With the encouraging completion of a first-in-human feasibility study, French manufacturer Cardiawave presented results from the first 10 patients at large cardiovascular meetings. This innovative start-up’s current clinical trial uses their Valvosoft platform and a completely noninvasive focused ultrasound technique to address aortic heart valve stenosis (narrowing) caused by calcification of the valve leaflets.

Cardiawave LogotypeCardiawave revealed 30-day safety and preliminary performance results at the Cardiovascular Research Foundation’s Transcatheter Technologies meeting, TCT 2019, held September 25–29, 2019, in San Francisco. When the American Heart Association (AHA) holds its 2019 Scientific Sessions November 16–18, 2019, in Philadelphia, Cardiawave will publish the study’s 90-day safety results and 30-day performance results as assessed by a third party. To learn more about this innovative company and its vision for treating “untreatable” patients with aortic stenosis, we interviewed Cardiawave CEO and Chairman of the Board, Benjamin Bertrand.

How was the company started?
The technology behind Cardiawave was initially developed in Paris, France, at Institut Langevin (CNRS/ESPCI) and PhysMed (INSERM/CNRS/ESPCI/PSL) in collaboration with an advanced cardiology laboratory at Hôpital Européen Georges-Pompidou (HEGP). At the end of 2014, three physicists from Institut Langevin and PhysMed, Mathieu Pernot, Mickael Tanter and Mathias Fink, a cardiologist from HEGP, Professor Emmanuel Messas, and I co-founded Cardiawave as a company. In April 2015, we completed our first round of financing.

Benjamin BertrandHow did you get involved in starting or joining the company?
I completed business school in France and became an entrepreneur in the life sciences about 15 years ago. At the time that the technology was ready, I was available for a new project. I was happy to meet the Institut Langevin, PhysMed and HEGP teams because I had learned about acoustic waves from my father. He knew Professor Mathias Fink, the physicist who founded Institut Langevin, who now serves on our Scientific Advisory Board. I also had a grandfather and great great grandfather who were American cardiologists. So I knew from day one that the Cardiawave project, combining ultrasounds and cardiology, was meant for me.

Tell us about your company structure: ownership, lead executives, and their roles.
Cardiawave is a privately held company with 20 full-time employees. The management team currently consists of myself as CEO and Chairman of the Board. Our Chief Medical Officer is Dr. René Spaargaren. We have a Quality and Regulatory Affairs Director named Luc Morisset and a Chief Technical Officer named Fabienne Betting. Furthermore, we have an excellent Board of Directors and an incredible Scientific Advisory Board, including Professor Alain Cribier, who invented transcatheter aortic valve replacement (TAVR).

In general, what is the current status of your company?
Cardiawave is an early clinical stage company. We are currently only developing one product – the Valvosoft system. We build and manufacture the system in house but plan to outsource production after completing the clinical phase. We designed and customized all of the device’s subsystems and developed all of the software in house. Our project timeline for Valvosoft includes presubmission to the US Food and Drug Administration (FDA) in early 2020, an early US feasibility study in 2021, and obtaining the CE Mark in 2022.

Valvosoft systemHow many years has the Valvosoft treatment platform been in development?
Valvosoft was initially called Valvopulse, but it has since been rebranded. The technology was developed at Institut Langevin ESPCI from 2009 – 2014. The completely noninvasive system is applied trans-thoracically through the chest of the patient. Its applicator houses both the echocardiography ultrasound transducer for imaging guidance and monitoring, plus the focused ultrasound therapeutic transducer for applying ultrasonic cavitation in the form of shock waves. The focused ultrasounds create microscopic bubbles and shock waves within the valve leaflets, and these shock waves make tiny cracks in the calcification that is embedded in the aortic valve leaflets. The mechanical energy also affects any fibrosis that has formed within the valvular tissue. Applying energy with very short pulses cracks and softens the calcifications in the leaflets. The softening of the leaflets restores some of the function that was lost and enables a wider opening of the aortic valve.

What are some of the technical challenges your group has to overcome to develop a fully noninvasive system?
Obtaining feedback between the imaging and the therapy was a big challenge. We also had to develop software for real-time imaging. Then, the team had to determine the optimal therapeutic parameters to go deep into the body with a small focal beam. We needed the smallest focal point and for the energy to travel past the ribs. It took a long time to find the right parameters for safety and efficacy.

Obtaining regulatory approval to begin clinical trials was another challenge, especially because there are currently no other devices that use cavitation bubbles as a form of treatment. There were no published studies in the literature and no third-party data. Therefore, we had to show only our data and reassure the officials that the data were valid and reliable. Our team worked extensively on this, and they proved the promise of the technology to be safe.

Which health conditions or diseases will your technology be used for?
As mentioned earlier, the first application is for aortic valve stenosis. Although our focus is currently a hundred percent in this area, we have also started working on treating deep vein thromboses in an animal model.

Tell us about your clinical studies and the results.
Our first in-human clinical trial was conducted in France and the Netherlands. We enrolled 10 patients: five in Paris at HEGP and five in the Netherlands at Amphia hospital. The patients that were enrolled had aortic stenosis that was in various stages of severity, but all were symptomatic and too ill to undergo an invasive procedure such as surgical or transcutaneous aortic valve replacement (TAVR). These patients were ineligible for other procedures mainly for their comorbidities or for reasons such as age, frailty, or access issues. Today, at least sixteen percent of patients with aortic valve stenosis are not candidates for invasive procedures, which leaves a remarkable unmet medical need for a device such as Valvosoft.

The primary endpoint of the study was no mortality after 30 days. The secondary endpoint was no adverse events at 30 days of any kind. The follow-up periods are at 3, 6, 12, and 24 months. A performance endpoint was an improvement in the dynamics of the valve, measured as the pressure gradient between the left ventricle and the aorta or as an improvement in the aortic valve area (AVA.)

Our initial results (presented at TCT 2019) showed that the treatment reached the safety endpoints. There were no mortality and no adverse events. Thus far, we have seen improvement in the condition of most of the patients. The AHA 2019 presentation will show additional data.

How does the Valvosoft treatment work?
During treatment, the focal beam is constantly moving and is controlled by an electronic steering process. The imaging probe protrudes from the therapeutic transducer, and it is designed to deliver energy between the rib bones. It has real-time visualization capabilities that deliver treatment based on pre-planned CT and echocardiographic measurements. Each treatment is individualized, but generally we aim to treat each of the three aortic cusps twice for 10 minutes each. Thus far, the maximum duration is 60 minutes and patients, especially those are very ill, become uncomfortable with long treatment times. Interestingly, half of the patients in the clinical trial were able to undergo treatment while fully conscious. This was a good surprise, because our goal is to develop an ambulatory treatment. If needed, we may be able to use sedation to allow longer treatment times.

Valvosoft treatment may have a risk of releasing calcium debris into the blood, which could create a risk for embolism or stroke. To assess these risks, our study includes neurological evaluations at 30 days. Thus far, we have seen no change in status. We are also evaluating quality of life (QOL) with the New York Heart Association (NYHA) questionnaire. Thus far, the treated patients have had QOL improvements ranging from 6 to 10 points.

What challenges will the company tackle next?
The next step, which should happen quite soon, is to begin a 10-patient clinical trial in Serbia. Our physician group in Serbia has a motivated care team and a large hospital with many untreated aortic valve patients. This is because Serbia has no TAVR programs. The 10 additional patients will serve as an extension of our initial clinical study, but we will also add brain MRI to hopefully demonstrate that the treatment does not increase the risk of stroke. The extended study also has the goal of longer treatment times and more energy application.

In terms of performance, our TCT presentation reported that we did not initially apply a high level of energy as a treatment dose for safety purposes in our first clinical study. The next trial will apply a higher level of energy to increase the performance of the therapy. We were initially cautious because we did not want to damage the valves’ fibrosa layer that is lined with endothelial cells because causing damage accelerates the inflammation and calcification processes, which could lead to regurgitation and worsening stenosis.

What are the benefits of your technology over companies?
Right now, we do not know of any other companies who are offering this type of treatment. There are two companies that are repairing the aortic valve with mechanical energy. One is Shock Wave Medical, which is working on a balloon valvuloplasty procedure with percutaneously applied unfocused ultrasound. A company called Pi Cardia, which is based in Tel Aviv, is also using an invasive catheter to score the valve and create a wider opening. We heard several presentations from these companies at the London valve meeting and at TCT.

Have you learned any lessons from watching the experience of the other companies?
Always, of course. We have learned strategies for designing clinical trials and for patient positioning. Cardiawave has such an innovative technology that cardiologists have envisioned its use for various subgroups of patients. One idea is to use the platform to soften heavily calcified valves prior to TAVR. It could also potentially prevent paravalvular leakage and provide a bridge to temporarily delay certain cardiovascular procedures. This type of delay becomes important in countries such as Canada and the Netherlands, where a patient might have to wait until the next year before their national healthcare system approves another procedure.

Furthermore, we aim to show that Valvosoft provides a durable effect; however, we also think it can offer a type of preventative treatment that slows disease progression. With the high cost of aortic valve replacement procedures (e.g., $100,000 for a TAVR), delaying a procedure so that a patient does not need to have it redone in 10 years offers considerable financial value. That, of course, is a long-term vision and we need to collect more evidence before we get to that point. But it’s very promising, and we are considering the financial implications of the technology.

Do you partner with other companies?
We have Research & Development (R&D) partners based on our specification. We would be interested in finding strategic partners for achieving three of our company goals: 1) industrial synergies for manufacturing 2) clinical synergies 3) future marketing and distribution. We would welcome any inquiries in these areas.

Is there anything else we should know about your company?
We are happy to be associated with the Focused Ultrasound Foundation. Its team members have been of great help to our company, especially those associated with FUS Partners.

The focused ultrasound therapy field is truly at an exciting point in time. There is so much going on with new startups and its potential is huge. I strongly believe it’s the medicine of the future for so many indications.

Past Coverage
Meeting Report: International Society for Therapeutic Ultrasound & European Focused Ultrasound Charitable Society Joint Meeting June 2019
Cardiawave Begins First Human Aortic Stenosis Clinical Trial May 2019
Cardiawave to Begin Aortic Stenosis Trials April 2019

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