Ample safety margins exist for clinical development of inhaled AIR001 (Sodium nitrite) in pulmonary arterial hypertension (PAH)

Inhaled AIR001 is being evaluated to relieve vasoconstriction and inhibit vascular remodeling pathognomonic of PAH, both by direct effects and by supplementation of diminished endothelial nitric oxide. The safety and tolerability of AIR001 has recently been demonstrated in a multiple ascending dose Phase 1 clinical trial (AIR001-CS04) in healthy subjects, as well as in 26-week rat inhalation and dog intravenous toxicology studies. In AIR001-CS04, nebulization of 90 mg (dose loaded into Solo-Idehaler) for six days caused no SAEs and was found to be the maximum tolerated dose (MTD). Comparison of the estimated lung deposited doses suggested an animal to human safety margin of 4-12. Calculated safety margin ratios at the animal No Adverse Effect Level (NOAEL), compared to the same measurements at the MTD in humans, revealed similar safety margins of 4-24 fold for plasma nitrite maximum concentration (Cmax) and area under the curve (AUC) as well as %methemoglobin (%MetHb). View this table: Safety Margin Ratios Evaluation of all of the animal and human safety data indicate that the toxicity of AIR001 is primarily, if not solely, due to methemoglobinemia, a monitorable and expected secondary pharmacodynamic response to nitrite. Comparison of the human MTD to animal NOAELs suggest that an ample margin of safety exists to continue further clinical development of AIR001 in PAH.