Periodic Reporting for period 4 - ReGenHeart (Clinical development and proof of principle testing of new regenerative VEGF-D therapy for cost-effective treatment of refractory anginaA phase II randomized, double-blinded, placebo-controlled study)
Okres sprawozdawczy: 2021-07-01 do 2022-12-31
What is the problem/issue being addressed?
The most common symptom of coronary heart disease (CHD) is angina, chest pain, and within this group of patients refractory angina constitutes a serious clinical problem. The European Society of Cardiology has emphasised this important clinical problem and defined refractory angina as a chronic condition (> 3 months) characterised by the presence of angina caused by coronary insufficiency due to coronary artery disease which cannot be controlled by a combination of medical therapy, angioplasty and coronary bypass. Despite the fact that better treatment methods have been developed for CHD patients in general, this group of patients suffer from significant symptoms and disability even with maximal medication. Thus, there is a significant unmet clinical need to develop new therapies for this rapidly increasing group of patients whose annual mortality is less than 4%.
Why is it important for society?
Patients with refractory angina usually have severely compromised quality of life leading to impaired ability to work and to perform physical activities including exercise and rehabilitation programs, both of which have been shown to improve the outcome. Refractory angina, due to its chronic nature, is also a psychological stressor further impairing the general health status. The economic burden imposed on the healthcare system as well as on the patients is high. Due to relatively low mortality these patients will require long-term treatment, including medical therapy and repeated use of devices, which means substantial costs for both patients and healthcare systems.
What are the overall objectives?
The aim of this study is to evaluate in a randomized, placebo-controlled, double-blinded, multicentre phase II study at 6 centres in the EU, the efficacy, proof-of-concept and safety of a new targeted approach based on the catheter-delivered endocardial adenovirus-mediated regenerative vascular endothelial growth factor-D (AdVEGF-D) gene transfer in 180 patients with severe CHD for whom revascularisation cannot be performed.
• Our primary objective is to demonstrate the efficacy of the gene therapy to improve exercise capacity and relief of angina pectoris symptoms 6 months after the treatment, as measured by a 6-minute walking test.
• As our secondary objective we will demonstrate the efficacy of the gene transfer to increase myocardial perfusion assessed with PET imaging at 6 months.
If successful, this trial will give proof of concept and clinical validation for this new percutaneous, cost-efficient, innovative state-of-the-art regenerative therapy for the rapidly growing group of refractory angina patients.
As the recruitment of patients continued up until the end of the project it has not been possible to draw any conclusions yet, these will come when the data are unblinded once all patients have undergone their 12 month follow up.
The most common symptom of coronary heart disease (CHD) is angina, chest pain, and within this group of patients refractory angina constitutes a serious clinical problem. The European Society of Cardiology has emphasised this important clinical problem and defined refractory angina as a chronic condition (> 3 months) characterised by the presence of angina caused by coronary insufficiency due to coronary artery disease which cannot be controlled by a combination of medical therapy, angioplasty and coronary bypass. Despite the fact that better treatment methods have been developed for CHD patients in general, this group of patients suffer from significant symptoms and disability even with maximal medication. Thus, there is a significant unmet clinical need to develop new therapies for this rapidly increasing group of patients whose annual mortality is less than 4%.
Why is it important for society?
Patients with refractory angina usually have severely compromised quality of life leading to impaired ability to work and to perform physical activities including exercise and rehabilitation programs, both of which have been shown to improve the outcome. Refractory angina, due to its chronic nature, is also a psychological stressor further impairing the general health status. The economic burden imposed on the healthcare system as well as on the patients is high. Due to relatively low mortality these patients will require long-term treatment, including medical therapy and repeated use of devices, which means substantial costs for both patients and healthcare systems.
What are the overall objectives?
The aim of this study is to evaluate in a randomized, placebo-controlled, double-blinded, multicentre phase II study at 6 centres in the EU, the efficacy, proof-of-concept and safety of a new targeted approach based on the catheter-delivered endocardial adenovirus-mediated regenerative vascular endothelial growth factor-D (AdVEGF-D) gene transfer in 180 patients with severe CHD for whom revascularisation cannot be performed.
• Our primary objective is to demonstrate the efficacy of the gene therapy to improve exercise capacity and relief of angina pectoris symptoms 6 months after the treatment, as measured by a 6-minute walking test.
• As our secondary objective we will demonstrate the efficacy of the gene transfer to increase myocardial perfusion assessed with PET imaging at 6 months.
If successful, this trial will give proof of concept and clinical validation for this new percutaneous, cost-efficient, innovative state-of-the-art regenerative therapy for the rapidly growing group of refractory angina patients.
As the recruitment of patients continued up until the end of the project it has not been possible to draw any conclusions yet, these will come when the data are unblinded once all patients have undergone their 12 month follow up.
Since the start of the ReGenHeart project the majority of the work undertaken was divided into two parts. Project partners were focused on either the Drug Product manufacturing activities or the administrative activities associated with gaining all required approvals for the clinical trial to begin. Achievements to date include gaining all required approvals for the Finnish, Danish, UK and Spanish clinical centres to start recruiting patients, as well as approval in Austria to open a control cohort with maximally medicated patients. The Drug Product and placebo were approved for release at the end of the second period and first release was to the Kuopio clinical centre. The project was affected by delays due to manufacture of the AdVEGF-D and the COVID-19 pandemic, but across the 4 sites where patients were recruited the situation at the end of the project was as follows:
Finland (Kuopio) – 21 patients randomised, 8 yet to complete the 12-month follow up
Denmark (Copenhagen) - 16 patients randomised, 2 still to complete the 12-month follow up
United Kingdom (London) – 6 non-blinded patients none of whom have completed the 12-month follow up
Austria (Vienna) – 20 patients consented before the end of December 2022, none followed up yet
The total for the project is 37 randomised and blinded with a further 26 non-blinded.
As the recruitment of patients continued up until the end of the project it has not yet been possible to evaluate, disseminate or exploit the results, this will come when the data are unblinded once all patients have undergone their 12 month follow up.
Finland (Kuopio) – 21 patients randomised, 8 yet to complete the 12-month follow up
Denmark (Copenhagen) - 16 patients randomised, 2 still to complete the 12-month follow up
United Kingdom (London) – 6 non-blinded patients none of whom have completed the 12-month follow up
Austria (Vienna) – 20 patients consented before the end of December 2022, none followed up yet
The total for the project is 37 randomised and blinded with a further 26 non-blinded.
As the recruitment of patients continued up until the end of the project it has not yet been possible to evaluate, disseminate or exploit the results, this will come when the data are unblinded once all patients have undergone their 12 month follow up.
Progress beyond the state of the art and expected results
Pro-angiogenic and regenerative treatments with genes encoding vascular growth factors and stem cells have attracted increasing interest in the recent years. VEGF-A has been used previously in clinical trials of patients with resistant angina with limited success. There is presently no established and approved gene therapy or cell therapy for patients with CHD or refractory angina. Therefore, there is urgent need to develop and test new innovative treatments for these conditions. However, it is difficult to standardize autologous stem cell therapy due to a large variation in the final cell product. There is also a large variation in the number of collected stem cells and the quality of cells varies from patient to patient. Considerable logistical problems also exist in the transportation of individual cells to and from hospital and the stem cell production centre. Gene therapy with pro-angiogenic and regenerative effective vascular growth factor may solve many of these problems, since it would be a new standardized drug which can be prepared in the hospital pharmacy for the rapid treatment of patients. Our extensive experience suggests that our approach, using adenovirus to transduce the myocardium with AdVEGF-D, will lead to a greater and longer lasting angiogenic and regenerative response and hence improvements in cardiac symptoms.
Potential impacts
The ReGenHeart project delivered impact by introducing and testing a new regenerative therapy. Our gene therapy has been tested in the clinic in a patient population that is an increasing burden to the healthcare and social care systems of the Western world and for whom medical therapy, angioplasty and coronary bypass surgery have failed to control the disease. Our belief is that the impact of the ReGenHeart project will be to reduce patients’ symptoms, morbidity, inability to work and potential mortality and thereby improve the patients’ quality of life and reduce health care costs and welfare payments throughout Europe. However, we will need to wait until all patients have completed their 12 month follow up before unblinding the data and evaluating the results. Additional future impact of the successful completion of the ReGenHeart project will be the creation of a new platform for biotech companies in Europe.
Pro-angiogenic and regenerative treatments with genes encoding vascular growth factors and stem cells have attracted increasing interest in the recent years. VEGF-A has been used previously in clinical trials of patients with resistant angina with limited success. There is presently no established and approved gene therapy or cell therapy for patients with CHD or refractory angina. Therefore, there is urgent need to develop and test new innovative treatments for these conditions. However, it is difficult to standardize autologous stem cell therapy due to a large variation in the final cell product. There is also a large variation in the number of collected stem cells and the quality of cells varies from patient to patient. Considerable logistical problems also exist in the transportation of individual cells to and from hospital and the stem cell production centre. Gene therapy with pro-angiogenic and regenerative effective vascular growth factor may solve many of these problems, since it would be a new standardized drug which can be prepared in the hospital pharmacy for the rapid treatment of patients. Our extensive experience suggests that our approach, using adenovirus to transduce the myocardium with AdVEGF-D, will lead to a greater and longer lasting angiogenic and regenerative response and hence improvements in cardiac symptoms.
Potential impacts
The ReGenHeart project delivered impact by introducing and testing a new regenerative therapy. Our gene therapy has been tested in the clinic in a patient population that is an increasing burden to the healthcare and social care systems of the Western world and for whom medical therapy, angioplasty and coronary bypass surgery have failed to control the disease. Our belief is that the impact of the ReGenHeart project will be to reduce patients’ symptoms, morbidity, inability to work and potential mortality and thereby improve the patients’ quality of life and reduce health care costs and welfare payments throughout Europe. However, we will need to wait until all patients have completed their 12 month follow up before unblinding the data and evaluating the results. Additional future impact of the successful completion of the ReGenHeart project will be the creation of a new platform for biotech companies in Europe.