Dose-Escalation, Safety and Pharmacokinetic Study of IC14 in Motor Neurone Disease

The objectives of this study are to determine:

• The safety, tolerability and immunogenicity of IC14 in patients with motor neurone disease (MND).
• The pharmacokinetics and pharmacodynamics of IC14 in patients with MND.
• The preliminary effect of IC14 on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in patients with MND.
• The preliminary effect of IC14 on forced vital capacity (FVC) and other clinical markers of disease severity in patients with MND.
• The preliminary effect of IC14 on patient-reported outcome measures.
• The preliminary effect of IC14 on disease biomarkers.

Ten patients with MND will be sequentially assigned to receive one of two dose regimens of IC14 in an unblinded manner:

• For the initial 3 patients: IC14 at a dosage of 2 mg/kg on Study Day 1, then 1 mg/kg once daily on Study Days 3-5 for 4 total doses.
• For the subsequent 7 patients: IC14 at a dosage of 4 mg/kg on Study Day 1, then 2 mg/kg once daily on Study Days 2-4 for 4 total doses.

Study participation will continue until 28 days after the last dose of study drug.

Inclusion criteria

A patient must fulfill all of the following criteria to be eligible for enrollment:

• Signed informed consent prior to initiation of any study-specific procedures.
• Familial or sporadic motor neurone disease (MND) defined as clinically possible, probable, or definite by Awaji-Shima Consensus Recommendations.
• First symptoms of MND within 3 years of informed consent.
• Age between 18 and 75 years at time of informed consent.
• Seated Forced Vital Capacity (FVC) ≥ 65% of predicted value.
• Not taking riluzole or on a stable dose of riluzole for at least 4 weeks prior to screening visit.
• Adequate bone marrow reserve, renal and liver function:

• absolute neutrophil count ≥ 1500/µL
• lymphocyte count < 48%
• platelet count ≥ 150,000/µL
• hemoglobin ≥ 11 g/dL
• Estimated glomerular filtration rate (eGFR) >= 40 mL/min/1.73 m2
• Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) ≤ 2x upper imit of normal (ULN), total bilirubin ≤ 1.5x ULN
• serum albumin ≥ 2.8 g/dL
• Females of childbearing potential should be using and committed to continue using one of the following acceptable birth control methods:

• Sexual abstinence (inactivity) for 1 month prior to screening through study completion; or
• Intrauterine device (IUD) in place for at least 3 months prior to study through study completion; or
• Stable hormonal contraception for at least 3 months prior to study through study completion; or
• Surgical sterilization (vasectomy) of male partner at least 6 months prior to study.
• To be considered of non-childbearing potential, females should be surgically sterilized (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 2 months prior to study) or be post-menopausal and at least 3 years since last menses.
• Males with female partners of childbearing potential must use contraception through study completion.
• Medically safe to have lumbar puncture to collect cerebrospinal fluid.
• Able to give informed consent and able to comply with all study visits and all study procedures.

Exclusion criteria

A patient fulfilling any of the following criteria at screening is to be excluded from enrollment in the study:

• Dependence on mechanical ventilation, defined as being unable to lay supine without it, unable to sleep without it, or continuous daytime use; presence of tracheostomy at screening; or presence of diaphragm pacing system at screening.
• Treatment with a drug or device within the last 30 days that has not received regulatory approval.
• Treatment within 12 months with immunomodulator or immunosuppressant agent (including but not limited to cyclophosphamide, cyclosporine, interferon-α, interferon-β-1a, rituximab, alemtuzumab, azathioprine, etanercept, infliximab, adalimumab, certolizumab, golimumab, anakinra, rilonacept, secukinumab, tocilizumab, mycophenolate mofetil, methotrexate, haematopoietic stem cell transplantation).
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other opportunistic infections or major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks.
• History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
• Presence of any of the following clinical conditions:

• Bleeding diathesis or receipt of anticoagulants within 7 days (or any other clinical condition that would, in the opinion of the investigator, place the patient at increased risk during lumbar puncture).
• History of one or more of the following: cardiac insufficiency (New York Heart Association [NYHA] III/IV), uncontrolled cardiac arrhythmias, unstable ischemic heart disease, or uncontrolled hypertension (systolic blood pressure > 170 mmHg or diastolic blood pressure > 110 mmHg).
• History of venous thromboembolic disease within 12 months, myocardial infarction, or cerebrovascular accident.
• Unstable pulmonary, renal, hepatic, endocrine or hematologic disease.
• Autoimmune disease, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to rheumatoid arthritis.
• Evidence of active malignant disease, malignancies diagnosed within the previous 5 years, or breast cancer diagnosed within the previous 5 years (except skin cancers other than melanoma).
• Human immunodeficiency virus infection or other immunodeficiency illness.
• Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days.
• Drug abuse or alcoholism within the past 12 months.
• Significant neuromuscular disease other than MND.
• Other ongoing disease that may cause neuropathy, such as toxin exposure, dietary deficiency, uncontrolled diabetes, hyperthyroidism, cancer, systemic lupus erythematosus or other connective diseases, infection with HIV, hepatitis B virus (HBV), or hepatitis C (HCV), Lyme disease, multiple myeloma, Waldenström's macroglobulinemia, amyloid, and hereditary neuropathy.
• Pregnancy or breastfeeding.
• Deprivation of freedom by administrative or court order.