Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects
Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects
This is a four-part study of the safety, tolerability, and PK profile of sodium nitrite
 inhalation solution (AIR001) of ascending multiple doses (Part A) and of escalating doses
 with steady-state sildenafil (Part B) to healthy male and female subjects, as well as
 assessment of the safety and tolerability of multiple doses of AIR001 to patients with
 pulmonary arterial hypertension (part C) with a single dose PK study of AIR001 utilizing
 three different nebulizers (Part D).
Pulmonary hypertension (PH) is an increase in the blood pressure (BP) in the small pulmonary
 vessels, arteries, veins or capillaries that results in progressive increases in right
 ventricular afterload, often leading to right ventricular failure and death. Pulmonary
 hypertension can result from a multitude of pathologies, including arterial etiologies,
 venous, chronic hypoxia related, thromboembolic, and other miscellaneous etiologies. In the
 recent Dana Point Classification, pulmonary arterial hypertension (PAH) was classified as
 Group 1. In Group 1 PAH, the pathologic lesion is localized to the small muscular pulmonary
 arteries, resulting in luminal narrowing and resistance to blood flow. Group 1 PAH includes
 idiopathic or sporadic PAH and heritable PAH which includes those with a family history of
 PAH. Associated PAH includes disease associated with connective tissue disease as well as PAH
 associated with congenital systemic to pulmonary shunts, portal hypertension, and human
 immunodeficiency virus (HIV) infection. Drug and toxin induced PAH is also in Group 1.
 Untreated, patients with PAH have an average life expectancy of 3 years, which declines to
 approximately 1 year if right heart failure is present.

 Inhaled nitric oxide (NO) is a potent acute vasodilator. Its acute administration results in
 improved hemodynamics in the 10 to 15% of patients with PAH who demonstrate acute
 vasoreactivity. However, the usefulness of NO for chronic therapy is limited by the need for
 continuous inhalation. In patients who demonstrate vasoreactivity during an acute challenge
 with inhaled NO or a prostanoid challenge, therapy with calcium channel blockers has been
 demonstrated to result in improved symptoms and survival. In patients who do not demonstrate
 an acute vasodilator response, available therapies for PAH include prostanoids, endothelin
 receptor antagonists (ERA), and phosphodiesterase type-5 (PDE-5) inhibitors. However, the
 route and frequency of administration of the prostanoids, the hepatotoxicity of the ERAs, and
 concerns about the sustained efficacy of both the ERAs and PDE-5 inhibitors suggests that
 many patients with PAH could benefit from an effective therapy which offers ease of
 administration and a favorable toxicity profile.

 Aires Pharmaceuticals, Inc. is developing a novel therapeutic, AIR001, for the treatment of
 PAH. The active ingredient in AIR001 is sodium nitrite, formulated in a buffered, pH-adjusted
 solution for nebulization. Preclinical data suggest that under the hypoxic, acidotic
 conditions present in the pulmonary hypertensive lung, inhaled sodium nitrite serves as a
 sustained release source of NO which will act as an acute pulmonary vasodilator. In addition,
 because decreased levels of NO have been shown to stimulate vascular remodeling, the
 increased NO resulting from nitrite inhalation is postulated to attenuate or reverse the
 pulmonary arterial remodeling process, resulting in both symptomatic improvement and
 pulmonary hemodynamic improvement in patients with PAH.

 Preclinical experiments have shown that AIR001 by oral, IV, and inhalation routes of
 administration is effective in treating PAH induced by hypoxia or monocrotaline when
 administered as infrequently as once weekly at doses that generate plasma concentrations of
 approximately 1 to 10 uM and above. While the precise mechanism by which AIR001 exerts
 anti-hypertensive actions in PAH models remains to be elucidated, nitrite itself has been
 demonstrated to be metabolized to NO in animals and humans.

 Single doses of AIR001 have been shown to be well tolerated in humans at dose levels that
 generate peak plasma concentrations (Cmax) in the target range established in preclinical
 models and no safety issues have been identified. AIR001 reduced PH induced by hypoxic gas
 inhalation in healthy volunteers at doses that are well tolerated. Preclinical and clinical
 data support further clinical investigation of inhaled AIR001 for the treatment of PAH.
 Before progressing to studies in patients with PAH, the safety and tolerability of multiple
 dose administration of AIR001 will be evaluated in Part A of the current study.

 The PDE-5 inhibitor, sildenafil, is approved for use in patients with PAH and commonly used
 in the initial treatment for PAH. AIR001 is converted to NO, which increases cGMP dependent
 vasodilatation. Because PDE-5 inhibitors prevent the catabolism of cGMP by phosphodiesterase,
 it is possible that an exaggerated drug effect could be observed when AIR001 is administered
 to patients being treated with sildenafil. Therefore, combination safety and tolerability (in
 particular orthostatic effects) of escalating single doses of AIR001 will also be evaluated
 in combination with steady-state sildenafil in Part B of the study.

 A cohort of patients with previously diagnosed PAH on stable background therapy will be
 assessed for safety and tolerability of multiple doses of AIR001 in Part C of the study.

 Part D of the study will assess the PK, safety and tolerability of single dose AIR001 with
 each of three different nebulizers in a randomized crossover design.
Inclusion Criteria:

 -  Be informed of the nature of the study and is able to understand and has provided
 written informed voluntary consent

 -  Be healthy males or females, of any race, at least 18 years of age or the legal age of
 consent (whichever is greater) and less than 56 years of age at the time of the first
 dose of study drug (or sildenafil)

 -  Have a body mass index (BMI) >=18.0 and <32.0 kg/m2 and weigh at least 50 kg

 -  Be in good general health with no clinically relevant abnormalities based on the
 medical history, physical examination, clinical laboratory evaluations (hematology,
 clinical chemistry, urinalysis, methemoglobin), and 12-lead ECG that, in the opinion
 of the Investigator, would affect subject safety

 -  Agree to comply with the study procedures and restrictions

 Exclusion Criteria:

 -  Any disease or condition that might affect drug absorption, metabolism, or excretion,
 or clinically significant cardiovascular, ocular, hematological, renal, hepatic,
 pulmonary, endocrine, gastrointestinal, immunological, dermatological, neurological,
 or psychiatric disease

 -  Clinically significant illness (including lower respiratory tract infection) or
 clinically significant surgery within 4 weeks before the administration of study drug
 (or sildenafil)

 -  Use of any commercially marketed mouthwash or oral rinse with agents other than tap
 water as well as tongue brushing or scraping from screening onwards through completion
 of study

 -  Currently a smoker or has a past history of smoking (of >10 pack years)

 -  History of bronchial asthma or sleep apnea

 -  Evidence of restrictive or obstructive lung disease (Forced Expiratory Volume in 1
 second (FEV1)/Forced Vital Capacity (FVC) <70%, FEV1 <70% predicted, and/or FVC <70%
 predicted)

 -  Family history of primary PH

 -  History of pulmonary embolism

 -  Evidence of supine hypertension or hypotension (systolic BP >180 mmHg or <90 mmHg
 and/or diastolic BP> 100 mmHg or <50 mmHg) pre-dose [NOTE: BP measurements may be
 repeated twice, at least 10 minutes apart]

 -  Orthostatic hypotension defined as a drop in systolic BP by >=20 mmHg or diastolic BP
 of >=10 mmHg at screening or predose or the development of significant postural
 symptoms (dizziness, lightheadedness, vertigo) when going from the supine to the
 standing position

 -  Personal or family history of congenital or acquired methemoglobinemia

 -  Personal or family history of RBC CYP B5 reductase deficiency

 -  Personal or family history or any evidence of hemoglobinopathy

 -  Known or suspected hypersensitivity or allergic reaction to sodium nitrite, sodium
 nitrate, or saccharin

 -  Glucose-6-phosphate dehydrogenase (G6PD) deficiency or any contraindication to
 receiving methylene blue

 -  History of hypersensitivity or idiosyncratic reaction to drugs from multiple drug
 classes

 -  If female, is pregnant or breast feeding, or has a positive pregnancy test result
 pre-dose

 -  If a sexually active female, is not surgically sterile (defined as having had a
 hysterectomy, bilateral oophorectomy, or tubal ligation at least 6 months prior to
 screening) or post-menopausal (defined as amenorrhea for the past 2 years if <50 years
 of age or for the past 1 year if <=50 years or, if on hormone replacement therapy
 [HRT], documented follicle stimulating hormone [FSH] >30 IU/L before starting HRT), or
 does not agree to utilize two effective methods of contraception consistently and as
 intended from screening until at least 4 weeks after the last dose of study drug.
 Subjects must use a barrier method (diaphragm with intravaginal spermicide, cervical
 cap with intravaginal spermicide, or partner using condoms plus use of intravaginal
 spermicide) in combination with at least one of the following methods of
 contraception:

 1. systemic hormonal contraceptive (oral, implant, injection, or patch)

 2. intrauterine device

 3. or male partner who has undergone a vasectomy at least 6 months prior to
 screening.

 -  Unless approved by the Sponsor, chronic use of any systemic medications (with the
 exception of systemic hormonal contraceptives and vitamins taken at standard
 supplement doses); use of a drug therapy (including herbal preparations, e.g., St.
 John's wort) known to induce or inhibit hepatic drug metabolism within 30 days before
 the first dose of study drug (or sildenafil); use of prescription medication within 14
 days before administration of study drug (or sildenafil) or over-the-counter [OTC]
 products (including natural products, vitamins) within 7 days before administration of
 study drug (or sildenafil). By exception, topical products without systemic absorption
 will be allowed. (NOTE: in particular, use of any PDE-5 inhibitor [e.g., sildenafil,
 tadalafil, vardenafil] is prohibited)

 -  Current history or evidence of drug abuse, history of regular alcohol consumption
 exceeding 21 drinks/week for men and 14 drinks/week for women (1 drink = 5 ounces [150
 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within
 6 months of screening or a positive screen for substances of abuse or alcohol at
 screening or pre-dose

 -  Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C antibody, or HIV
 antibody

 -  Receipt of an investigational product or device, or participation in a drug research
 study within a period of 30 days (or 5 half-lives of the drug, whichever is longer)
 before the first dose of study drug (sildenafil)

 -  Blood loss or blood donation of >550 mL within 90 days or plasma donation >500 mL
 within 14 days before administration of study drug (or sildenafil)

 -  Any food allergy, intolerance, restriction, or special diet that, in the opinion of
 the Investigator, should preclude the subject's participation in this study

 Part B Only:

 -  Known or suspected hypersensitivity or allergic reaction to sildenafil or other
 therapeutics of similar chemical structure or any of the components of Revatio®
 tablets

 -  Any medical condition that constitutes a contraindication or risk to taking
 sildenafil, including a history of hereditary degenerative retinal disorders such as
 retinitis pigmentosa

 -  Ingestion of grapefruit or grapefruit juice within 72 hours before sildenafil
 administration