A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure

– Subject is male or female and at least 30 years old.

– Subject must meet the diagnostic criteria of snOH, as demonstrated by a sustained
reduction in BP of ≥20 mm Hg (systolic) or ≥10 mm Hg (diastolic) within 3 minutes of
being tilted-up to ≥60o from a supine position as determined by a tilt-table test.

– Subject must score at least a 4 on the Orthostatic Hypotension Symptom Assessment
Question #1 at randomization visit.

– For subjects with PD only: Subject has a diagnosis of PD according to the United
Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria (1992).

– For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of the
Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman
Criteria (2008).

– For subjects with PAF only: Subject has documented impaired autonomic reflexes,
including the Valsalva maneuver performed within 24 months from the date of
randomization.

– Subject has plasma NE levels >100 pg/mL after being in seated position for 30 minutes.

Exclusion Criteria:

– Subject has a known systemic illness known to produce autonomic neuropathy, including
but not limited to amyloidosis, and autoimmune neuropathies.

– Subject has a known intolerance to other NRIs or SNRIs.

– Subject currently uses concomitant antihypertensive medication for the treatment of
essential hypertension unrelated to autonomic dysfunction.

– Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives,
whichever is longer, prior to randomization or requires concomitant use until the
follow-up visit.

– Subject has changed dose, frequency, or type of prescribed medication for orthostatic
hypotension within 7 days prior to V1.

– Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior
to V1.

– Subject has a known or suspected alcohol or substance abuse within the past 12 months
(DSM-IV-TR® definition of alcohol or substance abuse).

– Subject has a clinically unstable coronary artery disease, or major cardiovascular or
neurological event in the past 6 months.

– Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to
randomization.

– Subject has a history of untreated closed angle glaucoma, or treated closed angle
glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk
to the subject.

– Subject has any significant uncontrolled cardiac arrhythmia.

– Subject has a Montreal Cognitive Assessment (MoCA) ≤23.

– Subject had a myocardial infarction in the past 6 months or has current unstable
angina.

– Subject has known congestive heart failure (New York Heart Association [NYHA] Class 3
or 4).

– Subject has a clinically significant abnormal laboratory findings (e.g., alanine
aminotransferase [ALT] or aspartate aminotransferase [AST] >3.0 x upper limit of
normal [ULN]; blood bilirubin [total] >1.5 x ULN; estimated glomerular filtration rate
(eGFR) <30 mL/min/1.73m2, or any abnormal laboratory value that could interfere with safety of the subject). - Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal behavior, as outlined by the C-SSRS (Columbia Suicide Severity Rating Scale) (Baseline/Screening Version) subject should be assessed by the rater for risk of suicide and the subject's appropriateness for inclusion in the study.