Phase Ib Study to Evaluate MOR103 in Multiple Sclerosis

Study Overview
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Brief Summary
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Multiple sclerosis (MS) is a chronic inflammatory disease associated with central nervous system (CNS) demyelination and subsequent axonal degeneration. Multiple sclerosis exhibits an unpredictable and variable clinical course. Multiple sclerosis plaques contain numerous types of cells and infiltrating macrophages have been identified to contribute significantly to demyelination in both clinical MS and animal models of MS. Granulocyte-macrophage colony-stimulating factor (GM CSF) stimulates proliferation and activation of macrophages, monocytes, neutrophils, eosinophils, dendritic cells and microglia with subsequent induction of proinflammatory biomolecules. Therefore blocking GM CSF activity might be a therapeutic approach for the treatment of MS.

Detailed Description
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Recent clinical studies demonstrated a possible dysregulation of the balance of pro and anti inflammatory lymphocytes, which may contribute to the pathogenesis of MS. It was shown in animal models of EAE that during the disease effect or phase GM CSF sustained neuroinflammation via myeloid cells that infiltrate the CNS proving an essential role of GM CSF in encephalitogenicity.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase Ib Study to Evaluate the Safety and Pharmacokinetics of MOR103, a Human Antibody to GM-CSF, in Patients With Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Biological: MOR103
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Outpatients with a diagnosis of RRMS or SPMS, who are currently not being treated and who have at least 1 of the following: At least 1 documented relapse within 1 year before Screening, or Two documented relapses within the past 2 years before Screening, or A new gadolinium (Gd)-enhancing lesion on magnetic resonance imaging (MRI) T1-weighted imaging within 1 year before Screening, or A new T2 lesion on MRI within 1 year before Screening. The patient must have 10 or less, Gd-enhancing lesions per T1-weighted MRI at Screening as assessed by a central reader. The patient must be able and willing to ambulate, with an Expanded Disability Status Scale (EDSS) score of ≥ 2.0 and ≤ 6.5 at both the Screening Visit and the Baseline Visit Key Exclusion Criteria: A patient with primary progressive MS (PPMS) A patient who has previously received at any time any of the following B-cell or T-cell depleting therapies Cytotoxic agents, any immunosuppressive/immunomodulating agents A patient who has not stabilized, in the opinion of the investigator A patient with any medical condition or uncontrolled disease states other than MS requiring or likely to require systemic treatment with corticosteroids or other immune compromising agents A patient with current or a history of major chronic inflammatory autoimmune diseases other than MS A patient with any type of infection Patients on chronic prophylactic or suppressive antibiotic, antifungal,or antiviral agents A patient with a history of tuberculosis. A patient with any signs of excretory hepatic or kidney dysfunction A patient with a positive test for Hepatitis B or Hepatitis C

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MOR103 0.5 mg/kg<br>6 doses of MOR103 0.5 mg/kg administered on Days 1 (Baseline), 15 (Visit 2), 29 (Visit 3), 43 (Visit 4), 57 (Visit 5), and 71 (Visit 6). | Biological: MOR103<br>* Anti-GM-CSF monoclonal antibody<br>|
| Experimental: MOR103 1.0 mg/kg<br>6 doses of MOR103 1.0 mg/kg administered on Days 1 (Baseline), 15 (Visit 2), 29 (Visit 3), 43 (Visit 4), 57 (Visit 5), and 71 (Visit 6). | Biological: MOR103<br>* Anti-GM-CSF monoclonal antibody<br>|
| Experimental: MOR103 2.0 mg/kg<br>6 doses of MOR103 2.0 mg/kg administered on Days 1 (Baseline), 15 (Visit 2), 29 (Visit 3), 43 (Visit 4), 57 (Visit 5), and 71 (Visit 6). | Biological: MOR103<br>* Anti-GM-CSF monoclonal antibody<br>|
| Placebo Comparator: Placebo<br>6 doses of placebo administered on Days 1 (Baseline), 15 (Visit 2), 29 (Visit 3), 43 (Visit 4), 57 (Visit 5), and 71 (Visit 6). | Other: Placebo<br>* Placebo to anti-GM-CSF monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Patients With Treatment-emergent Adverse Events (TEAEs) or Treatment-emergent Serious Adverse Events (TESAEs) | The safety of multiple doses of MOR103 in patients with relapsing-remitting or secondary progressive multiple sclerosis (MS) was assessed by evaluation of the incidence of TEAEs and TESAEs. A full listing of adverse events recorded during this trial can be found in the Adverse Events section. AEs were regarded as treatment emergent if they started on or after the first date of study drug administration or if they were present prior to the first date of study drug administration and increased in severity or relationship to study drug during the study. AEs were coded using MedDRA version 16.1 | From the first dose (week 0) to study endpoint (week 20) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Patients Negative for Anti-MOR103 Antibodies in Serum Samples | To assess the potential immunogenicity of MOR103, a central bioanalytical laboratory (Eurofins Medinet BV, Breda, The Netherlands) tested serum samples obtained at baseline and at 3 post-treatment time points (week 14, week 16, and week 20/end of study) for anti-MOR103 antibodies. | Baseline, week 14, week 16, and week 20/end of study | 
| Mean Serum Concentration of MOR103 Over Time | MOR103 serum levels were measured at each visit. At all visits during the dosing period (weeks 0, 2, 6, 8, and 10), serum samples were taken before MOR103 administration (pre-dose) and 1 hour after the dose. In addition, at week 0 (first dose) and week 10 (last dose), additional samples were obtained at 2 hours and 4 hours after MOR103 administration. At visits that followed the dosing period (weeks 12, 14, 16, and 20), a single serum sample was obtained at any time during the visit. | Week 0 (dose 1) to week 20 (end of study) | 
| Mean Maximum MOR103 Concentration (Cmax) After the First and Last MOR103 Doses | At the week 0 (first dose) and week 10 (last dose) visits, serum samples were obtained at pre-dose and at 1, 2, and 4 hours after the dose. Cmax values for each patient were calculated based on these data, and the mean Cmax values for the dose cohort are presented here. Because Cmax refers to the maximum serum concentration, only one value is presented for each dose cohort on each day; values at each PK time point are not applicable, as they represent the concentration of MOR103, but not the Cmax. | Week 0 (first dose) and week 10 (last dose) | 
| Mean Time to Maximum MOR103 Concentration (Tmax) After the First and Last MOR103 Doses | At the week 0 (first dose) and week 10 (last dose) visits, serum samples were obtained at pre-dose and at 1, 2, and 4 hours after the dose. Tmax values for each patient were calculated based on these data, and the mean Tmax values for the dose cohort are presented here. Because Tmax refers to the time to maximum serum concentration, only one value is presented for each dose cohort on each day; values at each PK time point are not applicable. | Week 0 (first dose) and week 10 (last dose) | 
| Accumulation Ratio for Area Under the MOR103 Serum Concentration Versus Time Curve (AUC) Over One Dosing Interval: Ratio of Week 10 (Last Dose) AUC to Week 0 (First Dose) AUC | At week 0 (first dose) and week 10 (last dose), serum samples were obtained at pre-dose and at 1, 2, 4, and 336 hours after start of dosing. To calculate the accumulation ratio, the apparent AUC calculated for the last dose was divided by the apparent AUC following the first dose using the described time points for each dosing. Because AUC is a summary outcome, only one value is presented for each dose cohort on each day; values at each PK time point are not applicable. | Week 0 (first dose) and week 10 (last dose) | 
| Number of New T1 Gadolinium-enhancing Lesions | Magnetic resonance imaging (MRI) tests were performed at screening (to confirm subject eligibility) and at Weeks 4, 8, 2, and 16. MRIs at post-screening time points were used to assess the number of new lesions as revealed by gadolinium (Gd) enhancement. Gd-enhanced MRIs reveal new brain lesions reflecting areas of active inflammation. MRI images were assessed centrally by Synarc A/S (Hamburg, Germany). | Week 4, week 8, week 12, and week 16. | 
| Number of New or Enlarging T2 Lesions | T2-weighted magnetic resonance imaging (MRI) tests were performed at Weeks 8, 12, and 16 to assess the number of new or enlarging T2 brain lesions, a sign of MS activity. MRI images were assessed centrally by Synarc A/S (Hamburg, Germany). | Week 8, week 12, and week 16. |