Evaluation of neurological changes in secondary progressive multiple sclerosis patients treated with immune modulator MIS416: results from a feasibility study

Abstract

Background: While disease progression can be readily monitored in early stage relapsing multiple sclerosis (MS), it is more challenging for secondary progressive multiple sclerosis (SPMS). This advanced stage of disease has distinct pathophysiology due to compartmentalization of neuroinflammatory activity within the central nervous system, resulting in increased incidence and severity of cognitive dysfunction. The shift in the dominant disease pathways is underscored by the failure of relapsing therapies to benefit SPMS patients, highlighting the need for novel treatment strategies and clinical trial endpoints that are well-aligned with potential benefits. The Expanded Disability Status Scale (EDSS) is widely used but is weighted towards ambulatory ability, lacking sensitivity to other aspects of neurological impairment experienced in more severely disabled SPMS patients, so may not effectively capture their clinical status.To investigate the feasibility of an alternative clinical trial endpoint model for a phase 2B trial of an immune modulator for SPMS, the potential for treatment efficacy-based patient-centered outcomes was assessed within the context of a before and after, 12-week clinical trial of safety and tolerability.

Methods: Patients treated with MIS416 for 12 weeks were evaluated for clinical status at baseline and end of dosing, using the established Multiple Sclerosis Functional Composite, Short Form Health Survey, and Expanded Disability Status Scale. Responder status was determined for eight outcome measures based on minimally important change, defined using published studies. To evaluate the patients' immune response to MIS416, blood plasma samples collected at baseline and pre- and 24-h post doses 1-4 were analyzed using multiplex cytokine quantification assays.

Results: Using a combination of patient-centered outcomes, MIS416 treatment was associated with improved clinical status for 10/11 patients: eight patients showed improvement on two to five outcome measures, five of which also showed improvement by EDSS. Multi-dimensional scaling analysis of MIS416-induced factors quantified in individual patients, revealed immune response patterns which had a strong concordance with the extent of the patients' clinical response.

Conclusions: The data support the feasibility of using patient-centered outcomes as additional clinical trial endpoints, for determining the efficacy of disease-modifying therapies, in secondary progressive multiple sclerosis patients.

Trial registration: ClinicalTrial.gov, NCT01191996.

Keywords: Immune modulator; MIS416; Myeloid cells; Neurological improvement; Patient-reported outcome; Performance related outcome; Plasma immune biomarker; Secondary progressive multiple sclerosis.

Conflict of interest statement

Ethics approval and consent to participate

The study was conducted in New Zealand and was approved by the Upper South A Health and Disability Ethics Committee (URA/10/01/011). Written informed consent for blood sample collection, analysis, and disclosure of anonymized data was obtained from all study participants prior to the trial.

Consent for publication

Not applicable.

Competing interests

Gill A Webster is an employee of Innate Immunotherapeutics. All other authors received no financial support in relation to their contribution to this work and have no financial relationship with any other organization or individuals that may have an interest in this work.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Multidimensional scaling DS plot illustrating similarities between patients based on their immune response to MIS416. The maximum level of immune factors detected in patient plasma following MIS416 treatment (Table 5) was used to compare each patient’s overall immune response to MIS416 with the group. Clusters of patients with similar immune responses are outlined as a group. The patient responder status based on clinical improvement as determined in this study (Table 4) is indicated

Fig. 2

MIS416 pharmacodynamic immune response of patients grouped according to change in clinical status. Immune proteins most important for discriminating differential immune responses to MIS416: (IFN-γ (a), MIG (b), MCP-1 (c), MIP-1α (d), IL-6 (e), and IL-10 (f)) were quantified at 24-hour (24 Hr) and 7 days (7 D) post doses (PD) 1–4 and values were compared between the patient groups defined as high responder (HR), medium responder (MR) or low responder (LR) based on their extent of clinical response. The patient ID numbers comprising each responder group are shown in parenthesis. Data shown are the mean values (pg/mL) ±SD. Statistical significance was determined by two-way ANOVA followed by Holm-Sidak’s multiple comparison: *p< 0.05;**p< 0.005; ***p< 0.0001