Safety Study of an Immunomodulating Microparticle to Treat Progressive Multiple Sclerosis

This is a single center, open-label, non-randomized, dose-escalation study, to be conducted in two phases:

• a dose-escalation (DE) phase, to evaluate the safety, tolerability, MTD, and PD of MIS416 administered IV once weekly for 4 doses; and
• a dose-confirmation (DC) phase, which will be a cohort expansion at or below the MTD (i.e., the RTD) of MIS416, dosed once weekly for up to 12 doses.

Subjects will be treated with a weekly IV dose of MIS416 in 28-day cycles: 1 cycle in the DE phase, and up to 3 cycles in the DC phase. Subjects will be evaluated and dosed weekly each cycle in each phase. Subjects will return for a follow-up visit 7 days after completion of the last dose of study drug.

The primary objectives of this study are:

• To determine the safety and tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended therapeutic dose (RTD) of intravenously (IV) administered MIS416 weekly in patients with chronic progressive multiple sclerosis (CPMS); and
• To assess the pharmacodynamic (PD) effects of MIS416, including effects on serum cytokine levels and peripheral blood mononuclear cell (PBMC) composition, cytokine/chemokine expression and function.

The secondary objectives of this study are:

• To document any changes in MS clinical status occurring during the 12-week MIS416 dosing period in the dose-confirmation phase, as determined by the Multiple Sclerosis Functional Composite (MSFC), Fatigue Severity Scale (FSS), Short Form Health Survey (SF-36), and Expanded Disability Status Scale (EDSS); the frequency of clinical relapses; and signs of clinical activity on serial cranial MRI scans; and
• To evaluate, in exploratory fashion, any correlations between clinical, radiological and PD outcomes.

Inclusion criteria

• At least 18 years of age.
• Diagnosis of MS, by the McDonald criteria.
• Chronic progressive MS (CPMS), defined as either primary progressive MS (PPMS) or secondary progressive MS (SPMS), per the criteria of the National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. [NOTE: In the dose-confirmation phase, only subjects with SPMS may be enrolled].
• MS is clinically active with worsening clinical status within the past 2 years, defined as an increase in EDSS by 1 point or more, sustained for at least 6 months.
• Expanded Disability Status Scale (EDSS) of 2.5 to 7.0 at Screening.
• The following laboratory values must be documented within 3 days prior to initiation of study drug:

• Absolute neutrophil count (ANC) >= 1 x 109/L
• Platelet count >= 100 x 109/L
• Serum creatinine =< 1.5 mg/dL
• AST (SGOT) and ALT (SGPT) =< 2 × upper limit of normal.
• Provide written informed consent to participate.

Exclusion criteria

• Relapsing-remitting MS or progressive-relapsing MS
• Any immunomodulatory drug therapy or immunosuppressive therapy within the previous six months, or vaccine or systemic corticosteroids within the previous 60 days, prior to initiation of study drug.
• Exposure to other experimental treatments currently under investigation in MS clinical trials, including alemtuzamab, rituximab, fingolimod, and clabribine.
• A diagnosis or history of collagen vascular disease (including Sjögren's syndrome and systemic lupus erythematosus), anticardiolipin antibody syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), sarcoidosis, vasculitis, Bechet's syndrome and/or Lyme disease.
• History of alcohol or drug abuse (with the exception of cannabinoids) within 2 years prior to initiation of study drug.
• Previous exposure to MIS416.