Periodic Reporting for period 4 - SMR (Stroke Management through RGTA®: SMR)
Periodo di rendicontazione: 2022-07-01 al 2024-05-31
Stroke is a high burden disorder worldwide and about 1.1 million of Europeans suffer a stroke each year (17 million worldwide). With 25.7 million stroke survivors worldwide, stroke is the second leading cause of disability after ischemic heart disease. As illustrated by the number of people that remain disabled after a cerebrovascular accident (2 out of 3 according to the US National Stroke Association), the extent of recovery is limited, and novel approaches are urgently needed.
Stroke has a major economic impact for Europe, as in 2015 it was estimated to cost the EU €45 billion a year split as follows: ~44% (~ €20 billion) is due to direct health care costs, ~22% (~ €9 billion) to productivity losses and ~35% (~ €16 billion) to the informal care of people with stroke (long-time sequelae management).
In Europe, stroke is the second most common single cause of death accounting for 405.000 deaths (9%) in men and 583,000 (13%) deaths in women each year. These figures are expected to increase in the next coming years: The “Burden of Stroke in Europe Report” published in May 2017 (http://strokeeurope.eu(si apre in una nuova finestra)) by SAFE (Stroke Alliance For Europe) has projected that between 2015 and 2035, overall there will be a 34% increase in the total number of stroke events in the EU (from 613 148 in 2015 to more than 800 000 in 2035).
Stroke can cause permanent damage, including partial paralysis and impairment in speech, comprehension and memory. The severity of the stroke ranges from minimal to catastrophic, and the sequalae can be long-lasting: After 15 years, two-thirds (63%) of survivors are living with disability, nearly two in five (39%) have depression and over a quarter (30%) have cognitive impairment. The disability-adjusted life year (DALY) is an aggregate measure of years of life lost due to premature death from a condition and years lived with a disability due to a condition, with one DALY equating to one healthy year of life lost. In 2015, stroke was the second cause of lost DALYs in Europe, responsible for 17.1 million DALY lost.
Although therapeutic options are available in Europe for stroke patients, the disease remains a significant burden with high mortality and morbidity rates. Improving stroke management for the acute ischemic stroke requires therefore new therapeutic development to achieve a better care and minimize the sequalae for stroke survivors.
SMR (Stroke Management through RGTA®) is a novel therapy for post-stroke care, using extracellular matrix-based technology to potentiate neuronal tissue repair once blood flow has been restored. Matrix therapy using ReGeneraTive Agent (RGTA®) compounds has already been developed for wound healing and is currently marketed by OTR3 for cutaneous lesions. To date, they have been used to treat successfully over 50,000 patients with diverse cutaneous lesions.
OTR3 has developed a new RGTA® called OTR4132-MD that has proved in preclinical models to be a promising neuroprotectant agent for ischemic stroke subjects.
The SMR project aims now at validating its clinical use and perform the regulatory steps to bring this product to the market.
Although SMR is first directed to acute ischemic stroke for a fast market entry and global commercialization, its innovative potential can be assessed for other therapeutic windows (post-acute, chronic) where there are even fewer therapeutic options available.
Stroke has a major economic impact for Europe, as in 2015 it was estimated to cost the EU €45 billion a year split as follows: ~44% (~ €20 billion) is due to direct health care costs, ~22% (~ €9 billion) to productivity losses and ~35% (~ €16 billion) to the informal care of people with stroke (long-time sequelae management).
In Europe, stroke is the second most common single cause of death accounting for 405.000 deaths (9%) in men and 583,000 (13%) deaths in women each year. These figures are expected to increase in the next coming years: The “Burden of Stroke in Europe Report” published in May 2017 (http://strokeeurope.eu(si apre in una nuova finestra)) by SAFE (Stroke Alliance For Europe) has projected that between 2015 and 2035, overall there will be a 34% increase in the total number of stroke events in the EU (from 613 148 in 2015 to more than 800 000 in 2035).
Stroke can cause permanent damage, including partial paralysis and impairment in speech, comprehension and memory. The severity of the stroke ranges from minimal to catastrophic, and the sequalae can be long-lasting: After 15 years, two-thirds (63%) of survivors are living with disability, nearly two in five (39%) have depression and over a quarter (30%) have cognitive impairment. The disability-adjusted life year (DALY) is an aggregate measure of years of life lost due to premature death from a condition and years lived with a disability due to a condition, with one DALY equating to one healthy year of life lost. In 2015, stroke was the second cause of lost DALYs in Europe, responsible for 17.1 million DALY lost.
Although therapeutic options are available in Europe for stroke patients, the disease remains a significant burden with high mortality and morbidity rates. Improving stroke management for the acute ischemic stroke requires therefore new therapeutic development to achieve a better care and minimize the sequalae for stroke survivors.
SMR (Stroke Management through RGTA®) is a novel therapy for post-stroke care, using extracellular matrix-based technology to potentiate neuronal tissue repair once blood flow has been restored. Matrix therapy using ReGeneraTive Agent (RGTA®) compounds has already been developed for wound healing and is currently marketed by OTR3 for cutaneous lesions. To date, they have been used to treat successfully over 50,000 patients with diverse cutaneous lesions.
OTR3 has developed a new RGTA® called OTR4132-MD that has proved in preclinical models to be a promising neuroprotectant agent for ischemic stroke subjects.
The SMR project aims now at validating its clinical use and perform the regulatory steps to bring this product to the market.
Although SMR is first directed to acute ischemic stroke for a fast market entry and global commercialization, its innovative potential can be assessed for other therapeutic windows (post-acute, chronic) where there are even fewer therapeutic options available.
Between October 2018 and May 2024, H2020 SMR project has progressed steadily towards the objectives. Biocompatibility studies have shown the preclinical safety of OTR4132-MD product, and a pilot clinical trial protocol has been written and submitted for clinical authorization. 2 preclinical confirmatory safety and efficacy studies have been carried out in independent laboratories. The pilot clinical trial has been accepted by the French National Ethical Committee (CPP) and the French competent authority (ANSM) in October 2021. 3 clinical centers were open, and 19 patients have been enrolled. The results of this pilot study show a safe profile for OTR4132-MD, with encouraging efficacy data. Alltogether, the preclinical and clinical data suggest to continue development with a randomised, placebo controlled trial.
2 patent applications have been submitted (not yet disclosed) to protect (1) an innovative therapeutic effect on the permeability of the Brain Blood Barrier during stroke that has been observed during preclinical studies, and (2) on the therapeutic dose that has emerged from the pilot study in coherence with preclinical studies.
2 patent applications have been submitted (not yet disclosed) to protect (1) an innovative therapeutic effect on the permeability of the Brain Blood Barrier during stroke that has been observed during preclinical studies, and (2) on the therapeutic dose that has emerged from the pilot study in coherence with preclinical studies.
Progress beyond the state-of-the-art
The biocompatibility studies showed the safety of OTR4132-MD and the animal studies showed both the safety and efficacy of OTR4132-MD in pertinent preclinical models (MCAO models in rats and marmoset).
Preclinical studies performed before the onset of H2020 have shown that OTR4132-MD has a positive effect in restoring the limited permeability of the Brain Blood Barrier (BBB). Increased permeability of the BBB is observed in the days following the stroke onset and is associated with a deterioration of the patient’s condition and lower recovery that is thought to be caused by increased local neurological toxicity. This unexpected effect of OTR4132 on the restoration of the BBB limited permeability could play a decisive role in the therapeutic effect observed in preclinical models. This very significant result has been patented by OTR3, CNRS and Université de Basse Normandie. This patent represents a fundamental step to ensure market value of the future product.
Expected results and potential impacts
Through the planned clinical trials, OTR3 is expecting to show the safety, performance and efficacy of OTR4132-MD in patients with acute ischemic stroke, or at least have some strong arguments allowing to raise funds for a Phase III multi-centre and international clinical trial.
The results deriving from the SMR project should allow an application for marketing authorisation (CE mark) for a first in class product on stroke (neuroprotectant).
The magnitude of the impact of the SMR project on the socio-economic burden of stroke or the societal consequences for patients, families and health care systems strongly depend on the results of the clinical trials that are planned in the project.
The biocompatibility studies showed the safety of OTR4132-MD and the animal studies showed both the safety and efficacy of OTR4132-MD in pertinent preclinical models (MCAO models in rats and marmoset).
Preclinical studies performed before the onset of H2020 have shown that OTR4132-MD has a positive effect in restoring the limited permeability of the Brain Blood Barrier (BBB). Increased permeability of the BBB is observed in the days following the stroke onset and is associated with a deterioration of the patient’s condition and lower recovery that is thought to be caused by increased local neurological toxicity. This unexpected effect of OTR4132 on the restoration of the BBB limited permeability could play a decisive role in the therapeutic effect observed in preclinical models. This very significant result has been patented by OTR3, CNRS and Université de Basse Normandie. This patent represents a fundamental step to ensure market value of the future product.
Expected results and potential impacts
Through the planned clinical trials, OTR3 is expecting to show the safety, performance and efficacy of OTR4132-MD in patients with acute ischemic stroke, or at least have some strong arguments allowing to raise funds for a Phase III multi-centre and international clinical trial.
The results deriving from the SMR project should allow an application for marketing authorisation (CE mark) for a first in class product on stroke (neuroprotectant).
The magnitude of the impact of the SMR project on the socio-economic burden of stroke or the societal consequences for patients, families and health care systems strongly depend on the results of the clinical trials that are planned in the project.