A Study in Subjects With Neurogenic Orthostatic Hypotension

Exclusion Criteria

• •1. Systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies.
• •2. Concomitant use of vasoconstricting agents for the purpose of increasing blood pressure (BP) such as ephedrine, dihydroergotamine, or midodrine must be stopped at least 1 day or 5 half-lives (whichever is longer) prior to dosing on Day 1 and throughout the duration of the study. Fludrocortisone use in the study will be limited to a stable dose of 0.1 mg once-daily (QD).
• •3. Supine SBP ≥ 170 mm Hg or seated SBP ≥ 140 mm Hg at Screening.
• •4. Subjects with clinically meaningful urinary retention who use or are likely to use α1-AR antagonists (e.g., tamsulosin \[Flomax\]), or other medications (e.g., trazodone).
• •5. Concomitant use of anti-hypertensive medication for the treatment of essential hypertension unrelated to autonomic dysfunction.
• •6. Evidence of any significant or unstable clinical disorder or laboratory finding that renders the subject unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine (excluding managed hypo and hyperthyroidism), metabolic, renal, or other systemic disease or laboratory abnormality.
• •7. History of malignant disease within 5 years, including solid tumors and hematologic malignancies (except \[a\] basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured; \[b\] low-grade adenocarcinoma of the prostate).
• •8. Any clinically significant illness or disease (apart from those typically associated with neurodegenerative disease) as determined by medical and surgical history, physical examination, 12-lead electrocardiogram (ECG) and clinical laboratory assessments conducted at Screening.
• •9. History of suicidal ideation or an episode of clinically severe depression as determined by the Investigator.
• •10. Clinically significant abnormalities of ECG, including QTcF \> 450 ms, for males and QTcF \> 470 ms for females, and/or HR \< 50 beats per minute, or evidence of clinically significant bundle branch blocks, as indicated by 12-lead ECG in a supine position at Screening.
• •11. A calculated eGFR of ≤60 mL/min/1.73m2 according to the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation at Screening.
• •12. Current use of any prohibited prescription medication during Screening or throughout study, unless approved by both the Investigator and the Sponsor Medical Monitor.
• •13. Prior treatment with any investigational drug ≤90 days prior to dosing (Day 1), or ≤5 half-lives of the drug (whichever is longer), or current enrollment in any other study treatment or disease study, except for observational studies.
• •14. Known or suspected alcohol or substance abuse within the past 12 months and/or positive test for alcohol or drugs of abuse at Screening.
• •15. Positive screening test for human immunodeficiency virus (HIV), hepatitis C antibody (HCV Ab) or current hepatitis B infection (defined as positive for hepatitis B surface antigen \[HbsAg\] at Screening).
• •16. Females who are breastfeeding.
• •17. Any other reason for which the Investigator considers it is not in the best interest of the subject to undertake the study.