Inhaled Fasudil and DETA NONOate CAR-Targeted Liposomes for PAH

Pulmonary arterial hypertension (PAH) affects ~15-50 individuals per million and claims ≥20,000 lives annually
in the United States. It affects every ethnic group, race, age and gender, and devastates high-risk patients
afflicted with HIV, systemic sclerosis, and sickle cell disease. The disease affects more women than men; adult
PAH patients do not live more than five years after the diagnosis. PAH even affects newborn infants and
toddlers: PAH-afflicted children do not survive past their second birthday, if left untreated. Current medications
fail to reduce mortality, extend survival time, or enhance patient quality of life. Many patients do not respond to
existing oral and inhaled anti-PAH drugs; thus, they must receive a continuous intravenous infusion of
prostacyclin analogs, or undergo lung transplantation. Unlike the “emperors of maladies” (cancer and stroke),
PAH has not received much attention from the drug-discovery establishment, so the progress toward
medication development and long-term management of this “orphan” disease has been minimal. Since PAH
affects only a relatively small number of patients, pharmaceutical manufacturers have not made it a priority to
find a cure for PAH, a disease that was first described in the 1950s. In this project, we propose to develop a
targetable and inhalable formulation of fasudil, a rho-kinase inhibitor, and DETA NONOate (DN), a nitric oxide
(NO) donor. We will develop this combination therapy by encapsulating both drugs, fasudil and DN, in
liposomes modified with a cyclic peptide, CAR (CARSKNKDC), which accumulates preferentially in
hypertensive pulmonary arteries. In a series of studies, we have demonstrated that CAR-modified liposomes
containing fasudil and DN reduce the mean pulmonary arterial pressure (mPAP), and this ameliorates various
features of pulmonary arterial remodeling. In this Fast-Track application, we will evaluate the potential for the
clinical translation and commercial development of our targeted liposomal formulation-based combination
therapy for PAH. In Phase I, we will study the effect of the long-term administration of the inhaled CAR-
liposomal formulation of fasudil-plus-DN on pulmonary hemodynamics, lung remodeling, and right ventricle
(RV) hypertrophy, and determine the sensitivity and specificity of assays for detecting nanogram levels of
fasudil and NO in plasma. In Phase II, we will conduct studies to determine the dose-response,
pharmacokinetics and safety of the formulations. The proposed studies will lay the foundation for an FDA IND
application and clinical translation, and will establish the CAR-liposomes of fasudil-plus-DN as a novel and
inhalable therapeutic option for PAH patients that will: a) specifically target the hypertensive pulmonary
vasculature, and b) provide synergistic therapeutic benefits through both the Rho A/Rho kinase and NO donor
pathways, without the additive adverse side effect of systemic vasodilation. Our approach is innovative,
because we will determine the chronic efficacy of a targeted two-drug inhalation therapy for PAH. We have a
robust commercialization plan in place, our CAR-modified formulation will be protected by a patent for CAR
peptide, and we have a team of investigators comprised of clinicians, statisticians, peptide chemists, lung
biologists, industry veterans and a pharmaceutical scientist. Importantly, we propose to address an unmet
medical need by developing an effective drug therapy for an under-investigated and devastating disease.Project Narrative
Pulmonary arterial hypertension (PAH) is a condition characterized by the obstruction of
small arteries in the lung, which causes high pulmonary blood pressure and has a high
mortality rate due to right heart failure. The Rho-kinase inhibitor Fasudil and the long-
acting nitric oxide donor DETA NONOate (DN) have shown to be effective in PAH
animal models, but like all other PAH drugs, they show low on-target specificity and may
therefore not be suitable for long-term treatment. The encapsulation of both Fasudil and
DN in liposomes, tagged with a PAH homing peptide CARSKNKDC (CAR), will result in
a new inhaled two drug therapy for PAH with selective affinity for hypertensive lungs.