Drug Treatment of Neuromyelitis Optica Spectrum Disorders: Out with the Old, in with the New?

Figures & data

Figure 1 Drugs for relapse prevention in NMOSD. Approved therapeutic agents (filled rectangles) and agents under clinical evaluation or development (framed rectangles) and their pharmacological targets. Colour of rectangles represents epitopes. Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, Nature Reviews Neurology. Papadopoulos MC, Bennett JL, Verkman AS. Treatment of neuromyelitis optica: state-of-the-art and emerging therapies., COPYRIGHT 2014.²⁴

Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; AQP4-Ab, aquaporin 4 antibody; BBB, blood-brain barrier; CDC, complement-dependent cytotoxicity; CDCC, complement-dependent cellular cytotoxicity.

Table 1 Overview of Clinical Trials

Trial (Phase)	PREVENT (III)^Citation61	N-MOmentum (II/III)^Citation63	SAkuraSky (III)^Citation59	SAkuraStar (III)^Citation58	TANGO (II)^Citation53	RIN-1 (II/III)^Citation52	Nikoo et al^Citation43
Design	Double-blind	Double-blind	Double-blind	Double-blind	Open-label	Double-blind	Open-label
	Time-to-event	Time-to-event	Time-to-event	Time-to-event	Time-to-event	Time-to-event	12 mo
Target	C5	CD19	IL6-R	IL6-R	IL6-R	CD20	CD20
Drug	Eculizumab vs Placebo	Inebilizumab vs Placebo	Satralizumab vs Placebo	Satralizumab vs Placebo	Tocilizumab vs Azathioprine	Rituximab vs Placebo; + Pred. (tapered)	Rituximab vs Azathioprine
Randomisation	2: 1	3: 1	1: 1	2: 1	1: 1	1: 1	1: 1
Concomitant IST	Yes	No	Yes	No	Yes (tapered)	No	No
Inclusion Criteria
NMOSD Criteria	Wingerchuk, 2006/2007	Wingerchuk, 2006/2007	Wingerchuk, 2006	Wingerchuk, 2006	IPND, 2015	AQP4-Ab pos. + optic neuritis or myelitis	IPND, 2015
Preceding disease activity	≥ 2 relapses in 12 mo or ≥ 3 relapses in 24 mo with 1 in 12 mo	≥ 1 relapse in 12 mo or ≥ 2 relapse in 24 mo	≥ 2 relapses in 24 mo with 1 in 12 mo	≥ 1 relapse in 12 mo	≥ 2 relapses in 24 mo or ≥ 3 relapses in 36 mo	n.a.	n.a.
Age	>18y	> 18y	12–74y	18–74y	>18y	16–80y	18–50y
Results
No. Patients	143	230	83	95	118	38	68 (pPP)
Serostatus	All AQP4-Ab pos.	213 AQP4-Ab pos.	55 AQP4-Ab pos.	64 AQP4-Ab pos.	103 AQP4-Ab pos.	All AQP4-Ab pos.	33 AQP4-Ab pos.
		17 AQP4-Ab neg.	28 AQP4-Ab neg.	31 AQP4-Ab neg.	15 AQP4-Ab neg.		35 AQP4-Ab neg.
Baseline EDSS	4.0* (ECU)	3.5* (INE)	3.83** (SAT)	3.9** (SAT)	4.5* (TOCI)	3.5* (RTX)	3.55** (RTX)
	4.0* (Plc)	4.0* (Plc)	3.63** (Plc)	3.7** (Plc)	4.5* (Plc)	4.0* (Plc)	2.40** (Aza)
Relapse rate (HR, 95% CI or p)	3% vs 43% (0.06, 0.02–0.20)	12% vs 39% (0.272, 0.15–0.496)	20% vs 43% (0.38, 0.16–0.88)	30% vs 50% (0.45, 0.23–0.89)	14% vs 47% (0.236, 0.107–0.518)	0 vs 37% (p 0.0058)	ARR Reduction: 1.09 vs 0.49 (p < 0.001)
Reference (NCT)	Pittock 2019^Citation61 (NCT01892345)	Cree 2019^Citation63 (NCT02200770)	Yamamura 2019^Citation59 (NCT02028884)	Traboulsee 2020^Citation58 (NCT02073279)	Zhang 2020^Citation53 (NCT03350633)	Tahara 2020^Citation52	Nikoo 2017^Citation43 (NCT03002038)

Notes: *Median, **mean.

Abbreviations: AQP4-Ab, aquaporin 4 autoantibody; ARR, annualised relapse rate; Aza, azathioprine; CI, confidence interval; ECU, eculizumab; EDSS, expanded disability status scale, HR, hazard ratio; INE, inebilizumab; mo, months; n.a., not applicable; IST, immunosuppressive therapy; y, years; Plc, placebo; pPP, per protocol population; RTX, rituximab; Pred, prednisolone; SAT, satralizumab; TOCI, tocilizumab.

Table 2 Dosing Regimens of Therapeutic Agents for Relapse Prevention in NMOSD

Agent	Application	Typical Dose	To Consider
Rituximab^Citation33,Citation44,Citation47	i.v.	Various regimens, e.g.: 1g at day 1, 1g at day 15; repeat 1g/d every six months	Allergic reactions during administration; monitoring of serum immunoglobulins
Mycophenolate Mofetil^Citation45,Citation47	p.o.	750–3000 mg/d	Bone marrow suppression, hepatotoxicity
Azathioprine^Citation34,Citation43,Citation47	p.o.	2.5–3.0 mg/kg body weight daily	Bone marrow suppression, hepatotoxicity
Satralizumab^Citation58,Citation59	s.c.	120 mg at day 1, day 14, day 28; then every four weeks	Hepatotoxicity, monitoring neutrophils
Eculizumab^Citation61	i.v.	900mg/week for four weeks; then 1200mg every two weeks	Vaccination against N. meningitides prior application
Inebilizumab^Citation63	i.v.	300 mg at day 1 and day 15; then 300mg every six months	Hypogammaglobulinemia
Tocilizumab^Citation53,Citation64	i.v. or s.c.	i.v.: 8 mg/kg body weight every four weeks	Monitoring neutrophils, platelets, lipids, and liver function

Abbreviations: i.v, intravenously; p.o., per os; s.c., subcutaneously; kg, kilogram; d, day.

Table 3 Drugs Under Development

Agent	Target	Mode of Action	Level of Development
Aquaporumab^Citation66,Citation67	AQP4	Prevention of AQP4-Ab induced ADCC	Mouse model of NMO
Bortezomib^Citation68	Proteasome inhibitor	Depletion of plasma cells	Phase II clinical trial for NMOSD (add-on) (NCT02893111)
Ravulizumab^Citation70^–^Citation72 (Ultomiris^®)	C5	Complement-inhibitor	PNH (approved by FDA, EMA); Phase III clinical trial for NMOSD (CHAMPION trial; NCT04201262).
Sivelestat^Citation74	Neutrophil elastase inhibitor	Reduction of inflammatory cytokines	Mouse model of EAE
Ublituximab^Citation76	Fcy receptor IIIa on CD20-positive B-cells	Depletion of CD20-positive B-cells, prevention of ADCC	Phase Ib clinical trial as add-on to steroids in NMOSD

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