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Heartware: A New Era Of Mitral Valve Repair Valtech Cardio, Ltd. PCR London Valves

The following excerpt is from the company's SEC filing.

September 22, 2015

Transcript

Valtech Cardio, Ltd. PCR London Valves, Cardioband: A New Era of Mitral Valve Repair, September 22, 2015

CORPORATE PARTICIPANTS

Prof. Eberhard Grube,

M.D., Ph.D., University of Bonn, Germany

Dr. Michael Mack,

M.D., Baylor Scott & White Health, Dallas, TX

Prof. Georg Nickenig,

M.D., University Hospital Bonn, Germany

Prof. Alec Vahanian,

M.D., Bichat Hospital, Paris, France

Prof. Karl-Heinz Kuck,

M.D., Ph.D., Asklepios Klinik St. Georg, Hamburg, Germany

Dr. Frank Ruschitzka,

M. D., FRCP, FESC, University Heart Center, Zurich, Switzerland

Prof. Francesco Maisano,

M.D., FESC, University Hospital, Zurich,

PRESENTATION

Prof. Eberhard Grube:

I would like to announce a little change in the program. I think that Professor Kuck will demonstrate the results and Professor Nickenig will be talking, or demonstrating a case, so thats a little switch. Both are very competent, as you all know.

So, the background is, for this session, the treatment for functional mitral regurgitation is all about risk benefit. Low-risk treatment of this disease will allow to treat earlier and potentially affect the course of the disease. Effective treatment that avoids surgical risk will allow to treat more patients and reduce symptoms and improve quality of life, and lower the cost for the healthcare system, while reducing hospitalizations.

The goal of this session today is to get first-hand impressions from the leading users of this technology, evaluate the potential to perform this new procedure in your own practice, get the most updated results and see the benefit to your patients, and, finally, imagine and brainstorm together where this new treatment can lead us.

That sets the stage for the upcoming speakers, and I think, Mike, you are the first speaker. Dr. Michael Mack doesnt need any introductions, ladies and gentlemen. Hes one of the leading cardiovascular surgeons in this world, not only in the US. Its a particular pleasure to welcome him here in Berlin. I know you had a long journey, a tough evening, and a tough night, depending. Percutaneous Annuloplasty: Another Step Towards Surgical Standards. Mike, welcome.

Dr. Michael Mack:

Thank you, Eberhard, for that kind introduction, I think. So, what I would like to do is to set the stage for the remainder of the session here and talk about Percutaneous Annuloplasty: Another Step Towards Surgical Standards. My conflict of interest is I am the co-principal investigator of the COAPT trial of

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Valtech Cardio, Ltd. PCR London Valves, Cardioband: A New Era of Mitral Valve Repair, September 22, 2015

MitraClip. So, in order to do this, lets talk about what are the surgical standards that we are aspiring to, and I think you have to break it down into primary and secondary MR, because the treatment is very different and the outcomes are very different. So, lets talk about primary or degenerative mitral regurgitation.

Its a very heterogeneous disease from fibroelastic deficiency, on the left, to Barlows, on the right, and the way we approach this spectrum of diseases is totally different. For Barlows, on the right, we tend to resect tissue. For disease on the left, fibroelastic deficiency, we tend to whats called respect tissue and use artificial chords rather than resective techniques.

So, heres a patient thats more on the Barlows end of the spectrum. You can see that the P2 portion of the posterior leaflet, theres a flail chord there and a triangular resection of the leaflet is being performed. Its been sewn together, and its a very simple straightforward technique. However, with degenerative disease, almost all the time there is annular dilatation that occurs as a result of the disease. Now, this is artificial chords; this is the Leipzig loop technique in which we make a series of loops that we sew to the head of the papillary muscle, that you see on the bottom here, and then we can adjust the chordal length to whatever we need in order to restore coaptation.

Now, as a part of this procedurewe never do one thing in surgery, we do multiple things, and as well as addressing the leaflet, we have to address the annulus. There is annular dilatation that occurs in both primary and secondary mitral regurgitation. It is dilation of annulus, but mainly in the septal-lateral diameter, and so the whole idea behind an undersized annuloplasty is we restore coaptation after the mechanical problem with the leaflet is fixed by putting an annuloplasty ring in place. It can be either a complete ring or a partial ring, and partial rings we refer to as bands, and oftentimes in degenerative disease we will only use a partial band. The most common one is called a Cosgrove Band, after Dr. Cosgrove with the Cleveland Clinic.

Now, for the transcatheter approach to degenerative disease, we have two devices that are available to address the leaflet, per se, the MitraClip device and artificial chords by the NeoChord device. The MitraClip device is approved in the United States for degenerative disease only. In the guidelines, its a IIB recommendation, level of evidence B, based upon the EVEREST trial. The artificial chord technique at the current time goes through the apex, the edge of the leaflet is grabbed and artificial chords are placed and then sutured on the outside of the apex.

Where I potentially could see this going is, MitraClip works quite well for degenerative disease, but it doesnt correct the annular dilatation, and I could see very easily combining a technique of MitraClip or artificial chords with a catheter-based delivery of a posterior band and have a fully percutaneous repair, exactly the same thing we are with surgery. Now, the results are very good with MitraClip, why would you think of doing this? I think that those patients with leaflet disease that have significant annular dilatation, we could improve the MitraClip results even more by adding an annuloplasty to it.

So, lets talk about secondary functional mitral regurgitation, and I think, as everybody in the room knows, its not a disease of the valve, per se, its a disease of the left ventricle, and the mitral regurgitation is caused by apical lateral distraction of the papillary muscles and tethering of the leaflets. The idea behind a surgical annuloplasty is using an undersized ring to correct the annular dilatation that occurs secondary, and again occurs greatest in the septal-lateral diameter, and restore coaptation, but it doesnt do anything to change the primary disease of the ventricle. This is an example of a typical patient that we do surgically with functional mitral regurgitation and we can acutely and completely correct it.

So there have been multiple different surgical annuloplasty rings. The first one was actually by Professor Carpentier in 1968, and it was a partial posterior band. The second one was a Carpentier-Edwards Classic ring. The one we use most commonly now is called the Physio ring. This is an Etiologix, which was designed actually by Dr. Adams and McCarthy, specifically for ischemic mitral regurgitation because of the increased annular dilatation in the P3 area. Then, lastly, we have the Cardinal device, which is an adjustable ring placed surgically, that you can dial in the degree of coaptation that you want.

So, theres a lot of debate in surgery regarding complete versus incomplete rings or posterior bands. This is an article in 2010, from Israel that looked and showed that the recurrence of mitral regurgitation is less with a complete ring as compared to a partial ring.

Now, what we look at the role of surgery in this, and we see that for chronic severe secondary mitral regurgitation the recommendation from the guidelines is a IIB recommendation, level of evidence B. However, the problem is that this is very seldom utilized. So, in the United States, in 2014, there were a total of 450 isolated mitral annuloplasties performed. So, even though its a IIB recommendation, the problem is we dont utilize it much in the United States, because its very invasive treatment and its uncertain that it has any benefit.

Now, we did undertake a trial in the United States, under whats called the CTSN, Cardiothoracic Surgery Network, which is a National Institutes of Health funded trial, and we found that replacement provided a more durable correction of mitral regurgitation than repair in severe ischemic mitral regurgitation. This was the result at 12 months. There was a 32% recurrence rate with repair and a 2.3% recurrence rate with replacement. However, in a sub-group analysis of this, if we look at the patients that were repaired that had recurrent MR, left ventricular remodeling did not occur. So, the main left ventricular end systolic volume index stayed the same. However, if a repair was successful, you can see that theres positive ventricular remodeling, even better than replacement, if you couldnt reliably do a repair that doesnt reoccur, and theres been a lot of work done of sorting out who those patients are, and Ill talk about that in just a minute.

Now, there was work done prior to this by Prof. Dion that actually says you can cure ischemic mitral regurgitation by restrictive mitral annuloplasty, and if you have a left ventricular end diastolic diameter of less than 65 millimeters, the results are actually great with a mitral valve repair. This shows the survival of patients that had smaller ventricles compared to larger ventricles in both left ventricular end diastolic and systolic volume. So, in other words, if the patients are treated before the ventricle is too dilated and the leaflets too tethered, the results of repair are great.

Now, the COAPT trial in the United States, I think is going to inform this field significantly. Theres never been a randomized trial of surgery versus medical therapy, and thats part of the reason we dont know whether surgery works or not. So, this is the COAPT trial, which is 420 patients randomized between medical therapy and the MitraClip. As of this month, there have now been 278 patients randomized at 84 sites in the United States. As you can imagine, its a very difficult trial to enroll, but hopefully by early next year this trial will be completely enrolled and we will be able to inform the field whether correcting mitral regurgitation, this disease, makes a difference compared to medical therapy.

Now, we do have a lot of transcatheter options. Theres been two devices that are CE mark, one in 2011, a coronary sinus device, and then the Cardioband direct annuloplasty device has recently received CE mark. The Cardioband device is a surgical band delivered by a transfemoral access route. Its implanted in a supra-annular position, the exact same way we do it with surgery, and then theres controlled adjustment at the end under echo guidance to correct the mitral regurgitation and cause coaptation of the leaflets again. You can see on the top the baseline mitral regurgitation and then, again, the total correction of it afterwards.

Now, if we look at the preliminary resultsand Im not going to spend any time with this because our other speakers are, but you can see on the left the Cardioband results in 17 patients and the degree of residual mitral regurgitation at one year afterwards compared to multiple surgical series at one year, and I think that the results are actually quite comparable. I must admit theres a couple things that I never thought would work. MitraClip was one of them. Two is I didnt think Cardioband was going to work as well as it is, because in surgery we just believe that you have to do complete rings, but these results are much better than I would have predicted.

So, we now have had a lot of movement in this field over the last eight weeks. There have been three transcatheter valve replacement devices that have recently been bought, as well as one mitral repair device. So, over these four companies, theres been $2 billion spent in the last eight weeks for these four companies. So, theres a lot of movement in this field happening right now and itll be interesting to see how this is sorted out. So, theres a lot of money that says, yes, correcting mitral regurgitation is going to make a difference in this disease.

So, how are we going to sort out repair versus replacement? Well, I think we know from the randomized trial in the US, as well as multiple other series, that repair is better than replacement under certain circumstances, and if theres a coaptation depth of less than one centimeter, a tenting area of less than 2.5 centimeters, a smaller left ventricle, less tethering, defined by anterior and posterior tethering angles being less, all of which I think will respond quite well to a repair technique. Anybody thats more severe with that, I think weve learned from the surgical series that they do tend to recur; the recurrence rate is always about a third at one year, and I think those patients may be better off treated by replacement.

So, why is the benefit of mitral regurgitation so hard to find? Well, theres multiple hypotheses. One is that the recurrence rate is at least 20% with surgery and theres a significant operative mortality in these patients, so it may be that were obscuring any benefit from this. Secondly, maybe there is no benefit, maybe mitral regurgitation is just a surrogate marker and not causally related to the outcome of the disease. Thirdly, maybe the benefit is limited to specific patient sub-groups that have not been well predefined in the current data sets, so maybe its the etiology of disease. I think it may well be that ischemic and non-ischemic cardiomyopathies are different diseases that are going to respond differently. It may be the duration and the severity of MR, how bad the ventricle is, the functional class.

The way I see the state-of-the-art right now, its like taking a group of patients with anemia and treating them all with B12, and its hard to pick up a signal of benefit. Indeed, its only the patients with pernicious anemia that are going to respond. So, I think that because we havent got a signal there, its like Vitamin B12, we cant say that it doesnt work because we havent defined the pernicious anemia here. Lastly, theres no randomized trials with appropriate controls and core lab assessment of mitral regurgitation; COAPT will be the first, and I think that will not only be specific to the MitraClip device, but will significantly inform the whole field.

Thank you very much.

Prof. Karl-Heinz Kuck:

Mike, I just may have one short question for you. The advantage and potential disadvantage of surgery is that at the time of surgery you have to fix as much as you can fix. So, you mentioned that you have to do the annuloplasty plus, if necessary, any intervention on the leaflets, the chords, or whatever. Now, the potential advantage, or again disadvantage, of an intervention procedure could be, particularly in patients with secondary disease, that you could implant the annuloplasty ring first, see how things develop over time, and then in a secondary step, if things are not moving in the right direction, then do an additional either clipping procedure, or whatever will come in the future. So, that could potentially lead, because you are doing it sequentially, to a reduction of this mortality that you were addressing in surgery, and if the result from an efficacy point of view would be similar to surgery, then the benefit that you are questioning as a potential mechanism, because of the initial high mortality, could be shown in such a patient population, was that something that you would follow?

So, I think absolutely, yes. So, Id say theres two disadvantages of surgery. One is we do the repair techniques in a non-hemodynamic situation. So, were fixing it and then were checking it afterwards, and if its not right we have to go back and redo it. The transcatheter technique, youre fixing it under real-time monitoring, which is a difference.

The second isas youre saying, we kind of have one shot to get it right and we cant do staged procedures, like youre suggesting, and I think that that is a good approach, and I think we will sort out who best is treated which way. I must say, I dont pretend to know which way this is going to sort out, but you could, as you say, do an annuloplasty first and then come with a leaflet technology, like MitraClip, afterwards, or do a MitraClip first and then, if it tends to recur, then do an annuloplasty afterwards

Male Speaker:

Or at the same time.

Dr. Michael Mack:

Or at the same time. Or, thirdly, you could do an annular repair first and then, if it tends to recur, then on down the line come with a transcatheter mitral valve replacement. So, I think the whole choreography of how these procedures possibly could be staged is a wide open field.

Thank you. Thank you so much. So, were going to proceed and I think now Georg Nickenig is ready to show a case of a Cardioband procedure, but before he does I just would like to mention that, again, I think the fascinating issue of this Cardioband procedure is that its the first technology, that at least Im working with, that really shows in a consecutive series of patients that you really can achieve what the goal of an annuloplasty procedure is; that is, to reduce the septal-lateral diameter. I think that Georg has a nice case to share with us where he can prove the concept. So, Georg, please.

Prof. Georg Nickenig:

Thank you, Karl-Heinz. I hope I can. The Company uploaded the file. Oh, okay. So, I think we have done like 14 cases, and I think the first three cases together with you, Francesco, or something, and the last 10/11 cases, and this is one of the cases. I have a very easy job, I just have to listen to the movie.

(Video presentation transcribed)

Prof. Georg Nickenig:

Hello, everybody. This is the cath lab from the University of Bonn. On the right side is Prof. Vanna (ph), there is Dr. Hammerstingl in the back on the echo machine, and my name is Georg Nickenig, and we would like to show you today a Cardioband procedure.

Its a female patient, as you can see, with a very extensive past medical history, suffering from arterial hypertension and ischemic cardiomyopathy. She suffered from myocardial infarctions between 2010 and 2012, and finally she underwent a CABG procedure in 2013, with a single LIMA graft to the LAD.

The imaging studies showed in the echocardiography a severely impaired left ventricular function, with an ejection fraction of 25%, and whats most importantly for this case, today, a severe mitral regurgitation, as you can see on the numbers, PISA 0.7, ERO 0.5, and the regurgitation volume 55 ml per beat, which is quite a lot for a functional mitral regurgitation.

Christoph, I can hand over to you.

Dr. Christoph Hammerstingl:

You can see a long axis here of the left ventricle and the mitral valve, and what you can see is that the left ventricular function is poor. She has this acuteness of the anterior wall and what you can see is the patient suffers from severe functional mitral valve regurgitation. If you switch over to the intracommissural view, we see that its brought a central jet of the mitral regurgitation located between P1 and P2. We have two accesses at the moment, one arterial access. This is important for later on, to see how the first and second screws may affect the circumflex artery. We have another venous access for the transseptal puncture, which you can see now in progress.

We are supposed to be very inferior and very posterior. We can show the echo procedure, where you can see that we are kind of on the posterior side. Maybe you can also measure the distance to the mitral valve. So, 3 centimeters3.2 centimeters was the distance we should have.

We can place the coronary catheter once we have heparin on board. So, this is the guide catheter, its called TSS, and it is 24 French, comparable to the systems which we use, for example, for the Evalve procedure, get it through the septum, so we have to aspirate at the same time in order to avoid any emboli. Now we connect the system to the stent. This is also readily done. Middle of the valve is fine. And like this, okay. Now, we have to flush the system and then advance it into the TSS.

Yes, its good, yes. So, you have anterior of the commissure.

On the fluoro, up front, first, we placed the TSS, which is the guide catheter. Thats the blue one here, in 24 French. Now, we have a second catheter, the GC, the guiding catheter for the Cardioband, which has been placed in the guide catheter, and obviously now we have to aim to the first positioning, which is at the P1 side of the valve, and as far as we can, we would like to place the first screws anterior of the commissure, and we are aiming to place two to three screws in this area, in order to get really a tight and stable adherence of the Cardioband to the annulus. I think we are nicely in place already for the first screw.

We do have an (inaudible) catheter sitting in the left ventricle, which helps us to orientate the system. You can see that on the fluoro. You can see that also on the 3D echo.

Yes, this is a surgeons view of the mitral valve. The aortic route is here, the anterior valve leaflet opening here, and the posterior mitral valve leaflet here. This is the commissure. In relation to the aortic route, the catheter is between the commissure and the aortic route, so we are anterior of the commissure, and we do not touch the leaflets of the valve.

Now, we have to check the depth of our system. This is an echo-driven procedure.

So, we have a bi-plan view of the annulus. On the left side, you cant see the mitral valve opening, but on the right-hand side you see a modified intracommissural view, and what you can see on this view, you see the catheter and the spool which is moving. The catheter is stable. Here are the mitral valve leaflets and here is the hinge point between the annulus and the mitral valve leaflet, and we are 4 to 5 millimeters away from the hinge point, and the angle of the catheter to the annulus is approximately 90 degrees, so we wanted to place the first hinge point.

So, this looks like a perfect positioning. What you also could judge here is that there is a separation between the spool, I will move it intentionally, and our guiding catheter, which is the most distal part of the catheter system, where you have this marker, this opaque marker, and you have the separation showing you that the spool is sitting on the annulus, and we are right, with our GC, right on the spot. So, Im going to stick to this system. Now, were going to place the first screw.

You see this screw here?

It looks good, right?

Dr. Christoph Hammerstingl:

It looks good, yes.

Okay. So, we are all agreed with the positioning of the screw, and then were going to release it. Yes, release.

I have to release the fabric.

You can see that this marker is to the proximal part of the catheter, which shows us that we released some of the Cardioband. So, what we check also is the vicinity of the circumflex artery. Sometimes we can be very close to it. We can visualize it on the TOE. Maybe you can also give us a clue where the circumflex artery is, Christoph? But we always do a fluoro at the same time. We have at least one centimeter of room to the circumflex artery right now. Even if you would screw through the circumflex artery, usually you can just unscrew the artery and everything is okay and reposition the system. So, we are confident that this is the right position.

In order to show that the system is really nicely attached to it, you can see on the fluoro, but you can also visualize it on the echo screen.

The movement of the annulus here

Oh, yes, wonderful. Now, were going to place the third screw. I think, from the fluoro, the positioning looks already nice. As I said, we

The positioning looks good here on the commissural side of the mitral valve. All three screws are close to each other and the trajectory, if you look in 3D, the trajectory looks still perfect.

Prof. George Nickenig:

Now, we have placed all the screws, you can see it nicely on the fluoro. Maybe you can show both screens, one after the after, the 3D echo image. So, now we have to get rid of the GC, which provided us with the Cardioband, and then we have to start with the cinching process.

If you look at the fluoro, now we have placed already the SAT. This is now before cinching. You can see nicely the MR with a regurgitation volume of 55 millimeters and a PISA of 7 millimeters. So, were going to start the...


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