Medtechs Bet On Transcatheter Mitral Valve Repair

The success of transcatheter aortic valve replacement has generated optimism that the much larger pool of mitral regurgitation patients can be similarly served. While big strategics bet on replacement, however, other companies are betting on repair, developing less invasive devices inspired by an array of established mitral valve surgical repair techniques.

• Big medtechs made a number of mitral valve replacement M&A deals in 2015, while other companies, including start-ups, are betting on mitral valve repair, a market that may be four times larger than TAVR.
• But the road for new mitral interventions may be rockier than it was for TAVR. Among aortic stenosis patients, it is much more obvious who needs TAVR, whereas for MR patients indications often are unclear.
• Due to the complexity of the mitral valve, it's likely that multiple minimally invasive devices will share the space in the future, perhaps in a stepwise or combination fashion.

The summer of 2015 saw massive strategic acquisitions by Edwards Lifesciences Corp., Medtronic PLC and Abbott Laboratories Inc. of transcatheter mitral valve replacement devices [See Deal][See Deal] [See Deal]; also in 2015 – Abbott’s transcatheter mitral valve repair device MitraClip saw its 25,000th patient. The success of transcatheter aortic valve replacement (TAVR) has generated optimism in the industry that the much larger pool of mitral regurgitation (MR) patients can be similarly served.

While big strategics bet on replacement, however, other companies are betting on repair, developing less invasive devices inspired by an array of established mitral valve surgical repair techniques. These companies are ambitious. For instance, Mardil Medical Inc. projects a $3.2 billion US market for its ventricle-reshaping device to treat MR.

Some estimate that the transcatheter mitral valve replacement/repair (TMVR) market opportunity is four times larger than TAVR’s; estimates for replacement alone are as high as $10 billion. New mitral valve options not requiring open-heart surgery could be on the market as soon as 2017.

However, many insiders say the road for new mitral interventions will be rockier than it was for TAVR. Among aortic stenosis patients, it is much more obvious who needs TAVR, whereas for MR patients indications often are unclear. Anatomical and technical problems relating to the mitral valve are also more challenging compared with the aortic valve.

Daring To Repair FMR

There are two main types of MR, a condition in which blood backs up abnormally into the left atrium through a compromised mitral valve as the ventricle squeezes blood out the aortic valve.

Degenerative mitral regurgitation (DMR) distorts the valve itself. Standard of care for advanced cases is surgical repair via a complex array of techniques, and sometimes replacement. Repair techniques include annuloplasty (optimizing size or shape of the ring at the base of the valve), leaflet reshaping or sewing, chord repair or replacement, and the Alfieri approach, which clips together the valve leaflets, creating two apertures instead of one and reducing regurgitation. In open surgery, this approach is usually combined with other repair techniques, including annuloplasty. MitraClip uses the Alfieri approach and is FDA-approved for patients with significant symptomatic DMR at prohibitive risk for mitral valve surgery.

By contrast, functional mitral regurgitation (FMR) is a disease of the ventricle that only secondarily affects the valve. The ventricle becomes abnormally dilated, often after heart attacks, and the valve’s leaflets are pulled apart. Few FMR patients are currently considered good surgical candidates, although many are treated with MitraClip.

Many early-stage repair companies are aiming at FMR, adapting an established surgical technique to a minimally invasive approach. Complicating their prospects, however, is a lack of consensus as to the gold standard treatment for FMR. In contrast, those companies aiming at DMR must compete with an accepted surgical gold standard. (See Exhibit 1.)

Exhibit 1

Selected Minimally Invasive Mitral Valve Repair Companies, By Technique

Company	Technology	Comments
Annuloplasty: reshaping or reducing size of fibrous ring, or annulus, at base of mitral valve
Cardiac Dimensions	CARILLON Mitral Contour System: double-anchor device in coronary sinus	Delivery through jugular vein; peri-procedural recapture possible; CE mark 2009; current multi-site randomized blinded trial, REDUCE FMR
Millipede	Adjustable mitral valve ring	Mimics surgical annuloplasty for FMR; first-in-human study completed; will release data in 2016
Mitralign Inc.	Mitralign System: pledgets across annulus	First-in-human study in FMR found significant reductions in ventricle and annular dimensions with 12% mortality rate and residual MR
MVRx Inc.	ARTO System: suture across valve for FMR	For FMR; lower-cost; CE mark anticipated in Q3 2017; MAVERIC trial underway
Phoenix Cardiac	BACE, or Basal Annuloplasty of the Cardia Externally: annuloplasty without open-heart	For FMR; requires sternotomy; lower-cost; CE mark study underway; goal is CE mark in Q4 2016 or Q1 2017
Valtech	Cardioband: flexible annuloplasty band	Allows for real-time adjustment of annular diameter during procedure; single-arm study of 45 patients found substantial reductions in MR at 12 months
Enhanced coaptation
Cardiosolutions Inc.	Mitra-Spacer: leaflet spacer consisting of balloon tethered at apex	Adjustable, allowing gradual reduction in FMR; lower-cost; CE mark trial in Europe in Q1 2016
coramaze technologies GMBH	mitramaze valve repair system: leaflet spacer consisting of balloon anchored in left atrium	Intended for use in FMR by cardiologists; received €4.5m Series A in Sept. for first-in-human
Guided Delivery Systems	Accucinch: cable across ventricle, pulling leaflets together	Case report of FMR patient: MR reduction from grade 3 to grade 1 at 30 days; completing feasibility trial
Shortening, repair, or replacement of chordae tendineae
Harpoon	Harpoon device: chord replacement in DMR	Transapical delivery of adjustable neochords; feasibility study found moderate to trace MR at 30 days; CE mark anticipated in Q2 2017
NeoChord	DS1000: chord replacement in degenerative mitral regurgitation (DMR)	CE marked and in clinical trials in Europe; 6 reported reoperations in study of 30 patients; raised $20m Series C in June
Valtech	V-Chordal: chord replacement in DMR	First-in-human study complete; trial timing not released
Edge-to-edge approximation of leaflets (Alfieri repair)
Abbott	MitraClip	FDA-approved in DMR; often used in FMR; over 25,000 patients treated; often residual MR
Extracardiac annuloplasty
Mardil	VenTouch: compressive sleeve placed around ventricle	Transapical delivery; adjustable fluid chamber; proof-of-concept study underway; CE mark trial and Series C anticipated in 2016

Medtech Insight

Reproducing Annuloplasty

Millipede Inc. believes it may have an FMR repair solution that more faithfully reproduces surgical solid-ring annuloplasty. Backed by Santé Ventures, Millipede has flown under the radar since its 2011 founding by Steven F. Bolling, MD, a mitral valve surgeon at the University of Michigan, and veteran device engineer and current CEO Randall Lashinski, who also co-founded the TAVR start-up Direct Flow Medical Inc. and the cerebral-protection start-up Claret Medical Inc. The company’s patented adjustable mitral valve ring compresses to a slender diameter, then expands to anchor in the stretched-out native annulus and contracts to reshape it, reducing the anteroposterior diameter of the annulus. (See (Also see "Millipede's Play In Percutaneous Mitral Valve Repair" - Medtech Insight, 28 Jan, 2016.))

According to Santé partner James Eadie, MD, the device allows for future repair or replacement options, including a surgical annuloplasty ring. That means Millipede could target younger, healthier patients who may need further mitral intervention down the road. The company completed early first-in-human studies and is now “well on our way” to developing a 32 French (32F) transfemoral delivery system, according to Eadie. It plans to publicly release data in 2016.

Bolling says Millipede’s is the only therapy that brings the dilated mitral valve annulus back to a normal size.

Mitralign Inc.'s Mitralign System is an annuloplasty device for FMR delivered transfemorally. Rick Geoffrion, president and CEO, believes the system could make a good frontline therapy option because its small footprint keeps future options open for the relatively young FMR patient population.

The company presented six-month data from its now-complete CE mark trial at the 2015 Transcatheter Cardiovascular Therapeutics (TCT) meeting held in San Francisco in October. The 41-patient study found statistically significant postprocedure reductions in the size of the ventricle and mitral annulus, as well as significant improvement in patient symptoms. These were sick patients with an average preprocedure ejection fraction (EF) of 32.7%. Residual MR from grade 1 to 4 remained in all patients; the six-month mortality rate was 12.2% due to five patient deaths within 60 days. That percentage is “lower than that reported by competitive technologies in the FMR population,” Geoffrion says.

“We showed statistically significant remodeling of the heart at six months, which we believe is a more accurate portrayal of how the heart is functioning than the measurement of pure MR,” Geoffrion says. “You’re literally reversing the course of the disease.”

As it awaits CE mark approval for its mitral device, Mitralign is enrolling patients in its US IDE SCOUT Study to investigate tricuspid repair using its platform.

This October at TCT, the angel-backed company MVRx Inc. presented results of its ongoing CE-mark MAVERIC trial of the ARTO System (Septal Sinus Shortening); at 30 days, every patient was noted to have at least a one-grade reduction in MR. ARTO consists of a 12F transfemoral delivery system that places a polyethylene suture across the mitral valve in FMR patients, reducing its anteroposterior diameter and reducing MR. Co-founder, president and CEO Robert T. Chang estimates the trial will conclude in 12 to 15 months and anticipates CE mark in third-quarter 2017.

Chang says ARTO’s cost and simplicity make it competitive “for parts of the world that can’t afford MitraClip. We also think it can compete directly with MitraClip and others in this space.”

In preliminary discussions with reimbursement authorities in the EU – the company will begin more detailed discussions during the trial’s final phase – Chang has found that Abbott has already partially cleared the path. MVRx aims for acquisition or partnership, as it does not plan to build its own sales force.

Cardiac Dimensions Inc. earned CE mark in 2009 for its CARILLON Mitral Contour System, a double-anchored annuloplasty device that is placed in the coronary sinus via the jugular vein. Last March, the company announced a $43 million funding round led by Life Sciences Partners and Aperture Venture Partners. CARILLON is currently undergoing a prospective, multicenter, randomized, double-blind trial launched in June 2015 called REDUCE FMR.

HeartWare International Inc. in September purchased Valtech Cardio Ltd., which is developing Cardioband, a transfemoral annuloplasty device that allows for real-time reduction in annular diameter and MR in the beating heart. At TCT this October, Valtech presented the results of a single-arm multicenter study of 45 patients in Europe receiving Cardioband, all with moderate to severe FMR and all high-risk surgical candidates. At 12 months, 95% of the patients had MR at or below grade 2. There were two deaths deemed not device-related. Some insiders believe this device may be the repair-side frontrunner. (See (Also see "More Than Just A VAD Maker: HeartWare Broadens Heart Failure Focus With Valtech Buy" - Medtech Insight, 2 Sep, 2015.).) Editor's note: Heartware and Valtech terminated this deal in January 2016.

In addition to the developed markets, Phoenix Cardiac focuses on emerging markets like India and China where cardiac disease is on the rise. BACE – Basal Annuloplasty of the Cardia Externally – is a lower-cost approach developed for FMR by cardiac surgeon Jai Raman, MD, PhD, of Rush University Medical Center. The procedure requires open chest incision and has so far been studied both as a stand-alone procedure and also as a concomitant operation with cardiac bypass grafting. But with BACE, the cardiac surgeon does not open the heart itself, instead plastying of the mitral valve annulus near the atrioventricular groove is performed. The annular diameter can later be adjusted in an outpatient setting via subcutaneous saline ports placed in the flank. In addition to post-op adjustability, the BACE device provides sub-annular support.

Fourteen people in India have received the operation alongside CABG. CEO Gopal Muppirala says that the first patient, implanted in 2008, continues to have an MR of grade 1, the lowest grade, and that there have been no major device-related significant adverse events. The company is now halfway through a five-country CE mark study that commenced in January 2013. Its goal is CE mark in fourth-quarter 2016 or first-quarter 2017, and it plans to meet with the FDA early next year to start the IDE process.

Phoenix’s founders were originally part of Mardil, but left to start Phoenix Cardiac as a self- and angel-funded concern in 2012 to continue the development of the BACE device. They licensed global IP rights to BACE from Mardil. Muppirala says BACE will be premium-priced at a little higher than annuloplasty rings, a key differentiator he says may aid Phoenix to serve patients who cannot afford percutaneous approaches such as MitraClip, as well as offer US hospitals the chance to keep a larger portion of a Medicare reimbursement for mitral valve repair.

“It’s going to be very hard for someone charging $10,000 or $20,000 just for the device itself to get in” to markets such as India, Muppirala says. Similarly, devices requiring hybrid surgeon-cardiologist teams may be at a disadvantage in less wealthy countries, whereas BACE, he says, takes surgeons 20 minutes to learn. Phoenix will soon talk to US strategics in hopes of an exit after CE mark.

“People should be thinking about making the device development more surgical-friendly,” Muppirala says. “Percutaneous is not the only way.”

Enhanced Coaptation Technologies

Rather than mimicking surgical repair approaches, the German medical device start-up company coramaze technologies GMBH aims to create a mitral valve repair system for severe FMR patients that pioneers spacer coaptation technology. Delivered via the transfemoral artery through a 12F delivery system, the mitramaze valve repair system places a spacer balloon in the mitral valve that is atraumatically anchored in the left atrium. The mitral leaflets close around the spacer balloon, closing the gap in the mitral valve. With a less-demanding delivery system that involves no suturing or clipping, says CEO Laura Figulla, PhD, the process is intuitive for cardiologists. “That is definitely something that will be important for market penetration, because not every hospital has a hybrid room,” she says, referring to an operating room designed for both interventional cardiologists and surgeons.

coramaze announced a €4.5 million Series A round on September 1, led by Israeli holding company Elron Electronic Industries Ltd. The funding covers a first-in-human study.

Employing a variant on this technique is Cardiosolutions Inc. This start-up’s device for FMR patients, Mitra-Spacer, consists of a transapically delivered (through the tip of the ventricle via the chest wall) balloon placed between the anterior and posterior leaflets of the mitral valve. The partially filled Mitra-Spacer balloon, which is tethered at the ventricular apex, then conforms to each leaflet, enabling them to seal against the balloon. The balloon’s size can be adjusted in an outpatient setting via a subcutaneous injection port, allowing for a gradual rather than abrupt reduction of MR.

“You don’t change any of the anatomy of the native mitral valve,” says John Wilson, senior technical director of clinical operations, who adds that the device could bridge a patient to future repair or replacement. (He should not be confused with Jon Wilson, the company’s former COO.)

Wilson says Mitra-Spacer costs about $150 to make, will be “value-priced” and will be attractive in an era of outcome-based reimbursement because it could keep patients from returning repeatedly to the hospital.

Contingent on funding, the company plans a CE mark trial in Europe in first-quarter 2016. Its IP relates to adjustability and tethering, and it shares some licensing with Edwards, which is pursuing a similar balloon strategy with its Forma device for the tricuspid valve. (coramaze holds tricuspid-related patents as well.)

Ventricular Reshaping

Whereas most repair and replacement approaches to FMR focus on the valve itself, Mardil Medical treats the dilated ventricle, which is the primary cause of FMR.

The company’s implantable device, VenTouch, is a woven sleeve that surgeons place around the beating heart through a small incision between the ribs. The sleeve helps reduce wall stress and “helps the heart to repair itself and result in a smaller size and improved shape,” says CEO Jim Buck. VenTouch also includes a prescriptively positioned adjustable fluid chamber, which is inflated to bring the leaflets of the mitral valve back together and further reduce the severity of the MR. (See (Also see "Mardil Medical Inc." - Medtech Insight, 21 Mar, 2014.).)

“We think the battle will be fought and won around improving heart health, not just reducing the regurgitation,” says Buck, a medtech veteran and the former CEO of SetPoint Medical Corp.

Winning that battle, according to Mardil’s estimates, could mean a US market as large as $3.2 billion.

Mardil builds upon the ideas and IP of several previous companies, including Acorn Cardiovascular Inc.and Myocor Inc., whose Coapsys ventricular-reshaping device demonstrated improved survival in a randomized study of FMR patients published in a 2010 Journal of the American College of Cardiology paper. The company currently holds about 100 patents in the US and Europe. The first patients received VenTouch in February 2014 in Malaysia, with what Buck says are “compelling results,” and now Mardil is in the midst of a proof-of-concept clinical trial in Canada and the EU that it expects to complete next spring. Buck says the firm will raise a Series C round and anticipates beginning a CE mark trial in mid-2016, as well as applying for an IDE with the FDA. Sales could begin as soon as late 2017, he estimates.

Guided Delivery Systems Inc.is also developing a ventriculoplasty approach in which it cinches the ventricle and reportedly reduces the circumference of both ventricle and mitral valve annulus. The company presented a case report at TCT this October of a patient with heart failure and severe FMR whose severity was reduced from grade 3 preprocedure to grade 1 postprocedure. GDS said at that time that it was completing its feasibility trial.

MitraSpan Inc., a stealth-mode company that has raised a Series B round, is testing a version of suture-based annular and ventricular reshaping via a size 5F to 9 F transapical system. Co-founder and CEO Jonathan Rourke says the system allows surgeons to implant suture spans across the annulus and ventricular cavity, durably anchoring them within the heart in structurally sound locations and reshaping the mitral apparatus and adjacent ventricular structures for greater efficacy. Over 25 years, Rourke has held leadership positions at Viacor Inc., TransMedics Inc., EndoTex Interventional Systems Inc. and Hewlett-Packard Co.

DMR Repair: An Unusual Niche

Unlike in FMR, for DMR, there are already safe and effective surgical options. Still, there may be advantages to a less invasive approach, and some repair companies are aiming at this type of MR.

Harpoon Medical Inc. is first exploring a beating-heart, transapical repair option for degenerative mitral valves, one intended to replicate the gold standard but highly invasive surgical approach to chordal repair. Its Harpoon device allows for the placement and anchoring of neochords made of ePTFE and delivered via a 9F system. The chords contain a pre-tied knot. The device fires them through the mitral leaflet at high speed, then the knot emerges on the atrial side, securing the chord in the leaflet and then to the ventricle. The chords’ length can be adjusted under image guidance in real time, allowing for fine-tuning based on the degree of remaining MR. The device is the brainchild of mitral valve surgeon James S. Gammie, MD, chief of cardiac surgery at University of Maryland School of Medicine.

The company hopes its approach will allow for earlier referral of patients with severe DMR, including low-risk surgical candidates, and for later replacement or repair if necessary. It estimates a potential $9 billion US market segment. (See (Also see "Harpoon Medical Inc." - Medtech Insight, 25 Jun, 2015.).)

At TCT, Harpoon presented the results of a two-site European feasibility study in early 2015 that enrolled 10 patients with severe DMR and an average EF of 61%. Results at 30 days ranged from moderate to trace MR, with no mortality; perioperative complications included two perioperative reoperations for cardiac tamponade and one late reoperation for recurrent MR.

Surgeons can learn the technique quickly, according to Harpoon president and CEO Bill Niland.

Unusually for this space, Harpoon is aiming at low-risk patients as well. “We feel we can repair these same patients with as good as or close to as good a repair as open-heart surgery,” Niland says.

The company will conduct a six-site CE mark study, planned to begin in first-quarter 2016; Niland anticipates a CE mark by second-quarter 2017, at which point it will follow patients in a registry.

Harpoon, too, plans to begin a US pivotal trial late next year, according to Niland. “[The FDA has] been very good, pushing us to move toward our pivotal trial sooner rather than later,” he says. “They don’t want to see the big lag of TAVI in the US compared with TAVI in Europe [with mitral technologies].”

Harpoon’s chief competitor is Neochord Inc., which targets early and/or asymptomatic DMR patients in a transapical beating-heart repair; it replaced damaged chordae by attaching leaflets to papillary muscles with a suture. As reported in October at TCT, a safety and feasibility study of 30 patients led to one death from post-cardiotomy syndrome with sepsis and six reoperations for failed repairs. Neochord’s DS1000 is CE marked and in clinical trials in Europe.

In addition to repair device Cardioband and replacement device Cardiovalve, Valtech is also developing V-Chordal, a chord-replacement device for DMR.

Repair, Replace, Or Both?

Insiders agree that, due to the complexity of the mitral valve, multiple minimally invasive devices will share the space in the future, perhaps in a stepwise or combination fashion. But getting to that point may take a while, as big questions remain. Will repair or replacement dominate? Which route is best? For which MR patients will devices be indicated? (See Exhibit 2.)

Exhibit 3

Minimally Invasive Mitral Valve Interventions: Repair Versus Replacement

Minimally Invasive Mitral Valve Intervention	Pros	Cons
Repair (compared with replacement)	May allow future interventions	May not completely correct MR
	May allow ventricular remodeling	Recurrent MR
	Failure may have lower stakes
	Ventricular-repair options may treat root cause of FMR
	Some options inexpensive
Replacement (compared with repair)	Less recurrent MR	Large valves in FMR make transcatheter packaging technically difficult
	May correct MR almost completely	Large valves in FMR may limit beneficial ventricular remodeling
		Failure may have higher stakes
		“Patient for life,” requiring anticoagulation
Both, versus surgery	May carry usual advantages of less invasive procedures, including less pain, greater safety, shorter hospital stay	DMR patients already have effective surgical options
		Mortality benefit and indications unclear for FMR intervention, whether surgical or minimally invasive

Medtech Insight

FMR leads to a vicious circle of ventricular damage and heart failure, with the mitral valve itself not only an effect of that damage but an exacerbator. Beyond a certain degree of heart failure, it’s not clear how much recovery the ventricle will undergo even after a successful mitral repair or replacement.

“The question of ‘repair/replace/do nothing’ has been raging in the surgical community for decades, even before consideration of catheter-based therapies,” Rourke says.

“If you take myopaths [patients with weakened, dilated heart muscle] with a lot of MR and just repair the valve, no one’s ever been able to show any mortality benefit,” says William E. Cohn, MD, a Texas Heart Institute cardiothoracic surgeon, device-industry veteran and venture partner with Millipede backer Santé Health Ventures. “Now people are saying, ‘Well, we should just replace the mitral valve in these patients instead of repairing them,’ … but that’s not been shown to have a big mortality benefit either."

“The only technology that I’m aware of that really showed a mortality benefit in these big dilated ventricles with bad MR is the Myocor device,” Cohn continues, referring to the now-defunct company whose Coapsys device consisted of a cable threaded through the heart that pulled the ventricle in on itself slightly. (Mardil inherited Myocor’s IP.)

Bolling, the mitral-valve surgeon and Millipede founder, also points out that in FMR the ring at the base of the valve, or annulus, gets so stretched that any replacement valve necessarily is much larger than a native valve. By consequence, he says, “the ventricle is then not allowed to come back down to normal size,” referring to potential ventricular remodeling. (The degree to which such remodeling occurs in FMR after repair, at least, may become clearer from MitraClip’s randomized multicenter US clinical trial, COAPT.)

So, large strategic bets notwithstanding, it’s still unclear whether patients with large, dilated ventricles and FMR will benefit by replacing those regurgitant valves.

Heavy Stresses

A replacement mitral valve is under heavy stresses, Rourke points out, calling this part of the body a “merciless environment. ... Every time the mitral valve closes, the entire systolic pressure of the heart is trying to pop the mitral valve into the atrium,” he says. Some transcatheter mitral valve manufacturers like Tendyne Holdings Inc. employ supplemental anchoring devices in the ventricle.

Rourke cites concerns about catastrophic fatigue failure with the commonly employed device material nitinol and the risk of paravalvular leakage and dislodgement of replacement valves that hold themselves in place exclusively by grabbing the anatomy around the annulus (as opposed to being anchored in the ventricle).

“I think it’s very, very much in question whether that concept can soon be made to work with sufficient reliability and safety, given the early results,” Rourke says. “These valves have to stand up to the absolutely sternest possible performance requirement. I think in all this rush of enthusiasm, a lot of history has been forgotten.” In the 1980s, the early-generation Bjork-Shiley replacement valve suffered catastrophic fatigue failures in some patients.

“Three years ago … longtime mitral people looked at catheter-delivered replacement valves as this challenging bridge too far,” Rourke adds. “Now there’s all this investor-driven enthusiasm. ... [With] repairs, notably so far with MitraClip, you fail back to where you started. With replacements, you fail and you very often face life-threatening complications.”

Which Patients? How To Study Them?

Determining indications in FMR patients may take longer than overcoming technical hurdles, says Ted E. Feldman, MD, director of the Cardiac Catheterization Laboratory at NorthShore University Health System in Evanston, IL. With FMR patients, there is no consensus on surgical benefits. For TAVR, it was clearer which patients would benefit, he says, but even with a mature technology like MitraClip, “we’re still, a decade into it, arguing about who’s the right patient.” Similarly, Bolling, the mitral valve surgeon, believes that it will be harder to demonstrate a clear mortality benefit for these devices in FMR patients than it was in aortic stenosis patients; the sickest ones may die of other causes despite having their MR corrected. Yet many insiders expect regulators will require studies of FMR interventions to begin with this very sick population.

Raj Denhoy, a managing director and senior research analyst with Jefferies, says early data suggest less sick patients may do better, citing Tendyne’s experience so far with its transapically delivered mitral valve: “The general consensus was they were very good about picking patients that were not super sick.”

“With most of these devices, where you can help the most is if you could intervene earlier in the process and stop people from getting to Class IV heart failure,” Chang explains.

Some insiders say that the potential efficacy of early intervention argues for repair over replacement, as repair can be undertaken in younger patients and leave more options for future repair or replacement.

Also in favor of repair is a surgical saying: A patient with a replaced valve is a patient for life. Such valves often require anticoagulation and lifelong monitoring, whereas at least in surgical experience, a patient with a mitral valve repair can walk away and do fine indefinitely.

That said, residual MR dogs repairs. Shmuel Banai, MD (a stockholder in replacement-valve company Neovasc Inc.) of the Tel Aviv Medical Center told a TCT audience in October that many repair procedures – including MitraClip, Mitralign and Cardioband – leave the patient with substantial residual MR, whereas so far, transcatheter mitral valve replacement does not. He predicted replacement will become standard of care for high-risk severe MR patients.

An article in the New England Journal of Medicine in November 2015 reported the Cardiothoracic Surgical Trials Network’s outcomes of a study of 251 FMR patients randomized to either surgical repair or surgical replacement. At the two-year mark, there were no significant differences in a measure of left-ventricular recovery or clinical outcomes. But the repair group showed much higher rates of recurrent moderate or severe MR than did the replacement group – 58.8% versus 3.8%.

In July, a multidisciplinary group of experts, the Mitral Valve Academic Research Consortium, or M-VARC, published research guidelines for studies of transcatheter mitral valve therapies. Co-author and Columbia University interventional cardiologist Gregg W. Stone, MD, told a TCT 2015 audience that, for instance, DMR and FMR shouldn’t be studied in the same pivotal approval trial, and devices for DMR should be compared with surgery while devices for FMR should be compared with medical care or, perhaps in the future, MitraClip. Such standards should help researchers to clarify the many unknowns in this space.

How Long A Wait?

This multiple-device scenario for mitral valves isn’t just around the corner, but it may not be long now, either.

“These things could be on the market in a couple of years. Companies are pushing,” says Denhoy. He suggests a product could be approved in late 2017 for the European market.

Rourke believes the field will undergo steady but not exponential progress, with no pivotal studies of replacement valves in the US for at least two to three years. “There won’t be a Big Bang in mitral,” he says.

Cohn says, “It wouldn’t surprise me if there weren’t aggressive marketing battles in the mitral space in the next three years – unless of course the data’s no good.”

In September, Joanne Wuensch of BMO Capital Markets projected a replacement product on the market in Europe in 2017 and in the US in 2020.

In the meantime, repair and replacement companies alike are treading unknown territory, with the lamp of TAVR precedent shining perhaps not as brightly as some investors might believe. As Cohn puts it, “There’s tons we don’t know. We don’t know more than we know.”

This article is adapted from Medtech Insight. IN VIVO brings selected complementary coverage from sister publications to subscribers.