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We spoke with Matt Holdren, Senior Director from Safety Assessment about the work that the group is doing in the COVID-19 space and the studies on these trials.
To enable the clinical evaluation of our investigational therapeutics, members of Safety Assessment (SA) collaborate with project teams to design and conduct toxicology studies that inform the clinical dose range and safety monitoring strategy in humans. SA representatives have been actively involved in reviewing clinical protocols, authoring regulatory documents, and providing scientific feedback to support the multiple COVID-19-related trials. This scientific feedback ranged from reviewing the safety of PD-L1 inhibition in nonclinical infectious disease models to inform the risk to Atezolizumab-treated cancer patients to supporting the clinical evaluation of the lytics franchise (alteplase and tenecteplase) described hereafter.
In 71% of COVID 19 mortalities, patients have met the diagnostic criteria for disseminated intravascular coagulation (DIC) and thrombolytic therapies are being actively pursued in critical care patients (J Thromb Haemost. 2020;18:1752–1755). Within Roche, there are currently several approved Phase 2 investigator initiated studies (IIS) for both alteplase and tenecteplase. Most of these trials involve the IV route of administration, similar to currently approved indications, as COVID 19 infection is associated with a high prevalence of coagulopathy and venous thromboembolism. However, there is also a trial underway in Great Britain (sponsored by London Royal Free Hospital) in which alteplase is being delivered via inhalation. Critically ill patients who require ventilation typically present with signs of acute respiratory distress syndrome (ARDS) and commonly have associated prothrombotic coagulopathies.
As the nonclinical safety representatives, Tom Gelzleichter and Wendy Halpern have been involved in reviewing clinical protocols and providing scientific guidance for protocol refinement. Of particular importance for IV administration has been their input on the risk of anti-drug antibody formation, as currently approved therapies are not indicated for longer duration treatment. Because there is an inhaled alteplase ISS, a planned series of nonclinical inhalation studies (currently supporting sulfur mustard gas indication) with alteplase has been accelerated, in the event that the Phase 2 ISS demonstrates clinical benefit. If a clinical benefit is observed early in Phase 2, a nonclinical safety study would be triggered early to further inform the potential therapeutic index and to help guide decisions during the Phase 3 program.
Thrombolytic therapy may prove to have significant benefit in critically ill patients who are on mechanical ventilation. As all prior clinical trials with alteplase and tenecteplase have been with very acute exposures, thus the toxicology data generated within Safety Assessment is being leveraged to provide insights on the safety of repeat administration.
This impacts critical care physicians who are struggling to optimize dosing regimens to maximize potential for efficacy while maintaining appropriate safety in the critical care setting.
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