Theravance Biopharma is advancing TD-0903, a lung-selective nebulised Janus kinase inhibitor (JAKi) into clinical development to assess its utility in preventing the cytokine storm associated with acute lung injury (ALI) in patients hospitalised COVID-19 patients. The goal is the prevention of disease progression to acute respiratory distress syndrome (ARDS).
Treatment with JAK inhibition is recognised as an important anti-inflammatory mechanism to potentially reduce the hyperinflammation seen in hospitalised COVID-19 patients who develop ALI and ARDS.1
The company plans to initiate a Phase I study this month in the UK, starting with single- and multiple-ascending doses in healthy volunteers to assess safety. Upon regulatory review and approval, the programme will then move to a nested Phase II study in hospitalised patients with COVID-19. The Phase 2 study will consist of two parts. The first part will assess the safety, tolerability and clinical response to treatment in sequential ascending dose cohorts of COVID-19 patients in the UK. This part of the study will not be formally powered for efficacy but will inform the selection of dose(s) for the second part. The second part of the Phase 2 study will be a larger, multicentre study conducted at hospital-based clinical sites in the UK, and potentially other clinical sites in the EU and US. Both of the latter territories would join the Phase II study programme following review and approval of the relevant regulatory filings required by the EU EMA and US FDA.
“In response to the unprecedented healthcare challenges presented by the emergence of COVID-19, we have combined our immunology and respiratory medicine expertise to accelerate development of our nebulised lung-selective JAK inhibitor, TD-0903. With great urgency, we have redirected our program to treat the acute lung injury caused by COVID-19,” said Chief Executive Officer Rick E Winningham . “We recognise how critical it is to help those suffering from shortness of breath and low oxygen levels, including those who need intensive care and ventilation, to address the effects of profound lung hyperinflammation. TD-0903 could provide benefit to hospitalised patients by preventing the progression of lung hyperinflammation and reducing the requirement for, or the duration of, assisted ventilation. As a result, this could improve utilisation of limited hospital critical care resources.”
“We are pleased to be able to direct our resources and expertise towards helping to treat COVID-19,” said Brett Haumann, MD, Chief Medical Officer. “Janus kinase inhibitors have the potential to inhibit a broad set of immune-modulatory pathways that could prove to be effective in dampening the abnormal immune response that occurs in the lungs of some patients. The nebulised formulation of our lung-selective inhaled JAK inhibitor will allow TD-0903 to be administered directly to the lung in a number of hospitalised settings, including patients who can breathe unaided in the ward, as well as in the ICU setting in patients who require non-invasive or mechanical ventilation. If our initial CTA submission for this study in healthy volunteers is approved and the study is successful, we intend to study TD-0903 in COVID-19 patients in the very near future. We are proud of the tremendous efforts of the global team of Theravance Biopharma scientists and physicians that has enabled us to rapidly progress TD-0903, and we are grateful for their collaboration and dedication to continue its advancement.”
TD-0903 is a lung-selective, nebulised 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 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 nebulised 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 hospitalised COVID-19 patients who become short of breath and whose blood oxygen levels begin to drop. These patients appear to be 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.
Source: OINDP News.
Link to Press Release.