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First effective pharmacotherapy for ARDS to lower mortality and improve quality of life of patients.

Periodic Reporting for period 1 - Impentri (First effective pharmacotherapy for ARDS to lower mortality and improve quality of life of patients.)

Reporting period: 2020-10-01 to 2021-09-30

Exvastat Limited were awarded €1.26m out of a total project cost of €1.80m to support development of its innovative treatment, Impentri™ (intravenous imatinib) for the treatment of Acute Respiratory Distress Syndrome (ARDS) related to COVID-19. The grant provides funding to establish a clinical trial to evaluate Impentri™ for the treatment of critically ill patients with COVID-19 induced ARDS in India.

ARDS is a condition which interferes with the lung’s ability to take in oxygen, frequently caused by pneumonia or sepsis. In the current coronavirus pandemic, ARDS is the immediate cause of death for patients suffering from this infection. Forty percent of the patients that suffer from the condition succumb to it and among the ones that survive, many of them face long-term physical and mental illness. 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 in addition to the effect on COVID-19 itself.

Exvastat Ltd is developing Impentri™ as a reliable and effective pharmacotherapy for ARDS as it targets the cause and trigger of the mortality associated with the condition. It is an intravenous formulation of a widely-used chemotherapeutic drug, Imatinib which has shown promising results in-vitro and clinical reports in ARDS like conditions. 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.

The overall objective of this project was for the clinical study of IV imatinib in ARDS related to COVID-19: to deliver the supplies of intravenous imatinib for the conduct of the Phase II study, obtain the required regulatory approval from the Indian regulatory authorities, initiate testing in patients and complete the Phase II Trial. Based on the results of these studies, additional investment will be sought to enable further development of Impentri™.
The focus initially for the project team was to prepare all of the documentation required to initiate a clinical trial, namely to write the Protocol, Investigator Brochure (IB), Investigational Medicinal product Dossier (IMPD) and patient consent forms that were required for review by the relevant ethics and regulatory authorities. In parallel, 5 clinical sites have been recruited from across India to conduct the trial, with a further 5 back-up sites identified. Regulatory and ethical approvals from the Indian authorities was secured in August 2021 and recruitment of the first patient into the trial is expected to occur in October 2021.

Vials of Impentri™ and placebo were shipped to India in August 2021, in readiness for the start of the clinical trial in October of this year, representing the culmination of a 12-month campaign of work. 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 has been developed. 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.
Results from a clinical study of oral imatinib for the treatment of patients with severe COVID-19 were published in June 2021 and demonstrated that oral imatinib reduces mortality by 49% in hospitalized patients and produces similar percentage reductions in duration of mechanical ventilation and days in the ICU. These are also of statistical significance. There were also fewer adverse events of Grade III or IV severity in the imatinib group than in the placebo group, reflecting a reduction in disease-related events.

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. To put the effect of imatinib into perspective, the current standard of care in COVID-19 for patients in need of oxygen supplementation is dexamethasone, which produces a reduction in mortality of around 22-25%. The effect of imatinib in similar-staged patients is to reduce mortality by approximately double this percentage. Moreover, the effect of imatinib is similar in patients treated with dexamethasone compared to those not so treated, indicating that the imatinib effect against pulmonary oedema is supplementary to the anti-inflammatory dexamethasone effect. Taken together, this is a very encouraging set of observations.

Confirmation of intravenous toleration and a treatment effect on pulmonary oedema in this EIC funded clinical study, would provide further evidence to support the development of Impentri™ 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.

Adopting Impentri™ will reduce mortality, improve quality of life and hence improve quality adjusted life year (QALY). Additionally, assuming Impentri™ could benefit 40% of ARDS patients and reduce mortality by 10%, it would provide a pharmacoeconomic value of €7 Bn. It would enable the healthcare systems to reduce costs and to secure their long-term economic trajectory.
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