Periodic Reporting for period 2 - OUTLIVE (OUTLIVE: a disruptive non-invasive ultrasound therapy to treat all patients affected with aortic stenosis.) Reporting period: 2020-04-01 to 2021-06-30 Summary of the context and overall objectives of the project Aortic stenosis (AS) is a life-threatening disease caused by the narrowing of the opening of the aortic valve which is the “gateway” from the heart to the body. With age, the aortic valve calcifies and stiffens, leading to poor blood perfusion. To date, the only medical response consists in replacing the aortic valve through open-heart surgery or a procedure called Transcatheter Aortic Valve Implantation (TAVI). This radical treatment is provided to very sick patients at high risk of sudden death, considered as severe and symptomatic. Only a minority of these severe symptomatic patients who represents 25% of all AS patients (2.5 million in Europe and US) benefit from a valve replacement due to lack of infrastructures, restrictions (limited number of procedures per year per center) or because they are not eligible. All other affected patients (75%) remain untreated, facing a truncated life expectancy. It represents an immense unmet medical need.French medtech Cardiawave has developed a revolutionary solution: Valvosoft, a real-time image guided medical device for the treatment of all AS patients. Because no surgery is required and because the procedure does not cause side effects, every AS patient would be eligible to the treatment. The device delivers focused high intensity ultrasounds which break the calcifications, soften the tissue and thus repair the aortic valve function. There should be lower risks, complications and costs. It is a game-changer for patients, physicians and health care establishments because it dramatically changes the way of treating AS throughout the world. It should become a new gold standard: every AS patients will benefit from Valvosoft.The OUTLIVE project has been undertaken in order to demonstrate Valvosoft’s clinical safety and efficacy in a European clinical trial. Cardiawave will refine current go-to-market strategy and develop an investor ready business plan following CE-mark of its medical device. Reliable trust relation with early-adopters and distributors will be established. OUTLIVE will accelerate the clinical validation of Valvosoft to obtain CE-mark and enable Cardiawave to market the first non-invasive therapy for aortic stenosis. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The aim of OUTLIVE is to bring the Valvosoft device on the market and to provide AS patients with a safe and efficient therapy. In order to reach this goal, Cardiawave manufactured two additional Valvosoft devices, identified important suppliers and secured agreements with the one providing critical parts of the device, finished the pilot phase of the clinical investigation and refined its go-to-market strategy.Cardiawave completed its first international trial in ten patients. The post-procedural echocardiographic results were presented at seven international conferences.The pilot phase was conducted as part of an international multicenter study which enrolled ten patients. These patients were not eligible for TAVI nor for open-heart surgery, mainly due to the presence of concomitant diseases or due to difficulties in accessing the blood vessels with a catheter. Therefore, they were left with no alternative treatment. Analysis of the post-operative echocardiographic data, performed by an independent centralized laboratory, and of the clinical results at 30 days, confirms that the primary objectives, which were to assess safety and feasibility of this procedure, have been met. No adverse events related to the Valvosoft device or procedure were reported and results have also shown that none of the patients encountered neurological issues. Based on the echocardiographic results from the day after the procedure, an improvement in the hemodynamic parameters of some patients has been noted along with an NYHA class improvement observed for the majority of the ten patients.Based on the careful review of these results and discussions with external KOLs and the Scientific Advisory Board, Cardiawave decided to extend the pilot phase of the clinical trial by enrolling ten additional patients in a new clinical investigation site in Serbia. This safety study, including MRI data acquisition aiming at ruling out risks of stroke, is currently ongoing.During the second part of the OUTLIVE project, an extension of the first-in-man clinical study will be performed in three to four clinical centers. The pivotal study will follow in 2021 throughout Europe. A new improved Valvosoft device will also be released to improve the safety, the performance, the usability and the maintenance of the device. The collection of data on safety and efficacy of the Valvosoft device in the treatment of AS will be compiled to obtain CE-mark. In the meantime, Cardiawave will be establishing close contact with users and payers to ensure swift and successful market access following CE-marking now expected at the end of 2022 or beginning of 2023. 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) Valvosoft is the first non-invasive therapy for AS patients. The current standard of care consists of valve replacement either by open-chest surgery of by a percutaneous trans-catheter approach. These procedures are highly invasive and risky, especially for frail patients.In comparison, Valvosoft offers a non-invasive approach with no adverse events and the possibility to repeat the treatment several times. On the contrary to the surgical valve replacement methods, Cardiawave offers to repair the patient aortic valve to promote its opening instead of replacing it.The feasibility has been demonstrated so far on 14 human subjects during this first phase of the trial and the results obtained are encouraging and progress beyond the state of the art. Despite the fact that the patients treated in the clinical study had serious co-morbidities, the safety objectives of the study have been reached. The clinical investigations will go on in order to obtain more data and get the CE-mark. Valvosoft aims to become a new gold standard in aortic stenosis treatment.It should extend the current indications by treating patients who are currently not eligible to valve replacement. In the long-term it could become a preventive treatment in order to treat patients at an earlier stage to slow down the progression of the disease and delay or avoid the valve replacement. It could also help treating other diseases such as other valvular heart diseases or deep vein thrombosis. The development of the Valvosoft device represents significance advances from both technical and medical viewpoints. The pulsed cavitational ultrasound therapy approach developed by Cardiawave is unique and based on a disruptive technology invented by the company’s founders. The development of this technology and its fitting into a medical device is an immense challenge and a very significant progress. There is currently no device on the market using such a non-invasive ultrasound therapy (cavitation bubbles). There isn’t a lot of scientific literature as only three or four academic institutes have the know-how and the electronics to produce this kind of energy. On the medical side, since the current therapeutic options for AS patients are extremely invasive, the development of a non-invasive solution, lacking adverse effects, and that can be proposed to patients non eligible to valve replacement also represents a major progress in patient’s care. Being non-invasive and potentially ambulatory, it should be cost-effective, improve quality of life and patients pathway and it should decrease risks and complications.