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Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial

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Summary

Background

Satralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder.

Methods

In this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18–74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov, NCT02073279.

Findings

95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23–0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups.

Interpretation

Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD.

Funding

Chugai Pharmaceutical (Roche).

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune neurological disease,1, 2, 3 with an estimated global pooled prevalence of 1·82 per 100 000 people.4 The disorder is characterised by inflammatory lesions in the optic nerve, spinal cord, brainstem, and cerebrum,5 causing potentially severe motor and sensory impairment, bladder dysfunction, vision loss, pain, and other debilitating symptoms.3, 5 Recovery is variable, and inflammatory attacks often result in permanent disability.1, 3 Untreated, the risks of severe disability or death are substantial.1 Prevention of relapses and reduction of the impact of symptoms associated with the disorder are the foremost priorities for disease management.6

NMOSD is distinct from multiple sclerosis,3, 7 the treatments for which are generally ineffective for NMOSD and, in some cases, might be harmful.6 However, patients with NMOSD can often be initially diagnosed with multiple sclerosis.8 Such misdiagnoses not only expose patients to inappropriate treatment, but also increase the risk of disability from untreated attacks,6 showing the importance of early and accurate diagnosis. Therapeutic strategies for the prevention of relapse have predominantly relied on off-label use of various immunosuppressants; however, the efficacy of these drugs in NMOSD has not been established in phase 3 trials.2, 6, 9

Autoantibodies against the water channel protein aquaporin-4 (AQP4) are implicated in the pathophysiology of NMOSD.10 AQP4 autoantibodies (AQP4-IgG) are a key diagnostic marker in the disorder and are not found in other demyelinating disorders.7 More than two-thirds of patients meeting clinical criteria for NMOSD are AQP4-IgG seropositive,7, 11 but some are AQP4-IgG-seronegative.5, 7, 11 The seronegative population is heterogeneous, with several potential mechanisms involved in disease pathophysiology.5

Research in context

Evidence before this study

A PubMed search up to Aug 5, 2014, for “[neuromyelitis optica], [NMO], [NMOSD], or [Devic's disease]” identified 23 publications relating to clinical trials or clinical studies in neuromyelitis optica spectrum disorder (NMOSD). Potential treatment options discussed in these publications included azathioprine, interferon-beta, anti-tuberculosis treatment, mitoxantrone, and rituximab. These trials were either retrospective and observational, or small and prospective in nature. With interferon-beta the effects of treatment on the disorder were negative, whereas for azathioprine, anti-tuberculosis treatment, mitoxantrone, and rituximab the effects were modest, associated with poor tolerability, or warranted further investigation in phase 3 clinical trials.

Two additional PubMed searches were done up to Aug 5, 2014, focusing on the role of interleukin-6 (IL-6) receptor blockade in NMOSD. These searches used the search terms “([neuromyelitis optica] OR [NMO] OR [NMOSD] OR [Devic's disease]) AND [IL-6 receptor blockade]”, and “([neuromyelitis optica] OR [NMO] OR [NMOSD] OR [Devic's disease]) AND [IL-6 receptor antagonist]”. Of the four studies identified, one was preclinical and suggestive of the potential benefit of IL-6 receptor-targeted therapy. The remaining three publications consisted of small, open label-studies (n=3–7) and a case report, all of which used an anti-IL-6 receptor blockade and showed the viability of pursuing treatments targeting this receptor to reduce the risk of relapse in patients with NMOSD.

Within the past 2 years, research in NMOSD has accelerated and yielded groundbreaking developments in potential therapeutic options, with positive results from trials of three distinct treatments: PREVENT (eculizumab, NCT01892345), N-MOmentum (inebilizumab, NCT02200770), and SAkuraSky (satralizumab in combination with patients' baseline immunosuppressants, NCT02028884). To date, eculizumab, a terminal complement inhibitor, has been approved by the US Food and Drug Administration, the European Commission, and Japan's Ministry of Health, Labour, and Welfare for the treatment of aquaporin-4 autoantibody seropositive NMOSD.

Added value of this study

SAkuraStar was a double-blind, randomised, placebo-controlled phase 3 study assessing the efficacy and safety of satralizumab monotherapy. Satralizumab is a monoclonal antibody targeting the IL-6 receptor, which was designed with recycling antibody technology that increases the half-life of the drug in plasma. SAkuraStar enrolled a diverse and global patient population, reflective of real-world NMOSD cohorts at the time of study initiation. The trial population included aquaporin-4 antibody seropositive and seronegative patients, and patients naive to NMOSD treatment.

Implications of all the available evidence

Satralizumab monotherapy was found to be effective in reducing the rate of NMOSD attacks and showed a favourable safety profile. These results were consistent with the reported efficacy and safety of satralizumab in combination with baseline immunosuppressants (SAkuraSky), suggesting that satralizumab could be a valuable treatment option for patients with NMOSD. The ongoing extension studies will offer further insight into long-term safety and effectiveness of satralizumab in this disorder.

Interleukin-6 (IL-6) is thought to have a key role in the disease activity of NMOSD.12 IL-6 promotes the differentiation of naive T cells into inflammatory T-helper-17 cells,13 which in the presence of IL-6 further stimulate the differentiation of B cells into plasmablasts that produce AQP4-IgG.14 IL-6 also increases the permeability of the blood–brain barrier, allowing penetration of AQP4-IgG and proinflammatory cells into the CNS.15 Within the CNS, IL-6 secreted by activated astrocytes16 might directly damage oligodendrocytes and axons, promoting demyelination and neurological deficits.17 IL-6 also regulates the expression of complement C3, a component required for complement pathway activation.16 Serum and CSF IL-6 levels are elevated during and after relapse, are associated with increased disability following relapse,12, 18 and correlate with CSF AQP4-IgG titres.19

Satralizumab is a subcutaneously administered, humanised monoclonal antibody that binds to membrane-bound and soluble IL-6 receptors, preventing IL-6 from binding and inhibiting the IL-6 signalling pathways involved in inflammation.20, 21 Satralizumab dissociates from the receptors at an acidic pH within endosomes and is returned to circulation,22 prolonging the plasma half-life of the drug.22

Satralizumab reduced the risk of relapse in NMOSD when added to baseline immunosuppressants in the SAkuraSky study.20 We did a phase 3 randomised trial (SAkuraStar) to assess the safety and efficacy of satralizumab monotherapy versus placebo in adult patients with NMOSD.

Section snippets

Study design

SAkuraStar was a phase 3, multicentre, randomised, double-blind, placebo-controlled parallel-group study of satralizumab monotherapy, followed by an open-label extension period. The study took place at 44 investigational sites, including university hospitals and clinics, in 13 countries: Bulgaria, Canada, Croatia, Georgia, Italy, Malaysia, Poland, Romania, South Korea, Taiwan, Turkey, the USA, and Ukraine. Approval was obtained from the local ethics committee or institutional review board at

Results

95 (57%) of 168 patients screened were randomly assigned to treatment with either satralizumab (n=63) or placebo (n=32; figure 1, table 1, appendix p 12) between Aug 5, 2014, and April 2, 2017. Numbers of patients enrolled by country is available (appendix p 13). The double-blind treatment period ended as planned, 1·5 years after the random assignment of the last enrolled patient. Disease history and baseline characteristics were well balanced overall, apart from sex; 77 (81%) of the 95

Discussion

Previous preclinical and clinical studies suggest a role for IL-6 in the pathophysiology of NMOSD.12, 17 In the phase 3 SAkuraSky study20 in patients with the disorder, satralizumab as an add-on treatment to baseline immunosuppressants was shown to reduce the risk of relapse (HR 0·38; 95% CI 0·16–0·88; p=0·018; risk reduction 62%). In this phase 3 trial, we showed that patients with NMOSD receiving satralizumab monotherapy also had significantly reduced rate of relapse compared with those

Data sharing

Qualified researchers may request access to individual patient-level data through the clinical study data request platform (http://www.clinicalstudydatarequest.com). For further details on Chugai Pharmaceutical's data sharing policy and how to request access to related clinical study documents see www.chugai-pharm.co.jp/english/profile/rd/ctds_request.html.

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