Safety, Tolerability, and PK Parameters of Sodium Nitrite Inhalation Solution in Healthy Subjects
Condition: Pulmonary Hypertension; Pulmonary Arterial Hypertension
MeSH terms: Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Study type: Interventional
Phase: Phase 1

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): 15 mg sodium nitrite inhalation solution; 90 mg sodium nitrite inhalation solution; 45 mg sodium nitrite inhalation solution; 120 mg sodium nitrite inhalation solution; 25% MTD sodium nitrite inhalation solution
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): 15 mg sodium nitrite inhalation solution Q8H; 90 mg sodium nitrite inhalation solution Q8H; 45 mg sodium nitrite inhalation solution Q8H; 120 mg sodium nitrite inhalation solution or placebo Q8H; Multiple oral doses of 20 mg sildenafil will be administered open-label Q8H to a single cohort of eight subjects on Days 1 to 6. A single dose of sodium nitrite inhalation solution equal to 25% of the maximum tolerated dose (MTD) identified in Part A (or placebo) will be administered on Day 4, a single dose equal to 50% of the MTD (or placebo) will be administered on Day 5, and a single dose equal to 100% of the MTD (or placebo) will be administered on Day 6.
Intervention MeSH terms: Pharmaceutical Solutions
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: vasodilator; nitric oxide; sodium nitrite; sildenafil; PDE-5; pulmonary hypertension; pulmonary arterial hypertension