Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by progressive loss of function by the
pulmonary vascular bed due to a variety of factors including obliterative vascular lesions,
vasoconstriction, and thrombotic occlusion of the pulmonary arteries. Ultimately, right-sided
heart failure ensues with severe limitation of exercise and eventual progression to death or
lung transplantation. While there are multiple FDA-approved therapies for PAH representing 3
major pathways of interest, no treatments are curative, and have additional limitations
including high expense, multiple side effects, and dosing inconveniences.

The strongest established risk factor for the progressively fatal disease pulmonary arterial
hypertension (PAH) is female sex (~3:1 female:male ratio). We and others have found higher
circulating estrogen levels, and enhanced estrogen signaling, in PAH patients. Preclinical
work by our group and others supports the concept that anti-estrogen therapy, is effective
for both prevention and treatment in PAH. Recent and ongoing clinical studies are underway to
assess these approaches in humans, including a recent study demonstrating the safety of
estrogen reduction in postmenopausal women.

Tamoxifen is the most commonly used selective estrogen receptor modulator (SERM). Due to its
extensive use in humans for over three decades, it has an excellent safety profile and its
long-term sequelae are well characterized. Furthermore, it is a generic drug which has been
FDA-approved for treatment and prevention of breast cancer, particularly those with estrogen
receptor-positive neoplasms.

To help to determine whether tamoxifen may be a safe and effective treatment for PAH in women
and men, we will conduct a single-center, randomized, double-blind, placebo-controlled Phase
II study of subjects with PAH. All subjects will also be treated with background standard of
care therapy at the discretion of their PAH care physician.

Inclusion Criteria:

- Previous documentation of mean pulmonary artery pressure greater than or equal to 25
mm Hg with a pulmonary capillary wedge pressure (or left ventricular end-diastolic
pressure) less than or equal to15 mm Hg and PVR greater than or equal to 3 WU at any
time before study entry, consistent Group 1 PAH classified by accepted international
classification.

- Diagnosis of PAH which is idiopathic, heritable, drug- or toxin-induced, or associated
with connective tissue disease.

- Age 18 years and older.

- WHO Functional Class I, II, or III status.

- Ability to perform a six minute walk test without significant limitations in
musculoskeletal function or coordination, with distance greater than or equal to 150m
and less than or equal to 550m.

- Informed consent.

Exclusion Criteria:

- Current treatment with estrogen, progesterone, or any form of sex hormone therapy.

- Current treatment with anti-sex hormone therapy (e.g., anastrozole, fulvestrant,
tamoxifen, leuprolide acetate (luporon) or other centrally-acting hormone agents.

- WHO Functional Class IV status.

- History of, or current, breast, uterine, ovarian, or testicular cancer.

- Current pregnancy, or prior pregnancy within 3 months of enrollment.

- Initiation of PAH therapy (prostacyclin analogues, endothelin-1 receptor antagonists,
phosphodiesterase-5 inhibitors, riociguat, selexipag) within three months of
enrollment; the dose must be stable for at least three months prior to Baseline Visit.
Of note, PAH therapy, including diuretics, which is stopped and then restarted or has
dose changes which are not related to initiation and up titration will be allowed
within 3 months prior to the Baseline Visit, and during the trial for subjects.

- History of thromboembolic event.

- Hospitalized or acutely ill.

- Renal failure (creatinine over 2.0).

- Hypercalcemia.

- Severe osteoporosis (t score < -2.0 OR t score < -2.5 if on bone modifying treatment).

- Current or recent (< 3 months) chronic heavy alcohol consumption.

- Enrollment in a clinical trial or concurrent use of another investigational drug (non
FDA approved) or device therapy within 30 days of screening visit.

- Enrollment in any pharmacologic clinical trial within one month of screening.

- Due to potential drug interactions with tamoxifen, subjects using bosentan (CYP3A4) or
selexipag (CYP2C8) will be excluded.

- Due to the concerns of pregnancy during PAH and with tamoxifen use, subjects will be
excluded who do not use at least two forms of contraception (e.g., IUD plus the use of
a barrier contraceptive method).