Periodic Reporting for period 1 - Impentri (Development of Impentri, an intravenous imatinib formulation for Covid-19 acute respiratory distress syndrome (ARDS).)
Reporting period: 2020-07-01 to 2021-06-30
The Impentri IMI2 consortium was awarded a €3.6M grant, to re-purpose an existing licensed oncology drug, imatinib for the treatment of Acute Respiratory Distress Syndrome (ARDS) induced by COVID-19. The project was awarded the grant in response to IMI2 Call 21: Development of therapeutics and diagnostics combatting SARS-CoV-2 infections and addresses both objectives defined in the scope of the call, Development of therapeutics to address a rapid response to the current Covid-19 outbreak and Development of therapeutics to address future SARS-CoV-2 outbreaks. Under the award, Exvastat is collaborating with Vrije Universitat, Amsterdam (VUmc), Amsterdam Medical Center (AMC), KABS and Simbec-Orion.
There is no effective pharmacotherapy for COVID-19 induced ARDS, or ARDS from any other cause, such as sepsis or pneumonia. Previous studies indicate that mortality rates for ARDS are 35-45% and that in those that do survive, patients have reduced exercise capacity and endure marked physical and neurocognitive deficit as a consequence of their initial illness. Thus, the substantial mortality, morbidity, and economic burden of ARDS, along with the absence of available therapy, mean this project has the potential to make a significant impact on society.
The immediate objective for the project team was to provide clinical data on the effectiveness of imatinib in the treatment of patients with severe Covid-19 to prevent their progression to critical status wherein ARDS may develop. The second objective has been to deliver IV imatinib (Impentri™) as an approved pharmacotherapy for the treatment of severe Covid-19 ARDS. ARDS patients are severely ill and usually treated in an intensive care unit (ICU) setting, where an intravenous therapy is most appropriate for this patient group. Based on the results of these studies, additional investment will be sought to enable Phase III clinical trials and regulatory approval of Impentri™ for emergency use for the treatment of COVID-19 ARDS and the treatment of all-cause ARDS.
There is no effective pharmacotherapy for COVID-19 induced ARDS, or ARDS from any other cause, such as sepsis or pneumonia. Previous studies indicate that mortality rates for ARDS are 35-45% and that in those that do survive, patients have reduced exercise capacity and endure marked physical and neurocognitive deficit as a consequence of their initial illness. Thus, the substantial mortality, morbidity, and economic burden of ARDS, along with the absence of available therapy, mean this project has the potential to make a significant impact on society.
The immediate objective for the project team was to provide clinical data on the effectiveness of imatinib in the treatment of patients with severe Covid-19 to prevent their progression to critical status wherein ARDS may develop. The second objective has been to deliver IV imatinib (Impentri™) as an approved pharmacotherapy for the treatment of severe Covid-19 ARDS. ARDS patients are severely ill and usually treated in an intensive care unit (ICU) setting, where an intravenous therapy is most appropriate for this patient group. Based on the results of these studies, additional investment will be sought to enable Phase III clinical trials and regulatory approval of Impentri™ for emergency use for the treatment of COVID-19 ARDS and the treatment of all-cause ARDS.
The IMI-funded Impentri project commenced on 1 July 2020. The focus for the project initially was to complete a clinical trial using oral imatinib for the treatment of patients with severe COVID-19 (named COUNTER-COVID), led by scientists at VUmc in Amsterdam and conducted at hospitals across The Netherlands. In parallel work was initiated to reformulate and manufacture IV imatinib (Impentri™) and to plan for the clinical trial of Impentri™ in critically ill COVID-19 patients with ARDS (named INVENT COVID).
The COUNTER-COVID trial of oral imatinib that was initiated by VUmc in March 2020 and aimed to recruit 386 patients, continued. Initial recruitment across hospitals in the Netherlands was excellent, but the inclusion rate dropped significantly in the summer months, as lockdown measures took effect and case numbers reduced. However, as patient numbers rose again in the Autumn, 50% inclusion was achieved at the end of October and the final patient was dosed at the beginning of January 2021. The results of the study were published in The Lancet Respiratory Medicine in June and showed that oral imatinib reduces mortality by 49% in hospitalized patients and similar percentage reductions in duration of mechanical ventilation and days in the ICU were reported and are also of statistical significance.
Analysis of blood samples taken from patients in the study at time points upto 9 days after the first dose, has enabled researchers at VUmc to develop a validated covariate model to explain and predict the pharmacokinetics of imatinib in COVID-19 patients. Over the next year, further analysis of samples will be conducted to develop biomarker models and also comparisons made with samples obtained from the on-going IV imatinib trial.
Plasma samples from patients have also been analysed to understand the pathophysiological changes that occur due to imatinib in patients with COVID-19. The results of these studies are expected to be published later this year.
Learnings from the COUNTER-COVID trial in terms of recruitment and safety informed the design of the trial of Impentri™ in critically ill COVID-19 patients with ARDS. Ethical and regulatory approvals were obtained for this study in Jan 2021.
Vials of Impentri™ and placebo were delivered to the AMC at the beginning of Jan 2021, in readiness for the start of the clinical trial in March of this year, representing the culmination of a 6-month campaign of work. The consortium partner responsible for the manufacture of Impentri™ was KABS, based in Montreal, Canada. To achieve this major milestone, KABS first developed a stability-indicating analytical method, which they then used to develop a formulation of imatinib in a sterile vehicle that was stable enough under various temperatures and humidities for a sufficient shelf life for practical use in a hospital environment. The formulation needed to be stable with respect both to potential chemical and microbiological degradation; and in addition, needed to demonstrate compatibility with the plastic materials of the syringe and tubing that will be used to administer the formulation to patients. Finally, once conducted in the laboratory, this process was scaled up to manufacture the thousands of vials that will be used in the INVENT COVID clinical trial. All of this work was conducted to international regulatory standards and then imported from Canada into the Netherlands.
The first patient in the INVENT COVID study was dosed at the AMC in March 2021 and initial recruitment rates into the trial were as expected. Additional study centres in The Netherlands, have joined the trial, but due to a fall in the number of COVID-19 infections in early summer, recruitment into the trial stalled. Following a recent wave of infections, however, numbers of patients in the trial have begun to increase and it is hoped that the final dose of this 90-patient trial, will be administered in the first quarter of 2022.
The COUNTER-COVID trial of oral imatinib that was initiated by VUmc in March 2020 and aimed to recruit 386 patients, continued. Initial recruitment across hospitals in the Netherlands was excellent, but the inclusion rate dropped significantly in the summer months, as lockdown measures took effect and case numbers reduced. However, as patient numbers rose again in the Autumn, 50% inclusion was achieved at the end of October and the final patient was dosed at the beginning of January 2021. The results of the study were published in The Lancet Respiratory Medicine in June and showed that oral imatinib reduces mortality by 49% in hospitalized patients and similar percentage reductions in duration of mechanical ventilation and days in the ICU were reported and are also of statistical significance.
Analysis of blood samples taken from patients in the study at time points upto 9 days after the first dose, has enabled researchers at VUmc to develop a validated covariate model to explain and predict the pharmacokinetics of imatinib in COVID-19 patients. Over the next year, further analysis of samples will be conducted to develop biomarker models and also comparisons made with samples obtained from the on-going IV imatinib trial.
Plasma samples from patients have also been analysed to understand the pathophysiological changes that occur due to imatinib in patients with COVID-19. The results of these studies are expected to be published later this year.
Learnings from the COUNTER-COVID trial in terms of recruitment and safety informed the design of the trial of Impentri™ in critically ill COVID-19 patients with ARDS. Ethical and regulatory approvals were obtained for this study in Jan 2021.
Vials of Impentri™ and placebo were delivered to the AMC at the beginning of Jan 2021, in readiness for the start of the clinical trial in March of this year, representing the culmination of a 6-month campaign of work. The consortium partner responsible for the manufacture of Impentri™ was KABS, based in Montreal, Canada. To achieve this major milestone, KABS first developed a stability-indicating analytical method, which they then used to develop a formulation of imatinib in a sterile vehicle that was stable enough under various temperatures and humidities for a sufficient shelf life for practical use in a hospital environment. The formulation needed to be stable with respect both to potential chemical and microbiological degradation; and in addition, needed to demonstrate compatibility with the plastic materials of the syringe and tubing that will be used to administer the formulation to patients. Finally, once conducted in the laboratory, this process was scaled up to manufacture the thousands of vials that will be used in the INVENT COVID clinical trial. All of this work was conducted to international regulatory standards and then imported from Canada into the Netherlands.
The first patient in the INVENT COVID study was dosed at the AMC in March 2021 and initial recruitment rates into the trial were as expected. Additional study centres in The Netherlands, have joined the trial, but due to a fall in the number of COVID-19 infections in early summer, recruitment into the trial stalled. Following a recent wave of infections, however, numbers of patients in the trial have begun to increase and it is hoped that the final dose of this 90-patient trial, will be administered in the first quarter of 2022.
The results of the COUNTER COVID study demonstrated that oral imatinib reduces mortality by 49% in hospitalized patients and similar percentage reductions in duration of mechanical ventilation and days in the ICU. The reduction in the number of adverse events of Grade III or IV severity in the imatinib group versus placebo adds to the positive outcome for this study. The scale of these benefits is highly encouraging and provides strong support for the further investigation of Impentri™ in patients with severe or critical Covid-19 infection.
Results from the INVENT COVID study are expected in mid 2022.
Confirmation of intravenous toleration and a treatment effect on pulmonary oedema would provide further evidence to support the development of IV imatinib for the treatment of patients with COVID-19 ARDS and ARDS from other causes. This approach would enable development for a condition with very high unmet need for which approved pharmacotherapy is lacking in an expedited time frame compared to other potential therapies.
Encouraged by the benefits observed in the Counter COVID study, SOLIDARITY and REMAP-CAP have incorporated imatinib into their global Phase III planning. Scale up of Impentri™ manufacture in the EU has been initiated to support studies by these groups and to prepare for rapid progression to provide emergency use supplies.
Scientific Advice has been sought and received from the EMA and MHRA and this guidance is shaping the development strategy.
Results from the INVENT COVID study are expected in mid 2022.
Confirmation of intravenous toleration and a treatment effect on pulmonary oedema would provide further evidence to support the development of IV imatinib for the treatment of patients with COVID-19 ARDS and ARDS from other causes. This approach would enable development for a condition with very high unmet need for which approved pharmacotherapy is lacking in an expedited time frame compared to other potential therapies.
Encouraged by the benefits observed in the Counter COVID study, SOLIDARITY and REMAP-CAP have incorporated imatinib into their global Phase III planning. Scale up of Impentri™ manufacture in the EU has been initiated to support studies by these groups and to prepare for rapid progression to provide emergency use supplies.
Scientific Advice has been sought and received from the EMA and MHRA and this guidance is shaping the development strategy.