Elsevier

The Lancet Neurology

Volume 7, Issue 9, September 2008, Pages 796-804
The Lancet Neurology

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Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study

https://doi.org/10.1016/S1474-4422(08)70173-XGet rights and content

Summary

Background

Repeated subcutaneous injections of a monoclonal antibody against the p40 subunit of interleukins 12 and 23, ustekinumab, were used to treat patients with relapsing-remitting multiple sclerosis (RRMS) to assess the drug's safety, efficacy, and pharmacokinetics.

Methods

In this phase II, multicentre, randomised, double-blind, placebo-controlled study, 249 patients with RRMS, aged 18–65 years, were eligible to be assigned equally (by a central randomisation procedure based on study site and presence or absence of gadolinium-enhancing T1-weighted lesions at baseline) to one of five groups that received placebo or four different ustekinumab dosages at weeks 0, 1, 2, 3, 7, 11, 15, and 19. Ustekinumab doses were 27 mg, 90 mg q8w, 90 mg, or 180 mg; the 90 mg q8w dosage group received placebo substitute at weeks 7 and 15. The primary endpoint was the cumulative number of new gadolinium-enhancing T1-weighted lesions on serial cranial MRI through week 23. Patients were followed up through week 37. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00207727.

Findings

From August, 2004, to December, 2006, 249 patients underwent randomisation (49 for placebo; 50 for each ustekinumab group). Ustekinumab treatment did not show a significant reduction in the primary endpoint for any dosage groups versus placebo. At week 37, adverse events occurred in 38 (78%) placebo-treated patients and 170 (85%) ustekinumab-treated patients, with infections most commonly reported. Serious adverse events occurred in one (2%) placebo-treated patient and six (3%) ustekinumab-treated patients. Malignant diseases were reported in two patients shortly after the initiation of ustekinumab treatment; both patients were withdrawn from the trial and given appropriate treatment, which resulted in complete remission. No serious infections, cardiovascular events, or exacerbation of demyelinating events occurred. A dose-dependent increase in serum concentrations of ustekinumab was recorded.

Interpretation

Ustekinumab is generally well tolerated but does not show efficacy in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions in multiple sclerosis.

Funding

Centocor Research & Development.

Introduction

Multiple sclerosis is a complex neurological disorder of the CNS, characterised by recurrent and multifocal inflammation, demyelination, and axonal damage. The clinical manifestations of multiple sclerosis, which include loss of visual, sensorimotor, autonomic, and cognitive functions, frequently have a profound effect on activities of daily life. Early investigations suggested that the disease is mediated by CD4+ effector cells specific to myelin antigens.1 Several treatments commonly used to reduce relapse and prevent radiological lesion formation in relapsing-remitting multiple sclerosis (RRMS) are believed to inhibit the differentiation or biological activities of myelin-specific effector cells, or block their transmigration across the blood–brain barrier.2, 3 However, these treatments are only modestly effective (eg, interferon [IFN] β and glatiramer acetate) or do not have long-term tolerability (eg, mitoxantrone and natalizumab).4, 5, 6, 7, 8 More specific immune interventions are clearly needed to interrupt pathogenic inflammatory pathways in multiple sclerosis without globally arresting lymphocyte and monocyte function.

The IL (interleukin) 12 p40 family of cytokines (IL12 and IL23) has been strongly implicated in the pathogenesis of both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model that mimics many clinical and histological characteristics of multiple sclerosis.9, 10, 11, 12 IL12 and IL23 are heterodimers, each composed of a unique chain (IL12 p35 and IL23 p19) and a common subunit (IL12/23 p40).13, 14 Both are produced mainly by activated myeloid cells (dendritic cells, macrophages, and microglia) and bind to receptors expressed predominantly on lymphocytes (T cells and natural killer cells). IL12 is a potent inducer of IFNγ in T lymphocytes and natural killer cells, and stimulates naive CD4+ T-cell differentiation along a T-helper (Th)1 lineage.14 IL23 promotes and stabilises IL17 production by CD4+ T cells.15 IL12 p40 and IL23 have been detected in multiple sclerosis lesions.16, 17 Circulating mononuclear cells from patients with multiple sclerosis express increased concentrations of IL12 and IL23.18, 19

Treatment with antibodies that neutralise IL12 p40 prevents clinical EAE in rodents and non-human primates.20 Mice genetically deficient in the common IL12 p40 chain or the unique IL23 p19 chain are resistant to EAE induction.9, 11 Conversely, reactivation of typically innocuous myelin-specific T-cell lines (derived from EAE-resistant or EAE-tolerant mice) in the presence of recombinant IL12 or IL23 unmasks their latent encephalitogenic potential.10, 12, 21 Furthermore, systemic injection of recombinant IL12 or intracerebral injection of an IL23 encoding adenoviral vector induces clinical relapses of EAE.9, 22

IIL12 and IL23 induce differentiation of IFNγ and IL17, respectively, which drive tissue inflammation and are upregulated in active multiple sclerosis plaques.23, 24 Data suggest that IL17 mediates an increase in cerebrovascular permeability during EAE lesion formation.25, 26 Although previous studies have shown that IFNγ is dispensible, and even has a regulatory role in some models of EAE,11, 27 IL12 directly stimulates murine myelin-specific T cells to express CNS homing molecules.28, 29 In contrast with the EAE studies, use of recombinant IFNγ to treat patients with multiple sclerosis was associated with clinical worsening.30

Ustekinumab (Centocor, Malvern, PA, USA) is a fully human monoclonal antibody against IL12/23 p40 that binds with high affinity and neutralises IL12/23 bioactivity as measured by inhibition of IFNγ production by phytohemagluttinin-stimulated human T-cell blasts.20 In a preclinical study, ustekinumab prevented EAE in marmosets immunised with myelin basic protein.20 In an independent study that used serial MRI, ustekinumab delayed white-matter demyelination, prevented T2 lesion accumulation, and suppressed inflammation of pre-existing brain lesions in marmosets with established EAE.31 In a phase I clinical study, single subcutaneous doses of ustekinumab were shown to be well tolerated in patients with RRMS,32 supporting its investigation in large clinical trials. We did a full dose-ranging, proof-of-concept study to assess the safety, efficacy, and pharmacokinetics of repeated subcutaneous injections of ustekinumab in patients with RRMS.

Section snippets

Patients

Patients aged between 18 and 65 years and with a diagnosis of RRMS, as defined by the International Panel on the Diagnosis of Multiple Sclerosis criteria,33 were eligible for this study. Inclusion criteria were a Kurtzke's expanded disability status scale (EDSS) score from 0 to 6·5,34 and at least two relapses of multiple sclerosis in the previous 2 years or one relapse in the previous 6 months (but not within 1 month before screening). Exclusion criteria included the use of immunomodulating

Results

Between August, 2004, and December, 2006, 249 patients were randomly assigned to placebo or to one of the four ustekinumab dosage groups (figure 1). Baseline demographics and disease characteristics were similar across groups (table 1). Most patients (70%) were female. Median values were: age 38 years, weight 69·3 kg, disease duration 1·9 years, EDSS score 2·5, and zero Gd-enhancing T1-weighted lesions on screening MRI. About half of the patients (47%) had at least one Gd-enhancing lesion at

Discussion

This study shows that use of a neutralising monoclonal antibody, ustekinumab, against the IL12/23 p40 chains during a 19-week dosing period did not substantially inhibit the formation of inflammatory white matter lesions or affect clinical events in patients with RRMS. The lack of therapeutic benefit of ustekinumab in multiple sclerosis is surprising in light of reports showing that lower antibody doses were efficacious in suppressing moderate-to-severe psoriasis,40, 41 inflammatory bowel

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