Study of Safety and of the Mechanism of BLZ945 in ALS Patients

The purpose of the study is to identify a dose (or doses) of BLZ945, that measurably decrease(s) TSPO binding in the brain of participants with ALS, and to evaluate the safety and tolerability of BLZ945 in participants with ALS at these doses and dosing regimen. PET imaging with a ligand selective for TSPO is widely used as a marker for microglial activation. Following microglia reduction, the repopulation of microglia in participants with ALS will be assessed at different times post dosing.

Inclusion Criteria:

1. Able to communicate well with the investigator, to understand and comply with the study visits and procedures of the study.
2. Written informed consent must be obtained before any assessment is performed.
3. Male and female participants who are 18 years old or older at screening, and who are diagnosed with familial or sporadic ALS according to the World Federation of Neurology Revised El Escorial criteria of either bulbar or limb onset.
4. Able to swallow medication capsules, in the opinion of the investigator.
5. Disease duration from symptoms onset no longer than 48 months at the screening visit.
6. Having a SVC (slow vital capacity) equal to or more than 60% predicted normal value per local standards for gender, height, and age at the screening visit.
7. Females of childbearing potential must have a negative pregnancy test at screening and baseline.
8. High-affinity binders (HAB) or mixed-affinity binders (MAB) to TSPO as evaluated by genotyping for the rs6971 polymorphism in the TSPO gene at the screening visit.
9. Baseline PET scan of sufficient image quality, as determined locally by the PET experts, to enable the measurement of [11C]-PBR28 volume of distribution (Vt) in the relevant CNS regions.
10. Treatment with riluzole and/or edaravone are allowed, but participants need to be on a stable dose and regimen for at least 3 months prior to baseline. For participants taking edaravone, BLZ945 dosing must be scheduled during the 20 days off-drug period of the edavarone treatment regimen.
11. Upper Motor Neuron Burden (UMNB) scale of at least 25 at the screening visit
12. BMI between 18-35 kg/m2 at the screening visit.

Exclusion Criteria:

1. A history of clinically significant ECG abnormalities
2. Active hematologic, hepatic, respiratory disorders that are clinically significant and may jeopardize the participant's safety if participating in the study or limit his/her participation in the study, including ability to tolerate the imaging studies.
3. Active dementia, neurologic diseases other than ALS, or psychiatric illness that in the opinion of the investigator would limit their participation in the current study.
4. Use of other investigational drugs within 5 half-lives of screening, or until the expected PD effect has returned to baseline , whichever is longer; or longer if required by local regulations.
5. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes.
6. Presence of human immunodeficiency virus (HIV) infection based on screening lab results.
7. Evidence of active or latent tuberculosis as assessed by Quantiferon testing at the screening visit.
8. Positive serology for hepatitis B surface antigen, or hepatitis C antibodies confirmed by an appropriate licensed test at screening.
9. Signs or symptoms, in the judgement of the investigator, of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to the screening visit.

   COVID-19 specifically: COVID-19 testing will be completed prior to first dosing. Positive results would exclude participants from being enrolled in the study.

10. Cardiac disorders, such as recent cardiac history (within 6 months of screening) of acute coronary syndrome, acute heart failure, or significant ventricular arrhythmia at the screening visit. Participants with cardiac failure class 3 or 4 of the NYHA classification, implanted cardiac pacemaker, or defibrillator.
11. Significant hematological laboratory abnormalities.
12. Clinical evidence of liver disease or liver injury or any of the following hepatic conditions at the screening visit:
13. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 14 days after last dose of BLZ945.
14. Pregnant or nursing female participants
15. Sexually active males unless they use a condom during intercourse while taking the drug during treatment, for 14 days after stopping BLZ945 and should not father a child in this period.
16. Any contraindications to MRI.
17. Taking medications prohibited by the protocol
18. Any contraindications to the arterial line sampling
19. History or presence of impaired renal function at the screening visit.
20. Active suicidal ideation.
21. History of drug abuse or harmful alcohol use within the 12 months prior to dosing within the judgement of the investigator, or evidence of such abuse as indicated by the laboratory assays conducted during screening.
22. Inability or unwillingness to undergo repeated venipuncture or arterial cannulation, or in the opinion of the investigator, participant would be at an increased risk for adverse events related to these procedures.