A Phase 2 Study to Assess the Effects of SUL-238 on High Energy Phosphates With ³¹P-MRS in Patients With Early, Untreated Parkinson's Disease

A Phase 2, Randomized, Double-blind, Placebo-Controlled, Single-Center Study to Assess the Effects of SUL-238 on High Energy Phosphates With Magnetic Resonance Spectroscopy (³¹P-MRS) in Patients With Early, Untreated Parkinson's Disease ("SHEPHERD" STUDY)

The main goal of the study is to investigate how well the new drug SUL-238 works in Parkinson's Disease (PD). This is done by means of an MRS scan. An MRS scan is similar to a regular MRI scan. It will also learn about the safety of new drug SUL-238. The main questions it aims to answer are:

• Does new drug SUL-238 improve the mitochondrial function in patients with Parkinson's Disease (PD)?
• What medical problems do participants have when taking new drug SUL-238?

Researchers will compare new drug SUL-238 to a placebo (a look-alike substance that contains no drug) to see if SUL-238 works to improve mitochondrial function in patients with PD.

Participants will:

• Take new drug SUL-238 or a placebo every day for 28 days
• Visit the clinic once every 2 weeks for checkups and tests during the treatment period and finally 28 days after the last dose of SUL-238
• Keep a diary of their symptoms and the number of times they use oral new drug SUL-238

Two different oral doses of SUL-238 (1500 mg t.i.d. or 500 mg t.i.d) or placebo will be administered to patients with early, untreated Parkinson's Disease (PD), aged ≥40 years. Patients will be randomly assigned to one of the 3 groups using 1:1:1 randomization, each group will consist of 15 patients. Patients will be stratified based on their sex in to ensure similar distribution of both sexes in each group. Drop-outs will be replaced with new patients to reach 15 patients in each group. Study drugs will be administered after fasting for a minimum of 1 hour prior to dosing and 1 hour after the administration of the study medication. However, for the third dose on Day 1 and the first dose on Day 14, subjects are required to fast for 4 hours due to Safety Lab assessments. Additionally, the first dose on Day 1 and Day 28, for which a fasting period of 8 hours is required, as the same conditions for 31P-MRS are requested to exclude any interference with food intake. Therefore, On Day 28 subjects should arrive at the unit in a fasted state (following the meal 1 hour after the third dose on Day 27) and remain fasted until completion of the 31P-MRS. Only morning dose will be given on day 28, there will be no dosing between days 29 and 56.

There will be three study periods per treatment group:

• A maximum of four-week screening period (Screening Period)
• A four-week treatment period (Treatment Period)
• A four-week follow-up period (End-of-Study Assessment)

Patients will be visiting the study center in the morning, in total five times for study assessments and collections of blood samples until day 56. Blood samples will be collected on days 1, 14, 28, and 56 (On day 1 [pre-dose baseline, post-dose at 1 hr], and days 14 [pre-dose], 28 [post-morning dose at 1 hr and 4 hr]).

Patients who agreed to provide CSF in each group will give one CSF sample on day 28 at 4 hours post-morning dose.

Voxel Metabolite Measurements:

MRI/MRS scans will be conducted on a Siemens 3 MAGNETOM Cima.X scanner located at the at the UMCG. Patients will undergo 31P-MRS scans to measure concentrations of the following mitochondria-related brain metabolites: ATP, phosphocreatine and inorganic phosphate, as well as membrane related phospholipids PME and PDE.

Preparation: A 31P/1H T/R head coil will be used. The head of the patient will be positioned at the center of the coil. Prior to 31P-MRS, T1 and T2 weighted structural images are acquired for reference purposes during voxel placement.

31P-MRS scans: First, a dynamic series of the whole brain will be acquired for the duration of 15 minutes. During this period, three epochs of three minutes rest are interleaved by two epochs of three minutes of paced, alternating fist clenching using both hands. Second, the MRS scan during rest is based on a 3D-CSI acquisition with a duration of 15 minutes. This allows localisation of the 31P-spectra bilaterally for precentral gryrus, substantia nigra, as well as the putamen with sufficient signal to noise ratio for further analysis.

Inclusion Criteria:

1. Untreated Parkinson's Disease (PD) patients diagnosed in accordance with the UK PDS Brain Bank Criteria for the diagnosis of PD. Patients must have bradykinesia and at least one of the following:

   1. muscular rigidity
   2. rest tremor (4-6 Hz)
   3. postural instability unrelated to primary visual, cerebellar, vestibular or proprioceptive dysfunction.

2. The duration of PD since diagnosis is ≤ 1 year.

3. Patients with Modified Hoehn and Yahr stage ≤ 2.0.

4. Patients with Montreal Cognitive Assessment (MOCA) score of ≥22.

5. Men and women aged ≥40 years at screening.

6. Able to understand the nature of the study and provide signed and dated written informed consent in accordance with local regulations before the conduct of any study related procedures.

7. Able to complete all study related testing and evaluations.

8. Patients must be, in the opinion of the Investigator, able to participate in all scheduled evaluations, likely to complete all required tests, and likely to be compliant.

9. Men and women of child-bearing potential with partners of child-bearing potential must agree to use highly effective contraception. For male patients, contraception should continue for 3 months after the last dose of investigational medicinal product (IMP, one spermatic cycle). For female patients, contraception should continue for 6 months after the last dose of IMP (one oocyte cycle).

10. Women of non-childbearing potential must be post-menopausal (the last menstrual period was at least 12 months ago, and follicle-stimulating hormone [FSH] at screening confirms post-menopausal status), or have no uterus, ovaries, or fallopian tubes (or have their fallopian tubes tied). All women must have a negative pregnancy test result before administration of test article. Women who are surgically sterile must provide documentation of the procedure by an operative report or by ultrasound.

Exclusion Criteria:

1. Atypical parkinsonism, including that due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, normal pressure hydrocephalus, or other neurodegenerative disease.
2. Any history of intellectual disability or psychiatric disorders, including substance use disorders, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, except a history of mild depression/anxiety that has been resolved for at least the past 3 months.
3. A positive answer to questions 3 through 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening.
4. A positive Hepatitis B surface antigen, Hepatitis C antibody, or Human Immunodeficiency Virus (HIV) antibody test at screening.
5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 1.5 times the upper limit of normal (ULN) at screening or between screening and first dose administration.
6. Received or used an investigational product (including placebo) or device within the following time period prior to day -1 in the current study: 90 days, 5 half-lives, or twice the duration of the biological effect of the investigational product (whichever is longer).
7. Use of non-prescription drugs, vitamins, herbal, and dietary supplements which has potential to influence the mitochondrial function (such as coenzyme Q10, carnitine, creatine, lipoic acid and vitamin E) within 30 days prior to day -1.
8. Use of drugs which are strong inhibitors of CYP3A4 or CYP3A4 substrates with narrow therapeutic index within 30 days prior to day -1.
9. History of clinically significant sensitivity to any of the study medications, or components thereof or a history of drug or other allergies that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
10. Women with a positive pregnancy test, are lactating, or are planning to become pregnant during the study or within 6 months of the end of this study.
11. A history or presence of any disease, condition, or surgery likely to affect drug absorption, distribution, metabolism, or excretion. Patients with a history of cholecystectomy should be excluded.
12. A history or presence of a clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, pulmonary, ophthalmologic, immunologic, hematologic, dermatologic, or neurologic (other than PD) abnormality.
13. At screening, any clinically significant abnormalities in rhythm, conduction, or morphology of the resting 12-lead ECG.
14. A clinically significant vital signs abnormality at screening or day -1, as determined by the investigator in accordance with the Dutch General Practitioner Guidelines (NHG Standards), corresponding to higher than 160 mm Hg systolic and 110 mm Hg diastolic blood pressure. Participants with a systolic blood pressure <90 mmHg or a diastolic blood pressure <50 mmHg will also be excluded.
15. In the opinion of the Investigator or Medical Monitor, the patient is unlikely to comply with the protocol or is unsuitable for any reason, e.g., known issues with ability to swallow tablets.
16. Women of child-bearing potential (WOCBP), or men, who are unwilling or unable to use accepted methods of birth control for up to 6 months following study participation.
17. Contraindications for undergoing an MRI.