Periodic Reporting for period 2 - Impentri (Development of Impentri, an intravenous imatinib formulation for Covid-19 acute respiratory distress syndrome (ARDS).)
Reporting period: 2021-07-01 to 2022-10-31
The 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. Under the award, Exvastat is collaborating with Vrije Universitat, Amsterdam (VUmc), Amsterdam Medical Center (AMC), KABS Canada and Simbec-Orion.
At the start of the project, there was no effective pharmacotherapy for COVID-19 induced ARDS, or ARDS from any other cause. Previous studies indicate that mortality rates for ARDS are 35-45% and that in those that do survive, patients endure marked physical and neurocognitive deficits as a consequence of their initial illness. The substantial mortality, morbidity, and economic burden of ARDS, along with the absence of available therapy, mean this project had 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 usually treated in an intensive care unit (ICU) setting, where they are unconscious and unable to swallow; an intravenous therapy is most appropriate for this patient group. Based on the results of these studies, additional investment was anticipated 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.
At the start of the project, there was no effective pharmacotherapy for COVID-19 induced ARDS, or ARDS from any other cause. Previous studies indicate that mortality rates for ARDS are 35-45% and that in those that do survive, patients endure marked physical and neurocognitive deficits as a consequence of their initial illness. The substantial mortality, morbidity, and economic burden of ARDS, along with the absence of available therapy, mean this project had 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 usually treated in an intensive care unit (ICU) setting, where they are unconscious and unable to swallow; an intravenous therapy is most appropriate for this patient group. Based on the results of these studies, additional investment was anticipated 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 project commenced on 1 July 2020. The focus initially was to complete a clinical trial using oral imatinib for the treatment of patients with severe COVID-19 (CounterCOVID), led by scientists at VUmc in Amsterdam and conducted at hospitals across The Netherlands. In parallel, work was initiated to reformulate and manufacture Impentri® and to plan for the clinical trial in critically ill COVID-19 patients with ARDS (named INVENT COVID).
The CounterCOVID trial of oral imatinib that was initiated by VUmc in March 2020 aimed to recruit 386 patients. 50% Inclusion was achieved at the end of Oct 2020 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 2021 and showed that oral imatinib reduced mortality by 49% in hospitalized patients, with similar proportionate reductions in duration of mechanical ventilation and days in the ICU. All these outcomes were of statistical significance. A study of the long-term (90-day) clinical outcomes of these patients substantiated the improved survival in COVID-19 patients treated with imatinib in addition to their shorter duration of invasive ventilation and improved clinical status.
The trial, however, did not meet its primary endpoint (time to discontinuation of supplemental oxygen), but did provide sufficiently positive clinical data for the project to progress to its second objective.
Exvastat discussed these results with regulators in the UK and the EU; there was significant interest in the outcome of the CounterCOVID trial, but even though pharmacotherapy for COVID-19 was at the time a critical public healthcare need, the results needed corroboration before regulatory approval could be awarded.
Learnings from the CounterCOVID trial in terms of recruitment and safety informed the design of the INVENT COVID trial. Ethical and regulatory approvals were obtained for this study in Jan 2021.
Vials of Impentri and placebo were delivered to hospitals at the beginning of January 2021, in readiness for the start of the clinical trial, representing the culmination of a 6-month campaign of work. To achieve this milestone, KABS first developed a stability-indicating analytical method, which was 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. In addition, it needed to demonstrate compatibility with the plastic materials of the syringe and tubing that would be used to administer the formulation to patients. The initial laboratory scale process was scaled up to manufacture the thousands of vials used in the INVENT COVID clinical trial. All of this work was conducted to international regulatory standards and product shipped from Canada to the Netherlands.
The first patient in the INVENT COVID study was dosed at the AMC in March 2021. Four additional study centres in the Netherlands, in and around Amsterdam joined the trial, and 50% recruitment into the study was achieved in November 2021. By January 2022, 65 patients had been recruited, but by this time, the vaccine roll-out caused numbers of patients to decline significantly. A further statistical analysis of the primary endpoint in the trial concluded that an analysis could be conducted with fewer than the planned 90 patients. Thus, with rates of inclusion into the trial extremely low, a decision was made in March 2022 to stop the study after 66 patients had been enrolled.
The results of the INVENT COVID, disappointingly, showed that Impentri® did not reduce pulmonary oedema or improve clinical outcomes in invasively ventilated COVID-19 patients with established ARDS. The reasons for the different outcomes in CounterCOVID and INVENT COVID are not fully understood, but could arise as a result of the different stages and severity levels of the disease; i.e. patients with critical COVID-19 in INVENT COVID were too ill to benefit, whereas progression of severe COVID-19 in CounterCOVID could be arrested by imatinib. Although the INVENT COVID trial does not support the application of imatinib to the general COVID-19 ARDS population, the results from the CounterCOVID trial have led to increased awareness of the potential utility of imatinib in the treatment of COVID-19.
The results from CounterCOVID, as well as the supporting pharmacokinetic and biomarker analyses, have been published in a number of peer-reviewed journals, such as the Lancet Respiratory Medicine, and presented at the European Respiratory Society (ERS) conference in September 2021 and the American Thoracic Society conference in May 2022. The results from the INVENT COVID trial of IV imatinib were presented at the ERS conference in September 2022 and a manuscript is currently under review.
The CounterCOVID trial of oral imatinib that was initiated by VUmc in March 2020 aimed to recruit 386 patients. 50% Inclusion was achieved at the end of Oct 2020 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 2021 and showed that oral imatinib reduced mortality by 49% in hospitalized patients, with similar proportionate reductions in duration of mechanical ventilation and days in the ICU. All these outcomes were of statistical significance. A study of the long-term (90-day) clinical outcomes of these patients substantiated the improved survival in COVID-19 patients treated with imatinib in addition to their shorter duration of invasive ventilation and improved clinical status.
The trial, however, did not meet its primary endpoint (time to discontinuation of supplemental oxygen), but did provide sufficiently positive clinical data for the project to progress to its second objective.
Exvastat discussed these results with regulators in the UK and the EU; there was significant interest in the outcome of the CounterCOVID trial, but even though pharmacotherapy for COVID-19 was at the time a critical public healthcare need, the results needed corroboration before regulatory approval could be awarded.
Learnings from the CounterCOVID trial in terms of recruitment and safety informed the design of the INVENT COVID trial. Ethical and regulatory approvals were obtained for this study in Jan 2021.
Vials of Impentri and placebo were delivered to hospitals at the beginning of January 2021, in readiness for the start of the clinical trial, representing the culmination of a 6-month campaign of work. To achieve this milestone, KABS first developed a stability-indicating analytical method, which was 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. In addition, it needed to demonstrate compatibility with the plastic materials of the syringe and tubing that would be used to administer the formulation to patients. The initial laboratory scale process was scaled up to manufacture the thousands of vials used in the INVENT COVID clinical trial. All of this work was conducted to international regulatory standards and product shipped from Canada to the Netherlands.
The first patient in the INVENT COVID study was dosed at the AMC in March 2021. Four additional study centres in the Netherlands, in and around Amsterdam joined the trial, and 50% recruitment into the study was achieved in November 2021. By January 2022, 65 patients had been recruited, but by this time, the vaccine roll-out caused numbers of patients to decline significantly. A further statistical analysis of the primary endpoint in the trial concluded that an analysis could be conducted with fewer than the planned 90 patients. Thus, with rates of inclusion into the trial extremely low, a decision was made in March 2022 to stop the study after 66 patients had been enrolled.
The results of the INVENT COVID, disappointingly, showed that Impentri® did not reduce pulmonary oedema or improve clinical outcomes in invasively ventilated COVID-19 patients with established ARDS. The reasons for the different outcomes in CounterCOVID and INVENT COVID are not fully understood, but could arise as a result of the different stages and severity levels of the disease; i.e. patients with critical COVID-19 in INVENT COVID were too ill to benefit, whereas progression of severe COVID-19 in CounterCOVID could be arrested by imatinib. Although the INVENT COVID trial does not support the application of imatinib to the general COVID-19 ARDS population, the results from the CounterCOVID trial have led to increased awareness of the potential utility of imatinib in the treatment of COVID-19.
The results from CounterCOVID, as well as the supporting pharmacokinetic and biomarker analyses, have been published in a number of peer-reviewed journals, such as the Lancet Respiratory Medicine, and presented at the European Respiratory Society (ERS) conference in September 2021 and the American Thoracic Society conference in May 2022. The results from the INVENT COVID trial of IV imatinib were presented at the ERS conference in September 2022 and a manuscript is currently under review.
The results of the CounterCOVID 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 results from the trial prompted the World Health Organisation to initiate SOLIDARITY PLUS, a large trial to evaluate oral imatinib for the treatment of COVID-19. Imatinib was selected by an independent expert panel for its potential to reduce the risk of death in hospitalized COVID-19 patients. The trial involves 600 hospitals in 52 countries and is on-going with results expected in 2023.
The team remains interested in continuing to study the effect of imatinib in other forms of pneumonia, with both preclinical and clinical studies under consideration, for instance in influenza.
The results from the trial prompted the World Health Organisation to initiate SOLIDARITY PLUS, a large trial to evaluate oral imatinib for the treatment of COVID-19. Imatinib was selected by an independent expert panel for its potential to reduce the risk of death in hospitalized COVID-19 patients. The trial involves 600 hospitals in 52 countries and is on-going with results expected in 2023.
The team remains interested in continuing to study the effect of imatinib in other forms of pneumonia, with both preclinical and clinical studies under consideration, for instance in influenza.