Clinical Effect Durability of TD-9855 for Treating snOH in Subjects With Primary Autonomic Failure

Phase 3, multi-center, randomized withdrawal study to evaluate the sustained benefit in
efficacy and safety of TD-9855 in subjects with primary autonomic failures (MSA, PD, or PAF)
and snOH. The study consists of 3 periods: (i) 16-week open-label (OL) treatment with
TD-9855, (ii) 6-week randomized placebo-controlled treatment, and (iii) 2-week follow-up
(only for patients who do not enroll in Study 0171 (long-term extension safety study)).

Inclusion Criteria (For 0169 Completers Group):

- Subject has completed 4 weeks of double blind treatment in Study 0169 (V6) and, in the
opinion of the Investigator, could benefit from continued treatment with TD-9855. No
minimum score of OHSA#1 is required to enter V1 of Study 0170.

- Subject has a minimum of 80% study medication compliance in Study 0169.

Inclusion Criteria (For De Novo Group):

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

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

- Subject must score at least a 4 on the OHSA#1 at V1.

- 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 impaired autonomic reflexes, as determined by
absence of Phase IV BP overshoot after release of the Valsalva strain.

- Subject has plasma Norepinephrine (NE) levels ≥ 100 pg/mL after being in seated
position for 30 minutes.

Exclusion Criteria (For 0169 Completers Group):

- Subject has a medical, laboratory, or surgical issue(s) deemed by the investigator to
be clinically significant.

- Subject has an uncooperative attitude or reasonable likelihood of non-compliance with
the protocol.

- Subject has a concurrent disease or condition that, in the opinion of the
investigator, would confound or interfere with study participation or evaluation of
safety, tolerability, or pharmacokinetics of the study drug.

Exclusion Criteria (For De Novo Group):

- Subject has a known systemic illness known to produce autonomic neuropathy, including,
but not limited to, diabetes mellitus, diabetes insipidus, diabetic neuropathy,
amyloidosis, or autoimmune neuropathies.

- Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake
inhibitors (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 V1 or requires concomitant use until the follow-up
visit.

- Subject has changed dose, frequency, or type of prescribed medication for orthostatic
hypotension (e.g., ephedrine, dihydroergotamine, or fludrocortisone), within 7 days
prior to V1. These medications must be tapered off post-randomization. Tapering will
follow the product's approved package insert (if applicable). Midodrine and droxidopa
must be tapered off at least 7 days prior to V1.

- Subject has known or suspected alcohol or substance abuse within the past 12 months
(Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
[DSM-IV-TR®] definition of alcohol or substance abuse).

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

- Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.

- 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 is unable or unwilling to complete all protocol specified procedures including
questionnaires.

- 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 finding (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/1.73 m2, 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 Columbia Suicide Severity Rating Scale
(C-SSRS)(Baseline/Screening Version). Subject should be assessed by the rater for risk
of suicide and the subject's appropriateness for inclusion in the study.