Safety, PK and Biodistribution of 18F-OP-801 in Patients With ALS, AD, MS, PD and Healthy Volunteers

A Phase 1/2 Study to Evaluate Safety, PK and Biodistribution of an Imaging Agent, 18F-OP-801, After Intravenous Administration to Patients With ALS, Alzheimer's Disease, Multiple Sclerosis, Parkinson's Disease and Healthy Volunteers

This is a Phase 1/2 study to evaluate the safety and tolerability of 18F-OP-801 in subjects with ALS, AD, MS, PD and age-matched HVs. 18F-OP-801 is intended as a biomarker for PET imaging of activated microglia and macrophages in regions of neuroinflammation.

Microglia and macrophages have emerged as key players in neurodegenerative and neuroinflammatory disorders of the central nervous system (CNS) such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), multiple sclerosis (MS) and Parkinson's disease (PD). Treatments that selectively target these cells will need to cross the blood-brain barrier (BBB) at levels high enough to produce therapeutic effects. Unfortunately, it is difficult to directly measure the amount of a therapeutic that actually reaches the CNS target tissue. Development of biomarkers that allow direct visualization of cellular targeting across the BBB could offer profound insight into drug actions on innate immune cells in the brain. Furthermore, the ability to track accumulation of activated microglia in the brain could allow early identification of patients at risk for neurodegenerative or neuroinflammatory disease, precise stratification of patients for clinical trials and an efficacy measure for therapies that target neuroinflammation.

Positron emission tomography (PET) is a noninvasive imaging technology that can provide quantitative biological information in vivo, and it plays an important role in disease diagnosis, therapy assessment, and drug development. PET allows evaluation of the biological process without pharmacological effects because the amount of radiotracer used in imaging studies is very low. Several PET diagnostics track neuroinflammation in the brain, but current methods are limited by high background signal in healthy tissues.

18F-OP-801 is selectively taken up only by activated but not resting microglia, offering the potential to detect neuroinflammation at lower levels and earlier stages of disease than any current clinical PET radiotracer. We propose to use 18F-OP-801 to image activated microglia and brain macrophages in subjects with ALS, AD, MS, and PD to assess the compound's utility as a biomarker of neuroinflammation

Inclusion Criteria:

1. Has the ability to understand and sign the written ICF and local medical privacy authorization forms, which must be obtained prior to the conduct of any study related procedures.

2. Female subjects of non-childbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before the Screening Visit) or postmenopausal, defined as spontaneous amenorrhea for at least 2 years, with follicle-stimulating hormone (FSH) in the postmenopausal range at screening, based on the local laboratory's defined ranges.

3. Female subjects of childbearing potential (i.e., ovulating, premenopausal, and not surgically sterile) and all male subjects must agree to practice abstinence from sexual intercourse or use a medically accepted contraceptive regimen (including hormonal contraceptives) during their participation in the study and for 90 days (males) or 6 months (females) after Day 1. Medically accepted contraceptive methods are defined as those with 90% or greater efficacy and are as follows:

   1. Male subjects: condoms or surgical sterilization of subject at least 26 weeks before the Screening Visit (i.e., vasectomy).

   2. Female subjects:

      1. Surgical sterilization at least 26 weeks before the Screening Visit (includes hysterectomy or bilateral tubal ligation, bilateral oophorectomy, or salpingectomy);
      2. Intrauterine device or diaphragm with spermicide for at least 12 weeks before the Screening Visit; or
      3. Hormonal contraception (oral, implant, injection, ring, or patch) for at least 12 weeks before the Screening Visit.

4. If male, subjects must agree to abstain from sperm donation through 90 days after the Day 1 Visit.

5. Female subjects may not be pregnant, lactating, or breastfeeding.

6. Female subjects of childbearing potential must have negative result for pregnancy test at Screening and Check-in.

7. Subjects must have an estimated glomerular filtration rate (eGFR) of >45 mL/min/1.73m2 at Screening.

8. C-reactive protein level ≤10 mg/dL.

9. Subjects must be willing and able to abide by all study requirements and restrictions.

   Inclusion Criteria Specific to ALS Subjects:

10. Adult (Age 18 to 80, inclusive) at the Screening Visit

11. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by the modified El Escorial criteria.

12. Forced vital capacity (FVC) of ≥50%; or if in the opinion of the investigator can lay flat for up to 90 minutes. If FVC has been performed within the past 6 months, this data may be used at the discretion of the investigator.

13. For ALS subjects, medication changes within 30 days prior to the Screening Visit should be discussed with the Medical Monitor.

    Inclusion Criteria Specific to AD Subjects

14. Adult (Age 40 to 80, inclusive) at the Screening Visit

15. Clinical diagnosis of early stage dementia, Alzheimer type, plus positive Aβ and tau PET imaging, cerebrospinal fluid (CSF) and/or plasma biomarkers consistent with 2018 NIA-AA criteria

16. MMSE score >20 at Screening

17. AD medication changes within 30 days prior to the Screening Visit should be discussed with the Medical Monitor.

    Inclusion Criteria Specific to MS Subjects:

18. Adult (Age 18 to 70, inclusive) at the Screening Visit

19. MS medication changes within 30 days prior to the Screening Visit should be discussed with the Medical Monitor.

    Inclusion criteria specific to subjects with RRMS:

20. Diagnosis of RRMS based on 2017 McDonald criteria

21. If not newly diagnosed, subjects should have at least 1 documented relapse in the last 24 months.

22. "Active disease" subjects should have at least 1 Gadolinium-enhancing (Gd+) T1-weighted brain or spinal cord lesion at Screening MRI.

23. "Disease in remission" subjects should have no Gd+ T1-weighted brain or spinal cord lesions at Screening MRI and stable clinical symptoms for at least 3 months prior to Day 1.

24. EDSS score between 2.0 and 5.5 inclusive at Screening

    Inclusion criteria specific to subjects with progressive MS:

25. Diagnosis of PPMS or SPMS based on 2017 McDonald criteria

26. EDSS score between 3.0 and 6.5 inclusive at Screening

27. No evidence of relapse in the prior 6 months

28. Neurological exam and symptom stability for ≥30 days prior to Day 1

29. Documented evidence of disability progression in the past 24 months not temporally related to a relapse

    Inclusion Criteria Specific to PD Subjects:

30. Adult (Age 55 to 80, inclusive) at the Screening Visit

31. Diagnosis of definite, idiopathic Parkinson's disease according to UK Parkinson's Society Brain Bank diagnostic criteria

32. PD medication changes within 30 days prior to the Screening Visit should be discussed with the Medical Monitor.

Overall Exclusion Criteria - For All Subjects:

Subjects meeting any of the following criteria will be excluded from this study:

1. Body weight >120 kg

2. Evidence of clinically significant or past medical history of hematologic, renal, endocrine, pulmonary, cardiac, gastrointestinal, hepatic, psychiatric, neurologic, immunologic, allergic disease (including multiple or clinically significant drug allergies) or any other condition that, in the opinion of the Investigator, might significantly interfere with the absorption, distribution, metabolism or excretion of study drug or place the subject at an unacceptable risk as a participant in this study

3. History of recurrent kidney or liver malignancy

4. Pacemaker or defibrillator or any non-removable metallic foreign objects in the body not compatible with MRI

5. Inability to lie in a PET/CT or PET/MRI scanner for up to 90 minutes at a time

6. Laboratory results (serum chemistry, hematology, coagulation and urinalysis) outside the normal range at Screening and Check-In and considered clinically significant in the opinion of the Investigator. Any elevation of aspartate transaminase (AST) and alanine transaminase (ALT) more than 3 times above the upper limit of normal at screening and/or check-in is exclusionary. One retest of an exclusionary laboratory result is allowed at the discretion of the Investigator and with approval from the Medical Monitor.

7. Resolved acute illness considered clinically significant by the Investigator within 10 days prior to Screening

8. History of alcoholism or drug abuse within 2 years prior to Screening. No cannabinoid drug use for at least 10 days prior to Day 1.

9. Positive urine drug test, marijuana test or cotinine test at Screening or Check-In

10. Any immunizations within the 28 days prior to screening

11. Received any other investigational medicinal product within 30 days or 5 half-lives (whichever is longer) prior to Day 1

12. Corticosteroid treatment (e.g., prednisone, solumedrol) within 30 days of Baseline

13. Treatment with any of the following classes of nonsteroidal anti-inflammatory drugs (NSAIDS): carboxylic acids, enolic acids, cyclooxygenase (COX) II inhibitors within 14 days of Day 1

14. Lost or donated >450 mL of whole blood or blood products within 30 days prior to Screening

15. MRI exclusion criteria: findings that may interfere with interpretation of the PET imaging, including but not limited to significant cortical/subcortical cerebrovascular disease, infectious disease, space-occupying lesions, hydrocephalus or other abnormalities associated with CNS disease not related to ALS, AD, MS or PD

16. CT exclusion criteria include any medical device or metallic implant that may interfere with image acquisition or affect image reconstruction (e.g., CT attenuation correction).

17. Investigator has reason to believe that the subject may be unable to fulfill the protocol visit schedule or requirements

18. Has any finding that, in the view of the Investigator and Medical Monitor, would compromise the subject's safety in the trial

    Exclusion Criteria Specific to MS Subjects:

19. Clinical signs or laboratory findings suggestive of neuromyelitis optica (NMO) spectrum disorders or myelin oligodendrocyte glycoprotein (MOG)-associated encephalomyelitis (i.e., presence of anti-NMO [aquaporin-4] antibodies or anti-MOG antibodies)

20. Diagnosis of progressive multifocal leukoencephalopathy (PML)

    Exclusion Criteria Specific to PD Subjects:

21. Secondary, atypical, or genetic parkinsonism

    Exclusion Criteria Specific to HV Subjects:

22. Clinically relevant finding on physical examination at Screening

23. Family history of neurological disease that may confound interpretation of imaging results

24. History of any central nervous system disorder or brain trauma that could cause imaging abnormalities in the opinion of the Principal Investigator and Medical Monitor