Safety and Dosimetry of a New Radiotracer to Detect Misfolded SOD1 Associated With Amyotrophic Lateral Sclerosis

A Single Center, Open Label Study to Evaluate Biodistribution, Pharmacokinetics and Safety of [89Zr]Zr-DFO-AP-101 PET (Positron Emission Tomography) in Healthy Volunteers and Amyotrophic Lateral Sclerosis (ALS) Patients

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease, is a rare neurodegenerative disease resulting in loss, primarily, of the motor neurons in the motor cortex, brainstem and spinal cord. It currently affects 3 of every 100,000 people in the US.

Currently, there is no diagnostic tool for ALS, resulting in misdiagnosis and significant disease progression before formal diagnosis. An imaging test for early detection of ALS and for monitoring disease progression would have significant diagnostic and prognostic value.

PET imaging with an appropriate radiotracer has great potential as a biomarker for ALS given that it would permit visualization of central nervous system (CNS) pathology in individuals living with the disease.

To that extent, the primary goal of this phase I study is evaluating the safety and biodistribution of the new tracer [89Zr]Zr-DFO-AP-101 in healthy volunteers and ALS patients.

Background: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease, is a rare neurodegenerative disease resulting in loss, primarily, of the motor neurons in the motor cortex, brainstem and spinal cord. It currently affects 3 of every 100,000 people in the US. Currently, there is no diagnostic tool for ALS, resulting in misdiagnosis and significant disease progression before formal diagnosis.

Design: This is a phase I clinical trial and a 2-part, single center, open label study in healthy volunteers (Part A) and confirmed ALS patients (Part B). The primary goal is evaluating the safety and biodistribution of the radiotracer [89Zr]Zr-DFO-AP-101 in healthy volunteers and ALS patients via PET/CT imaging.

Objectives: The primary objectives of this study are:

(Part A) To evaluate, by PET imaging, the safety, biodistribution and dosimetry of [89Zr]Zr-DFO-AP-101 in healthy men and women and in ALS patients

Intervention and Follow-up: Following a screening visit, eligible participants will come to the research center for all study assessments.

• On Day 0, a single intravenous dose of [89Zr]Zr-DFO-AP-101 40 MBq will be administrated and a 45 min whole body PET/CT acquisition will be performed at two hours post injection. Physical exam, ECG, vital signs and blood/urine samples will be collected.
• Further PET acquisitions and same data/samples collection will be repeated at days 1, 3, 7 and 10 post-injection.
• Participants will be contacted for a final follow-up visit approximately 14 days after injection.

Inclusion Criteria:

1. Aged of:

   1. For healthy participants: Male or female subjects aged 50 years or older
   2. For ALS patients: Male or female subjects aged 18 years and older

2. Able to remain in a lying position for up to 45 minutes without respiratory support.

3. A) For ALS patients, confirmed diagnostic of definitive ALS according to El-Escorial criteria14 B) for healthy participants: no neurologic condition (confirmed by physical exam)

4. Have venous access sufficient to allow for blood sampling

5. Are reliable and willing to make themselves available for the duration of the study and are willing to follow CRCHUS-specific study procedures.

Exclusion Criteria:

1. Are currently enrolled or were enrolled in the last 12 weeks in any other clinical trial involving a study drug or off label use of a drug or device, or any other type of medical research judged not to be scientifically or medically compatible with this study.

2. Female participants who are pregnant or breast feeding; or women of childbearing potential (<50 years old) and men who are sexually active who are not willing to use an accepted effective contraceptive method.

3. Plan to have surgery or other invasive procedure during the course of the study (up to 14 days post-injection)

4. Have a progressive medical illness including, but not limited to, any cardiovascular, hepatic, respiratory, hematological, endocrine, psychiatric or neurological disease, convulsions, or any clinically significant laboratory abnormality at screening and at first visit (D0) that, in the judgment of the medical doctor, indicate a medical problem that would preclude study participation.

5. Have one of these conditions (for both patient groups):

   1. hepatic disorder such as hepatic encephalopathy, hepatic laboratory abnormalities (ALT or AST ≥3 × ULN or total bilirubin ≥2 × ULN) and hematology abnormalities at screening.
   2. severe chronic kidney disease (eg, an estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m or requires chronic dialysis) at screening.
   3. Have severe active psychiatric illness.
   4. Have a diagnosis of another neurodegenerative disease (e.g. Parkinson disease, Alzheimer's disease, etc).
   5. Have a significant infection or known inflammatory process on screening or at Day 0.
   6. Alcohol or drug abuse based on patient auto-report
   7. Have a history of relevant atopy or drug hypersensitivity or allergy to antibodies;
   8. Have an abnormal blood pressure (supine) defined as a diastolic blood pressure >90 or <45 mmHg and/or a systolic blood pressure >160 or <90 mmHg. Re-testing may occur once during the screening visit within 2 hours of the initial abnormal blood pressure measurement at the discretion of the investigator.

6. For ALS patients:

   1. Have undergone a tracheostomy for ALS symptoms.
   2. Are on nasal intermittent positive pressure ventilation (NIPPV) >4h during the day, while awake for the treatment of ALS related symptoms.
   3. Have other causes of neuromuscular weakness.

7. Have received treatment with biologic agents (such as monoclonal antibodies, including marketed drugs and AP-101) within 3 months or 5 half-lives (whichever is longer) prior to study drug injection.

8. Have received any blood or blood products within the 3 months prior to screening.

9. Cannot communicate reliably with the investigator.

10. Are unwilling or unable to give written informed consent.

11. In the opinion of the medical doctor or his/her delegate, are unsuitable for inclusion in the study.