Periodic Reporting for period 2 - Duo (Duo: A minimally invasive device to treat all patients with tricuspid valve disease) Reporting period: 2021-06-01 to 2022-05-31 Summary of the context and overall objectives of the project BACKGROUND: Heart failure is the leading cause of death for both men and women affecting 15 million patients across Europe and the US. In patients with heart failure, the right heart expands, resulting in the tricuspid valve not closing properly and blood leaking backwards. This is called tricuspid valve regurgitation. The past decade has witnessed a revolution in the treatment of heart valve disease. For the aortic valve, patients no longer need to have their chest cut open and their heart stopped in order to have their valve replaced. While the same revolution is already on its way for the mitral valve, the tricuspid valve has remained largely forgotten due to unique functional and anatomical challenges. Although there are 550,000 new tricuspid valve disease cases diagnosed every year in the US and EU, less than 1% of these patients are treated. This is due to the fact that open-heart surgery is still the only treatment option, which is very risky. Without suitable treatment options, all that doctors can do is to manage their patients’ symptoms with diuretics. These patients face worsening quality of life and eventually die. The prognosis is bleak with 3 of every 5 patients dying within 3 years.DUO SOLUTION: DUO is a minimally invasive device uniquely tailored to the anatomical challenges of the tricuspid valve. Designed by a leading interventional cardiologist, DUO is the only minimally invasive tricuspid valve that works in tandem with the native valve. An innovative adjustable anchor holds the device in position between the tricuspid valve leaflets, anchored against the venous wall, where it does not touch the fragile cardiac tissue or the native tricuspid valve leaflets. The DUO-TF (Duo-transfemoral) device is a next generation device, designed to support delivery through a vein in the leg is the focus of the FTI project. Patients have restrictions that prevent transjugular delivery due to the size of the vein or the presence of a previously implanted devices. Additionally, it changes the procedure from one requiring general aesthetic to one where only local sedation is needed, minimising impact to the patient and increasing adoption.FTI PROJECT: This FTI project will progress and finalise the development of the Duo device and enhance Duo’s profile by developing clinical evidence with the next generation device, demonstrating the clinical benefits to the patient. This consortium is a group of innovative and complementary SME’s that are uniquely positioned to undertake the activities necessary to accelerate the device to market and maximise penetration. The main goal of the project is to strengthen the position of Duo as the Gold Standard treatment for Tricuspid Regurgitation, thus saving the lives of thousands of patients suffering with this condition and reducing the high healthcare burden associated with their care. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far During the second 12 months of Project Duo, the consortium has further developed the technology and completed testing to initiate clinical testing. Additionally, more detailed clinical and regulatory activities have been completed to defined the pathway to commercialisation. All work described in this objectives overview section of the report is described in further detail in the subsequent work package reviews.Completed design and volume manufacturing specification documentsAchievements: During this period, the focus has been on ensuring we can deliver and anchor the device through transfemoral delivery, along with ensuring the long term biological response to the device is aligned to expectations for a prosthetic heart valve. • Longer term animal studies (out to 140 days) to understand the biological response the tissue causes in vivo. There was some indications at an earlier timepoint (50 and 90 days) of a potentially higher than expected inflammation response. • Detailed interrogation of factors that might cause an increased inflammation response and optimisation of tissue processing and washing methods to reduce this response.• TF design optimisation including preformed rail updates and handle modifications, Complete verification activities, per FDA’s requirements, to demonstrate the device is ready for US Early Feasibility Study.Achievements: Design verification involves testing of a large number of devices, built per a finalised design with controlled documentation, to demonstrate the device meets all design requirements and is ready for clinical implants. • Chronic Animal Testing• Durability Testing: • Fatigue Testing: • Biocompatibility TestingFinalised the pre-submission review process with the FDA which included interactive reviews of the protocols for the above tests. Additionally, the submission is being drafted, with the outline structure defined. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) As the demographics of our population in Europe and the Western world continues to age, Tricuspid Regurgitation will become more prevalent. In 2020, there are approximately 56 million US citizens and 140 million EU citizen over the age of 65. Tricuspid valve disease is a disease of old age, occurring in 3.5% of patients over 70 years of age. Currently only 1% of these patients receive surgical treatment due to the poor outcomes of open-heart surgery. This results in patients being turned down for surgery, suffering low Quality of Life and needing multiple hospitalisations. Including a transfemoral device, along with the transjugular device will expand the patient population, ensuring patients with smaller jugular veins and pacemaker implants can be treated with a minimally invasive procedure. Health economic studies demonstrate that reducing hospitalizations have significant cost benefits for the healthcare system. Delgado et al. found that, in Spain, one year health care costs for Heart Failure patients with no hospital admissions (EUR 1,857) is less than 1/4 the cost of patients with one admission (EUR 8,475) and less than 1/10 the cost of patients with multiple admissions (EUR 21,022). Other health economic studies in the US, Europe and Australia indicate similar short term cost benefits of improving the rate of hospitalization. The Duo device will offer gold standard treatment that is safe and easy to use. It can reduce re-hospitalisation at 1 year by >70% and reduce pressure on the European healthcare costs.Minimally invasive devices are the future of heart valve disease. There are two other minimally invasive approaches to fix the tricuspid valve: Repair and Replacement- Repair: Reducing the size of the expanded/dilated valve back closer its healthy size or clamping the leaflets together to help leaflet coaptation and sealing- Replacement: Fully replacing the tricuspid valve with a prosthetic valveHowever, repair & replacement don’t address key clinical requirements and so will see limited market penetration. The DUO system is a disruptive approach combining the advantages of both repair and replacement, without their complications: implanting a valved spacer to work in tandem with the native valve.