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We were able to speak with Sally Fischer, Senior Director and Senior Principal Scientist, and Montse Carrasco-Triguero, Principal Scientist, about the work BAS has been doing in the COVID space and the Actemra trials.
Critically ill patients with COVID-19 present clinical features that suggest a dysregulated immune response with elevated interleukin 6 (IL-6) resulting in adult respiratory distress syndrome (ARDS) and multi-organ failure. Therefore, an immunomodulator like tocilizumab (TCZ, Actemra) has potential as a treatment for severe COVID-19 pneumonia.
Roche has sponsored four interventional clinical trials evaluating Actermra treatment in COVID-19 pneumonia, COVACTA, MARIPOSA, REMDACTA and EMPACTA. In addition, Roche is supporting multiple Investigator Initiated Studies and Real World Data initiatives evaluating the efficacy of tocilizumab in COVID-19 pneumonia. COVACTA was the first global, randomized, double-blind, placebo-controlled phase III study to evaluate the safety, efficacy, pharmacodynamics (PD) and pharmacokinetics (PK) of TCZ added to standard of care in adult patients hospitalized with severe COVID-19 associated pneumonia, compared to placebo plus standard of care. The other three studies answered additional questions related to dose (MARIPOSA study), combination with the approved antiviral drug remdesivir (REMDACTA study) and response in patients who belong to minority and high risk populations (EMPACTA study).
The COVACTA study did not meet its primary endpoint and data from this study is still being evaluated. This data together with the results from the global EMPACTA study, which met its primary endpoint and additional data from different sources will determine in which patients and disease characteristics TCZ can be beneficial for patients with COVID-19 pneumonia. Despite the study results, COVACTA is a great example of our commitment to improve patients’ lives by initiating and conducting a global phase III clinical trial faster than ever before to answer a clinical question triggered by early observations with Actermra in a small study in China. The COVACTA study completed enrollment in only two months and took less than 6 months from concept to the primary analysis readout on day 28. This experience will enable us to bring new medicines to patients even faster.
BAS as a member of the Actemra COVID-19 biomarker team, worked on the biomarker strategy and implementation to ensure that the team can generate the data needed in a timely manner to help answer key questions on treatment of patients with severe COVID-19 pneumonia.
The biomarker strategy for COVACTA included 3 biomarkers related to Actemra treatment response and 17 exploratory biomarkers related to various aspects of COVID-19 disease (e.g. lung edema, fibrosis, acute respiratory distress syndrome symptoms, alveolar damage and IFN responses).
For the treatment response biomarkers, our assay selection approach was based on the availability of already validated assays for the Actemra program and the tight timeline requirements for the COVACTA trial.
For the exploratory biomarkers, BAS led the strategy for selecting the assay platform and contract research organization (CRO). The Protein Simple platform was chosen as it allowed for custom multiplexing of the biomarker assays in four or eight-plex options. To meet the tight timelines for COVACTA, a streamlined approach was used for assay qualification with no testing in house prior to transfer. Covance was the best suited CRO for assay implementation based on its experience with Protein Simple assays, ability to provide quality data and to meet the tight program timelines. In addition, BAS coordinated with the vendor to build 4 multiplex assay kits for the 17 biomarkers and established close interactions between the vendor and the CRO to simplify and expedite the assay evaluations for the studies in COVID-19 disease.
This assay strategy for the exploratory biomarkers was implemented for COVACTA and was used or adjusted for other studies in COVID-19 pneumonia both with TCZ (MARIPOSA and REMDACTA studies) or with other therapeutics in the pipeline (COVASTIL study). Using the same assay platform across studies will ensure consistency of the data, which is important to expand our knowledge of COVID-19 disease and to understand how immunomodulatory therapies alone or in combination with an antiviral can help patients. From these studies, including further analysis of the COVACTA study data, we will gain insights on biomarker relationships to disease progression, identification of patients that may benefit from our drugs and biomarker relationships to other COVID-19 disease clinical characteristics.
The data delivered from this biomarker work will help answer questions related to any program targeting COVID-19 disease, including identification of the right patient to treat, the right dose, the right time, how the drug works in COVID-19 and what the longer term outcomes of COVID-19 disease are. Having reliable assays to fit the program questions and timelines requires close collaboration across the organization and a streamlined approach for assay transfer and qualification. It has been a pleasure to work with the COVID-19 biomarker subteams and with our BAS colleagues Denise Nazzal and Sylvia Lee who championed the assay outsourcing. We are looking forward to seeing how all the biomarker data from these studies will inform not only the Actemra program but also future drug development in COVID-19 disease.
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