	Phase 3 study is ongoing (NCT04963270)
Tofacitinib	Intracellular signalling disruption by inhibition of Janus kinases	AChR+ or seronegative MG	Oral, 5 mg twice a day	Early phase 1 study is underway (NCT04431895)
Miscellaneous
Subcutaneous immunoglobulin	Broad spectrum immunomodulator	AChR+, MUSK+ or LRP4+ MG	1–2 g/kg over 4 weeks, equivalent to IVIg doses	Prospective open label trial has been completed. Phase 2 study is underway (NCT04728425)
CAR T cell therapy	Targeted depletion of autoimmune cells with genetically modified T cells	All antibody subtypes of MG	IV infusion	Phase 2 study is ongoing (NCT04146051)
CAAR T cell therapy	Targeted depletion of autoantibody- expressing immune cell clones with genetically modified T cells	AChR+ or MuSK+ MG	IV infusion, multiple dosage regimens	Phase 1 open label study for MuSK MG is underway (NCT05451212)
Autologous HSCT	Immune ablation and repopulation	All antibody subtypes of MG	-	No ongoing trials, class IV data

Abbreviations: APRIL, a proliferation-inducing ligand; AChR+, acetyl choline receptor antibody positive; BAFF, B-cell activating factor, CAAR, chimeric autoantibody receptor; CAR, Chimeric antigen receptor; FcRn neonatal Fc receptor; HSCT, haematopoietic stem cell transplantation; IL-6, interleukin 6; IV, intravenous; IVIg, intravenous immunoglobulin; LRP4+, low density lipoprotein receptor-related protein 4 antibody positive; MG, myasthenia gravis; MuSK+, muscle specific kinase antibody positive; SC, subcutaneous; siRNA, small interfering ribonucleic acid.

Figure 1 Targets of novel therapeutic agents in myasthenia gravis.

Table 2 Summary of Systematic Reviews, Randomized Trials, and Prospective Studies of Rituximab in Myasthenia Gravis

Authors	Type of Evidence	Study Population	Dosage Schedule	Outcomes
Nowak et al, 2021 (BEAT-MG study)^Citation67	Phase 2 randomized controlled study	52 AChR+ mild to moderate MG on a minimum of 15 mg/day prednisolone (25 received rituximab and 27 placebo)	2 cycles of weekly 375 mg/m^2 for 4 weeks at 6-month intervals versus placebo for 52 weeks	No significant steroid sparing effect (primary outcome) was noted in the treatment group compared to placebo (60% vs 56%). Requirement for rescue therapy for exacerbations was lower in the intervention group.
Iorio et al, 2015^Citation68	Systematic review and meta-analysis of studies with 2 or more patients from 2000–2014	168 patients (91 AChR+, 70 MuSK+, 7 seronegative) from 37 studies	Variable dosage regimens	Positive response was reported in 83.9% with no significant difference between the antibody subtypes
Tandan et al, 2017^Citation69	Systematic review and meta-analysis of case reports and series from 2000–2015	169 patients (99 AChR+, 57 MuSK+) from 47 publications	Variable dosage regimens	MM or better was achieved in 44% and remission in 27%. MuSK+ MG had better outcomes than AChR+ MG (MM in 72% and 30% respectively, and remission in 47% and 16% respectively)
Di Stefano et al, 2020^Citation70	Systematic review of observational studies with ≥5 patients from 1999–2019	165 AChR+ MG from 13 studies	Variable dosage regimens	Marked clinical improvement in 68% and remission was maintained > 1 year
Li et al, 2021^Citation71	Systematic review and meta-analysis of observational studies from 2008–2020	260 refractory AChR+ MG from 21 studies	171 were treated with routine dose and 89 with lower dose regimens	Clinical improvement was documented in 77% patients with no significant difference between the two dosage groups
Zhao et al, 2021^Citation72	Systematic review and meta-analysis of case series and observational studies from 2000–2021	417 refractory MG from 24 studies (242 AChR+, 155 MuSK+, 20 seronegative)	Variable dosage regimens	64% achieved MM or better and 81% could withdraw oral immunosuppressant therapy. MuSK+ MG and mild to moderate severity group had better response to therapy
Anderson et al, 2016^Citation73	Prospective, open label study	14 refractory MG (6 MuSK+, 5 AChR+, 3 seronegative)	375 mg/m^2 weekly for 4 weeks and then monthly for 2 months or 750 mg/m^2 every 2 weeks for 1 month	All patients showed marked improvement at the end of follow up of 22.6 months
Hehir et al, 2017^Citation74	Prospective review, multicentric	55 MuSK+ MG; 24 treated with Rituximab and 31 with no exposure to rituximab	4 weekly doses of 375 mg/m^2 with retreatment as clinically indicated	Rituximab therapy was significantly associated with improved outcome (58% vs 16%) and reduced prednisolone requirement after >3.5 years follow up
Jing et al, 2017^Citation75	Prospective study	8 AChR+ refractory MG	Low dose 600 mg induction and 600 mg maintenance after 6 months based on clinical status	All patients had clinical improvement at median 6 months follow up. B cell depletion for 6 months was achieved with low dose
Beecher et al, 2018^Citation76	Prospective open label study	22 refractory MG (10 AChR+, 9 MuSK+, 3 seronegative)	Induction (either 4 doses of 375 mg/m^2 or 2 doses of 750 mg/m^2) followed by maintenance doses during clinical worsening	Significant improvement of manual muscle test scores, reduction in prednisolone dose and increased time to relapse with rituximab; mean 28.8 months follow up
Landon-Cardinal et al, 2018^Citation77	Prospective study	12 severe (MGFA IV or V) and refractory AChR+ MG	1 g on days 0 and 14 and after 6 months	Post-intervention improved status was noted in 55% at 12 month evaluation, only 1 patient achieved primary outcome of 20-point improvement in MMS
Du et al, 2022^Citation78	Prospective single arm study	13 new onset AChR+ MG	Low dose rituximab of 100 mg repeated weekly for a maximum of 3 times, with maintenance of 100 mg; individualized based on clinical status and CD19 counts	All patients achieved MM or better with a low cumulative dose of rituximab over a median follow up period of 19 months

Abbreviations: AChR+, acetyl choline receptor antibody positive; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; MM, Minimal manifestations status; MMS, Myasthenic Muscle Score; MuSK+, muscle specific kinase antibody positive.

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