This study will examine the long-term safety of buntanetap in participants with PD. This will be a 36-month open-label safety study. This study will be conducted with two cohorts. Cohort 1 will enroll via invitation only for PD participants who have previously participated in buntanetap clinical trials. Cohort 2 will be for PD participants who are receiving deep brain stimulation (DBS) treatment. Qualified participants will receive buntanetap 30mg QD after a screening period of up to 42 days.

This study will examine the long-term safety of buntanetap in participants with PD. This will be a 36-month open-label safety study. This study will be conducted with two cohorts. Cohort 1 will enroll via invitation only for PD participants who have previously participated in buntanetap clinical trials. Cohort 2 will be for PD participants who are receiving deep brain stimulation (DBS) treatment. Qualified participants will receive buntanetap 30mg QD after a screening period of up to 42 days. MMSE, MoCA, C-SSRS, and MDS-UPDRS will be assessed by clinicians who have successfully completed the requisite certifications/trainings for each assessment. Each participant shall be assessed by the same clinician throughout the study. Cohort 1 participants will stop standard of care Parkinson's medications 12h before baseline and annual clinical visits to ensure clinical OFF-state during visit. Cohort 2 participants will stop standard of care Parkinson's medications 12h before all clinic visits. The night before the baseline and annual clinic visits (or early termination visit), Cohort 2 participants will return DBS settings to their initial baseline settings.

Inclusion Criteria:

1. Diagnosis of idiopathic PD according to MDS Clinical Diagnostic Criteria for Parkinson's Disease (Postuma et al., 2015) and

   a. Cohort 1: Participated in a prior PD clinical trial with buntanetap. i. A legally authorized representative is required for any participant whose MMSE <21 at screening.

   b. Cohort 2: Has been receiving DBS treatment in either 1) the subthalamic nucleus or 2) the globus pallidus internus for at least 12 months after a successful DBS surgery that achieved the goal.

   i. Female or male adults aged 40 to 85 years. ii. H&Y stage 1-3 in ON state. iii. MMSE 21-30 at screening and baseline.

2. Have a support person who will accompany the participant on study visits at designated times.

3. Female participants of childbearing potential* must have a negative urine pregnancy test at screening, must be non-lactating, and must agree to use a highly effective method of contraception (i.e., a method resulting in a failure rate of less than 1% per year when used consistently and correctly) during the trial and for one month after the last dose of trial treatment, such as:

   1. Oral, intravaginal, or transdermal combined (estrogen plus progestogen) hormonal contraception associated with inhibition of ovulation,

   2. Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation,

   3. Intrauterine device (IUD),

   4. Intrauterine hormone-releasing system (IUS),

   5. Bilateral tubal occlusion,

   6. Vasectomized partner (a vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the participant, and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used),

   7. Sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant).

      • Non-childbearing potential includes surgically sterilized or postmenopausal with no menstrual bleeding for at least one year prior to study start.

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4. Male participants must be sterile or sexually inactive or agree not to father a child during the study and one month after the last dose of study medication and must agree to use a barrier method for contraception. Female partners of male participants must adopt a highly effective method of contraception with a failure rate of less than 1% per year when used consistently and correctly such as:

   1. Oral, intravaginal, or transdermal combined (estrogen plus progestogen) hormonal contraception associated with inhibition of ovulation,
   2. Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation,
   3. IUD,
   4. IUS,
   5. Bilateral tubal occlusion.

5. No evidence of current suicidal ideation or previous suicide attempt in the past month as evaluated in the C-SSRS.

6. Stability of permitted medications for at least 4 weeks prior to screening. Refer to Concomitant Medications section above for details on prohibited and permitted medications.

   1. Standard of care anti-parkinsonian medication,
   2. Cholinesterase inhibitors and/or memantine medication,
   3. Anticonvulsant medications used for epilepsy or mood stabilization, or neuropathic pain indications, and have not had a breakthrough seizure 3 years prior to screening,
   4. Mood-stabilizing psychotropic agents including, but not limited to, lithium,

7. Adequate visual and hearing ability (physical ability to perform all the study assessments).

8. Good general health with no disease expected to interfere with the study.

Exclusion Criteria:

1. Cohort 1 only: Is currently receiving DBS treatment. (Participant may enroll in Cohort 2 if they meet the corresponding inclusion/exclusion criteria).

2. A history of psychiatric disorder such as schizophrenia, bipolar disorder, or major depression according to the criteria of the most current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), unless their symptoms have been mild, and they are stable on treatment or no longer need treatment. Mild depression or history of depression that is stable on treatment with selective serotonin reuptake inhibitors (SSRI) or serotonin and norepinephrine reuptake inhibitors (SNRI) medication at a stable dose is acceptable. Refer to Concomitant Medications section above for details on prohibited and permitted medications.

3. A history of seizure disorder. If stable on medication, it is acceptable. Refer to Concomitant Medications section above for details on prohibited and permitted medications.

4. A history or current evidence of long QT syndrome, Fridericia's formula corrected QT (QTcF) interval ≥ 450 ms for men and ≥ 460 ms for women, or torsades de pointes.

5. Bradycardia (<50 bpm) or tachycardia (>100 bpm) on the ECG at screening and deemed medically significant by the PI.

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6. Uncontrolled Type-1 or Type-2 diabetes. A participant with hemoglobin subunit alpha 1c (HbA1c) levels up to 7.5% can be enrolled if the investigator believes the participant's diabetes is under control.

7. Clinically significant renal (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] <50 mL/min/BSA [body surface area]) or hepatic impairment (Alkaline phosphatase [ALP] > 2.0X the upper limit of normal [ULN] and/or total bilirubin > 2.0X ULN).

8. Any clinically significant abnormal laboratory values. Participants with liver function tests (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) greater than twice ULN will be excluded.

9. Is at imminent risk of self-harm, based on clinical interview and responses on the C-SSRS, or of harm to others in the opinion of the investigators. Participants must be excluded if they report suicidal ideation with intent, with or without a plan or method (e.g., positive response to Items 4 or 5 in assessment of suicidal ideation on C-SSRS) in the past 2 months, or suicidal behavior in the past 6 months.

10. Cancer or has had a malignant tumor within the past year, except participants who underwent potentially curative therapy with no evidence of recurrence (participants with stable untreated cancer are not excluded).

11. Alcohol / Substance use disorder, moderate to severe, in the last 5 years according to the most current version of the DSM.

12. Participation in another clinical trial with an investigational agent and have taken at least one dose of study medication, unless unblinded on placebo, within 4 weeks prior to the start of screening, or five half-lives of the investigational drug, whichever is greater. The end of a previous investigational trial is the date the last dose of an investigational agent was taken.

13. A learning disability or developmental delay.

14. Participants whom the site PI deems to be otherwise ineligible.

15. A known allergy to the investigational drug or any of its components.

    Inactive ingredients of the investigational medicinal product:

    • Silicified microcrystalline cellulose
    • Dibasic calcium phosphate dihydrate
    • Mannitol
    • Stearic acid
    • Hypromellose (capsule shells structure)
    • Titanium dioxide (opacifier of the capsule shells)

16. Is currently pregnant, breast-feeding, and/or lactating.

17. Uncontrolled hypertension (systolic >160mmHg and/or diastolic >95mmHg) or hypotension (systolic <90mmHg and/or diastolic <60 mmHg) and deemed medically significant by the PI.