Sunday, June 1, 2025
6/1/2025
Inhaled Pitavastatin for the Treatment of Asthma: A New Therapeutic Paradigm - PROJECT SUMMARY: Asthma is the most common respiratory disease worldwide affecting the entire life spectrum. Current systemic and inhaled therapies do not adequately control symptoms or prevent acute asthma exacerbations. There is an ongoing urgent need for alternative and effective inhaled bronchodilator therapies. Over the past decade the Zeki Lab has investigated the HMG-CoA-reductase inhibitors (i.e., the ‘statins’) as a novel therapy for the treatment of airway disorders including asthma and chronic obstructive pulmonary disease (COPD). Beyond their known lipid-lowering capacities in the treatment of cardiovascular diseases, the statins also possess immunomodulatory, anti-inflammatory, anti-proliferative, anti-oxidant, and anti-fibrotic properties. In pre-clinical models of asthma systemic statin therapy works, however, human clinical trials using oral statins were inconclusive. We have shown that orally ingested statins in human subjects have poor airway penetration resulting in undetectable airway drug levels. This led us to pivot and innovate the statin drugs for inhaled delivery. We have identified Pitavastatin as the lead statin for inhaled drug development. Before progressing to more expensive testing in human populations (i.e., Phase 1 and 2 clinical trials), we intend to test our proprietary formulation in a human-relevant airway hyperresponsiveness (AHR) asthma model using rhesus macaque non- human primates (NHP). To address this important and pivotal point in drug development, we hypothesize that inhaled Pitavastatin will (a) improve lung function as a monotherapy and (b) enhance the efficacy of existing standard-of-care (SoC) asthma medications as a combination therapy, in a NHP model of asthma. We will address this central hypothesis via two Specific Aims: AIM 1: To determine the efficacy of inhaled Pitavastatin as a bronchodilator in a rhesus macaque model of AHR in vivo. We will use the California National Primate Research Center’s established asthma model of AHR to test our novel inhaled Pitavastatin formulation as a monotherapy (delivered as a nebulized aerosol to the airways using established drug dose ranges) in a crossover clinical trial design. AIM 2: To determine the efficacy of Pitavastatin as a combination therapy with b2- agonists and/or corticosteroids using PCLS ex vivo from juvenile and adult rhesus macaques. The Zeki Lab has established the use of precision-cut lung slices (PCLS) including those from mice and human lungs. Using our established protocols, we will generate plentiful lung slices from rhesus macaques across the lifespan. Naïve lungs will be pre-treated with Type 2 pro-inflammatory cytokines to model an asthmatic airway. We will use pre- and post-treatment approaches using a combination of Pitavastatin, Formoterol, and Dexamethasone with appropriate controls. We will also test the anti-inflammatory effects of Pitavastatin ± Dexamethasone by measuring secreted cytokines/chemokines in lung slice media. Accomplishing this work will bring us closer to developing inhaled statins, in particular Pitavastatin, for the treatment of asthma. Accomplishing this goal will usher in a new drug class for the treatment of obstructive airway diseases.
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