February 23th 2021
With more than 50 products into development, including 10 in clinical phase, Mitral Regurgitation (MR) market apparently looks a dead zone for new investors. If one benchmark with the three great success stories of Transcatheter Aortic Valve Replacement (TAVR) it appears that late entrants are fighting hard to find a buyer. 15 years after company creation, Jenavalve is still a stand-alone company after more than 190 MM USD invested (14 investors including Neomed, Bain, Andera, GIMV…). Would Transcatheter Mitral Valve Replacement/ Repair (TMVR) market will experience the story of TAVR?
It’s very unlikely!
Looking to what happened, it shall be pointed out that TAVR companies’ founders have been able to address a crucial unmet medical need. By using a transfemoral route which is a noninvasive access that can be performed by Interventional Cardiologists (vs. surgeons) the first players have dramatically changed the game. Today almost 90% of aortic valve replacement are done through transcatheter avoiding complications dealing with open heart surgery and recovery time. An historical and irreversible shift that changed disease management and saved lives. It’s efficient, cost saving, much more acceptable by the patient and one would even say “elegant”. As a consequence, market leaders (Medtronic, Edwards, Boston Scientific…) have massively invested to be in this market including Abbott with the mega acquisition of St Jude Medical (Portico™). Today there is almost no need for further acquisitions as the unmet need is addressed and incremental improvements managed by internal life cycle development.
The situation is totally different for mitral valve replacement/ repair technologies.
First, the epidemiological burden of mitral valve deficiency is the double than for aortic valve with poor survival outcomes at 2 and 5 years. In the US, 4 million of patients have stage 3 and 4 Mitral Regurgitation (the most severe cases) and only 50’000 patients get surgery per year. This massive number of untreated patients that lead to survival rate similar to the worst cancers is emphasized by the ageing of the population that will increase the number of patients ineligible to open heart surgery. The future needs a solution as “elegant” and safe than for TAVR. An extremely limited number of companies are working to overcome the transfemoral route challenge (Cardiovalve, Innovalve, Cephea, Altavalve) with other under the radar screen working hard on it.
Second, the challenges to perform transcatheter mitral valve replacement are overwhelming when compared with TAVR. The etiology of MR is multiple (primary vs. second MR) and often leads to a decision tree with numerous entries. The valve chordae, leaflets, papillary muscles, annulus, the overall heart structure or underlying infection (endocarditis) could be all or partially involved in this irreversible degradation. This immediate environment is also extremely unstable, moving and often fragile pushing the need to more sophisticated anchoring technologies. The variety of etiology and patient profiles make the medical arbitrage sophisticated and sometimes questionable. Finding a device suitable for a large number of clinical situations that will block MR recurrence sounds like holding the “holy grail”.
Last but not least, the debate between mitral valve repair vs. replacement is still unsolved for many situations. While valve reparation could be handled by using a transfemoral route (annuloplasty, chordal repair, edge to edge/ clips) the challenges to fold a full valve below 18-20 Fr (6-6,5 mm) raises almost insoluble technical questions. Finding the material flexible enough to navigate through the femoral vein and inferior veina cava and rotate at 90 ° after crossing the interatrial septum sounds like pure sciences fiction. As of today, four companies are officially focusing to make this dream a reality; nonetheless, the first clinical datas let us know that lethal risks dealing with the procedure are high. More creativity and hard work are then needed to be able to shrink a valve as sophisticated and big than the mitral one and to unfold and anchored it on site. The most advanced development with available clinical datas are the ones using the transapical route. While less invasive than open heart surgery, transapical valve implantation potentially exclude the most vulnerable patients (age, comorbidity, previous open-heart surgery…). It’s not a small procedure as a mini thoracotomy is needed with potential risks of ventricular injury and bleeding complications. Epidemiological studies often lead to controversial outcomes to measure the best choice (repair vs replacement) in term of survival rates. However, it appears as a given fact that MR recurrence, rehospitalization and more generally quality of life and cost benefit is much improved with a full replacement procedure. Two years after mitral valve reparation, up to 2/3 of patients have MR recurrence…. Thus patient profile will be closely studied and debated by a pluridisciplinary team (surgeon, cardiologist..) in order to pick the best option. As of today, many companies have been funded and VC supported in both segments (repair vs. replacement).
MITRAL VALVE REPAIR:
· Edge to edge: today, there are two players in this game. Abbott with Mitraclip™ and Edwards with Pascal™. By clipping the edge of the two mitral leaflets through a transfemoral/ transseptal procedure, it has been shown that Mitraclip™ is a safe and effective approach in order to decrease MR severity, at least for the short term. This 1-to-3-hours procedures is suitable for patients with severe and symptomatic MR but without extensive annular dilatation. However, the MITRA-FR study performed by Dr Jean-François Obadia (Lyon, France) shows no prognosis improvement at 12 months (mortality, unplanned heart failure hospitalization) vs. Medical Therapy alone. The COAPT study (US) shows more supportive outcomes. Thus, long-term expectations remain mixed. Owing to the lack of immediate alternative and the need for non-surgical procedure, short term sales should continue to grow intensively (690 MM USD in 2019 for Mitraclip™). As a consequence, there is still an avenue to develop other technics with more durable medical and pharmacoeconomic outcomes.
· Annuloplasty: annular dilation is an important component of MR and is about to be the most competitive TMVR sub market. By reducing the size of the valve annulus, the leaflets can coaptate and stop MR. Recurrence is unfortunately substantial (>1/3) and the procedure appears not curative with reversible effects for a significant number of patients. With improvement of image guidance technics, it is likely that recurrence will decrease but long-term outcomes are still questionable. Edwards / Cardiobands™ and Boston Scientific/ Millipede™ develop direct annuloplasty device (direct anchoring in the Mitral valve annulus) Edwards shows supporting 1 year outcomes with Cardioband™. Many other players are developing transcatheter annuloplasty including Carillon™ from Cardiac Dimension (LSP, Lumira Ventures, Aperture…) with supportive 12 months datas.
· Chordal repair: both transapical and transfemoral solutions are explored. Harpoon™ (Epidarex) developed a transapical procedure and has been granted CE mark in 2012. It was acquired in 2017 by Edwards. The latest ones (Chordart™, Avvie™, Cardiomech™) have developed transfemoral devices but have been poorly supported by private investors. Patient segmentation and number of devices have progressively shrink the market size and potential return on investment.
MITRAL VALVE REPLACEMENT:
· It’s highly likely that transcatheter mitral valve replacement will dominate this market. Bringing a device with more predictable and complete MR resolution through a minimally invasive procedure is indeed the most desirable target product profile. Owing to the incredible challenge that the size of the device stresses, the first products in development have used the transapical route. Transposing TAVR for TMVR replacement looks utopian as folding a large and sophisticated radial deployment valve in a capsule small enough to use the transfemoral/ transseptal path is extremely difficult. Looking to Highlife™ (Sofinnova Partners, Andera, USVP…) their combined procedure (annuloplasty + valve replacement) is a kind of its own. More generally, combination of transcatheter mitral repair (annuloplasty + chordal…) will likely be a future standard. Bringing a new complete valve anchored in a ring in the mitral annulus has good chance to fit within the portfolio of one of the four big Medtech players. More recently Innovheart recently raised 20 MM € in Series B totalizing 35 MM € (Panakes, Genextra, Indaco, CDP). Their unique device is a threefold one: mitral valve, annular structure and "connecting arms"offering a more complete and predictable solution. The procedure remains a transapical one with available preclinical datas (pig and sheep). A transfemoral/ transseptal project is under development with no/ limited available information. Looking to the future, one of the legitimate expectations would be to develop a pure transfemoral TMVReplacement. It remains one of the most incredible medical/ technical challenge to overcome. Most of the mitral valve remain too big (30-36 Fr/ 10-12mm) to navigate through the venal system. The overall material should be flexible enough to navigate easily, particularly after the transseptal perforation to reach the left atrium. Fast healing of the septum will also turn out to be a crucial issue if the capsule is too big. Size matters! Looking to Cardiovalve™, the pioneer of transfemoral TMVReplacement, it is obvious that most of the above challenges are still to be handled. The first clinical outcomes have underlined the consequences of not having a device small enough for the navigation and deployment of the valve. In a small EU studies done on 5 patients, all of them died 30 days later. Three of them for reasons directly related to the procedure and two others for fatal bleeding. Duplicating the revolution of TAVR for TMVR need to think totally differently. Other players tried to bypass this issue by sending a small valve and create a “waterproof” natural or artificial tissue surrounding the device. It will then be critical to better understand the patient eligibility for such medical strategy (e.g. secondary MR?). Another point to be further investigated: does a radial deployment of a “normal size” mitral valve still possible? As long as this question remains unsolved or an innovative way to do it differently is available, there will still be room for a new Medtech team to change the game.
VC BACKED TMVR SOLUTIONS
Source: Crunchbase/ public datas
INVESTMENT PRIORITY IN TMVR
The four Medtech leaders have done strategic investments in the field of MR but holes remain in their portfolio. A significant number of external growth deals have been handled by Edwards Lifesciences; they are now active in all MR repair and replacement segments. TMVR leader Abbott with Mitraclip™ will need to secure its franchise through more acquisitions. Boston Scientific and Medtronic have been shy for the moment in building a strong and solid MR pipeline. Missing a market with a forecasted CAGR ranged between 15-30% for this decade is a nonsense. More aggressive forecaster even state that this market will tripled by 2025. If one considers the huge unmet need boosted by the ageing of population/ comorbidities, the extraordinary technical challenges about to be overcome, the aggressive competition, the regulatory & reimbursement clarity, it’s obviously not too late for VCs to enter the game. Looking to the crowdy TMVRepair landscape (which will address micro eligible group of patients), priority should be given to mitral valve replacement devices with minimally invasive procedure (transfemoral).
Edouard Caram