25 June 2020 - - The first COVID-19 patient has been dosed in a Phase 2 study of TD-0903 for the treatment of hospitalised patients with acute lung injury caused by COVID-19, Cayman Islands-based biopharmaceutical company Theravance Biopharma, Inc. (NASDAQ: TBPH) said.

TD-0903 is a lung-selective, nebulized Janus kinase inhibitor in development for the potential treatment of hospitalised patients with Acute Lung Injury caused by COVID-19. 

The company believes TD-0903 has the potential to inhibit the cytokine storm associated with ALI and prevent progression to Acute Respiratory Distress Syndrome.

The initiation of the Phase 2 study in patients in the United Kingdom (UK) follows the successful completion of dosing in the Phase 1 study in healthy volunteers at the same clinical unit in the UK, allowing for a rapid transition to Phase 2.

The Phase 2 study consists of two parts. The first part will assess the safety, tolerability and clinical response to treatment in sequential ascending dose cohorts of hospitalized COVID-19 patients, with each patient being dosed for 7 days.

Patients will be enrolled if they demonstrate hypoxia (lack of oxygen in the blood) as that is believed to be a marker of underlying hyperinflammation (cytokine storm) in the lung.

More information can be found on clinicaltrials.gov, identifier number: NCT04402866.

The second part will be a larger, multi-center study conducted at hospital-based clinical sites in the UK, as well as other European countries and in the United States, pending appropriate Ethics Committee and regulatory approvals in those territories.

JAK inhibitors function by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2) that play a key role in cytokine signaling.

Inhibiting these JAK enzymes interferes with the JAK/STAT signaling pathway and, in turn, modulates the activity of a wide range of pro-inflammatory cytokines.

Limiting JAK inhibition to the lung is expected to improve the therapeutic index relative to systemic inhibition. Thus, inhaled JAK inhibitors with lung-restricted exposure are of high interest as potential treatments for respiratory illness.

TD-0903 is a lung-selective, nebulized pan-JAK inhibitor that was discovered and developed at Theravance Biopharma.

TD-0903 has been shown in experimental murine models to have potent, broad inhibition of JAK-STAT signaling in the airways following challenges with multiple cytokines.

By its mechanism, TD-0903 has the potential to block the release of cytokines and chemokines that may be associated with Acute Lung Injury and the initiation of a cytokine storm syndrome.

Preclinical studies suggest that TD-0903 has a very high lung: plasma ratio and rapid metabolic clearance resulting in low systemic exposure, compatible with its lung selectivity.

TD-0903 is administered via a nebulized inhalation solution, which further enhances its lung selectivity. Preclinical pharmacodynamic studies indicate that TD-0903 has an extended duration of action that should enable once or twice daily dosing in humans.

As disclosed initially at Theravance Biopharma's December 2018 Research and Development Day, the company indicated the initial clinical application of TD-0903 would be to explore its utility in preventing/delaying graft rejection among individuals receiving lung transplantation.

Although this is still a potential clinical application for TD-0903, in response to the current COVID-19 pandemic, the company has prioritised activities toward assessing the potential for TD-0903 to treat hospitalized COVID-19 patients who become short of breath and whose blood oxygen levels begin to drop.

These patients are at increased risk of respiratory complications including ALI and ARDS.

They may also require prolonged hospitalisation, continuous oxygen and, in the most severe cases, admission to ICU to assist their breathing with non-invasive and/or mechanical ventilation.

Treatment with JAK inhibition is recognised as an important anti-inflammatory mechanism to potentially reduce the hyperinflammation seen in hospitalized COVID-19 patients who develop ALI and ARDS.

Theravance Biopharma is a diversified biopharmaceutical company primarily focused on the discovery, development and commercialisation of organ-selective medicines.