Intravenous Immunoglobulin (IVIG) and Blood-Brain Barrier Disruption in Amyotrophic Lateral Sclerosis (ALS)

This study is a prospective, single-arm, open-label, multiple-ascending dose (MAD), phase I trial to evaluate safety, feasibility, pharmacodynamics, and pharmacokinetics of enhanced delivery of IVIg 0.4 or 0.8g/kg to the primary motor cortex in 6 patients with ALS by using a single BBB opening procedure targeting the primary motor cortex in both brain hemispheres. Six participants will be enrolled in two sequential cohorts. The first cohort (n = 3) will receive 0.4g/kg of IVIg divided in two doses, while the second cohort (n = 3) will receive a 0.8g/kg of IVIg divided in two doses. In both cohorts, the second dose of IVIg will be accompanied by a single BBB opening procedure targeting the primary motor cortex in both brain hemispheres with focused ultrasound (FUS) using Next Generation Dome Helmet and intravenous microbubbles (DEFINITY®, Lantheus Medical Imaging Canada, Inc., Montreal, QC, Canada). This FUS procedure will occur during 2 weeks after the first dose administration. Follow-up visits will occur over the span of 24 weeks from the first dose.

Inclusion criteria

• Diagnosed with ALS as per the Gold Coast Criteria;
• Aged 18 years or older;
• Capable of providing informed consent and complying with study procedures;
• If taking Riluzole, on a stable dose for at least 4 weeks prior to Baseline;
• If taking Edaravone, on a stable dose of one completed cycle prior to Baseline;
• Respiratory Function Criterion:

• Able to lie supine without BiPAP or breathing discomfort; OR
• Forced vital capacity or slow vital capacity ≥50% of the predicted value for sex, height and age, if available
• Able to communicate sensations during the Dome FUS procedure.
• Qualified fit for the anesthesia by an anesthesiologist, ASA I-III.

Exclusion criteria

• MRI findings:

• Active infection/inflammation
• Acute or chronic hemorrhages, specifically > 4 lobar microbleeds, and no siderosis or macrohemorrhages
• Tumor/space occupying lesion causing significant mass effect
• Meningeal enhancement
• Intracranial hypotension
• More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp
• Clips or other metallic implanted objects in the skull or the brain, except shunts
• Significant cardiac disease or unstable hemodynamic status including:

• Documented myocardial infarction within six months of screening
• Unstable angina on medication
• Unstable or worsening congestive heart failure
• Left ventricular ejection fraction below the lower limit of normal
• History of a hemodynamically unstable cardiac arrhythmia
• Cardiac pacemaker
• Severe hypertension (diastolic BP > 100 on medication)
• Patient has right-to-left, bidirectional, or transient right-to-left cardiac shunts
• QT prolongation observed on screening ECG (QTc > 450 for men and > 470 for women)
• Uncontrolled hypertension (systolic > 150 and diastolic BP > 100 on medication)
• Patients should not take medications known to increase risk of hemorrhage (e.g., aspirin or class I and III anticoagulants) for at least 7 days prior to treatment or lumbar puncture; patients should not take Avastin for 30 days prior to treatment
• History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or use of anticoagulants, specifically recent thrombosis or stroke in past 3 months; abnormal coagulation profile (PLT < 100,00/μl), PT (> 14 sec) or PTT (> 36 sec), and INR > 1.3
• No more than 1 non-strategic lacune &lt;1.5 cm
• Known cerebral or systemic vasculopathy
• Significant depression and at potential risk of suicide
• Known sensitivity/allergy to gadolinium (an alternative product may be used) and DEFINITY®.
• Any contraindications to MRI scanning, including:

• Large participants not fitting comfortably into the scanner
• Difficulty lying supine and still for up to 3 hours in the MRI unit or claustrophobia
• Any contraindication to lumbar puncture for collection of cerebral spinal fluid, including:

a. Intracranial hypotension

• Untreated, uncontrolled sleep apnea
• Impaired renal function with estimated glomerular filtration rate < 30 mL/min/1.73m2 or on dialysis.
• IVIg use in the previous 6 months.
• Live viral vaccination within the 30 days before study entry
• Currently, or in the last 3 months participated in a clinical trial delivering an investigational product or non-approved use of a drug or device or in any other type of medical research.
• Respiratory: chronic pulmonary disorders e.g. severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, patients with a history of drug allergies, uncontrolled asthma or hay fever, and multiple allergies where the benefit/risk of administering DEFINITY® is considered unfavorable by the study physicians in relation to the product monograph for DEFINITY®.
• Motor cortex atrophy deemed severe enough to limit targeting
• Previous major allergic or anaphylactic reaction to IVIg
• Known IgA deficiency with anti-IgA.
• Known frontotemporal dementia;
• Definitely or possibly pregnant (if applicable);
• Known auto-immune condition with or without neurological manifestations (e.g., multiple sclerosis (MS), systemic lupus erythematous (SLE), Rheumatoid arthritis).
• Current, planned or previous use of oral, intramuscular or intravenous steroid drugs (such as prednisone, prednisolone, dexamethasone, triamcinolone, methylprednisolone, oxandrolone, and others), immunosuppressant drugs (azathioprine, mycophenolate, tacrolimus, sirolimus, cyclophosphamide, and others) or NSAIDs (ibuprofen, naproxen, celecoxib, and others) in the past 30 days;
• Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the participant unsuitable for enrollment