Elsevier

The Lancet

Volume 394, Issue 10206, 12–18 October 2019, Pages 1352-1363
The Lancet

Articles
Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial

https://doi.org/10.1016/S0140-6736(19)31817-3Get rights and content

Summary

Background

No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD.

Methods

We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770.

Findings

Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150–0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo.

Interpretation

Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD.

Funding

MedImmune and Viela Bio.

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is a severe, autoimmune, inflammatory CNS disease with a prevalence of 0·5–4·4 cases per 100 000 people.1 NMOSD presents with optic neuritis and transverse myelitis,1 and less commonly, diencephalic, brainstem, and cerebral hemisphere attacks. Incomplete recovery from attacks is typical, and patients are at risk of death from respiratory failure.2

Previously considered to be a variant of multiple sclerosis, NMOSD is now recognised as a distinct disease,2 characterised by astroglial injury, demyelination, and substantial neuronal loss; most injury occurs during acute attacks.3 A highly specific serum autoantibody against the astrocyte water channel aquaporin-4 (AQP4), AQP4-IgG,4 is detected in 60–80% of patients and is likely to be pathogenic.5, 6, 7 In the presence of a complement or inflammatory T-cell response, AQP4-IgG causes disease-specific CNS injury.5 Multiple lines of evidence suggest that NMOSD is predominantly a B cell-mediated disorder resulting from pathological autoantibody production, pro-inflammatory cytokine secretion, and B-cell antigen presentation.8

No approved therapies for NMOSD exist, and randomised controlled trials have been initiated only since 2013. Immunosuppressants, such as azathioprine, corticosteroids, and mycophenolate mofetil,9 and the B cell-depleting drug rituximab10 are used empirically to prevent attacks. Although no prospective randomised controlled trial data are available for CD20 B cell-depleting antibody rituximab in NMOSD, evidence from retrospective studies and meta-analyses suggests a clinical benefit.11 On the basis of retrospective, observational evidence, rituximab has been incorporated into treatment guidelines.12

Research in context

Evidence before this study

A search from inception to Jan 31, 2014, with no restriction on language, was done in the MEDLINE, Embase, and Cochrane databases, using the search terms ([neuromyelitis optica] OR [NMO] OR [NMOSD] OR [Devic's disease]). The search identified 2438 articles, which were screened for relevance with regard to treatment options, and 105 studies were included in a review of the evidence.

Most of the 105 studies were small, retrospective, observational studies with no comparator that rarely included sufficient detail on the trial methodology to evaluate selection bias, information bias, or confounding factors. After the identification of highly specific serum autoantibodies against the aquaporin-4 water channel expressed on astrocytes in the CNS in 2004, and the altered diagnostic criteria for patients with neuromyelitis optica spectrum disorder (NMOSD) in 2006, the characteristics of patients included in trials before and after these landmarks differed. Moreover, no safety data were reported in most of these studies; therefore, no benefit–risk assessments could be done, and the dosing regimens and durations of therapy differed greatly. Finally, no unified and accepted definition of an NMOSD attack was used.

Of the studies identified, seven summarised the effects of the immunosuppressant azathioprine, with or without corticosteroid treatment; all seven were uncontrolled case studies, three of which reported large multicentre retrospective case studies. Significant reductions in annualised relapse rate (ARR) were reported before and after treatment in six out of seven of these case studies. Ten uncontrolled, retrospective case series reported on the use of rituximab, an anti-CD20, B cell-depleting antibody in patients with NMOSD (134 patients in total). Nine of these studies reported an apparent reduction in ARR, and seven out of eight studies claimed an improvement on the Expanded Disability Status Scale (EDSS) after treatment.

The use of cyclophosphamide with or without steroids was examined in three uncontrolled, retrospective cases (12 patients in total), methotrexate with or without steroids was examined in two small case studies, and mitoxantrone with or without corticosteroids was examined in a further three case studies. In all but one of these studies, disease stabilisation was observed. One study reported that cyclophosphamide was ineffective and was associated with adverse events.

A further ten small case studies assessed an additional eight therapies, including mycophenolate mofetil, eculizumab, and natalizumab. Most of these studies reported reductions in ARR and EDSS scores without a reference control group, although subsequent studies have suggested that natalizumab treatment in NMOSD might be ineffective, and possibly harmful.

All of these studies were limited by bias inherent to the study design, and none of them were randomised. Therefore, although reductions in ARR or EDSS scores could be caused by treatment effect, they could also be attributed to regression to the mean, selection bias, or both.

Added value of this study

To date, no approved therapies exist for NMOSD, and randomised controlled trials have only recently been initiated. Currently, medications are used empirically to prevent and treat attacks. Although guidelines recommend the use of immunosuppressants in NMOSD, only low-level clinical evidence supporting this practice is available, based exclusively on uncontrolled or retrospective studies. Without randomised controlled studies, the benefits and risks associated with the use of off-label medications in NMOSD are not well established. Thus, there is a clear unmet need for effective, evidence-based treatments to delay or prevent attacks in NMOSD. N-MOmentum is a double-blind, randomised placebo-controlled phase 2/3 study assessing the efficacy and safety of inebilizumab in patients with NMOSD. The trial was designed to be acceptable to patients, physicians, ethics boards, and regulatory authorities, with safety as a key consideration, and it included independent study oversight and objective adjudication of NMOSD attacks according to predefined criteria.

Implications of all the available evidence

N-MOmentum is the first large, randomised controlled trial of any disease-modifying therapy to demonstrate superiority over placebo in reducing the risk of an NMOSD attack, disability worsening, MRI lesion activity, and disease-related hospitalisations in patients with NMOSD.

Effective, evidence-based treatments to delay or prevent attacks in NMOSD are clearly needed.13 Inebilizumab is a humanised, affinity-optimised, afucosylated IgG1 kappa monoclonal antibody that binds to the B-cell surface antigen CD19. Compared with anti-CD20 monoclonal antibodies that recognise and deplete a small subset of CD20-expressing T lymphocytes (in addition to B lymphocytes),14 anti-CD19 antibodies recognise and deplete a wider range of lymphocytes exclusively from the B-cell lineage. Inebilizumab depleted CD19 B cell populations in preclinical models15 and phase 1 clinical studies in systemic sclerosis16 and multiple sclerosis,17 with an acceptable safety profile. The aim of the N-MOmentum study was to assess the efficacy and safety of B-cell depletion with inebilizumab as a monotherapy in reducing the risk of attacks and disability in NMOSD.

Section snippets

Study design

We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 trial with an open-label extension period (appendix p 7). Participants were screened at 99 outpatient specialty clinics or hospitals in 25 countries (appendix p 4). Institutional review boards or ethics committees at each study site approved the protocol. The study is registered with ClinicalTrials.gov, number NCT02200770. The study was conducted in accordance with the provisions of the International Conference on

Results

From Jan 6, 2015, to Sept 24, 2018, 467 patients were screened at 99 participating sites in 25 countries. 231 (49%) patients were enrolled, with 175 (76%) randomly allocated to inebilizumab (of whom 161 [92%] were AQP4-IgG-seropositive; one AQP4-IgG-seronegative patient was not dosed and was not included in the intention-to-treat population) and 56 (24%) randomly allocated to placebo (of whom 52 [93%] were AQP4-IgG-seropositive; figure 1). 17 AQP4-IgG-seronegative participants were treated,

Discussion

The N-MOmentum study successfully recruited diverse participants from 25 countries in the first randomised trial of a B cell-depleting therapy in NMOSD. The study demonstrated efficacy of inebilizumab over placebo in reducing the risks of attack, disability, MRI lesion activity, and disease-related inpatient hospitalisations. Most study participants (213 [93%] of 230) were seropositive for anti-AQP4 antibodies; similar results for all outcomes were found in this subgroup and in the overall

Data sharing

Anonymised data sets for defined study outcomes will be made available on reasonable request by a suitably qualified individual. Proposals should be directed to [email protected]. Requestors will be required to sign a data access agreement. Requests will be considered up to 3 years after article publication.

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  • Cited by (0)

    Prinicpal study investigators are listed at the end of the Article and in the appendix

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