Effect of PXS-4728A on Microglia Activation in Participants With Isolated Rapid Eye Movement Sleep Behaviour Disorder

Inclusion Criteria:

1. Ability to provide written informed consent in accordance with GCP, InternationalCouncil for Harmonisation (ICH) and local regulations.

2. Male or female aged 50 to 80 (inclusive) as of the date of Baseline visit.

3. Clinical diagnosis of iRBD according to International Classification of SleepDisorders (ICSD)-3 criteria.

4. Objective evidence of 1 or more features of parkinsonism, impaired olfaction and/orimpaired color vision discrimination, which have been associated with an increasedrisk for transitioning to a synucleinopathy in the opinion of the Investigator.

5. Screening PET scan demonstrates robust PK11195 signal in striato-cortical region ofinterest in the opinion of the Investigator.

6. Liver Function Tests (LFTs): alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤ 3 × upper limit of normal (ULN); total bilirubin ≤ 1.5 ×ULN; serum albumin ≥ 2.8 g/dL.

7. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (human chorionic gonadotropin [hCG]) at Screening. WOCBP who engage in heterosexualintercourse and men whose sexual partners are WOCBP must agree to use highlyeffective, double barrier contraception during the study and for a period of 90 daysfollowing final dosing. Double barrier contraception is defined as a condom and 1other form of the following:

8. Contraceptive pill

9. Depot or injectable birth control

10. Intrauterine Device (IUD)

11. Contraceptive skin implant, (eg, Implanon NXT®)

12. Hormonal vaginal ring, (eg, NuvaRing®)

13. Documented evidence of surgical sterilization at least 6 months prior to theScreening visit, (ie, bilateral tubal ligation, oophorectomy, salpingectomy, ortotal hysterectomy for women or vasectomy for men). Must be willing to remain on their current form of contraception for the duration ofthe study. Note: For participants with same-sex partners or who are otherwise abstinent fromheterosexual intercourse, total abstinence (defined as abstinence frompenile-vaginal intercourse), when this is the preferred and usual lifestyle ofparticipants, may be considered an acceptable form of contraception.

14. Women not of childbearing potential must be postmenopausal for ≥ 12 months.Postmenopausal status will be confirmed through testing of follicle-stimulatinghormone (FSH) levels ≥ 40 IU/L at Screening for amenorrheic female participants.Willing and able to have the types of diagnostic procedures required by theprotocol, such as neuroimaging, phlebotomy, and other testing.

15. Willing and able to take oral drug therapy according to the study protocol.

16. Willing and able to undertake radiological scans (PET, MRI) and utilize smartphoneapps/ devices to complete assessments.

Exclusion Criteria:

1. Meets diagnostic criteria for a degenerative neurologic disorder such as Parkinson'sdisease, Multiple System Atrophy, Dementia with Lewy Bodies, etc.

2. Screening PET scan does not demonstrate robust PK11195 signal in striato-corticalregion of interest in the opinion of the Investigator.

3. RBD associated with narcolepsy.

4. Dementia (Mild Cognitive Impairment permitted).

5. Unstable medications (stable use [minimum 4 weeks] allowed for treatment ofaffective symptoms [mood disorders] and dream enactment [eg, melatonin, clonazepam,etc]).

6. Untreated or uncontrolled severe obstructive sleep apnea (OSA).

7. Females who are pregnant or breastfeeding.

8. Body mass index (BMI) > 35.0 kg/m2.

9. Any known hypersensitivity to the IP, radioligand or their constituents.

10. Serious neurological disorder, such as uncontrolled epilepsy or stroke.

11. History of psychotic symptoms requiring antipsychotic treatment or exposure totypical or atypical antipsychotics or other dopamine blocking agents within 6 monthsprior to Screening.

12. History of suicidal attempt/s or ideation/s within the prior 6 months.

13. Gastrointestinal conditions that may affect the absorption of IP (eg, ulcerativecolitis, gastric bypass, or active duodenal or gastric ulcers).

14. History of significant medical event/s within 6 months prior to the Screening visit,at the discretion of the PI. This includes, but is not limited to, a cerebrovascularevent or a myocardial infarction.

15. Any significant uncontrolled cardiac arrhythmia, including but not limited to secondand third degree atrioventricular (AV) block.

16. History of head trauma with loss of consciousness for more than 5 minutes within thepast 6 months.

17. Use of drugs historically associated with liver injury, hepatic steatosis, orsteatohepatitis in the 4 weeks prior to Screening.

18. History of liver cirrhosis (fibrosis stage 4), or hepatic decompensation (eg,ascites, hepatic encephalopathy, variceal bleeding, etc.) or history of other formsof chronic liver disease (for example Hepatitis B, Hepatitis C, autoimmune liverdisease, primary biliary sclerosis, primary sclerosing cholangitis, Wilsons disease,hemochromatosis, A1At deficiency, history of liver transplantation).

19. Active known chronic or relevant acute infections, such as HIV (HumanImmunodeficiency Virus), viral hepatitis, or tuberculosis. Participants with apositive test result may participate in the study, at the discretion of theInvestigator, if further diagnostic analysis (according to localpractice/guidelines) establishes conclusively that the participant has no evidenceof active infection.

20. Solid liver lesions other than hemangiomas.

21. Suspicion or diagnosis or history of hepatocellular carcinoma (HCC).

22. Sustained supine hypertension ≥ 180 mmHg systolic or 110 mmHg diastolic, exceedinglevels defined by local guidelines ie, ≥ 140/90 mmHg per UK standards. Sustained isdefined as the average of 3 observations, each at least 10 minutes apart, with theparticipant having been supine and at rest for at least 5 minutes prior to eachmeasurement. Uncontrolled cases of elevated BP, based on PI discretion, will bediscussed on a case-by-case basis with the Sponsor in consultation with the MM andPI.

23. History of symptomatic orthostatic hypotension (OH) which interferes with theparticipant's day to day level of functioning. OH is defined as a decrease of ≥ 20mmHg systolic or ≥ 10 mmHg diastolic when changing from supine to standing position,after having been in supine position for at least 5 minutes.

24. Current unstable angina.

25. Congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).

26. Heart rate ≤ 50 beats per minute (bpm) as tested on 3 occasions, 10 minutes apart.

27. Abnormal 12-lead ECG results, which in the opinion of the Investigator will preventparticipation in the study.

28. Uncontrolled diabetes defined as an HbA1c ≥ 9.5% in the 3 months prior to or atScreening.

29. Prior diagnosis of cancer and evidence of continued malignancy within the past 3years (with the exception of adequately treated basal cell or squamous cell skincancer, in situ cervical cancer or in situ prostate cancer with normalprostate-specific antigens post resection).

30. Any major surgical procedure within 30 days prior to the Screening visit. Minorsurgery is per the discretion of the Investigator.

31. Severely impaired renal function with creatinine clearance < 30 mL/min.

32. Active alcohol or substance use disorder within the past 12 months, at thediscretion of the Investigator.

33. Depression of moderate severity or more on the Patient Health Questionnaire (PHQ-9) ≥ 10 at Screening. Note: participants with scores ≥ 10 due to indications inQuestions 3 (sleep), 4 (tiredness), and/or 7 (concentration), with no clinical signsof depression, can be included at the discretion of the Investigator followingdiscussion with the Sponsor and MM.

34. Participants with clinically significant abnormalities (as determined by theInvestigator) in clinical laboratory tests at Screening, as assessed by thestudy-specific clinical laboratory. A single repeat test may be conducted if deemednecessary.

35. Participation in any trial of a device (including, but not limited to transcranialmagnetic stimulation [TMS], near-infrared [NIR], and red-light therapy [λ = 600-1070nm]), investigational medicinal product, supplement, surgical treatment,cognitive/behavioral therapy, physiotherapy, or active exercise study within 30 days (or 5 half-lives of an investigational medicinal product, whichever is longer) priorto Screening.

36. Any reason which would impede the ability to safely undertake radiological scans (PET, MRI) such as metal implants, claustrophobia, inability to lie still in thescanner for the scanning period etc.

37. Chronic inflammatory or autoimmune disorder.

38. Receipt of any live vaccine within 4 weeks or any vaccine within 2 weeks prior toScreening.

39. Regular use of anti-inflammatory/immunomodulating medications including prednisoloneor other oral steroids (within 3 months of Screening), non-steroidal antiinflammatories including high dose aspirin (> 75 mg), diclofenac, and meloxicam (within 2 weeks of Screening), and immunosuppressant drugs including mycophenolate,methotrexate, rituximab, cyclophosphamide, and alemtuzumab (within 6 months ofScreening).