Phase IIa: Safety, PK, & Tolerability of Sodium Nitrite in Patients With Peripheral Arterial Disease-SONIC

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and a strong
predictor of cardiovascular (CV) mortality. The systemic disease of atherosclerosis in
these patients results in arterial stenoses in the arteries supplying the muscles of the
lower extremities. During exercise, the stenoses limit the ability to increase blood flow,
which leads to an oxygen supply/metabolic demand mismatch, a bio-energetic deficit, and
subsequent muscle contractile dysfunction. Thus, the primary pathophysiology of PAD is
related to the limitation in blood flow and abnormal hemodynamics (reduced tissue perfusion
pressure and blood flow) of the lower limbs during exercise. Patients with PAD commonly
present with symptoms of intermittent claudication (IC), often described by patients as a
cramping, aching, or fatigue sensation in the calf muscles of the legs that occurs during
physical activity. Notably, the symptom of claudication pain is due to exercise-induced
ischemia in the muscles of the leg, causing a significant limitation of functional exercise
capacity and adversely affecting quality of life.

Sodium nitrite is being investigated as a potential new therapy for improving function in
patients with PAD. The overall goal of this dose-ranging study is to evaluate the safety,
pharmacokinetics, tolerability, and potential biological activity of multiple doses of oral
sodium nitrite in patients with PAD. As described above, the primary pathophysiology of PAD
is related to the limitation in blood flow of the lower extremities, resulting in limited
exercise tolerance and decreased quality of life. PAD is highly prevalent in patients with
diabetes, leading to poor outcomes and accelerated disease progression compared with
non-diabetic counter-parts. A common feature of both patient groups is endothelial
dysfunction, decreased NO bioavailability, and depletion of NO stores, a finding that may be
compounded when PAD and diabetic conditions coexist. Sodium nitrite is an inorganic salt
that is found and metabolized in vivo. At physiological concentrations, sodium nitrite is
known to cause vasodilation, a feature which is enhanced in hypoxic or ischemic
environments. The nitrite anion acts a NO reservoir and can be readily converted to active
NO by a non-enzymatic reaction with deoxyhemoglobin, making it a unique candidate for
potential therapeutic effect in ischemic tissues. Accordingly, this study is designed to
assess the safety and tolerability of sodium nitrite as well as the pharmacokinetic and
pharmacodynamic relationship of sodium nitrite at two different doses versus placebo.
Sodium nitrite's effects on endothelial function, a marker of NO bioactivity, and measures
of functional walking capacity will also be assessed.

Inclusion Criteria:

- The subject is between and including 35 and 85 years of age.

- Subjects must be either male or females post-menopausal, sterilized or using suitable
birth control. Suitable birth control must be total abstinence, male partner
sterilization or double barrier method paired with using oral contraception,
injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring,
percutaneous contraceptive patches, or intrauterine device (IUD).

- History of Peripheral Arterial Disease (PAD) confirmed by medical chart or an ankle
brachial pressure index at rest ≤0.90.

- If receiving medical standard treatment for cardiac risk factors, subject must have
been on a stable treatment for at least 1 month prior to Screening. Treatments must
have not changed significantly in the last month and are not expected to change over
the duration of the study.

- If subjects experience claudication symptoms, subjects must have stable lower
extremity symptoms for at least 1 month prior to Screening.

- Ability to provide written informed consent and willingness as documented by a signed
informed consent form.

Exclusion Criteria:

- Non-atherosclerotic PAD.

- Lower extremity surgical or percutaneous revascularization, evidence of graft failure
or other peripheral vascular surgical procedure within last 6 months prior to
Screening.

- Anticipated lower extremity revascularization within the treatment period.

- Myocardial infarction, unstable angina, cerebrovascular accident or transient
ischemic attack within 3 months prior to Screening.

- Poorly controlled diabetes (HgA1c > 10.0).

- Poorly controlled hypertension (systolic blood pressure (SBP) ≥ 160 mmHg or diastolic
blood pressure (DBP) ≥ 100 mmHg) despite therapy.

- Systolic blood pressure ≤100 mmHg on current medical regimen.

- Hypersensitivity to sodium nitrite or related compounds.

- Renal insufficiency documented as eGFR < 30 mL/minute/1.73 m2.

- Pregnant or nursing women.

- Life expectancy < 6 months.

- A chronic illness that may increase the risks associated with this study in the
opinion of the investigator.

- Active malignancy requiring active anti-neoplastic therapy that will, in the opinion
of the investigator, interfere with study treatment or participation.

- Active infection.

- NYHA CHF Class III or IV.

- Recent hospitalization (< 30 days) for acute coronary syndrome, myocardial
infarction, congestive heart failure or stroke.

- Recent (< 30 days) coronary revascularization.

- Previously treated with angiogenic factors or stem cell therapy within 1 year prior
to Screening.

- Involvement in another PAD clinical trial within past 1 month prior to Screening.

- Exposed tendon, muscle or bone or a diagnosis of critical leg ischemia.

- Previous amputation within 3 months prior to Screening or planned amputation that
would limit walking (e.g. small toe is allowed).

- The subject's ability to perform the 6 minute walk test is limited by symptoms other
than claudication.

- Current diagnosis of alcohol or other substance abuse.

- History of methemoglobinemia, [met-Hb > 15%].

- Inability to speak English (due to need to administer standardized English-language
questionnaire).

- Evidence of anemia.

- History of chronic hemolytic condition, including sickle cell disease.

- Chronic use of anti-migraine medication such as Imitrex or sumatriptan.

- Have a positive screen for glucose-6-phosphate dehydrogenase deficiency at screening.

- Subjects who regularly take the following medications: Allopurinol, PDE-5 inhibitors,
sedative tricyclic antidepressants, antihistamines, meperidine and related central
nervous system depressants, and nitrates.