Department of Molecular Biology, Princeton University
NMOSD is associated with elevated levels of the pleiotropic cytokine interleukin-6, making the cytokine an apt therapeutic target.
NEUROMYELITIS OPTICA SPECTRUM DISORDER (NMOSD), also known as Devic disease, is a rare, debilitating autoimmune disorder of the central nervous system that preferentially damages the optic nerves and spinal cord.1-4 Women and people of African or Asian descent are disproportionately affected.4 A single episode of attack may be enough to result in disabilities such as total blindness, muscle damage, and paralysis.1,5,6
Most patients with NMOSD will subsequently experience severe relapses that can cause permanent neurological damage and, in some cases without treatment, death.4,5 Distinct from relapsing-remitting multiple sclerosis (MS),4,5,7 NMOSD is mediated by the humoral immune system; consequently, NMOSD does not respond to standard treatments for MS, which is primarily a cell-mediated autoimmune disorder, by comparison.4,7 Emerging therapies targeting specific molecules related to NMOSD pathogenicity are needed for patients who are refractory to standard treatments for NMOSD, which includes high-dose corticosteroids, apheresis therapies, and off-label use of immunotherapies for relapse prevention.5,7
NMOSD is associated with elevated levels of the pleiotropic cytokine interleukin-6 (IL-6).4,8 IL-6 signaling through both membrane-bound (classic signaling) and soluble forms of the IL-6 receptor (IL-6R; trans-signaling) regulates inflammatory immune responses (FIGURE).2,5,8,9 Dysregulation of IL-6 expression or signaling contributes to NMOSD pathogenesis.5,10 The resulting inflammatory feedback loop triggers secretion of astrocyte-damaging anti–aquaporin4 immunoglobulin G (AQP4-IgG) autoantibodies.1,3,7
IL-6R is thus a key therapeutic target for NMOSD.1 Anti–IL-6R monoclonal antibodies (mAbs), such as the investigational tocilizumab (Actemra; Genentech) and satralizumab (Enspryng; Chugai and Roche), are effective in blocking IL-6 signaling, inhibiting AQP4 autoantibody production, and mitigating pain and general fatigue in patients.3,4,8,9 Moreover, these anti–IL-6R therapeutics reduce the severity of NMOSD and even prevent relapses in patients who cannot tolerate standard immunosuppression therapy.5,7
Tocilizumab was most recently approved by the FDA in 2017 for T-cell–induced cytokine release syndrome after its original 201 approval.8,9,11 In the open-label, multicenter, randomized, phase 2 TANGO trial (NCT03350633)12,13 that included 118 patients with NMOSD, intravenous tocilizumab administered at 8 mg/kg every 4 weeks was associated with reduced risk of relapse and improvement in the relative risk of 24-week confirmed disability progression, by 78%, in patients with refractory NMOSD compared to those treated with azathioprine.8,9,12
Satralizumab also is a humanized mAb targeting IL-6R administered subcutaneously. It was bioengineered from tocilizumab via novel recycling antibody technology, which prolongs its availability in the circulation.3,8 It was approved in 2020 for the treatment of AQP4-IgG–positive NMOSD in adults (and adolescents in Canada),3,8 after results of the multinational, randomized, double-blind, placebo-controlled phase 3 SAkuraStar (NCT02073279)14,15 and SAkuraSky (NCT02028884)2,16 clinical trials demonstrated its efficacy in patients seropositive for AQP4-IgG. The primary end point in both studies was the time to first relapse, defined as new or worsening objective neurologic symptoms, as determined by independent review committees.2,15
In SAkuraStar, 95 patients with NMOSD who were AQP4-IgGseropositive, aged 18 to 74 years, were randomly assigned (2:1) to monotherapy with a dose of 120 mg satralizumab or placebo at weeks 0, 2, and 4, followed by a dose of 120 mg every 4 weeks thereafter.8,9,15 Patients experiencing clinical relapse in the prior 30 days were excluded, though patients included were required to have had a relapse in the prior year.15 Concomitant immunosuppressant use was prohibited. A total of 76% and 72% of patients on satralizumab were relapse-free at weeks 48 and 96, compared with 61.9% and 51.2%, respectively, with placebo. The hazard ratio (HR) of satralizumab to placebo in patients who were AQP4-IgG seropositive (n = 64) for clinically defined relapse was 0.26 (95% CI, 0.11-0.63).
In SAkuraSky, satralizumab (n = 42) or placebo (n = 41) was added to baseline immunosuppressant therapy for 83 patients aged 12 to 74 years.2,8 Patients treated with any drug targeting the IL-6 pathway were excluded. In contrast to SAkuraStar, patients were required to have experienced at least 2 relapses in the prior 2 years, with at least 1 in the previous year. Patients were randomly assigned to satralizumab or placebo (1:1) with a dose of 120 mg at weeks 0, 2, and 4, followed by a dose of 120 mg every 4 weeks thereafter. A total of 89% and 78% of satralizumab-treated patients were relapse-free at 48 and 96 weeks, compared with 66% and 59%, respectively, with placebo. In the subgroup of patients who were AQP4-IgG seropositive (n = 55), 11% of satralizumab-treated patients had a protocol-defined relapse, compared with 43% of those receiving placebo (HR, 0.21; 95% CI, 0.06-0.75). Meanwhile, relapse in the AQP4-IgG–seronegative subgroup was not statistically different between patients receiving satralizumab and placebo.
The results of these pivotal studies indicated that satralizumab decreased risk of relapse and was well tolerated when administered with or without accompanying immunosuppressant therapy, making satralizumab an attractive treatment option for patients with NMOSD.2,3,5 The pharmacokinetics of satralizumab are not affected by patient age, sex, or race.3 Serious adverse effects (AEs) were reported in SAkuraStar and SAkuraSky, with both placebo and satralizumab groups having similar rates.2,3,5 The most common AEs with satralizumab in both studies included headache, arthralgia, and injection-related reactions.3
For patients with refractory NMOSD, clinical improvement will depend on the development of therapeutics that can target different key players in NMOSD pathologic autoimmunity. The primary goal of this treatment, whether administered as monotherapy or in combination with other agents, is to prevent relapse and reduce the severity of attacks. Larger and longer trials should be undertaken to clarify optimal dosing regimens, efficacy, durability, and safety of satralizumab for long-term use. As AQP4-IgG–seropositive patients are encouraged to maintain therapy for years after an attack, less invasive and more effective drugs like satralizumab could be the key to these patients functioning much more independently.
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Department of Molecular Biology, Princeton University, Princeton, NJ