A Biomarker Study to Evaluate MN-166 in Subjects With Amyotrophic Literal Sclerosis (ALS)

This is a multi-center, open-label study of MN-166 (ibudilast) in subjects with ALS. To be eligible subjects must meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. Safety, tolerability, blood, neuro-imaging biomarkers, and clinical outcomes will be collected on all subjects. Subjects will receive study drug for 36 weeks.

The study will consist of a Screening Phase (up to 6 weeks), an Open-Label Treatment Phase (36 weeks) and an Off-Treatment Follow-up Phase (4 Weeks).

Number of Subjects (Planned):

Approximately 45 subjects are planned to be screened with the goal of enrolling 35 subjects.

This is a multi-center, open-label study of MN-166 (ibudilast) in subjects with ALS. To be eligible subjects must meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. Safety, tolerability, blood, neuro-imaging biomarkers, and clinical outcomes will be collected on all subjects. Subjects will receive study drug for 36 weeks.

The study will consist of a Screening Phase (up to 6 weeks), an Open-Label Treatment Phase (36 weeks) and a Off-Treatment Follow-up Phase (4 Weeks).

During the Screening Phase, eligible ALS subjects will sign an informed consent form and the following screening assessments will be performed: review of inclusion/exclusion criteria: El Escorial ALS Diagnostic criteria, medical history and demographics, ALS diagnosis history, physical and neurological examination, U. Penn upper motor Neuron Burden (UMNB), pulmonary function tests, vital signs including height and weight, blood for safety labs including TSPO affinity test, ECG and review and documentation of concomitant medications and therapies.

Screening Phase (up to 6 weeks) The Treatment Phase will consist of a Baseline visit and 3 subsequent clinic visits at Weeks 4, 12, 24, and 36. Telephone follow-ups will occur at Weeks 1, 2, 8, 16, 20, 28, and 32.

Open-Label Treatment Phase (36 weeks) At the Baseline visit, subjects will return to the clinic and the following assessments will be performed/administered: review of inclusion and exclusion criteria for continued eligibility, vital signs, blood for safety labs and biomarkers, ECG, ALSFRS-R questionnaire, slow vital capacity (SVC), baseline strength as measured by hand held dynamometry (HHD), and Columbia Suicide Severity Rating Scale (C-SSRS). At this visit, study drug will be dispensed, and adverse events, concomitant medications and therapies will be assessed and documented. At subsequent visits during the Treatment Phase, similar assessments will be performed.

In addition, a \[11C\]PBR28-PET scan will be performed once between the Screening and Baseline visit, and once between the Week 12 and Week 28 phone calls. The ALSFRS-R, SVC and U Penn Upper Motor Neuron Burden will be repeated on the same day as the PET scans.

The follow-up visit will consist of a telephone call to document adverse events and concomitant therapies

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must be diagnosed as having possible, probable, probable-laboratory supported, or definite ALS, either sporadic or familial according to modified El Escorial criteria.
2. Age 18 or above, able to provide informed consent, and safely comply with study procedures.
3. Vital capacity (VC) of at least 50% predicted value for gender, height and age at screening visit, or in the opinion of the study physician, able to safely tolerate study procedures. (Not applicable to flexible arm)
4. Subject must be able to swallow oral medication at the Baseline Visit and expected to be able to swallow the capsules throughout the course of the study.
5. Subject must not have taken riluzole for at least 30 days or be on a stable dose of riluzole for at least 30 days, prior to screening (riluzole-naïve participants are permitted in the study). (Not applicable to flexible arm)
6. Women must not be able to become pregnant (e.g. post-menopausal, surgically sterile, or using adequate birth control) for the duration of the study and 3 months after study completion.
7. Males should practice contraception for the duration of the study and 3 months after completion.
8. Ability to safely lie flat for 90 min for PET procedures in the opinion of the study physician. (Not applicable to flexible arm)
9. High or mixed affinity to bind TSPO protein (Ala/Ala or Ala/Thr) (not applicable to flexible arm).
10. Upper motor Neuron Burden (UMNB) Score ≥25 (out of 45) at screening visit. (Not applicable to flexible arm)

Exclusion Criteria:

1. Abnormal liver function defined as AST and/or ALT \> 3 times the upper limit of the normal.
2. Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal.
3. The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the participant to provide informed consent, according to PI judgment.
4. Clinically significant unstable medical condition (other than ALS) that would pose a risk to the participant if they were to participate in the study.
5. History of HIV, clinically significant chronic hepatitis, or other active infection.
6. Active inflammatory condition of autoimmune disorder (Not applicable to flexible arm)
7. Females must not be lactating or pregnant.
8. Active participation in another ALS clinical trial or exposure to an off-label ALS experimental treatment within 30 days of the Baseline Visit (Not applicable to flexible arm)
9. Exposure to immunomodulatory medications within 30 days of the Baseline Visit. (Not applicable to flexible arm)
10. Any contraindication to undergo MRI studies such as

    * History of a cardiac pacemaker or pacemaker wires
    * Metallic particles in the body
    * Vascular clips in the head
    * Prosthetic heart valves
    * Claustrophobia (Not applicable to flexible arm)
11. Radiation exposure that exceeds the site's current guidelines (Not applicable to flexible arm)
12. EKG finding of QTc prolongation \> 450 msec for males and \> 470 msec for females at screening or baseline.
13. Not on any prohibitive medication or known QT prolonging medication: