Good afternoon. I'm Ryan Weispfenning, Vice President and Head of Medtronic Investor Relations. Welcome to the Investor Briefing here at the American Heart Association Annual Scientific joining us around the world today on our webcast. The next slide. Before we get started, I want to note that we could make some comments that may be considered forward looking statements and actual results might differ materially from those projected in any forward looking statement.
Additional information concerning factors that could cause actual results to differ is contained in our periodic reports and other filings that we make with the SEC, and we do not undertake to update any forward looking statement. I encourage you to go back and read the slide. The slides we are presenting today will be available for download shortly after the completion of today's event on our website at investorrelations. Medtronic.com. Also, I want to note that we're in our quiet period following the end of our 2nd fiscal quarter, and thus we won't make any qualitative or quantitative comments about the quarter, including topics such as sales, market growth and market share We're taking questions today beyond the Ardian business.
We plan to update you on our Q2 earnings call, which we expect to hold 2 weeks from tomorrow on Tuesday, November 22. While today's event is about Ardian, I do encourage you to check out the 3 year results from the progressive AF Study that were presented as a late breaker today at and published in the New England Journal of Medicine. These data show that Medtronic cryoablation significantly reduces AF progression and and is a superior initial treatment compared to drug therapy. You can read more by clicking on the business and regional news at news. Medtronic.com and reading our news alert from today.
Session. Now back to Ardian. Today is a big day for our renal denervation business. As a little over an hour ago, we issued a press release on our OnMed trial data and the data were presented here at today.
Session.
To provide insights on our Ardian data, We have Jason Weidman, Senior Vice President and President of our Coronary and Renal Denervation Business and Doctor. David Kinzari, Chief Piedmont Heart Institute and Cardiovascular Services and Lead Principal Investigator of the SPIRAL HN OnMed study. Session. Go to the agenda here. Here's the agenda for today's event.
Jason will make some introductory remarks on our Ardian program. And then next, Doctor. Kinzari will discuss the 6 month OnMed clinical results. Then Jason will come back up to provide an outline of our commercial and regulatory strategy for renal denervation. And then we'll take questions from the audience.
So So with that, I'll turn it over to Jason to make some introductory remarks. Jason?
Good afternoon. Thanks everybody for being here. We're super excited to talk about Medtronic's Renal Denervation Program session, as well as our go forward plans to really help the 1,000,000,000 plus patients out there that have hypertension. Session. I think I'll start by saying that despite running the OnMed trial during an unprecedented global pandemic, We were actually pleased to see the results of this trial and they validated the blood pressure lowering effect of Ardian.
So when you look at the most common blood pressure measurement used in clinical practice today, office blood pressure measurement, we saw a statistically significant and clinically meaningful reduction in blood pressure for Ardian versus the control. And while we did miss the primary endpoint In ambulatory, we think those results are clearly explainable. So via the ambulatory measurement, You did see a reduction in blood pressure with Ardian, but we also saw an unexpected reduction in the sham, but that was due to medication increases and COVID's impact on the ABPM testing environment. And Doctor. Kinzari will talk about this in more detail here in a few minutes.
Across all of our studies, really importantly, the SIMPLICITY blood pressure procedure has demonstrated excellent safety and resulted in absolute blood pressure reductions that are remarkably consistent. And I think what's great about this is the consistency of the results is both in the short term and the long term. This is a big opportunity for us. Our view of the market potential has not changed. And if you look at our target segments that we'll reach over time, we look at this and we say that when we see that just 1% penetration of the target market segments Results in greater than $1,000,000,000 of market opportunity in the long term.
Now, of course, the first step in getting to that market is regulatory approval. And that's why we're super excited today to announce that we did file with the FDA our PMA for the SIMPLICITY spiral device. And I can tell you, we are very, very confident in the totality of our data. And obviously, that includes our already reported Positive pivotal trial, the OFF Med study. And the last thing I'll note is that we are preparing for market launch and preparing to build this market and investing to continue to lead in the future.
Session. We're going to I'm just going to spend a little bit of time. I think it's worthwhile making sure we're all grounded on hypertension here. And so obviously, hypertension impacts more than 1,000,000,000 people worldwide. It's the largest contributor to death.
And there's over or about $500,000,000,000 in direct spend in the health care systems across the globe. And we know consistently from the clinical literature that very small reductions in blood pressure confer pretty significant benefits. So if you look at the data in the literature, just 2 to 5 millimeters of mercury in absolute office systolic blood pressure that drops will give you about a 10% reduction in cardiovascular adverse events. And drugs certainly work, but people just don't take them. So right now, if you look across the globe, only 1 in 4 people have their hypertension under control and about 50% of people stop taking hypertension medications at 1 year.
Session. So we very much believe that Ardian is a solution. It's very safe. It's a simple procedure without a permanent implant. And its always on effect can help to lower blood pressure and or lessen the drug burden.
And this then results in a pretty enormous opportunity. And so again, starting with 1,000,000,000 patients overall, But we definitely see this technology first being utilized in those patients that are of the greatest need. So if you focus on the left side of the screen here, In our world, those patients, the sickest patients are the resistant uncontrolled hypertensive patients. But over time, we would session. We expect to move to the right of this slide and start to access more and more of these patient segments.
And as I said, when you look at these segments on the screen, 1% penetration results in more than $1,000,000,000 of market opportunity. Session. And I can tell you, we strongly believe that we have the right device to access this market. So, the Simplicity spiral device is a one size fit all catheter, can be used in all different vessels. It was definitely designed to maximize patient applicability.
And we also believe very, very strongly in the ease of use advantages of this device, and that includes very, very simple setup. It's just plug and play. Session. It has 6 French guide catheter compatibility, which is really important to physicians and it has excellent deliverability that allows it to get through torturous anatomy into whatever
Session. So
I think the most important thing that I want to hit about our program here is that we have a tremendous amount of clinical data, positive clinical data in support of this therapy. And in fact, I would call this an unprecedented amount of positive clinical data for a therapy that is not yet approved. If you look at the published literature, we have more than 12,000 patient years of positive published data with the Medtronic Renal Denervation System. And we continue to enroll new trials to support this therapy. And so I think with that introduction and ending on the clinical piece here, I think that's a great time to introduce Doctor.
David Konzieri. David as Ryan said, David was the PI of our trial and has been part of the program in this renal denervation journey for about 10 years. So you'll be able to walk everybody through the OnMed results, specifically as well as some of the totality of the data.
Thank you, Jason. Terrific. Well, good evening, everyone. This is a welcome opportunity to be with you this night to this evening. And perhaps it's not uncommon in many instances at a meeting like session.
To have a program that didn't meet per se its primary endpoint and yet there's much to celebrate here from the Spiral HT and OMIDS program. As Jason introduced, renal denervation has traveled a very storied path over more than the past decade, from the SIMPLICITI Section 3 study that now in fairness to that has some validation from our recent 3 year publication in the journal Lancet to a succession of sham controlled randomized Trial is demonstrating quite consistent findings. And indeed, we have now to date in this space of renal denervation therapy, session. 9 sham controlled randomized clinical trials. And so no other device technology, cardiovascular medicine or otherwise has been held to such rigor and to such a standard.
And all of these studies uniquely, even with 2 different imaging 2 different technologies, 2 different modalities of renal denervation therapy, have all consistently demonstrated meaningful reductions in blood pressure with renal denervation therapy, despite some variance with the sham control group. Session. Jason had asked that perhaps we just begin very briefly by sharing with you something perhaps many of you are familiar with, but the methodology in terms of how we perform these trials with regard to catheter based device therapies for renal denervation and hypertension altogether, With regard to the endpoints of ambulatory blood pressure and office systolic blood pressure, specifically ambulatory blood pressure is an endpoint that we've transitioned to based on our early experience from the SIMPLICITI HTN3 study. It is more commonly used indeed for research. It is representative of the burden of hypertension over a 24 hour period.
So specifically, an individual wears this monitor for a 24 hour period, during which time, Every 30 minutes in the waking hours, the blood pressure is assessed and every 1 hour during the nighttime hours, and we have pre specified criteria for what constitutes a valid reading of the ABPM. ABPM, by averaging the blood pressure over 24 hours and expectedly for most of us, our blood pressure goes down when we're Sweep is typically lower on average than the office systolic blood pressure during waking hours. And it is susceptible though a bit less than office blood pressure to variance in compared to the office blood pressure. But by all means, session. The ambulatory blood pressure can vary from individual to individual from time to time.
And we've observed this, in fact, in our off meds clinical trials in which patients are not taking antihypertensive medications. And we can see, for example, 0 to 3 months that there are some individuals whose ambulatory blood increases 3 to 5 millimeters mercury and others in the absence of medicines who change over the short time period as well. And of course, you can manipulate the ambulatory blood pressure too through lifestyle changes, whether you're taking medicines or not, whether you stop smoking or start exercising or Sizing or weight loss or other interventions as well. In comparison, office blood pressure is by far the most commonly used metric to inform clinical decision making when you and I are in the clinic as patients and certainly when I see patients in clinical practice as many other health care Sessions Worldwide. It is the office systolic blood pressure and office diastolic blood pressure too that serve as the criteria for societies and guideline endorsement recommendations for target goals.
It's not an ambulatory blood pressure goal. It's an office systolic blood pressure goal as targets for defining hypertension and how to treat hypertension worldwide. And moreover, the office blood pressure session really has been the primary endpoint for many other SENTINEL clinical trials, the SPRINT trial being one such example, a major trial that has highlighted the benefits of more intensive blood pressure lowering that invite therapies like renal denervation therapy to the space for more intensive blood pressure lowering. Those trials have been based on office blood pressure as well. To summarize from our presentation earlier this afternoon of the with the totality of data with radiofrequency energy delivery and as Jason shared with more than 12,000 patient years of experience that this therapy and this trial compared not only in the randomized cohort, but also with a pre specified goal compared with a performance goal of over 250 patients treated with renal renovation, Proved exceptionally safe.
There were no major procedural complications, no major clinical adverse events. And once again, we continue to survey these Sessions through imaging at 6 months follow-up. And although it always has been a theoretical concern, we see no occurrences of renal artery stenosis, for example, which to be fair is really case reportable if it were to occur. Despite the absence of reduction, which we'll talk in much more great detail with regard 24 hour ambulatory blood pressure compared with the sham, the blood pressure reduction for office systolic blood pressure remained remarkably Significant and remarkably consistently significant across all elements of the trial. Recall this is a Bayesian analysis.
So we combine, If permissible, if the data match and align, we can use up to 80 patients in the initial pilot randomized trial, which demonstrated at 6 months A significant reduction in office systolic blood pressure, and we combine that with the expansion cohort of 257 patients. And Herein, even in the expansion cohort, we see a significant reduction in office systolic blood pressure. And the absolute magnitude, which we'll soon discuss in a few moments, is almost to the decimal point extremely consistent with what we've achieved with renal denervation and many prior sham controlled randomized clinical trials. Unusually, unexpectedly, the ambulatory blood pressure, however, did not mirror the significance with regard to the office blood pressure Reduction, but to be sure, the ambulatory blood pressure reduced by clinically meaningful amount, the absolute reduction, of course, 6.5 millimeters mercury in this clinical trial. But the comparison with the sham control group was missed with regard to statistical significance.
I don't mean to amplify that absence of difference more. But even a 2 millimeter reduction in ambulatory blood pressure is what many drug therapies may be approved on, in fact, today, but not in this case with regard to statistical modeling. In the expansion cohort, as mentioned, renal denervation therapy was effective at reducing blood pressure by 5.9 millimeters mercury in the expansion cohort. This is the 24 hour ABPM, but it was a 5.8 millimeter reduction in the sham control group. And what we have what's very different, for example, From our nascent experience with renal denervation, for example, in the SIMPLICITI HTN3 study is that we have now the fidelity, the granularity of clinical trials to really understand what was occurring in the sham control group.
I don't think there's any debate in the medical community, does renal denervation work from this clinical trial. In EBPM and office blood pressure, as I've shared, is exactly identical and consonant with previous trials. It's really now what's going on with the sham control group here. And we have two observations from the study that provide insight to it. One is that more than 80% of the patients in this expansion cohort experienced their follow-up during the COVID pandemic.
And we identified quite statistically significant, but meaningful differences in the patterns of ambulatory blood pressure between patients enrolled during the COVID period versus the pre COVID period. And these differences occurred for daytime ABPM, nighttime ambulatory blood pressure and even 24 hour Ambulatory blood pressure. And it tells us in some ways that there's something different about this COVID patient population. And certainly, this is not unique to this study As we've seen even here today at the or during the other studies for iron supplementation and others showing some COVID effect and COVID sensitivities being employed in the clinical Studies. But I think the more even more striking, even more relevant and tangible issue is that there are quite remarkable differences in medication changes between the sham controlled group and the renal denervation group in this expansion cohort that we didn't witness in the prior sham controlled randomized pilot study session that were observed in the expansion cohort that significantly favored the sham control group.
And specifically, as I presented earlier this evening, 22% of Patients in the sham control group had a net change in their medicines, meaning either an escalation of medication number or dose and not decreasing their medicines Prior to the ascertainment of the 6 month endpoint compared with only 2% of the patients in the renal denervation group, that's a tenfold difference. And those all of those changes occurred despite protocol, session despite a protocol that mandates no changes in medicines and patient compliance and it all occurred before the ascertainment of the primary endpoint. And finally, as I shared with you, the absolute reductions that we observed, again, in this trial with renal denervation are quite consistent with previous studies. So as introduced earlier and sharing with you in a bit more detail, although we observed statistically significant differences in the OnMed's pilot randomized study with regard to ABPM and office blood pressure at 6 months. Again, in the OnMeds expansion group, no significant differences compared with the sham, But definitely a reduction of 5.9 millimeters mercury and then a significant difference even in the Omnis expansion group with regard to office systolic blood pressure.
So again, across the pooled analysis, across the individual components of the study, statistically significant reductions in office systolic blood pressure. Session. As I've also shared with you, 80% of the patients were followed in the expansion cohort during the COVID pandemic. And just to recall per protocol to share with you how these studies are performed and this is not unique to this study is that for blood pressure assessment during clinical follow-up, A patient is asked not to take your medicines that morning. You come into the office and you have the office blood pressure initially assessed And then there is witnessed pill intake.
And then the application of the 24 hour ambulatory blood pressure is performed. And so if a patient, for example, is taking a higher number of medicines or higher dose of medications, it's going to be even more amplified after the witness pill intake for the ambulatory blood pressure assessment. As I shared with you 2 in the pre versus the during COVID enrollment population, And the during COVID enrollment population was quite sizable, approaching nearly 200 patients that we saw very striking differences in the patterns of ambulatory blood pressure as well, not just for the overall 24 hour period, but for daytime and nighttime as well. And this again may reflect behavioral changes in patient patterns session that have been described elsewhere in the context of the COVID pandemic. And then most striking as I've also introduced is that despite Similarity in the baseline number in the medication number and medication burden at baseline, medication burden representing medication number, dose and class.
Despite similarity at baseline by the process of randomization, they emerged very quickly at 3 months and at 6 months and even amplified at 6 months statistically significant differences with a higher medication number and burden in the sham control group, again, all of which occurred prior to the 6 month ascertainment of the primary endpoint. And we confirm this importantly by drug testing, by drug testing session with urine and serum assays. And this is, I think, highly explainable for the sham controlled reductions that we observed in this clinical trial. And in many ways to me, it tells you that at least for ABPM, but certainly not for office systolic blood pressure, one can escalate his or her medicines to try to get to a similar but not greater reduction in blood pressure with escalation of medicines, but it's at the cost
session of a higher medication number
and burden. And we know that's an independent predictor of adverse events. And as we'll soon discuss, that's likely not sustainable from our experience of clinical trials, both from renal denervation and even trials like the SPRINT study. So we observed this tenfold difference in the expansion cohort and medication changes that would favor a reduction in blood pressure. And even more striking in the black ethnicity population Representing nearly 20% of the study population, the sham control group had 55% of those patients randomized to sham experienced an escalation in drug number and or dose with no reductions in their medicines compared with, for example, 21% of patients who session.
In the renal denervation group, a decrease in their medicines in that subgroup. So if you have an opportunity at home to measure your blood pressure And it's looking better. And even though you don't know your treatment status, you start to take less medicines perhaps. But alternatively, If your blood pressure remains high or is even going higher, you're more likely to increase your medications as well or maybe a provider outside of the trial is willing to do so as well. And indeed, about 1 in 5 patients in this study were taking more medicine that was even on their prescription list in this trial as well as I shared in our discussion panel this evening.
But renal denervation therapy once again consistently not only reduces blood pressure observed in this trial and reduced significantly off of systolic blood pressure, but it also won, so to speak. It won with the win ratio. And We have shown this in previous studies with medications as well that when we look at a hierarchical analysis and consider it of the opportunity for renal denervation to reduce blood session, but also perhaps to reduce the medication burden, which is quite clinically meaningful to patients. Again, it's a predictor of non adherence That renal renovation in this therapy won with 27,000 patient comparisons. I'm happy to perhaps in discussion if anyone is interested and describe to you the methodology for this, but We compare patient to patient to patient across this trial 21,000 times to look at who won versus ABPM reduction and who won versus medication reduction and renal denervation in this case 1.
As I've also introduced, the absolute blood pressure reductions, whether it's in the Context of medicines or in the absence of medications, call that in the OfMed setting, including the OfMed's pivotal trial, that demonstrated success compared with GM Control. We were remarkably consistent, demonstrating 9 to 10 patient survey of real world practice And PIK like patients that would be enrolled in the clinical trials like OnMed and OffMed, those absolute reductions are at least consistent at 13 millimeters mercury. And then even in the HTN3 study, now with even longer term follow-up, those reductions are consistent as well. Session. As I shared though, the strategies that we've observed in patients who have not been treated with renal denervation therapy In our trials like the long term follow-up of SIMPLICITI HTN3 pilot study excuse me, SIMPLICITI HTN3 and the ONMeds pilot study now both through 3 years of follow-up, both of which have been published in the journal Lancet, demonstrate that for those individuals who do not get renal denervation therapy and remain persistently hypertensive, That there is, if not anything, a waning efficacy with their medications over time that their blood pressure control, if anything erodes and goes even higher, Despite the escalation of medicines in an effort to reduce blood pressure, and this is also the instance recently published within the past month in the SPRINT trial, A pivotal landmark trial that changed guidelines practice for more intensive blood pressure lowering, and it shows that blood pressure goes down in the intensive group during the trial period, during session.
The Hawthorne effect, the period of surveillance, but then thereafter following these patients over longitudinal follow-up, temporarily, There's this progressive erosion in their blood pressure control, and it actually returns to that of the standard therapy group with higher blood pressure, and they lose all of the clinical benefit of the 20% mortality reduction that was identified earlier in this trial. And so I think as a final data element to share with you before returning back to Jason, again, what is unique about This effect with renal generation is indeed, as Jason introduced, this always on effect that we see in this As disparate for its medications with regard to the pharmacokinetic profiles, the dosing regimens and certainly with patient adherence, We see this always on effect, this 24 hour always on effect with renal denervation therapy that in trials like HDN3, trials like the OMIDS pilot study now through 3 years, Not only is there durability in the blood pressure reduction and persistent safety importantly as well, But if anything, the blood pressure reductions, if anything, are modestly amplified over long term follow-up. And very importantly, this is not explainable by an increase in medication dose or number as it is in the control groups.
Thank you. And Jason.
Thanks, David. I'm just going to spend a couple of minutes here on the regulatory and commercial strategy. So you know what our plans are going forward. Most importantly, as I mentioned at the start, we did file the final module of our PMA today. So that went in today.
We have been working with the agency collaboratively Session for some time now, for several years. And so as part of that, we've actually used a modular submission strategy. And so what that means is that, in session. In fact, 4 of our 5 modules for our submission had previously been submitted and at this point, are preliminarily closed out. Session.
We'll continue to answer FDA's questions as they come and we'll continue to work collaboratively with them. As I said at the beginning, we're very, very confident in the totality of our data supporting this submission and that does include, obviously the pivotal study, the OFF Med Society as well as our other randomized trials and our registries. Moving on to thinking about Market development here. If you look at Medtronic over the last 60 years, I would say the one thing or there's many things, but one thing session. Medtronic has been consistently very good at it.
It's creating new markets and building them. And so we're we know how to do this. This is something we do well, and we're ready to do this again with hypertension. So, there is a lot of activity that has been gone that's been ongoing, that's going to enable us to do this, that will enable us create demand, actually convert that demand into procedures and execute and ultimately for us sustain our leadership position. As I mentioned, there's a lot of activity ongoing right now, but I'll call your attention to a few things that I think are particularly important.
One is that, obviously, for a new procedure like this to ultimately get great market adoption, It's going to need to be incorporated into the medical guidelines. And really the first step there is to mobilize the physician and the KOL community session around support for the therapy, so support for renal renovation. And so we've been spending a lot of time over the past few years doing just that. And I think a great example of how that's going well is that in the past 2 years, 12 separate physician societal consensus statements have been published across the globe in support of renal denervation. And so this is really the precursor to guidelines.
And so we're well along that path of what we need to do in order to eventually get into the guidelines. Couple of other things I'll call out. One is, in relation to our trials, something that you may not know is that the vast majority session of the on and off med patients in our trial were actually they actually got into the trial through direct to patient recruitment. And we did most of that digitally. And so even if you look at just the select markets we went to across the country to run these campaigns, Obviously aligned with our trial sites, we had over 150,000 patient opt ins.
So I think that gives you a little bit of an idea of how interested patients are in finding an alternative treatment for their hypertension. And so the learnings that we got during those processes are definitely applicable to the commercial setting and something that we'll just transfer over as we have commercial approval. Another thing to note is that we do have great relationships with our coronary sales force with interventional cardiologists. So we plan to have them sell and support renal denervation going forward, so we can take advantage of those relationships and their knowledge of the hospital systems. Session.
However, we do plan to augment that with a separate therapy development field organization and that organization will be focused 100% on Ardian. Think of that as being very akin to what Medtronic and Edwards did session with their therapy development organizations to build the TAVR market. Moving on to reimbursement. This is, I think clearly session, one of the largest barriers and it'll take time. It's different all around the world.
But what I will say is that we have the most experienced session and the best people at Medtronic working on this and we are spending a lot of time trying to ensure we have success. If I focus on the United States, we have been meeting with CMS as well as large commercial payers for some time now. So Ardian is not going to be a new thing or a surprise to them. If you think from the CMS perspective, There's likely to be multiple routes to coverage and we'll be prepared for all of those different routes. From a Private payer perspective, this is going to be a situation where we need to go 1 by 1 by 1 by 1 with every commercial payer.
And frankly, I would expect that every specific coverage decision and the associated timing will be pretty heterogeneous with all of these commercial payers. Last thing I'll mention in the U. S. Is coding and payment. These are pretty process driven And we've done all of the steps we need to do and we'll be in good shape by the time we launch.
In Europe, we do have approval, but indeed reimbursement has been a bit of an obstacle. Payers in Europe are very different country to country, but one thing I would say that's fairly consistent is most of them do look to the guidelines, as I mentioned earlier. And in Europe, the predominant guidelines are the ESC guidelines. I think what's very important to note is that the last update to the EFC guidelines was in 2018, and those guidelines actually say that Renal denervation should only be used in a clinical trial setting. So obviously, that's going to hamper adoption.
And so as I mentioned before, we're working with the physicians to Try to get those guidelines updated. We feel confident that during the next update, they will be in favor of renal denervation. But unfortunately, the next scheduled update for the ASC guidelines aren't until the fall of 2024. So it's a little ways away. The only other thing I'll note here in Europe and the situation there with reimbursement is that generally payers care a lot more about economic evidence than they do in some other parts of the world.
And so now that we have our full data package complete, it allows us to move forward with Our cost effectiveness analyses. We have some planned here for publication over the next I'll just call it in the near term. And what I can tell you is that we will fall within or we expect to fall well within the acceptable thresholds for cost effectiveness. Session. Last thing I'll note is, we are investing heavily in our pipeline as well.
And we are as I said earlier, we're very, very confident in the spiral device. We think it's the best device out there, but we also know that devices can get better And we intend to make them better. So we have 4 active pipeline programs right now. And we have over 75 People working on Ardian product development and that will ramp to well over 100 as we get into the next calendar year. We fully intend to be the technology leaders
session in this space in
the long term. Okay. Just before we head to Q and A, I just want to reiterate The key takeaways here. And for me, 1st and foremost, hypertension is a global health crisis. So patients desperately, desperately need and they want new solutions.
And overall, if you look at the overall Medtronic session to lower blood pressure and or to reduce medication burden. And we know that renal denervation provides clinically meaningful absolute blood pressure reductions that are very consistent, as Doctor. Kinzari showed, and they're durable. And this is an incredibly safe procedure. So again, we filed for our PMA today, and this is a multibillion dollar market opportunity, and we're committed to leading in the long term.
Session. Go to the first question here, Chris.
Thanks. Appreciate you guys taking the time tonight. Chris Pasquale from Nephron. Doctor. Kinzari, a couple of questions for you.
The focus on office BP specifically, I find that a little interesting. It's sort of like a dietitian saying, I don't care what you ate for lunch on Monday. And clearly, the rest of the week matters and the goal is to get blood pressure down consistently for these patients. So if changes in BP session. Changes in medication were really the culprit around the ambulatory blood pressure measurement.
Why do you think those didn't show up in the office comparison? And did you look at the subgroups that had no changes in medication chain and medication regimen?
Thank you for those questions. I'm just trying to recall all of them in order. But I like the analogy of the dietitian except to say that Whether it's office or ambulatory blood pressure, ambulatory even then is just 24 hours of the day of a year, right? And so, it still has its limitations. And instead of To your point though, instead of office or ambulatory, really the goal is to look at a more continuous following of patients with regard to, For example, office blood pressure, as we've done in the concept called time and therapeutic range, where we're kind of taking the analogy of glycemic control in diabetes and looking at the long term burden of hypertension, in this case, glycemic control in diabetes.
And we've shown though that in comparison to patients not getting renal renovation in these trials, The time and target range is substantially better. And moreover, we've shown in the GlobalSimplicity Registry that intuitively, the greater IMU spend in target range by office systolic blood pressure translates to lower risks of death, stroke and heart attack as well. So that's a brief comment About ABPM versus office. But I would also say too that in this trial, office blood pressure is all the sham group is also affected. Session.
So recall, they have a 5 millimeter reduction in their office systolic blood pressure when in theory, they should not have any reduction as well. And so the changes in medication certainly affected office blood pressure too, but to a lesser extent, because of the protocolized way of after Witness pill intake, your and then the next morning too, the patient's ABPM has been placed after witness pill intake. The next morning, he or she is also taking that higher medication burden. But when they come into the clinic for the office blood pressure assessment, we ask them not to take it. So we're seeing Two things happening there.
We're seeing the trough of their medications, even if they're higher, and they are higher, so you're going to see some sham effect. And secondly, Maybe they're not taking those medicines before they come into the clinic anyhow. So you might not you might see a diluted effect as well. Can I just jump
in really quickly there? One of the things, If you were in the session today with the drug trials, you'll notice that they even specifically noted on their endpoint that they always try to measure at the drug trough. And so that's more similar to what we saw in the office. The other simple way I try to think about this is with the protocol here is, It's totally fine when you're taking your meds. It only makes a difference when there's an unbalanced increase of meds between the two arms.
And so the timing and we can refer back to that timing thing at another time. The timing essentially means that you The office is taking into account changes of meds once, but the ABPM is kind of taking it into account twice.
And did you look at patients that had stable medication regimens?
Yes, great question. So two things. One is that, when a third of the study population has changes in their medicines And you try to exclude those who didn't make medication changes, there's 2 challenges with that. Some might call it like a per protocol analysis. And the answer is that we don't see still differences.
And the reasons are very important why. One is that you've already markedly reduced your sample size by about 33 Session. So your statistical power has gone to no. And secondly, if you think about taking out the patients who made medication changes, and remember, Medication changes can go both ways. If your blood pressure is high, you can go up.
But if it's looking really good with renal denervation, you stop taking them, right? And so if you exclude those patients with medication changes, you're almost converging towards the null, towards the middle, because the people who had high blood pressure and who are taking more medicines that would show greater difference with session are taken out of that equation. And the people with renal denervation who had a really good blood pressure and we're starting to take fewer medicines are also taken out. So You're getting more of a narrow comparison, but it's largely underpowered anyhow.
You take out the highest blood pressure shams In the lowest blood pressure Ardium. So you're kind of left with an unequaled comparison. Yes. The other thing I'll note on that is We did anticipate that there could be a situation where you have these unequal medication changes. And that's why the win ratio analysis was pre specified, and it deals with that type of situation.
And then to David's point that he explained earlier, win ratio will allow you with the full sample size to account for both medication changes and changes in blood pressure.
Thanks. Larry Biegelsen, Wells Fargo. One for Doctor. Kansari, one for Jason. Doctor.
Kansari, subgroups, were there any important differences in subgroups? I'm interested in U. U. S. Versus OUS, 65 above and below, dippers, non dippers, blacks and non blacks.
Session. And so we didn't see that, I don't think in the presentation. And then Jason, what can you talk about the financial goals that you had, the $500,000,000 in 2026 calendar year, dollars 2,000,000 to $3,000,000,000 in 2,030. And I'm curious like why you didn't reiterate that today. You sound confident in the totality of the data.
I get that. But if you were, I think one could infer if you were really confident in it still, You would reiterate the financial goals you put out a year ago. So why not? Thanks.
With regard to subgroups, Larry, session. We really have just received this data and we're putting it together and so we haven't performed all the subgroup analyses and predictors of treatment effect. One group though that does stand out in terms of a negative predictor is the black ethnicity cohort, but I think it's explainable by the considerable medication changes that you saw in the sham control group as well.
Okay. And with respect to the market, as I said earlier, our view of the potential of this market, Larry, hasn't changed. We still see this as a multi session. The potential of this market, Larry, hasn't changed. We still see this as a multibillion dollar opportunity.
Hypertension, as I said, is 1,000,000,000 people Session. Desperately in need of solutions, and there's a big opportunity. I think the easiest way for us to think about it is 1% penetration is Greater than $1,000,000,000 of opportunity. Now the exact ramp to get to that full market potential, I think, is going to depend on a few variables that we're going to have to see how that plays out. And that's like timing of I'll say a few, timing of approvals, exact labeling and reimbursement.
And I think I'll dive into reimbursement just as an example of changes, right? So Last year, we thought that we would be a candidate for MCIT. And then MCIT was repealed. So then we were going down the path of something different. And now CMS has proposed TCET, but we don't exactly know what that is yet.
So that's an example of one of those variables where we just don't know how it's going to play out yet. We're going to have And that will help determine the ramp.
Let's go to Josh.
Session. Thanks a lot. Josh Jennings from Cowen. First, I just wanted to ask about Clinical endpoints. And there are clinical endpoints in the secondary outcome measures that are listed on clinicaltrials.gov, I think, new stroke, new MI Mortality.
Do they become more important with these results either for the clinical community or On the reimbursement side and will we see those results? I think the clinical trial design is out to 3, 6 months looking at these clinical endpoints.
Session. And just as an aside, we're going to follow these patients through 3 years in a subgroup even through 5 years of follow-up. And one of the issues It's always a challenge in renal denervation trials. There's also the compounding when there's crossover from the sham control group and there's a large number of patients Altogether from the study treated that you don't have a good adequate comparator. In terms of but just in terms as a broader statement with regard to clinical outcomes, As you know well, there were no major adverse events or differences between the two groups.
If anything, one new stroke in the sham control group, but not in the renal denervation group, Very consistent with the previous studies. And we'll pull the totality of data for long term follow-up with clinical outcomes as well. I also am always reminding myself too though that there's no reason that the blood pressure reduction with renal denervation therapy shouldn't translate into clinical benefit Just as a calcium channel blocker or an ACE inhibitor could do so. We also have some insight to this from as I was sharing the time and therapeutic range data from Global SIMPLICITI Registry. And we don't hold the drugs that I routinely prescribe, as I will tomorrow morning in clinic.
Session. We don't hold them to a mortality reduction as well. It's a blood pressure reduction upon which they're approved and upon which they're used as well. Session. So as the breadth of evidence as the evidence basis continues to accrue, I think we'll have better opportunity to look into the true heart events though.
I mean, on the payer side, just with your discussions around Clinical outcomes and just they were baked into the trial design. That's just why I'm asking. And then my follow-up is just with the submission and just the labeling of Ofmen as the pilot, session. On this and the expansion, is there anything we should read in this or should we be thinking other regulators can be more heavily weighting the off line results versus on line results? Thanks a lot.
Generally, Josh, I think that for all of the stakeholders, whether you're talking the regulators or the payers, They're going to value the totality of the evidence. I don't think that there's necessarily a method where they score 1 more than the other, but I think they're going to look at the totality of the evidence, which is very
small. Go to Robbie. Thanks. Robbie Marcus, JPMorgan. You talked about Couple of different pathways you're ready for in reimbursement in the U.
S. And you talked about needing guidelines in Europe most likely. How are you thinking about what some of those different pathways might be in the U. S? Do you expect an FDA panel?
And how long are you session for reimbursement to come through after approval. Should we be thinking 1 to 2 years or is this something that might take longer? Okay.
So sorry, I'm going to try to get all of your questions down, so I don't
The different So
there's different pathways, which I was really speaking to CMS. And then there's panel, which is approval related. And then how long for reimbursement? Yes.
Is
that what you're saying? Okay. So I'm going to try to put the reimbursement questions together and then why don't I take the I'll take the approval one first. Session. So, whether we have the panel is up to the FDA.
And so, but we'll be preparing as if we will need a panel. Session. We would likely find out sometime, I would guess, in the Q1 of next year whether we need a panel or not. That would be my guess on that, but that's up to them. In terms of reimbursement, so the different pathways I was speaking of with CMS is you could go for a national Coverage decision and those typically come with evidence development.
We could go to each of the Medicare MACs 1 by 1 by 1, which is there's 7 of them. So you just go locally to the different Medicare MACs or there's this new TCEP regulation that legislation that's been Session proposed, but there's no details. But we're guessing that CMS is going to provide more details at the beginning of this next calendar year. That's our best guess. We have requested time with CMS to discuss this further and try to narrow in on what might be the best scenario for us given this new TCEP-one.
In terms of the timing for reimbursement, session. Generally, I would think that for Medicare, for all of these pathways, usually about a year session to get reimbursement, typically, don't know on TCIP. And then for private payers, There will be some that will be early. There will some that will be really late. Like I said, they're going to be really heterogeneous.
And if I could sneak one more in. Doctor. Kinzari, I didn't see the chart in the presentation about responded or didn't respond? And how do you think that will impact physician utilization?
Yes. And this is not a good question, but sorry, just to go back before we lose Momentum on this, I just wanted to say, although the guidelines documents in Europe, for example, aren't, as you said, scheduled for 2024, there is we have a document from the European Society of Cardiology. It's a consensus document that is currently underway in publication that has far moved from reserving this for research to session identifying which patients in clinical practice should be used. Responder analyses are hard for me to answer, in part because It depends on when you look and what your cutoff criteria are. So no significant differences here, though, with regard to responders from all of our previous trials depending on how you wish to identify it.
And indeed, it would make sense because the absolute reductions for office and ambulatory blood pressure are completely consistent with the previous studies. Part of the in terms of identifying non responders, session. There's no consensus on how that is defined. But for people who don't necessarily have a blood pressure reduction, it's Predefined. This is a space of ongoing study for us, to be sure.
Right now, the greatest predictor of blood pressure session. Independent of the Ardian technology is having a higher blood pressure at baseline. There are some session. Other biomarkers and things that are suggestive for us that we're looking into, but I think this is an area still of ongoing science for us.
Just want to note too that, certainly, we would like to better understand responders and have a 100% response rate, But there are other medical devices and drugs that don't have most drugs don't have a 100% response rate. So it's always been curious to me how we really focus in on that session for renal renovation where we don't for the blood pressure medications or others. And in fact, for blood pressure medications, I do know that the response rate is exactly 0 when you don't take your drugs. Session.
Let's go to Ryan.
Thanks. Ryan Zimmerman, BTIG. I saw on the presentation, a trial entitled AFFIRM. I'm just wondering, Jason, if that is a post market study that you're preparing for session or if there is going to be prerequisites given the data today for post market studies from payers in order to seek reimbursement And how you're thinking about that currently?
Yes. So again, several questions there. So, AFIRM is a study that is ongoing right now. It's already enrolling. In fact, session.
The PI is sitting next to me, so he can speak to it as well. But primarily, we will be one of the big purposes of Affirm is to look at some of those session. Patient subsets that were excluded from the on and off med trials. So we're looking at isolated systolic hypertension, chronic kidney disease and diabetics. So those are all in there.
That was agreed upon with the FDA and there's a performance goal. In terms of whether there will be any other Post market requirements, and that would be from the FDA from a regulatory standpoint. That's to be determined through the next many months session as they review our submission and we go back and forth on that. It's too I can't comment on that. It's too early to tell.
Session. Then you had some
No, no, that was it.
That was it? Okay. Okay. I got it. Good.
Go ahead, Travis.
Travis Steed, Bank of America. Thanks for hosting the event tonight. I did want to on the FDA, maybe you covered this earlier and I missed it, but It's curious if you expect the label to be a broad label or limited to a certain patient population? And then when you think about tonight's results, Do you think it impacts the amount of investment that you need to spend to develop this market? And then I think you're already spending close to $100,000,000 if I'm correct on RDN.
Does that Celebrate and step up from here now that you move into commercial phase or kind of stay consistent?
Okay. So walk me through the all three of them. Sorry.
Yes, sorry. FDA label was the first one. Label, okay. And then Investment, just tonight's results change the amount of
Do we need more because the results Exactly. Generally, are we going to invest more in?
Exactly. Yes, from here. Okay.
Great.
Okay. Label, we intend or we've proposed a broad label, which is what we've said before. Nothing has changed because of that. We feel our data supports that. And so but that will ultimately be up to the FDA and that's kind of some of the final stuff that happens during the process.
So again, that will be up to the FDA, but we've proposed a broad label. In terms of investments, Session. I don't think that we need more investment because of what we saw in the results today. And most of the physicians that we've talked to, and If you were in the room, the panel was pretty okay with the results and it made sense to them. We saw This good effect of Ardian.
And then we had this drug impact in the sham part of things. And so most of the physicians I've talked session. So far have all been pretty favorable. And so I would say there's no additional investment needed because of this trial, certainly not. In terms of additional investment to prepare for market, certainly, that's something that we're doing now.
We're like I said earlier, we're going to have a separate field Therapy Development Force, all of those things are additional investments. So there's most of that added investment is going towards prepping for commercialization.
Session. That's helpful. And then on the pipeline, since you did put it on the slide, just curious on timing and do you need new trials to do that? And how you think it impacts the market opportunity? And like, For example, like the other energy sources that you mentioned, like how do you think that impacts the procedure or the opportunity?
Yes. So I think generally, I'm not going to talk about session. Specific timelines of the product pipeline, but what I will say is our plan is to have a pretty steady cadence of introductions over time. Session.
Thanks. Cecilia Furlong, Morgan Stanley. I wanted to go back just and you kind of touched on it a bit, but Focus on OBP versus ambulatory and really the more clinically relevant. As you think about just the results today, do you see At least initially a change in how physicians are thinking about kind of the initial patient population that they're looking at to commence utilization of HCN in post approval. Session.
To begin with, just as we introduced and as you suggested, office blood pressure is the dominant metric for Session Making. We don't routinely perform ambulatory blood pressure in the clinical setting, at least certainly in the United States and in most other geographies. As I've also introduced, office blood pressure is the sole criterion that sets the targets for therapeutic goals by societies and consensus documents. And it's been the primary endpoint of many other major trials just outside the space of renal denervation. So I think that will still be the main criterion that doctors are going to be using in terms of informing their decisions or to session.
And the shared decision making process for renal denervation for their patients. In fact, in the AFFIRM trial, for instance, We're looking now at not ambulatory per se, but office criteria as one of the many, but the principal metric that we're following in these patients given its Session. And I'm sorry, there was a second part to that?
It was really just one and you kind of addressed it. Would you session. See a change in how physicians based off of this clinical data think about just the target patient population that they initially start to utilize this in?
No, I think that as consistent with, like Jason shared, 12 documents that have come back and come out forward in the past 2 years from societies and consensus documents both in the U. S. And abroad from Asia to Europe to the United States session proposing considerations for patient selection. They're really still all about patients with uncontrolled hypertension in the presence or absence of medicines, But also focusing more I think the focus will be not only on hypertension alone, recognizing that 60% of the patients in the United States with hypertension do not meet their societal or guideline recommended target goals. I think renal renovation brings to the space session.
Greater awareness of hypertension. It usually has fallen to the side when patients come in complaining of other knee pain or other symptoms. And now blood pressure will come more to the forefront because of this new therapeutic opportunity. And secondly, I think So a patient with uncontrolled hypertension, but who also poses high cardiovascular risk for death, stroke, myocardial infarction Or poses high risk for what's called hypertension mediated end organ disease, kidney failure, heart failure, Stroke among others.
So generally, if you look at those consensus statements on where Ardian should be used, they kind of fall into 3 categories: resistant uncontrolled, Uncontrolled hypertension with high cardiovascular risk factors, other risk factors like David just talked about or in or the 3rd category is intolerant to medications or significant patient preference to try something other than medications. And that's pretty consistent across those consensus statements. Session.
Okay. And if I could just follow-up really quickly, you talked about to a large percentage of the patients in the clinical trials came through session. The outreach patients are much more motivated maybe in the ones that were enrolled versus kind of your typical patient population. Can you speak to just session. How you think about kind of how those results translate into what we saw?
And then as you're targeting patients, just your outreach efforts, how you build that momentum in the market? And then Pipeline question as well as you think about the further opportunity to enhance this procedure, feedback has been one area that I've heard a few times. So just your thoughts on being able to augment the procedure via feedback and potential timelines. Thank you.
Session. Just as a qualifying statement, the direct to the patient advertising, so to speak, of the clinical trial, it's by all means not to the exclusion of the primary practitioner. We go to them as well. We've done a shotgun approach. And the beauty of I'll just say the beauty of renal innovation too, just as an aside is, session.
As an interventional cardiologist, unlike carotid stenting or other procedures that have been divisive among disciplines, we've enveloped this has been a uniform approach across multiple disciplines from the very beginning, hypertensionists, endocrinologists, nephrologists, internal medicine doctors, non invasive cardiologists, cardiologists among others. So And when you see people as part of these clinical trials or part of these programs, it's truly a multidisciplinary approach at the global leading cause of death and disability. Secondly, that said, however, there is clearly a patient population that is considerable, that is seeking an alternative to existing therapies for drugs and lifestyle interventions for session. And on the one hand, as a clinical trialist, it certainly facilitates it because you have more people coming to look for a therapeutic alternative. Session.
And sometimes they're told in the treatment resistant patients, they have no therapeutic options, and this is a great opportunity for them. The other though is that we have and in fact, just a few moments ago, I received from the editor that they're going to publish this as soon as they can, but we've done a patient preference study as Part of our program. Others have done patient performed patient preference studies in Asia and in Europe. And when asked Session. Or would you rather have a single base catheter procedure, a catheter based procedure, at least 30% of those individuals would session.
First, such a therapy, such as renal denervation and in the most rigorous, I call it, discrete choice experiments that we've performed, Depending on the scenarios of blood pressure reduction and durability that we offer, anywhere from 30% to 70% of patients would prefer a therapy such as renal denervation. Session. And what's interesting about those studies is that the biggest driver for them for is for selecting renal denervation is to, a, have an improvement in blood pressure. And sometimes it's not even nearly what we've observed like 10 millimeters mercury in the trial, But that trumps even safety of the procedure for these patients as well. But fortunately, it's very safe too.
And they also secondly look for durability and we've demonstrated that now at least through 3 years of follow-up. Okay.
Go there and then we'll wrap up with Chris.
Thanks for taking the question. It's Dave Rascott with Truist Securities. Just to Follow-up on some of the comments you made about the longer term development aspects of the product. I'm just wondering if any of these things in the pipeline are More related to things that need to be done ahead of the launch or these more longer term opportunities and thus essentially the product in its current state is session of what you would go to market with?
The product in its current state is great, and that's what we're going to market with. These are after. Thank you.
I agree. Yes, I should answer that question. Yes. Very user friendly.
Finish with Chris.
Thanks, Ryan. Chris Pasquale, Nephron. On along those lines, there was significant heterogeneity in terms of the number of lesions, session, number of energy ablations delivered per patient. Was that strictly based on anatomy? Or was it up to the physician to sort of tell when they're done?
Great question, Chris. Session? It's exclusively based on anatomy. So specifically per protocol, we target the distal branch arteries of the renal artery architecture as well as the main renal artery. And then we even are able to treat what we call accessory renal arteries.
Some people have 2 major arteries to their kidney rather than just one. And that occurred in a quarter of the 26% specifically of the study population. So it really just depends on how many branches an individual has And how many renal arteries an individual has. So it's purely anatomically based.
Okay. And then maybe just to wrap things up. Doctor, if this was available tomorrow And reimbursement was not a consideration, who would you use this technology on in your practice?
Session. It would be very much the patients, for example, that we're currently enrolling in the AFFIRM trial. The AFFIRM study is a 1,000 patient study that, As Jason introduced, is examining renal denervation therapy in a much less selective broader patient population, Representative of those we encounter in clinical practice like in today's trial, but also a broader group with other coexisting illnesses that would have been excluded from the trial. So put simply, in patients who are on medications and still have uncontrolled hypertension on patients Less common, but certainly existent and routine in practice, people who have so many intolerances that they can't take a number of medicines or just very few, but have session. And then especially focusing, as I shared earlier, on patients who have uncontrolled hypertension and still poor session.
Our high cardiovascular risk or risk for end organ failure like renal disease as well. So quite a broad population in other words. Yeah.
Session. Okay.
I want
to thank everyone for attending tonight. I want to thank Doctor. Kinzari for participating. Thank all the Medtronic people that helped and assisted in preparing for tonight's program. Thanks a lot.
And if you have additional questions, you can reach out to me or a member of my team. And that concludes the program. Thanks.