DUBLIN – Can an investigational drug best known for reducing itch in dermatitis patients really lower the risk of COVID-19 patients progressing to acute respiratory distress syndrome (ARDS)? It might seem like a stretch, even in the midst of a pandemic, but New York’s largest health care provider, Manhasset-based Northwell Health, appears sufficiently convinced by the biological rationale to get behind a phase III trial of tradipitant, a neurokinin-1 (NK1) receptor blocker, which Washington-based Vanda Pharmaceuticals Inc. is already testing in phase III trials in atopic dermatitis, gastroparesis and motion sickness.
What links those apparently disparate indications is a signaling pathway that has multiple biological functions. The neurokinin-1 receptor is a G protein-coupled receptor (GPCR), which preferentially binds substance P, a neuropeptide secreted by neuronal cells and inflammatory cells that has multiple effects in different tissues. NK1 receptor antagonists initially came to prominence as antiemetics. Merck & Co. Inc., of Kenilworth, N.J. gained FDA approval in 2003 with Emend (aprepitant) for preventing chemotherapy-induced nausea and vomiting.
In COVID-19, an overwhelming immune cascade is considered the key driver of the pathogenesis. An uncontrolled host immune response to the viral infection leads to an infiltration of immune cells to the lower respiratory tract, resulting in a build-up of fluid and injury to type I alveolar cells, which facilitate gas exchange between the blood and the lungs, and to type II alveolar cells, which secrete the surfactant required for the alveoli to function. Collapse of the alveoli leads to ARDS, which can in turn lead to systemic inflammatory response and to septic shock.
Vanda aims to show that tradipitant can benefit COVID-19 patients by reducing neurogenic inflammation – that is inflammation triggered by the release of neuropeptides, such as substance P, from nerve cells – in the lower respiratory tract.
It has long been established that neurogenic inflammation is a significant cause of acute lung inflammation and injury. Triggers include smoke and noxious gases. Animal studies have also shown respiratory syncytial virus infection can cause neurogenic inflammation. The interaction between the NK1 receptor and its substance P activates one of the key signal molecules that contributes to that pathology, nuclear factor kappa B (NF-kappaB), which in turn promotes the production of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein 1beta (MIP-1beta) and interferon gamma.
However, NK1 receptor activation is not the only trigger of NF-kappaB signaling. The pathway is activated by several other signal molecules, including Toll-like receptor 3 (TLR3) and mitochondrial antiviral signaling protein. Conversely, cytokines such as IL-6 and IL-2 are not solely induced by NF-kappaB.
The key question that the present trial, dubbed Odyssey, is designed to answer is whether damping down this one component of the inflammatory cascade by NK1 receptor inhibition will be enough to interrupt the pathological process to a clinically relevant extent. Several other firms are testing biologic therapies directed at other pro-inflammatory mediators, including IL-6, IL-2 and granulocyte macrophage colony stimulating factor (GM-CSF). Others are testing small molecules with anti-inflammatory effects, including JAK inhibitors and BTK inhibitors.
The Odyssey study aims to recruit about 300 patients with confirmed pneumonia and oxygen saturation less than 92%. They will be randomized in a 1-to-1 ratio to receive either an oral 85-mg dose of tradipitant twice daily or placebo, in addition to standard of care. The primary endpoint comprises normalization of fever and blood oxygenation levels by day 14. The first patient was enrolled at Lenox Hill Hospital in New York earlier this week, and initial results are expected to emerge in the coming months.