A TRPA1 Inhibitor Suppresses Neurogenic Inflammation and Smooth Muscle Contraction for the Treatment of Asthma
Barrier tissues are highly populated with both resident immune cells and sensory innervation that work in partnership to protect the host against infections and diseases. However, as this partnership can also lead to exacerbated inflammation and collateral tissue damage, modulating the neuro-immune axis may represent a novel therapeutic approach for complex disorders. In particular, lungs are predominantly innervated by nodose sensory neurons that utilize a plethora of “detectors” to sense environmental and internal signals and act accordingly being able to regulate bronchoconstriction, vasodilatation, mucus production and inflammation. One of these “detectors” is the transient receptor potential cation channel, member A1 (TRPA1) that acts as a sensor for airway irritants and proinflammatory mediators increased in asthma and other respiratory conditions. Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. TRPA1 agonists are elevated in human asthmatic airways and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain and itch demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
Alessia Balestrini1, Victory Joseph1, Justin Elstrott1, Alexis Rohou1, Daniel Bravo-Perez1, Jens Kortmann1, John Liu1, Eric Suto1, Cary Austin1, Xiaoying Yang1, David Lee1, Steven Magnuson1, Matt Volgraf1, Rebecca Bauer1, Lorena Riol-Blanco1