Dr. Thomas Nero discusses current therapy with Factor X inhibitors, the new research with Factor XI inhibition and specifically the enrolling Milvexian clinical trials with Dr. C Micahel Gibson. In addition they discuss, the addition of these medications along wiht anti-platelet therapy, Lp(a) and other interesting current and future research in cardiovascular disease.
Dr. Thomas Nero discusses current therapy with Factor X inhibitors, the new research with Factor XI inhibition and specifically the enrolling Milvexian clinical trials with Dr. C Micahel Gibson. In addition they discuss, the addition of these medications along wiht anti-platelet therapy, Lp(a) and other interesting current and future research in cardiovascular disease.
[00:00:00] Dr. Thomas Nero: Good afternoon and welcome to Future Pulse. I'm Dr. Thomas Nero today we have the pleasure of discussing Factor XIa inhibitors with Dr. Michael Gibson. Dr. Gibson is an interventional cardiologist, a cardiovascular research and educator. He's the CEO of the Baim Research Institute at Harvard Medical School.
He has offered thousands and thousands of papers on clinical trials in interventional cardiology, preventive cardiology, public health, and has studied anti-platelets, anti thrombotics, , Statin therapies, device trials. , there's almost no part of modern cardiology that Dr. Gibson hasn't touched. , in addition, he's the founder of Wiki Docs, , and is an accomplished painter.
, and mostly, , I'm just grateful that you had time to speak with us today.
[00:00:49] Dr. C. Michael Gibson: Most of all try and be a good dad, but thanks,
[00:00:52] Dr. Thomas Nero: We're all trying to do that. I think some are better than others. , but it's a daily struggle, isn't it?
[00:00:57] Dr. C. Michael Gibson: it is.
[00:00:58] Dr. Thomas Nero: Today we're gonna be focusing on factor 11 A inhibitors, and specifically the axian clinical trials, uh, for atrial fibrillation and acute coronary syndromes. , just to bring every one up to speed, what do you find so exciting about the factor XIa inhibitors?
[00:01:14] Dr. C. Michael Gibson: Well, we've had a pretty good run over the past few decades, , largely. In this little space of blood clotting driven by aspirin. You know, aspirin when it came along, , reduced mortality by 40% when combined with the thrombolytic agent. That was a big, big advance. , and it's been a great drug.
And then we had a period where people like you and I were putting stents in. And aspirin really wasn't enough. And we added in , the thienopyridine , that, , also work on the platelet. And that has been pretty good. An emphasis on the pretty good part. The sad part is we still have about 10% to 15% of people dying or having a heart attack or a recurrent stroke.
A year after their first event, and that's this far too high. , there's about 800 heart attacks a year in the US and about, , 20, 30% of those are recurrent heart attacks. So we have a lot of repeat customers out there, and we have an unmet need. One way we could reduce those is by adding, not another anti-platelet, but an anticoagulant.
And the platelets are held together by fibrin strands. , think of it like tinker toys. The platelets are the round thingy, and the straight thing is like the fibrin. And if you wanna really knock a clot out, you could attack , both parts of the Tinker toy. So we're gonna attack those girders by blocking them and you know, will it work?
We've tried it several times before and it worked every time. , certainly if you come into the hospital with a heart attack, you are gonna get an anti clotting drug like heparin. . And why not give one of those drugs when you leave the hospital? The problem has been, yes, we reduce mortality by giving anticoagulants in, the three trials after people leave the hospital, but there was more bleeding, and the goal is to reduce those heart attacks and strokes and deaths, but to do it safely.
And that's where factor XIs come in. , people are familiar with hemophilia. Well, there are really some dangerous types of hemophilia that we think about, but then there's some very, very mild forms where people don't really bleed. But what they have is they don't have strokes and they don't have as many arterial events.
And that's what we're trying to do. We're mimicking the biology of these kind of mild forms of hemophilia with an eye, towards reducing the number of heart attacks and strokes, but doing it safely. And that's why we're so excited. And some of the early data from this field shows that, um, if you have a knee replacement, And you get one of these factor elevens, you reduce your risk of a blood clot, good news, but you also do it more safely.
. So that's the freed lunch we want. We want reducing the bad blood clots that form in your bloodstream, but allowing the good clotting that keeps you from bleeding to death to continue.
[00:04:43] Dr. Thomas Nero: As we bring patients outta the cath lab, , we're usually on dual antiplatelet therapy and there's been a lot of discussion about the utility of dual antiplatelet therapy . And , what are the big questions? All of us as interventional cardiologists have is how much time you're going to spend on due antiplatelet therapy.
, do we continue them on for one month, three months, six months, 12 months? And with acute coronary syndromes, we're really leaning towards six to 12 months because of increased, , thrombin activity in patients acutely. , do you think that, , this class of drugs will do better with that. And going back to, , one of the other trials, , that you were very closely involved with the ATLAS trial in factor X inhibitors. Then do you think that this will improve upon those outcomes? , with less cost? And when I say that, I mean cost of pleading.
[00:05:34] Dr. C. Michael Gibson: , that's a great question. , lot of moving parts here, right? There's aspirin, there's thienopyridine like clopidogrel and ticagrelor and prasugrel and there's all these different ways we combine them with an anticoagulant. , I've tallied it up before, particularly , if you have AFib. There's about 2.2 million combinations of all the drugs we have and.
Things are changing very quickly, as you said. , we used to think you had to give these drugs for six months to a year after you acute coronary syndrome, but some of the more recent data suggests you could pull back to three months, perhaps even one month of, uh, dual antiplatelet therapy. The results are very provocative.
You definitely get less bleeding, no doubt about that. None whatsoever. , but I have to say. In terms of, to be intellectually honest, they were somewhat underpowered. They were a little too small to make sure that we weren't doing harm in terms of recurrent MI and stroke. Now, certainly there was no big safety signal there that we were increasing those ischemic events, but , as a trialist, I wouldn't say we're absolutely certain about, missing some efficacy events?
On the other hand, I also have to say there is a patient attached to the stent. , we wanna keep the stent from thrombosis, we wanna do it safely, , and we wanna do it without bleeding. On the other hand, We're not just treating the stent, we're also treating all those other plaques that they have that are at risk of rupture.
, and that's secondary prevention, not just preventing stent thrombosis. So every patient's different and we have got to, , decide, , is this person at high risk of bleeding? In which case we might shorten the. Dual antiplatelet therapy to a month, , or is this person at high risk of ischemic events?
They have a left main stent or , a whole bunch of stents or clot where their stent was, or complex bifurcation disease, in which case that might push us towards six months or 12 months. , so it is , an individualized decision for each patient, but the hope. And the aspiration of this class of drugs is we could get rid of the bleeding.
, we often talk about number needed to treat. How many people would you need to treat to prevent an event? We often talk about. NNH number needed to harm. How many would you need to treat to cause a bleeding event? But I like to say in interventional cardiology, we look at the N N B, the number needed to blame.
, and we really take it personally. If someone bleeds, , the person doesn't come into your office saying, well, you know what? Thank you for preventing that heart attack or stroke or death. That never happened.
They don't know about that. What they do know is they've had some, some gum bleeding or maybe a nose bleed, and it's very manifest. It's obvious. So the side effects are. Manifest, but the events we prevent are not there. And so there's this asymmetric battle in our patient's mind and our mind about the benefits.
So if we could cut down on the bleeding, we would probably have greater adoption of all these strategies. It is interesting, you know, bleeding and effectiveness are related to each other because if you bleed a lot, you're not gonna get effectiveness because people are gonna stop the drugs. So the safer we can make them, Probably the more effective we can make them as well.
[00:09:07] Dr. Thomas Nero: , , and you will only know when we're wrong if we stop the medication earlier and they have another event. Well, clearly we should have kept it on longer, , if we keep it on long enough so that they have a bleeding event.
Well then that was too long. Which is one of the issues with the new class of medications, with their marked decrease in bleeding, or at least phase two trial, showing marked decrease in bleeding, , that they really have an opportunity to change the way that we're looking at both.
Interventional cardiology , and also with atrial fibrillation, , once you get the bleeding risks down to the 0.5% rate or below, then you really have to start rethinking the way that we're gonna be adjudicating who gets these medications, right? Do we give them to CHADS-Vasc 1 patients, or even CHADS-Vasc 0 because they're not without events.
, do we then eliminate the use of left atrial occlusion devices like Watchmen, because. They're on in order to decrease the risk of bleeding. They don't dramatically decrease the risk of, , strokes. It's the bleeding benefit that we're getting from them. So do we just stop that whole pursuit, because we don't require it anymore?
, and are we going to get, , multiple different effects from these agents, from the decreased thrombin generation that's they'd have fewer cardiac events, , non- stroke events.
[00:10:27] Dr. C. Michael Gibson: Yeah, , It's interesting , the device side continues to evolve, you know, just like the drug side. And so on the watchman side, there will be new coatings, , that are less thrombogenic, , that heal quicker and re endothelialize quicker, , and have a reduced thrombotic risk. For those people who are particularly high risk of bleeding, we might see some interesting combinations of, a drug like a factor XI inhibitor along with a watchman device.
The factor XI inhibitors block that side of the clotting cascade that's triggered. By foreign substances like a Watchman device. So it might be a nice, uh, marriage, but , it's gonna take data to sort, all of this out. You mentioned an important point also is the chronic risk, particularly over in the a c s side, when you have an a c s event, your platelets are really angry.
, and then they calm down over about 30 days, and that's part of why we can deescalate on the anti-platelet side. But what we do know is that over on the thrombin side, people who have a c s events tend to have elevated levels of thrombin out a couple of years. So it's a chronic. I, I, I don't wanna overstep it, but it's a little bit like a chronic risk factor.
Some people's rheostat on the clotting side is turned up. I like to say thrombin is the new cholesterol. And the other thing people don't realize is thrombin is the thing that makes your platelet, the angriest that activates it the most. And what people don't realize is that aspirin, clopidogrel, ticagrolor prasurel none of them.
None of them block your platelet getting activated by thrombin. So it's an unchecked pathway,
[00:12:18] Dr. Thomas Nero: we've been using, , and to my opinion, not using quite enough rivaroxaban, , in patients with, with, , chronic coronary artery disease, , as per the ATLAS trial, which you were involved with. But my understanding is that the factor XIa inhibitors decrease the thrombin generation, , significantly more than the factor 10 inhibitors.
Without having the risk of bleeding that the factor 10 inhibitors, , currently have. , do you have a feeling why the factor 10 inhibitors are not utilized quite as much for chronic coronary artery disease? Have you have great data from the Atlas trial and, and it's written?
Yeah.
[00:12:54] Dr. C. Michael Gibson: End into the Compass trial and another drug that worked in a similar way Vorapaxar in that study where you blocked thrombin binding to the plate, that also reduced events. So that, along with the other Atlas study, TIMI 46, there's four trials that show a benefit. sad thing is, I think was characterized by some of the.
Competitors in a way that was probably not fair. Yes, there was an increased risk of bleeding what was never taken into account is the fact that it was over two years, not one year. The risk of bleeding accumulated over two years, so you kinda have to cut that risk in half. So we had a 1.2% increase in major bleeding, but on an annualized basis it was 0.6%. And that 0.6% is the same increased risk of bleeding that see with Ticagrilor and probably less than Prasugrel because Prasugrel had fatal bleeding. So, you know, the. The Ticor people got out ahead of it. They said the risk of bleeding's tripled, you know, but when you characterize it in absolute terms and do it on an annualized basis, it was the same as ticagrelor.
But you know, perception is as important as reality. And it was probably out in my 35 year career in research was my single biggest failing and, and saddest thing. This was a good drug. It could have done good things but I think we can further improve on it, with the factor XI strategy.
, the problem with Reva is it blocked some of the pathway that leads to the good clots. The clots that you prevent you from bleeding. The thing about the factor 11 is it's more potent. Against the bad clots that form in your arteries that cause a heart attack or stroke. So there's an interesting positive feedback loop that they block.
, thrombin causes the factor 11 to go up, which causes the thrombin to go up. So it's a positive feedback loop that this factor 11 plays a role in. We're gonna block that and that is going to reduce the Bad clots selectively. And you'll continue to form the good clots over on the other side of the pathway.
So it's the ideal strategy, you know, and you know, as I son, I told my son about this. He's a quantitative genomicist, and I, he asked, you know, what are you up to dad? I said, well, you know, we're gonna do these big trials, this factor 11 inhibitor, and. I don't know if you have sons that age, but he rolled his eyes in the back of his head and he said, come on dad.
You know, when are you guys gonna stop these trials? Let me show you something. Dad, let me walk you over to the uk Biobank. And he logged on and within five minutes he had the day he said, he just said, huh. Maybe you're right. You know, these factor 11 deficient patients, they don't have strokes and they don't have venous clots, so maybe you're onto something.
I said, oh, well thanks, thanks. You know, that's, that's why we're enrolling 50,000 people in this trial. , he said, , Nature has already done the randomized trial. Nature randomized some people to factor 11 deficiency and other people not. And in that randomized trial there was a reduction.
And you know, the other thing is these are lifelong risks, not just a year or two. So, if my son's optimistic, he's quite skeptical. I guess I need to be optimistic too.
[00:16:19] Dr. Thomas Nero: When you did the, , Riva trials they were all with an antiplatelet on as well, either aspirin and or a Thienopyridine. And now in patients with atrial fibrillation after stenting, there's been some discussion about whether long-term you need to be on a factor 10 inhibitor.
And an antiplatelet agent , my personal feeling is that they probably don't there is an increased risk of bleeding when you put them all together. Together. But when you look at it mechanistically, there may be some benefit of having both on board. If you had to predict with the factor elevens?
Do you think that a dual. Pathway, antithrombin antiplatelet is going to be beneficial, or do you think that there's going to be rarely where we're getting almost all the, the benefit from the factor 11 inhibition and not require long-term antiplatelet.
[00:17:07] Dr. C. Michael Gibson: Yeah, nature's pretty smart. I mean, nature has a lot of redundancy, a lot of ways to trigger clotting. I'd hate to depend on any one pathway, but what is interesting is there is a prize fight that continues been going on 20 years now between aspirin and clopidogrel and you know, Clopidogrel is one twice now in several big studies.
Doesn't have the same GI bleeding as aspirin. So you'll have probably, I think if. If you look at some of the upcoming guidelines, they will incorporate some of the post exam trial data along with, you know, some of the earlier data from the nineties from Capri, and show that, probably a safer alternative chronically than aspirin.
So someday I think we'll be looking at a combo probably of a thienopyridine clopidogrel is generic, very inexpensive, and probably, , if this. Factor 11 strategy successful. That might be the other choice, that probably would be safer than what we've done in the past.
[00:18:09] Dr. Thomas Nero: So there's multiple different factor 11 inhibitors that are coming down the pike now. I believe there are four or five that are moving from phase two to phase three clinical trials. They're, they each have some slight different aspect to them. One of the things that I find extremely interesting is patients with renal insufficiency and whether or not we can be giving them safely in patients with renal insufficiency and specifically in patients with who are on hemodialysis.
Because none of the current factor 10 inhibitors have been looked at in those patients. Whereas we know that they both, they increased fibrin degeneration. They have an increased thrombin degeneration, they have increased bleeding, they have increased events. It's a disaster, but we don't have a lot of good data .
And I think that some of the trials may be looking at that including some of the Milvexian trials that you're involved in.
[00:19:03] Dr. C. Michael Gibson: Yeah, , there's a lot of different ways you can inhibit factor 11. There are some drugs that are given subcutaneously that lasts for a month or two. That's the kinda. One for the road shot. You know, you've been hospitalized you've had some kind of event and you know, you just give this person a shot and they go home.
There's some, uh, there's some beauty in that. That's, that kind of strategy might be very well suited for a medically ill patient who's just, you know, been hospitalized, has risk of venous thrombosis, goes home over on the a ACS side. We have a few entrance in that area. Milvexian along with, the Bayer compound or both competing in that area , but.
Bayer has tabled their, their product right now. So I'm not sure where they will go. On the stroke side, you have a couple of entrances both from Bay and again, BMS, J&J both have horses in that race, as it well in the AFib race, you bring up the renal area, which is a very high risk area. You know, one of the problems in the renal side is they're not, you ask a nephrologist, they're not quite sure what to do.
There's many camps as to what to do in the patient, with af is it a anticoagulant or anti-platelet for many of these patients. The other thing they have. As a risk in that group of patients is fistula thrombosis. So there are some companies doing trials trying to prevent fistula, thrombosis and to do it safely.
So you will see some results in that field, but they have a lot of work to do figuring out what the right combination of all these drugs are. In dialysis patients in general, and then in dialysis patients with af that field means a lot of work. I'm glad to see some people are trying out different things.
[00:21:01] Dr. Thomas Nero: Yeah, me, me too. When I was recently at E S C a group of us got together to discuss looking into these drugs in those patients. Because , they're at, very high risk. There's already a lot of significant costs in their care.
, but on the, on the flip side, the The benefit, the sort of from the pharmaceutical industry is really going to be in ACS and atrial fibrillation. I understand their desire to focus on those larger populations first. Uh, plus all of the,
[00:21:28] Dr. C. Michael Gibson: I think the other challenge in the hemodialysis patients is yes, we don't see clinical bleeding really with the factor elevens, but. , if you've put a dialysis catheter in and you pull it out, it may prolong the bleeding time and someone has to hold pressure longer.
And, you know, dialysis centers are very, very sensitive to any kind of time delays. So, even though it's safe and even though it's more effective, they're exquisitely sensitive to those kind of delays. So it'll be interesting to see how that
[00:22:00] Dr. Thomas Nero: Yeah. And in addition, we, when you look back , the factor tens did not include dialysis patients in those trials, and we're going to be comparing our trials directly to them, right? They, I mean, most of the trials are modeled after a pair of factor 10 inhibitor trials. And so without that, Grouping.
They don't, they don't wanna include them in th this trial so that they can compare apples to apples. , One of the other clinical factors that we find very interesting right now, a lot of people are talking about lipoprotein a and the increased risk of thrombosis that occurs with patients with elevated l p A.
Increase in risk for, uh, CS and acute m i partially because of its blocking of Plasminogen. Do you see that there's gonna be a role potentially for these drugs and even before we get onto the factor elevens for factor 10 inhibition?
.
[00:22:49] Dr. C. Michael Gibson: . Well, as someone who has elevated Lp(a), this is is of tremendous interest to me. 20% of our population has an elevated Lp(a). The majority of them don't know it. And exercise isn't gonna get it down. Diet's not gonna get it down. Uh, statins. Um, mixed reads there may get it down some, but sometimes the statins may increase it.
, PCSK nine inhibitors, variably get it down. Sometimes they do by 20%, sometimes they don't. Sadly, PCSK nine inhibitor did not get my Lp(a) down. So, , until we have drugs that target that. , it's best to do whatever else they can. And there is some data showing that aspirin is a particular benefit in Lp(a) patients uh, patients with elevated Lp(a) and people like me do take aspirin.
But based upon what we saw in Compass , with Rivaroxaban, certainly that could be a good add-on. As well, particularly if you have known disease or have had an event in the past you know, there's some data showing that an elevated calcium score is as high of a risk as having had an event.
So, , I find that strategy very reasonable. Obviously every patient's different and you've gotta weigh the risk and benefit, but, uh, that would be a reasonable strategy in many patients.
[00:24:11] Dr. Thomas Nero: , I hope that with the Milvexian and a c s trial that there'll be a substudy involved looking at the Lp(a) patients, or at least a, secondary analysis , so the last question I have, is for factor 11 a inhibitors and the potential for mechanical valves.
You know, we've been stuck in the Warfarin era with mechanical valves. You and I both have put in a lot of percutaneous valves which of course have a shorter lifespan on them. And we're all stuck with that 60 year old patient in our office going, well, which way are we gonna go here? You know, a a root enlarging, , open surgical valve replacement, and then hope that we can get two percutaneous valves in later.
Or do we, you know, go straight for a percutaneous valve. But the mechanical valves, if we could do a mechanical valve with having a decreased risk of bleeding that would be a really nice sort of middle ground. Do you foresee any role of these medications, especially with a, antiplatelet, uh, agent on board as well as a, uh, as a potential strategy in the future?
[00:25:13] Dr. C. Michael Gibson: Well, I would say potential, you know, the factor tens didn't do too well in that space. Um, so it's, it'll depend, you know, the difference with the factor 11 is it does target. The clotting caused by those foreign surfaces, the intrinsic pathway. So, you know, maybe we have a better shot on goal. Uh, and again, if it's safer, it might be safer to combine with other drugs like either aspirin or clopidogrel.
But we'll have to see. We'll have to see. I'm gonna, my crystal ball is a little cloudy, you know, it's been rolling a little bit, so I think, you know, we're gonna have to do a little, little study
[00:25:49] Dr. Thomas Nero: Yeah, we've all, we've all, uh, had that, that, uh, malfunction of the crystal ball as well.
[00:25:54] Dr. C. Michael Gibson: it does malfunction now
[00:25:55] Dr. Thomas Nero: And, and actually I have to say, I lied. There was one other question I did have sort of on my mind. What is, is the potential of using it upstream in patients going to the cath lab? So the current, a ACS trial is going to be including patients with Milvexian within seven days of their events.
But how about. Before we get into the lab, or Right when we see the thrombus in the lab, that we do it intravenously.
[00:26:18] Dr. C. Michael Gibson: Yeah, no, that's a great idea. You know, I, um, every trial I try and get the drug used in the cath lab or upstream. Every trial I get shot down. Uh, so, you know, we'll do it just like we do always. We'll give it after acs and then we'll circle back and say, well, it did pretty good after acs. Why don't we try and give it right when someone comes into the hospital?
So, um, we'll see, you know, if it does work well why not have a, you know, right when the person shows up to discharge strategy. But that, that'll have to be evaluated. There's, it makes good sense.
[00:26:54] Dr. Thomas Nero: Is there anything that you're using as far as looking at the efficacy? Of any of these medications as far as actually looking at thrombin levels at discharge, post discharge and follow up. I know we're gonna be looking at those as part of the trial, but is there any markers that you are using clinically ?
[00:27:12] Dr. C. Michael Gibson: Clinically, no. , we have shown that , you have elevated thrombin and. If you do have elevated thrombin, you tend to have more events, in fact, or 10 inhibitors bring the thrombin down, and that's related to better events. But yeah, I haven't really seen that used clinically. There's another tool that's out there that's maybe gonna gain some steam.
We're. Probably gonna do a trial with it. And that is TEG Thrombinelastography. What that does is it measures the strength of the clot and could be a marker of people who are at higher risk. So, , there's still more work to be done in looking at risk factors over on that side of things, and stay tuned on the TEG side.
[00:27:54] Dr. Thomas Nero: Well, that was excellent. I, I can't thank you enough again for taking your time today I hope that if you don't mind that I could circle back a year or two from now and we can get an update on where the trial is and how things are going and and the things that are interesting you, um, on, just on one other sort of side question, is there, is there any research that you're really.
You really think it's sort of exciting right now. You, you have your, you know, you have your fingers everywhere
[00:28:20] Dr. C. Michael Gibson: I might say some things that are somewhat surprising. I think some of the research that was presented at E S C at the heart failure meeting there on Neurimmune's drug that actually is an antibody directed against amyloid and actually removed amyloid from hearts. It's really exciting. I mean, 10 to 20% of the mass of the heart.
Can be amyloid in these old people. And this drug didn't just stop the production. It got the amyloid out of the heart. So, you know, fair chunk of people walking around with heart failure have amyloid. Particularly elderly people. That's hot. I think some of the other hot stuff that I see come along, it's m I know it's in mice.
I get it, it's in mice, but, uh, gene therapy for hypertrophic cardiomyopathy. Pretty hot. If we could get a one and done gene therapy there, that would be hot. You know, I know there are approaches with gene therapy moving upstream. Also in LDL reductions, Bayer has a drug to reduce LDL from birth.
There's also PCSK nine inhibitor drugs, gene therapy coming along. Those are exciting. And then the small, I inhibiting approaches to Lp(a). Are very exciting, but I think the overarching thing, and my team works on it night and day, is going through and looking at all these obesity compounds. If we can really treat obesity as a lifelong disease, uh, we can put u n I kind of out of business, you know, um, I think these are gonna be, that class of drugs is GLP and then there's gonna be dual agonists and triple agonists and all that.
And, uh, leptin, sensitizers, that's gonna change atherosclerosis. I think we gotta make peace with the fact that obesity is not moral failing. Obesity is a disease. And, um, the sooner we treat it like that and the sooner we turn people's appetites down, the better. I, with my high calcium score, decided I wanted to lose some weight.
I had high triglycerides. I gotta tell you, my appetite went way down. I had early satiety on a on a G L P agonist and lost 30 pounds. My numbers changed dramatically. You know, uh, my L D L came down, my H D L went up, you know, so I keep your eye on that class. I think, um, that's gonna end up being one of the biggest advances we've had.
If we can make peace with the fact that this is not a moral failing.
[00:30:54] Dr. Thomas Nero: I, I can't agree with you more. And we are involved with the surmount outcomes trial for non-diabetics, which we're, we're extremely, extremely excited about. And as we say for our group, the weight reduction gets them in the door. It's gonna be the cardiovascular reduction that really, uh, is going to impress us.
. And unfortunately it's gonna take us a couple years to identify those outcomes. But, you know, I definitely think it's going to be worth it. Well once again, thank you again for taking so much time to speak with us today and we will be speaking with you again hopefully very, very soon.
[00:31:26] Dr. C. Michael Gibson: Thanks for having me.