Q2 2022 CinCor Pharma, Inc Earnings Call

Find listen Mo a Chris or non suffication will follow the formal presentation if anyone should require operating during the conference. Chief STR and theo and which for the phone key pank. I'd now like to take the conference over to ky kilum Chief. Good morning and welcome to syncor conference call we. We will be sharing the top line results from the face to brighton trial. Joining me today are mark the gararyel CEO , DR Mason Freeman, Chief Medical Officer, ktherine pice are Chief Operating Officer, Co founder, and DR D Pak BT, Executive Director of interventual cardiovascular programs at Brigham and women's hospital and Professor of medicine at Bart medical schoolplease note that on today's call we will willbe making forward looking statements, including statements relating to the clinical results and the, therapeutic commercial potential and regulatory status of our investigational product candidates, the expected timeing of clinical trials results, milestone sufficiency of syncor's cash resources, expectation with respect to sycor's growth and prospects and statements with respect to human capital, among others. Various risks may cause incor'sactual results to differ materially from those stated or implied in such forward looking statements. For description of the risks and uncertainties that we face, please state risk factors contained in our filings with the se C including risk factors section of our annual report on Form 10-K . court undertakes no obligation to revise or update any forward looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities law. I will now turn the call over to Mark to get started. Mark, Please go ahead. Good morning everyone. F exciting the today for us and full millions of patients around the world while three to report top line brighton trial results.

These results, in our view, open a new era of innovation. For more than 20 years, many drug companies have tried to selectively block aldosterone synthase for the treatment of hypertension. Now we believe that the strat has succeeded.

These two top line results suggest that we have given up the treatment that is potential for patients with treatment resistant hypertension.

These are patients who have been on three or more blood pressure drugs as they are maximally tolerated doses, including a diuretic, and we are still unable to achieve the blood pressure goals.

The results from the Phase II Brian trial of back-dose strident patients with treatment-resistant back-eclampsia suggests that we have developed what we believe, subject to confirmation in Phase III trials, is a very effective, safe, and well tolerated treatment in a large, hard to treat US population estimated to be up to 15 million patients.

The abstract showed an impressive double digit millimeters of mercury reduction in this 12 week trial while the safety profile was compelling with no observed cortisol effect and very low rates of hypokalemia reported.

We believe that the results we are seeing from the Bion trial truly represent an important scientific breakthrough supporting the potential of back-dose stress to emerge as a new mechanism of action in the hypertension treatment paradigm and to potentially be the first meaningful innovation in the treatment of blood pressure in decades.

And we believe the data we are about to show you will confirm the tremendous value for patients needing to reduce their blood pressure.

These data is summarized in 3D numbers in the middle of the slide. For patients in our 2 milligram along, we saw systolic blood pressure reduced by 20.3 millimeters at the end of the slide. And then we saw the systolic blood pressure reduced by 20.3 millimeters. And then we saw the systolic blood pressure reduced by 20.3 millimeters.

As a reminder, in 2001, there was a study published that in older patients with isolated, systemic hypertension, lowering SVP by 10 millimeter of mercury reduces the risk of stroke by 30% and may it cause infection by 23%

We are talking about double this number, which we believe is absolutely spectacular

The next number you need to remember is a placebo-corrected blood pressure reduction in the 2mg arm. We have heard from KOLs, payers and investors that a double digit reduction would be a home run in their opinion. We are very pleased to report that back-to-the-strategies and 11mm of mercury placebo-corrected blood pressure reduction with the 2mg dibbles.

Finally, in a 2mg arm, the statistical significance of this result is extremely impressive with a p-value below 0.0001.

Additionally, on the safety side, there were no observed defects on cortisol levels and very few incidents of cytopalemia were reported.

The successful outcome follows on the heels of our announcement last week regarding the completion of full enrollment of our second phase two trial, Halo, which is expected to read out in the second half of this year. Halo is exploring the safety and efficacy of baguette strats in patients with uncontrolled hypertension. Themyatettoneinkle.com

If formation presents you the bright and result in a comprehensive way, I would like to summarize them for you.

Let me start with the efficacy results from this 248 patient trial, in which the number of patients was well-balanced, the cause three-dose strength harms, and that's one placebo.

Beyond the very impressive Ciceroic blood pressure reduction achieved with the 2 milligram dose, we also saw very nice dose response with the 1 milligram dose delivering a 7.17 point high v-meter of mercury, absolute reduction, and then 8.1 placebo corrected reduction in Ciceroic blood pressure.

Both the 1 milligram and 2 milligram dose results were highly statistically significant at p values of 0.003 and B001 respectively.

But what was also interesting was that we saw greater dose response in patients with higher baseline specific pressures above 145 millimeters of mercury, which that people adjusted the reduction of 12.1 and 11.5 millimeter of mercury for the 2 milligram dose is respected.

Importantly, no serious adverse events attributed to backs of stress after 12 weeks of treatment were reported. Although treatment-emergent SAEs were reported in 10 patients and deemed by investigators to be unrelated to backs of stress.

And while there were some isolated instances of hyperkalemia, no drug-related instances led to drug or trial discontinuation.

Again, Mason will travel as he's more detailed with you shortly.

We believe the potential market opportunity from back-to-striped is substantial and includes the broad patient population with significant unmet needs in hypertension, decayed patients with hypertension, primarily high blood se?unku z

Based on recently completed claims and analysis and tolerance data, it is estimated that up to 15 million patients in the US are food to the US. And additional 30 to 35 million patients are considered uncontrolled. This brings the estimated total addressable market in the US alone to 43 to 50 million patients. on farm bank's

Our Brighton trial addresses the resistance hypertension market, while HELLO is studying the much larger and comfortable population. And we look forward to sharing the top-lying data from HELLO in the second half of this year with the Navy and compete in all of them in good life. The Navy and compete in all of them in good life.

Let me know in the call to Dr. Mason Freeman, our chief medical officer, who will work you through the exciting top line results from the Biden trial. Dr. Mason, please go ahead.

Thank you Mark, and good morning everyone. Before jumping into the results, I want to take you through a couple of minutes to highlight backstarts mechanism action and some key attributes of the drug. And some key attributes of the drug.

To understand Bactristat's novel mechanism and how it might contribute to the management of hypertension, one needs to understand the importance of the renin-angiotensin-aldosterone system, also known as RAS, and specific hormones within RAS that regulate blood pressure in humans. The RAS pathway is likely the most highly entering twice a year for table adopted differently.

Studied and analyzed pathway in the scientific and clinical communities related to fluid and electrolyte balance. Many of the current blood pressure medicine is worked by inhibiting different steps in the RAS pathway. Despite this, there are no current medications approved for hypertension. The block the synthesis of aldostone, which is the final hormone produced in the RAS cascade. That is the fundamental mechanism of action of backstarts.

On this slide are two key steroids since the pathways in the adrenal gland. On the right, you see the catalyzing enzyme that converts the final precursor of cortisol, two cortisol, and that enzyme is called SIP-11B1. And on the left-hand side, you see there's an enzyme called SIP-11B2 that converts corticosterone into the precursor of aldosterone, and then into aldosterone in a two-stage enzymatic reaction. And then into aldosterone in a two-stage enzymatic reaction.

The key innovation with Backstreet is that the major medicinal programs at pharmaceutical companies had great difficulty synthesizing an aldosterone lowering compound that also reducing cortisol levels.

until back to your stat.

These two enzymes are 93% sequin similar. And it was the Roche chemistry group that ultimately cracked the code here on how to make a drug that could block the left hand pathway without affecting the right hand pathway.

previous drugs

Eventually failed in hypertension clinical development because of lack of selectivity between these two enzymes.

So, the key medicinal chemistry breakthrough of Bactrostat is that it does not impact cortisol levels while blocking aldosterone production.

Next slide.

Now I'm going to turn to the design of our clinical trial and its data. This is the outline of the Phase II Brighton trial and patients who have resistant hypertension. The final trial is the final trial. The final trial is the final trial.

When we say someone has resistant hypertension, it means patients must be on three or more antihypertensive agents at their maximally tolerated dose, one of which must be a diuretic. Many of the patients in our trial were actually taking four or five or more medications upon entry into the trial. We do counsel these patients during a run-in period to make sure they're taking their medicines, using a 70% compliance rate on background therapy as the threshold for inclusion in the trial.

We then reconfirmed that their blood pressure was above the 130 over 80 millimeters of mercury threshold which is the blood pressure goal for most professional medical societies.

The lowest estimated glomerular filtration rate in the study, which is a measure of kidney function, was allowed to be 45 milliliters per minute. So this is not a severely impaired CKD trial, nor is it a typical heart failure patient population that also commonly has impairments in the renal function. This is a relatively healthy hypertension population. This is a relatively healthy hypertension population.

I do want to also point out that in the Brighton trial, blood pressure was measured as the average of three seated in-office measurements in a five to ten minute span using an automated office blood pressure monitoring cuff.

The primary endpoint of Brighton was the change in cystogbote pressure from randomization to trial and at 12 weeks, comparing doses of 0.5 milligram, 1 milligram and 2 milligram of Baxter stat, 2 placebo.

The goal of BRIGHTEN was to identify effective doses of the drug and to characterize baccera sets, safety and tolerability, and treatment risks in hypertension patients.

We had secondary endpoints that Mark previously mentioned, which were changed in the diastolic pressure, and the percentage of patients achieving response of their systolic pressure to the target below 130 millimeters of mercury.

On slide nine, you see a description of the trial population.

We randomized 275 patients since this trial. One of them was not dosed, and therefore the modified intention to treat population defined as the...

population on which we do our statistical analysis is one fewer than the total randomized, or 274 patients.

You see the distribution across the dosing range.

They're well balanced between the different arms of placebo and different doses of active drug. And in a table below, we describe patients who withdrew from the trial. The total number of patients in the trial that completed is 248 patients out of the 275 that were randomized.

The table provides reasons for which are all. The ones of greatest interest would be which are all due to adverse events. A A

As you can see, there's only one withdrawal in each of the one and two milligram cohorts due to adverse events. So this is a very low number.

On the next slide, I'd like to spend one more minute on some operations around the timing with withdrawals from the trial. The mass majority of the withdrawals occurred in the first eight months of the trial when COVID was full blown, and before a vaccine was readily available. We think that many of the patients may have declined to come back because of COVID-related issues and fears of exposure clinics. The first five months of the trial, we're going to be able to do a few more minutes, and we're going to be able to do a few more minutes, and we're going to be able to do a few more minutes,

We also want to point out that after the midpoint of the trial, when the CDC mask requirement was lifted, you can see very few discontinuations in the trial at the right of that time point. Withdrawals across all doses, including placebo, were relatively equal, so we really don't think there is a drug-related concern about these trial withdrawals.

Now if we turn to slide 11, I'll provide some data on the demographics and characteristics of the patients in the trial. The mean age was 62. We had more men than women, which is typical in a hypertensive population. We had quite a diverse population with good representation of African Americans and Caucasians and a small representation of Asian and other ethnicities. We had a fairly large representation within the Caucasian portion of Hispanics or those of Latino background.

largely driven by the fact that many of the troughs sites were in Florida, Texas and California, where those populations tend to live.

On the right-hand side, you can see which background drug subjects we're on. Just a reminder, the predominant initial drug therapy and hypertension in the world today is a drug targeting the renin-angiotensin-aldosterone system, typically an ACE or an ARB, and 93% of Brighton patients took one of those drugs.

100% of patients were on diuretic by definition, of any sense, must be on a direct to be treatment resistant. And about 2-thirds of the people were taking a calcium channel blocker, 60% were taking a beta blocker.

And a very small number of other less commonly used anti-hypertensins fill out the remainder of the background regiments. texture onto the SpiderWinter profile oil coat. Now into the rest of the teammate. the background regiments.

Slide 12.

Now, again, presenting the blood pressure results in a graphic presentation. You can see that there is a clear dose response. As Mark has previously said, the 2 milligram dose delivered an absolute reduction in systolic blood pressure of 20.3 millimeters of mercury, and a placebo-adjusted reduction of 11, but the remarkably powerful statistical significance with a p-value of 0.001. The 1 milligram dose produced a 17.5 millimeters of mercury absolute reduction in systolic blood pressure.

with a placebo-corrected 8.1 mm reduction, which was also highly significant with a p-value of 0.003.

It looks like the 0.5 milligram dose provided some blood pressure reduction, certainly on an absolute basis, but on a placebo-adjusted basis, the reduction did not meet statistical significance.

As is always the case in any Phase II trial, you hope you're identifying the doses that will be taken into Phase III development programs.

In this trial, we believe we accomplished that goal in the resistant hypertension population.

And then on the right side of the slide, you see the diastolic pressures. The two milligram dose produces a 14.3 millimeter of mercury reduction with a placebo corrected 5.2 millimeters of mercury reduction, which is statistically significant. While the absolute reduction for the one milligram dose has yet to face.

was 11.8 millimeters mercury, we don't quite reach statistical significance on that dose.

Turn to slide 13 now and we'll review the safety results. These are the top line data. These are all the treatment inversion events, so this is any adverse event that occurs after a patient signs the informed consent form. You can see that the total numbers across the whole trial at the top of the chart, this is a slightly greater number of overall adverse events in the active course, but when you begin to look at where these adverse events were deemed to be related drugs.

As the third line on the table, you'll see that it's a much, much smaller number for those considered drug related. When you go to the serious adverse events, which is probably most important to physicians, you'll see that there were 18 total serious adverse effects recorded in the trial, these 18 events occurred in 10 subjects, one subject alone experienced six adverse events. This is a patient who had presumed Eurosepsis kidney failure and a variety metabolic disorders, all of which were determined by the investigators to be unrelated to the drug.

In fact, investigators in the Brighton trial deemed that none of the serious adverse events were related to the use of our drug. When you look down at the nose below the table, you'll see that there were no instances of discontinuation of drug or discontinuation for the trial to the instances of hyperculemia, which I'll be discussing more on the next slide.

On slide 14, we'll now be reviewing some more details of the potassium results in the trial. With any RAS modifying therapy, we know a key area of discussion is around sodium and potassium management. This is around sodium and potassium management.

Focus relates to the basic biology of an aldosterone, which blocks.

works by blocking kidney ion...

channels that are responsible for reabsorbing salt and fluid. Aldosterone is the hormone most responsible for the maintenance of your fluid and salt set in the body and therefore is a key contributor to your blood pressure. As one would expect, when you lower aldosterone in order to enhance sodium excretion, you see an accompanying retention of potassium in the blood. To be clear, this is entirely expected as it's part of the mechanism of action of the drug. And so you would expect to see that the serum potassium would rise. And when you're showing here.

is the magnitude, and it's the magnitude that's most important. As you can see in the placebo group, the potassium doesn't change over the course of the trial.

Looking at the active doses, we see changes that are not entirely dose dependent, but in a range of 0.19 mEq per liter to 0.36 mEq per liter across the three active doses.

The graph on the left shows the potassium over the course of a trial.

A common medical definition for mild hypercadlenemia is a potassium above 5.5. Modern hypercadlenemia is defined as above 6.0 and severe hypercadlenemia is defined as above 6.5. So immunizing serenpetassium of approximately 0.3 million equivalents from a normal baseline range of 3.5 to 5 would not typically put a patient at any risk of a hypercadlenemia complication.

It is generally understood in the medical community that a significant risk for cardiac complications only occur when potassium levels of 6.0 or higher are reached.

The instance of potassium levels greater than or equal to six are shown in the serum potassium table on the bottom right. You can see that moderate hypercadelemia, again, defined as greater than or equal to six by no, occurred in three individuals. They were all on backstarts, which is not unexpected. Of the three, one is the individual previously described with presumed urelocepsis, which is hypercadelemia was to the not related to the drug. the drug. Thank you.

The other two had per protocol, a temporary cessation of study drug was not known if they were on a placebo or a backstress at a tie, but they had to stop taking that drug because of the elevated potassium. They were both restarted on their study drug, one within two days and one within six days. Neither had a recurrence of their hypocrisy, leave me during the remainder of the trial and both completed the trial with a normal potassium level. And both completed the trial with a normal potassium level.

It is very important to note that no instances of drug-related hyperculemia led to drug or trial discontinuation. It is also important to note that no patients at... It is also important to note that no patients at...

Trial completion, cat hypergaining.

Now if we turn to slide 15, I'd like to provide you some additional insights. We think are very compelling about how backstress that worked.

When you do a blood pressure trial, you measure blood pressure in a clinical setting. But what you also want to understand is how the drug achieves that blood pressure effect. And how the drug achieves that blood pressure effect.

And that's what you're seeing on this slide.

These are mean measurements of aldostrone on the left. And you can see that the aldostrone fell in all the active treatment groups, whereas aldostrone levels for those receiving placebo were essentially constant through to the end of the trial. All of the active treatment groups reduced aldostrone with the two milligram dose doing so on a statistically significant matter. And they were doing so on a statistically significant matter.

On the same slide, you see a measurement of the physiologic consequences of aldosterone.

When you stop retaining sodium and fluid, you excrete them, and you achieve a state of sodium depletion, which is the condition producing blood pressure reduction. This is how the drugs should be working.

There's a barometric pressure reader in the kidney, and it recognizes lower fluid and cell content, and it responds by directing kidney cells to make a hormone called renin.

The expected mechanistic response to an aldosterone-alluring drug should be an increase in renin. And again, over on the right, you see an absolutely beautiful dose-dependent rise of renin, which is precisely the physiology that we'd expect from the use of this drug.

So we're not just measuring a blood pressure in the strut, we're also measuring the mechanism by which the drug works, and it works beautifully as evidence by the rise in reenin levels..

On slide 16, we're going to show you another thing we think is beautiful, but maybe you have to be a clinical pharmacologist to actually describe it with that word. This is the drug exposure data at different doses. It is really unusual to be able to see such a clear and absolutely pristine dose response in an outpatient clinical trial.

You can sometimes get this kind of response in an in-house multiple sending dose trial where all parameters for what the patient's behaviors are under control. But to get this in an outpatient trial is rare. It's just a spectacular demonstration of the well-behaved and the patient's behavior is really rare. It's just a spectacular demonstration of the well-behaved

attributes a back to set the reason this is so exciting to us is when you do drug development you have consistency like this on drug exposure you have much greater confidence in drug performance and future clinical trials

On the next slide, I'll take you through the data on a pre-specified subgroup analysis and trial population, which is for those patients whose baseline is 6,000 blood pressure greater than or equal to 145 mm Hg and those that had values below that cut point.

Historically, we have seen that blood pressure

trials typically show better blood pressure reductions.

And the higher the starting blood pressure is. As a reminder, we allowed people in stril to be randomized as 6 out of blood pressure of 130 millimeters of mercury or higher. Starting with the left chart, you can see that we get a better placebo corrected blood pressure response and the subjects that had starting cyst out blood pressures above 145. Again, as Mark already presented, Baxter stat achieved 11.5 and 12.1 millimeters of mercury reductions for those.

in the one and two milligram dose strengths respectively in this higher blood pressure cohort. And those reductions are highly statistically significant compared to the placebo response.

It's important to point out that all hypertension trials have different patient populations.

and entry criteria can also differ. So it can be helpful to view our data in the context of hypertension drugs used in resistant hypertension previously.

Looking at the data on this slide, remember that this is not a head-to-head trial nor a crossover trial. So this is not a rigorous scientific comparison. We're comparing Baxersat to publish data from a well-known resistant hypertension trial called Pathway 2.

It's important to point out that the minimum baseline systolic pressure for inclusion pathway two was higher than used in our trial. That is higher than 130 millimeters of mercury. What you can see is that the pathway trial measures the blood pressure in two ways. They did a home blood pressure measurement, which is typically lower because you're moving some of the anxiety and stress people feel when they come into a medical facility. There means systolic home blood pressure in 335 patients was 147.6.

but they also measured the blood pressure in the same patients in a clinic setting and the baseline pressure was approximately 10 points higher at 157 millimeters of mercury.

Their placebo corrected chain from baseline using this clinic-based measurement, which is what we did also, was 9.9 millimeters of mercury. In our subgroup it announced the patient's just dog blood pressure was greater than equal to 145. We had a hundred and 55 subjects representing more than half the people in our trial. The mean baseline just dog blood pressure for this group was a hundred and fifty six millimeters of mercury. So we think this number compelters well to the baseline just dog blood pressure on the clinic-based data from the pathway.

is extremely encouraging, as is the tolerability of the agents when viewed in the context of the concurrent use of multiple background antihypertensive medications.

I'll now turn to slide 18, which is an introduction to Dr. Baud.

Dr. Deepak Bhatt is the Executive Director of International Cardiovascular Programs at Brigham and Women's Hospital and he is a Professor of Medicine at Harvard Medical School in Boston.

Deep back is going to share his perspectives and clinical experiences in treating patients with resistant hypertension and reflect on how backstatt might fit into the treatment paradigm for these patients in light of the bright and trial results. For these patients in light of the bright and trial results.

Thank you very much.

Hopefully you can hear me well. And let me say, you know, it's really a pleasure to be with you and to share my own perspectives in treating hypertensive patients over several years, as well as my involvement in numerous clinical trials, including in the space of hypertension. So before just getting into my thoughts, first let me congratulate you on the successful completion of the BRITE hypertension trial and, of course, the positive results that you achieved..

Overall, I'd say that the double digit reduction in blood pressure, the well tolerated safety profile, the titratable dose response with once daily documented by the doctor that the stat has.

Will potential to address multiple unmet needs in the treatment of resistant hypertension patients? Will potential to address multiple unmet needs in the treatment of resistant hypertension patients? Will potential to address multiple unmet needs in the treatment of resistant hypertension patients?

There are many patients like this in real-world clinical practice that have resistant hypertension as well as poorly controlled hypertension.

When patients are maxed out on currently available, blood pressure lowering, that there are limited options for their treatments at the present time. And the introduction of a novel mechanism of action for a low end blood pressure, I think is really quite overdue and would be welcomed by physicians who are struggling to treat their resistant hypertension patients.

Given the recognition by physicians of the importance of aldosterone's regulation of blood pressure, I would expect them to be excited and comfortable with back-order stat if approved. And comfortable with back-order stat if approved.

And well, Scrono lactone has been around for a long time. The concerns about gynecumastia, breast tenderness and sexual dysfunction have limited its use. And the concerns also have been there about hypercalemia, which I think were in part magnified by lack of education or appropriate marketing to physicians to guide its optimal and appropriate use. And the concerns about hypercalemia are limited to physicians to guide their own and appropriate use. And the concerns about hypercalemia are limited to physicians to guide their own and appropriate use.

The low rates of hyperkalemia seen in bright hypertension are encouraging since more than 90% of the bright hypertension participants want background anti-hypertensives that are often challenging to use because of the risk of hyperkalemia that they cause when they're co-administered with aldosterone blocking agents. So overall, I'd say I'm really very excited about this science and I think there's a lot of potential here in terms of a major advance in patient care.

So with that, let me turn things back over to the synchro team. Thank you very much for sharing your thoughts Dr. Bat.

I'd like to quickly summarize our Q2 results. As indicated in our second quarter release earlier today, Stincor ended the quarter with a strong balance sheet. As of June 30th, 2022, our cash and cash equivalence totaled $294.3 million, as compared to $314.2 million at March 31st, and no debt. We expect this cash balance will fund our operations through 2024, including completing all of our ongoing Phase 2 trials.

our currently planned Phase III clinical program and hypertension, GMC development and GMP batch production, and the additional activities needed to complete our planned NDA submission.

Other expected areas include scaling up manufacturing, preparation for regulatory submissions, initiating our pre-commercialization activities, and finally funding our company's ongoing operating expenses.

In summary, following our successful IPO in January and the earlier private financing rounds, we believe Sincor is well positioned to explore the full potential of backstarts set for the benefit of patients, clinicians, and our shareholders.

We look forward to keeping you updated on our future private.

With that, I'll turn the call back over to Mark for some concluding remarks. Mark.

Thanks Thierry. With the brilliant data in hand, we intend to quickly move towards requesting an annual Phase II meeting with the FDA, which we would expect to take place before year-end.

That meeting and the results from Bryden together with the anticipated results from the ELO trial which recently completed its randomization and is expected to read out in the second half of this year.

The tenable S to design of the two programming X attention, which we hope to stop in the first hour of 2023.

In 22 2022, we initiated an open label extension trial, which we call OLE trial, and which will study the safety and tolerability of bags or straps in patients for up to 52 weeks.

Patient from the LL trial has the option to enroll in that trial as they complete the 12 weeks in HELLO and I'm pleased to report that more than 95% of the patients who have already completed the LL source. The patients who have already completed the LL source.

to transition into the OLE trial.

Also, in Q2, we initiated our phase 2 clinical trial in chronic kidney disease patients with uncontrolled hypertension.

This trial is called fightin CKD and top-line data for this trial is expected in this to read in the second half of 2023 the aim of the fighting Trial is to understand the breadth of the CKD population which can potentially be safely treated with a diverse threat

Finally, our Facebook clinical trials sparked P8, but initiated in 2021 to evaluate better stratum patients with primary alatheracianism, or P8. And we expect to report offline data just to go to half of 2022. And just to go to half of 2022. And just to go to half of 2022.

We believe both programs in CKD and PA represent a potential upside to the already large height potential.

opportunity.

Conclusion!

We believe that with the results obtained in the Brighton trial a new and exceptionally important chapter in the treatment of hypertension is beginning.

This is a combination of 20 years of research in the other side of the field, which we are now leading. And we are just getting started.

By your end, assuming positive results from our AIL trial, we should be able to report how BACSOS TREAD could also address the unmet medical need with the uncontrolled eye potential population, which is nearly threefold the size of the resistance eye potential population. Assuming success in the AILO population and expanding the label for BACSOS TREAD is approved, could amplify the market's opportunity beyond what we believe is already drug-buster potential and perder, whether through much easier the case could and take the pension.

We are very proud of the results that she today and be able to potentially bring to market and he brought in two old doctors to combat hypertension. He brought in two old doctors to combat hypertension.

Finally, I want to thank all the patients, medical staff in the clinics, and all our finger-to-beam who have contributed to the success of the Brighton trial. We have contributed to the success of the Brighton trial.

Looking forward to continuing to explore the full potential of vagal stress and most importantly to bring this novel therapeutic option to millions of patients needing to control their breath pressure. Story.

Thank you. We will now take questions.

Please bear in mind that we will be preserving more details from the trial, including, for example, subpopulation analysis of future publication and conference consideration.

In addition, we just received the Brighton trial results past in the process of doing cellular analysis.

Operator, please begin the Q&A session.

Thank you very much. At this time, we will be conducting a question and answer session. If you would like to ask a question, please press star and then one on your telephone keypad. A confirmation tone will indicate your line is in the question queue.

You may press star into if you would like to remove your question from the queue.

For participants using speaker equipment, it may be necessary for you to pick up your handset before pressing the star keys. One moment please while we poll for questions.

The first question comes from Umer Raffert from Evercore ISI. Please proceed with your question, Umer.

Hi guys, thanks for my question. Thanks for taking my question. Congratulations on the data. Maybe a couple for the expert on the cause as well as one for you guys as well. The five millimeter mercury observation on a dot-stallic but pressure, I feel like it'll be interesting to hear Dr. Pot, your take on the clinical relevance of that outside of all the SBP findings, as well as how you would characterize today's results, acknowledging all the cross trial limitations versus pathway two.

And then just quickly for the company management as well, I know on slides you mentioned no observed effect on cortisol. I'm assuming that was on a trial mean basis. Could you also speak to any observations on an individual level basis? Well, even if they weren't worsen. Thank you very much.

All right, so we'll start. Dr. But will respond first and then Mason will respond on the cortisol. Dr. That.

Yeah, those were really great questions, I should say. Let me start with the first one, which I particularly like about diastolic blood pressure. And you're right. I mean, there was a significant about five millimeter mercury placebo-corrected drop in diastolic blood pressure with the highest dose. And I think that's really important. Physicians tend to focus on systolic blood pressure in general, and I think are not in all cases aware of the fact that diastolic blood pressure counts too, that it's really important. honour, patients.

Thank you very much for sharing your thoughts doctor, but I.

I'd like to quickly summarize our Q2 results as indicated in our second quarter released earlier to date Syncor ended the quarter with a strong balance sheet as of June 32022, our cash and cash equivalents totaled $294 3 million as compared to $314 2 million at March 31, and no debt we expect.

This cash balance will fund our operations through 2024, including completing all of our ongoing phase II trials.

Our currently planned phase III clinical program in hypertension, CMC development, and GMP batch production and the additional activities needed to complete our planned NDA submission.

higher systolic blood pressure and worse, worse cardiovascular outcomes, but we also found an independent association with diastolic blood pressure. So diastolic blood pressure is important too. It's harder to influence. So to me in terms of the potential for this to reduce cardiovascular outcomes, I think the fact that there was a large double digit decrease and blood pressure is very, very encouraging, but on top of that, a reduction in diastolic blood pressure one would protect.

Other expected areas include scaling up manufacturing preparations for regulatory submissions initiating our pre commercialization activities and finally funding our company's ongoing operating expenses in summary, following our successful IPO in January and the earlier private financing rounds, we believe <unk> is well positioned to explore the full.

Potential at Baxter set for the benefit of patients clinicians and our shareholders.

that there would be a substantial benefit and with respect to cardiovascular outcomes. As far as your second question goes, pathway two and so forth, I thought that was a good trial, by the way. You know, I think.

We look forward to keeping you updated on our future progress.

With that I'll turn the call back over to Mark for some concluding remarks mark.

Thanks, Terry with Brian and the data in hand.

Here with this drug, we're seeing a double digit reduction in blood pressure with the highest dose, even placebo corrected. So, and in real life, of course, we're just looking at what blood pressure reduction occurs with medicine. There's no placebo in real life. That's more important in the context of clinical trials and regulatory filing and so forth. So in real life, it's really quite a substantial blood pressure reduction that the doctor and the patient could see as the drug's approved. But with respect to the placebo corrected reduction, even that with the...

Intend to quickly move towards requesting amendment phase two meeting with the FDA, which we would expect to take place before year end does.

At that meeting and the results from Brighton together with the anticipated results from the <unk> trial, which recently completed its randomization.

It to readout in the second half of this year.

Enable us to design, our phase III program unites attention, which we hope to stop in the first half of 2023.

In Q2 of 2022.

Initiated in the open label extension trial, which we call <unk>.

And which will study the safety and Tolerability of Douglas dropped patient for up to 52 weeks.

<unk> from the Arrow trial have the option to enroll that trial until we completed the 12 weeks Hello, and I am pleased to report that more than 95% of the patients who have already completed a halo chose to transition into the OLED trial.

pathway to. You know, a challenge with spironolactone is just real life. That is, every medical student used to learn and still learns, you know, that spironolactone can cause gynecomastia. And that's really a problematic side effect when it occurs. It is typically painful, so it's not just a potential cosmetic issue. It's actually a painful issue. And then also the potential for sexual dysfunction. So the fact that these truly exist as side effects.

Also in Q2, we initiated our phase II clinical trial in chronic kidney disease patients with uncontrolled hypertension.

This trial is called <unk> and top line data for this trial is expected.

To read in the second half of 2023.

The aim of the Titan.

While to understand the breadth of the CTD population, which can potentially be safely treated with your bedroom strep.

And additionally, every physician, if they know nothing else about Sporanolactone has been forced to memorize those side effects, you know, has really hampered the use of Sporanolactone. And you know, it's obviously a generic drug, and I think a good drug, by the way. But the fact that there isn't anyone out there, you know, marketing it or educating about it has further hampered its uptake. The hyperclemia associated with it as well also hurt it because when it came out,

Finally, our phase two clinical trials <unk> was initiated in 2021 to evaluate <unk> in patients with primary Aldosteronism Opa and we expect to report topline data in the second half of 2023.

We believe both programs in <unk> NPA represent potential upside to the already large pension opportunity.

In conclusion.

initially if you would call, there would then a number of reports of hypercalemia. Honestly, I think it was sort of a little bit too much, but that was the problem. There was no one sort of educating how to use spirono-lactone appropriately when good data came out about it. I'm talking about some of the older heart failure trials like valves. And then it has got tarnished with this image on top of the gynecumastia, I don't know, now it also is causing hypercalemia. More so, as I think physicians were comfortable with at the time. So that's really...

We believe that with the results obtained in the Brighton trial.

A new an exceptionally important chapter in the treatment of hypertension is beginning.

This is a combination of 20 years of research in the field, which we are now leading and we are just getting started by year end, assuming positive results from our <unk> trial, which would be able to report our backfill scrap could also address the unmet medical need with the uncontrolled hypertension population, which is real.

Three fold the size of the resistant hypertension population assuming success in yellow population.

The label for <unk>, if approved could amplify the market opportunity beyond what we believe is the already blockbuster potential.

Since like the pension.

We're very proud of the results achieved to date and be able to potentially bring to market are important tool for doctors to combat hypertension.

Finally, I want to thank all of the patients medical staffing the clinics.

Our <unk> team, who have contributed to the success of the bright in the trial were.

So overall, I think.

The data are quite strong and when viewed in the context of history of Spur on a Lactown here, I think the lack of mechanism for side effects like gynecumastia and sexual dysfunction will be very differentiating. And I think the ability for the company to launch a drug, again assuming it's approved, to launch a drug that would also fall in appropriate education and use, you know, should make it much, much more appealing and safer to use and Spur on a Lactown.

We're looking forward to continuing to explore the full potential of <unk> and most importantly to bringing this novel therapeutic option to millions of patients to control their blood pressure.

Thank you.

Now take questions.

Please bear in mind that we'll be presenting more details from the trial, including for example, a subpopulation analysis for future publication in conference consideration.

In addition.

We just received the Brian <unk> trial results as soon as the process of doing something right analysis.

Operator, please begin the Q&A session.

Thank you very much sir.

At this time, we will be conducting a question and answer session. If you would like to ask a question. Please press star one on your telephone keypad.

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adrenalin and sufficiency discovered, reported, are seen and bright.

All participants using speaker equipment, it may be necessary for you to pick up your handset before pressing the star keys, one moment, please while we poll for questions.

Thank you very much.

Thank you. We can take the next question or barrage.

The next question comes from Dennis Bing from Jefferies. Please proceed with your question, Dennis.

Yes.

Thanks for taking the question and congratulations on the data. And congratulations on achieving the double digit reduction that the data looks really strong. So two questions from me. Can you just comment on your thoughts on the lead through to the Halo study? Specifically, how should we think about the insect size moving into earlier lines? And maybe just comment about the range of placebo effects in this earlier population too.

The first question comes from Ross <unk> from Evercore ISI. Please proceed with your question there.

Hi, guys. Thanks for my quick Thanks for taking my question and congratulations on the data maybe a couple for the expert on the call as well as one for you guys as well.

Five.

Five millimeter mercury observational or diastolic blood pressure I feel like it'll be interesting to hear Dr. Paul Your take on the clinical relevance of that outside of all of the SPP findings as well as how you would characterize today's results acknowledging all the cross trial limitations versus pathway too.

And then my second question is more around the safety, specifically hypercolineia. Can you comment on what was the percentage of patients who had a response to full mislead between your coronavirus operations?

And then just quickly for the company management as well I know on slide you mentioned new observed effect on cortisol.

We're above 5 or 5.5 milliequivalents. And is there a breakdown in terms of severity for the 2 milligram arm? And if you can put that into context with spironolactone, what it showed, that'd be very helpful too. Thank you.

I'm, assuming that was on a trial basis could you also speak to any observations on an individual level basis, well, even if they werent worrisome. Thank you very much.

Alright, so serious.

Dr Vascular they respond first and then the basin, we don't respond on the cortisol, but Tibet.

Okay, thanks. So, this summation is going to take those questions, the kids to achieveiamo question.

Those were really great questions I should say, let me start with the first one which I, particularly like about diastolic blood pressure and Youre right. I mean, there was a significant about five.

Jason.

I think there are certain elements of a read through to Halo that would be encouraging from Brighton to predict that the probability of success is higher in Halo now that Brighton has been published. But there are also some caveats about making any conclusion in an ongoing trial where you haven't unblinded the data. Clearly the drug behavior and the measurements on the hormones that we showed, there's no reason to believe that we won't replicate those. I believe in Halo. But when it comes to a completely different population of people who have

Millimetre of Mercury, a placebo corrected drop in diastolic blood pressure with the highest dose and I think that's really important.

<unk> tend to focus on systolic blood pressure in general and I think are not in all cases aware of the fact that diastolic blood pressure accounts too that it's really important with patients. So I think a lot of patients don't realize it.

Portance of diastolic blood pressure in 2019, I was the senior author on our paper and the narrow <unk> medicine.

It was a collaboration with Kaiser health care system, we looked at over a million patients and they're large.

The greater health care system, and electronic Health records with over 6 million blood pressure measurement. So big data analysis, and we found of course, a significant association between higher systolic blood pressure and worse comes worse cardiovascular outcomes, but we also found an independent.

done yet. And furthermore, there's always the possibility that you will get variations in the placebo response depending on the patients that actually agree to be in the trial. And so, I don't believe that we can predict the halo outcome with certainly any certainty as a result of the BRIGHTEN trial. But I'm certainly highly encouraged by our hormonal responses, which I believe should be quite similar in that study. And I think that the blood pressure results will follow according to how we lower the raldosterone and...

Association with diastolic blood pressure, so diastolic blood pressure is important to it's harder to influence so to me in terms of the potential for this drug to reduce cardiovascular outcomes. I think the fact that there was a large double digit decrease in blood pressure is very very encouraging but on top of that.

<unk> diastolic blood pressure one would predict.

There'll be a substantial benefit.

With respect to cardiovascular outcomes as far as your second question goes pathway to and so forth I thought that was a good trial by the way.

Thank you.

Here with this drug we are seeing a double digit Roe.

Reduction in blood pressure with the highest dose even placebo corrected so in real life of course, we're looking at what blood pressure reduction occurs where the medicine. There is no placebo in real life, that's more important in the context of clinical trials and.

Regulatory filings and so forth so in real life, it's really quite a substantial blood pressure reduction with the doctor and the patient could see if the drug is approved but with respect to the placebo corrected reduction even that with the two milligrams is double digit so.

whether that will be the same in the Halo study or not. With respect to your potassium question, what I think is interesting is the evolution, I believe, and maybe Dr. Botcan make a comment about that, the evolution, the thinking about potassium, in part, things that he said about Sprone Black, John Sprone Black, so made potassium a lot more of a concern in the medical community because of the hypercaling make risk after the raw study, which was a heart failure study. And I think what is a little appreciated by...

Most physicians, who see this data would view it as a really important advance I think that's sort of a psychological threshold, where physicians say, yeah. That's really important with respect to blood pressure changes, it's not that single digit reductions when consistent are important they are but just in terms of what gets physicians really excited.

people who haven't delved deeply in this and I've spent a good part of the last 15 years, I actually helped contribute to make one of the first potassium lowering drug called Paterma, so that Sprenolactone might be used more aggressively because of the benefit of the heart failure trial. But I think people didn't realize that the hyperkalemia and Sprenolactone came from large part because of clinicians in the community using inappropriate doses, doses that were not used in that trial.

I think the double digit we will do that now with respect to pathway to challenge with sprawling of Lockdown is just real life that is every medical student you still earn it still learns.

Spring of Lockdown can cause gynaecomastia, and that's really a problematic side effects when it occurs.

Typically painful alright, so its not just a potential cosmetic issue, it's actually a painful issue and then also the potential for sexual dysfunction. So the fact that these truly exist as side effects and Additionally, every physician if they know nothing else about spring of Lockdown has been.

and also because they didn't recognize the need to very selectively pick the patients for those trials. So I think those are two things that have made that hypercalemia risk seem greater than I've taken in appropriate care setting it might be. But the point is that potassium levels are now reported mostly around grade and the six because cardiac complications and I'd love to have Dr. Bot common on this, really don't appear to occur until you get above six. And you don't really don't appear to occur until you get above six.

<unk> been forced to memorize those side effects.

We hampered the use of square on a lockdown.

Obviously, a generic drug and I think a good drug by the way, but the fact that there isn't anyone out there.

Marketing it or educating above it has further hampered its uptake.

We did measure potassium, of course, at all levels throughout the study. Nowadays people often report the number, they don't even report the number, it's about 5.5, unless they're consecutive measurements. Meaning it's been confirmed because you don't take people off the drug and you can do it. And I can just tell you, on top line, the number of people they consecutive low measurements in the chart was very, very, very low. So we're comfortable as was our SAB and all of the KOLs we've talked to at the potassium levels with our Dr. Linda Musons voyages.

Hyperkalemia associated with it as well also hurt it because when it came out.

Actually if you recall that within a number of reports of hyperkalemia honestly I think it was sort of a little bit too much but that was the problem. There was no one sort of educating how to use <unk> grown our lactone appropriately when good data came out about it I'm talking about some of the older heart failure trials like walls and then if it's got <unk>.

With this image on top of the Gynaecomasty I don't know and I would also was causing hyperkalemia.

More so.

Physicians were comfortable with at the time, so that's really hurts grown our lactone I think having in this case, a branded medicine that can reduce blood pressure substantially, but where there would be appropriate educating and marketing about yes, you have to work out for hyperkalemia I think can make it a very <unk>.

And physicians are used to measuring potassium, for that matter, creatinine, other electrolytes when they're initiating ACE inhibitors, OBS. I mean, we always check those bloods after initiating those drugs. So measuring potassium per se isn't really an issue. I think Mason really pointed out the issue with spironolactone was when it was, again, was really launched, when the great data for heart failure came out and there should have been a large spike in its use. It didn't happen because of the initial use.

<unk> potential issue and the actual numbers that we're seeing here in the trial I thought looked pretty good in terms of.

The threshold of hyperkalemia, where doctors, where we get nervous when it gets above six so overall I think.

The data are quite strong and when viewed in the context of <unk>.

Our history of strong Lockdown here I think the lack of a mechanism for side effects like kind of capacity and sexual dysfunction will be very good.

was inappropriate. So it wasn't just that there was high potassium, it's that physicians were using way higher doses that were actually used in the trial and weren't monitoring the potassium appropriately. I mean, those are all consequences of, you know, there not being a spironolactone launch where there would have been appropriate education and appropriate marketing around it to make sure that the right patients were getting the drug at the correct dose with the correct sort of laboratory monitoring afterwards. So, you know, here presumably with what would be a commercial drug launch that those sorts of issues would come into play.

<unk> and I think the ability for the company to launch a drug again, assuming it's approved to launch a drug.

Also fold in appropriate education and use should make it much much more appealing and safer to use in spring of lockdown by Mr. Generic which is sort of launch by nobody just buy data and then really never got the uptake, but it deserved.

Thanks.

So Nathan can you comment on the cost to go over to a question from Omar.

And then we just need to compliment that, we are going to invest medical affairs at this organization at Post-Brighten because now that we have those results, we start the education around physicians about the importance of allocereontal op-reg could be an important treatment in the future if approved. Vence.

So the question was yes, we have no reduction of cortisol level on a mean.

Estimate, but it was there any evidence of any adrenal insufficiency in any patient in the trial of the answer to that is no there was no.

Adrenal insufficiency discovery reported are seeing in Brighton.

Thank you very much.

Next question, operating.

I think you can take the next question operator.

Yeah.

Thank you. The next question comes from Jay Orton from Wappenheim, please proceed with your question, Jay.

Thank you. The next question comes from David <unk> from Jefferies. Please proceed with your question Dennis.

These really impressive results and thank you for taking the questions. I have a question for Dr. Bhat. If you could please comment on the importance of the very strong dose response and the magnitude of reduction in systolic blood pressure. And based on that profile, how he expects Baxter's that to fit into clinical practice in terms of when he would prescribe which doses and to which patients. The hard work heEd is that what you are correct on is how lots of people's reactions and the magnitude of famine are more difficult to get to.

Hi, good morning, Thanks for taking the question and congratulations on the data and congratulations on achieving the double digit reduction.

The data looks really strong so.

Two questions from me can you just comment on your.

Your thoughts on the read through to the Halo study.

Specifically, how should we think about the effect size moving into earlier lines and maybe just comment about the range of placebo effect in this earlier population too.

And then maybe one safety related observation about the magnitude of...

And then maybe one safety related observation about the magnitude of serum potassium level increases, What I'm going to see you because but maybe it or not?

And then my second question is more around the safety specifically hyperkalemia can you comment on what was the percentage.

seemed very small with BaxterSat and really nice to see especially in patients taking multiple antihypertensives. So any comments you could share from a biological perspective on the overall rates of hyperplasia would be great. Thank you.

Ah patients who.

We're above $5 $5 5 million equivalents.

And is there a breakdown in terms of severity for the two milligram arm and if you can put that into context with <unk>.

Yeah, I think those are terrific questions and points that you raised in the question. So just starting with the blood pressure, I mean, you know, these are large blood pressure reductions for sure. When we're looking again in real life, a physician or a patient would see the actual blood pressure reduction, there won't be a placebo-corrected reduction, of course. So, you know, having a 20-millimeter reduction with the 2-milligram or, you know, a 17-ish millimeter of mercury reduction with the 1-milligram, those are large reductions by anyone. So that's sort of estimation and...

<unk> with its showed that'd be very helpful too. Thank you.

Okay. Thanks.

So Jason is going to take those to the question of the read through of at OMB.

No question.

Awesome.

Yeah, well I think there are certain elements of a read through to hail that would be.

Encouraging from Brighton to predict that the probability of success is higher and Halo now that Britain has been published but there are also some caveats about making any conclusion, then an ongoing trial, where you have an unblinded the data I mean.

Clearly the drug behavior and the measurements on the hormones that we showed there is no reason to believe that we won't replicate those I believe in halo, but when it comes to a completely different population of people who have.

Less severely are aggressively treated hypertension is so don't are not people on two or more drugs. They are not required to be honest there I radically.

In our trial will be other on and Acer and our orientation are plus a diuretic orientation or a plus of calcium channel blocker.

blood pressure can translate into significant reductions in heart attacks, stroke, heart failure, kidney failure. So this, if, if, if, uh, uh, encoded the calculations, you know, would extract weight out to pretty substantial reductions in cardiovascular risk based on, you know, again, observational data. So, to me, the results really are quite large and impressive. And, you know, if you think about renal derivations, for example, obviously that's a device, not a drug, my hope is that'll also ultimately get FDA approved, you know, it's...

Understanding what the result will be in that trial would require detailed subgroup analysis of Brighton around all of those features I just described which has not been done yet and Furthermore, theres always the possibility that you will get variations in the placebo response, depending on the patients that actually agree to be in the trial and so.

I don't believe that we can predict a halo outcome with certainly any certainty.

Got some data in the resistant hypertension space, but we're not really seeing to date in sham controlled studies at least blood pressure reductions that are quite this large, yet I think that therapy will still get approved. So here to have something that with a pill can provide such incremental blood pressure reduction over and above at least three got pertensives. I think physicians will unequivocally view this as a major advance. And I think there's a lot of exciting stuff happening in the resistant hypertension space. So be nice.

As a result of the bright and trial, but I'm certainly highly encouraged by our hormonal responses, which I believe should be quite similar in that study and I think that the blood pressure results will follow.

According to Howe.

Lower their aldosterone and.

Yeah.

Lead to activation and reading, indicating theyre, an assault depleted state placebo responses, we as before we got the result, we have been measuring.

Mentioning a meta analysis by Patel, where the.

But the placebo responses had varied from about five to a little over eight we had nine in this study. So we had a little higher placebo response than we thought that we were likely to have but not much higher. So I don't know whether that will be the same in the halo study or not.

With respect to your potassium question.

What I think is interesting is the evolution I believe and maybe Dr. Bob can make a comment about that the evolution in the <unk>.

Thinking about potassium.

Things that he said about spring lack jonesboro made.

medicine, even if it doesn't meet the classic definition. There's a lot of these folks out there. So, and physicians don't know what to do with them right now. And a lot of times they're landing in an emergency room or something because the blood pressure is really high. They call their primary care physician. Primary care physician here is this high number. They get sent to the emergency department. So, you know, it's not just the cardiovascular risks associated without a control, resist and hypertension. It's also the healthcare resource utilization, which tends to be high. So, I make physicians.

Made potassium a lot more of a concern in the medical community because of the hybrid Caitlin risk. After the routes study, which was a heart failure study and I think as little appreciated by people, who haven't delve deeply in this and I've spent a good part of the last 15 years I actually helped contribute to make one of the first <unk>.

The first potassium lowering drug called procurement.

So that <unk> might be used more.

More aggressively because of the benefit in the heart failure trial, but I think people didn't realize that the hyperscale.

Again, assuming that drugs approve for this indication would really welcome it and embrace it is what I would predict. And as far as the hypochemia, not part of your question, you know, there I think this is at least what we can see in the context of this phase. 212 seems to be a really manageable low level of hypochemia. The initial users of this medicine, I mean, prescribers by users are going to likely be physicians that are particularly expert in hypertension and for them, you know, this degree of hypochemia is an even better.

Hypokalemia in front of Lockdown came from large part because of clinicians within community using inappropriate doses doses that were not used in that trial and also because they didn't recognize the need to very selectively.

Pick the patients for those trials. So I think those are two things that have made that hyperkalemia risk seemed greater than I think and an appropriate care setting it might be but the point is that potassium levels are now reported mostly around greater than six because cardiac complications and I'd love to have talked about comment on this really don't appeared.

just are on their radar of concerns and you know, SIMCORs already sort of chatted with many of the leading hypertension experts to get their pulse and to date at least the folks that I've heard a pine on it in private to SIMCOR haven't found this to be an issue. Obviously, you know, there needs to be a larger phase three, 12 more data is coming with halo and other planned studies, but what we consider to date to me looks really encouraging in terms of something that's highly effective for low-end blood pressure.

To occur until you get above six we did measure on <unk>.

Potassium is of course at all levels throughout the study nowadays people often report the number of.

They don't even report the number of about $5 five unless theyre consecutive measurements mean, it's been confirmed because you don't take people off the drug and you can do it and I can just tell you top line the number of people by consecutive low measurements as Joe was very very very low so.

and also appears to be quite safe. Okay, thanks Dr. Bhat. So we'll take probably the next question and I know we are running a bit behind some.

We're comfortable as was our SAP and all of the Kols, who we've talked to at the potassium levels that we have achieved but more work will be done and further analyzing that question to see if one can separate out the patients who tend to have a bigger ryzen and others.

Thank you. The next question comes from Jeff Hulme from Morgan Stanley . Please proceed with your question Jeff.

Congratulations on the update and thanks for taking my questions. First I guess how high did the potassium levels go in the three patients who had potassium above six? And then for Dr. Butt for this patient population just to clarify, can you talk about the patients who you think might be better treated with backstreet stat and are there any subgroups of patients who might not be as good candidates for treatment? Thank you.

Yes.

Okay.

I don't really have much that other than I would corroborate that last point that I think the sort of.

Level, where physicians will get concerned and as actionable as with respect to potassium would be above six physicians are used to measuring <unk>.

Potassium for that matter of creatinine other electrolyzed when they are initiating ace inhibitors or arbs I mean, we're always check those floods.

Thanks. I'm going to ask the highest potassium in those three patients with 6.3. The highest potassium in those three patients was 6.3.

Initiating those drugs, so measuring potassium per se isn't really an issue.

In 1 of them.

I think it makes it really pointed out the issue with square in a lockdown was when it was.

The others were lower than that. Okay. Dr. Bat, can you comment on the... Okay.

Again, it was really launch when it.

Great data for heart failure came out and there should have been a large spike in its use it happened because of the initial use within appropriate. So it wasn't just that there was high capacity. Mr. Physicians were using way higher doses that were actually used in the trial and then werent monitoring the potassium appropriately I mean, those are all consequences of there not being a sprawling lactone.

The sub population.

I have to comment on which subpopulation.

Where the drug could be particularly effective or safe.

We do have.

Where could be what could you repeat that? It sort of cut out there for a minute. I sure. But that's the fact that just looking for whether there's any reason to believe that there might be some populations that would be particularly benefited by this drug that you could have done. Oh, yeah, that's a terrific question. So first of all, I think the population is it was defined here, resistant hypertension, meets the rigid official definitions. And I would say that population.

Launch, where they would have been appropriate education and appropriate marketing around it to make sure that the right patients were getting the drug at the correct dose with the correct sort of laboratory monitoring afterwards so.

Presumably with what would be a commercial drug launch of those sorts of issues come into play.

And then maybe just to complement that we are going to invest.

Maybe you could I fasteners the organization.

Post brightened because now that we have those results. So we stopped the education.

Around the physicians adopt importance of industrial.

Our drug could be an important.

<unk> if approved.

Next question operator.

Thank you. The next question comes from Jay Olson from Oppenheimer. Please proceed with your question James.

Some of these really impressive results and thank you for taking the questions I have.

increasing centers that focused on treating resistant hypertension. And once there are effective approved therapies, that tends to lead to more awareness of disease states among.

A question for Dr. Bob If you could please comment on the importance of the very strong dose response, and the magnitude of reduction in systolic blood pressure.

physicians among hospitals starting thinking of starting programs among patients themselves But I think the potential convergence of a drug that may get approved for resistant hypertension and Devices that may improve for resistant hypertension will lead to a lot more attention to the therapeutic area I mean, it's what happens you think about pulmonary hypertension for example It's been around forever. It's been a big problem for but nobody really

Based on that profile, how he expects Baxter stats are fit into clinical practice in terms of.

When he would prescribe which doses into which patients and then maybe one safety related observation about the magnitude of.

Serum potassium muddle increases, which.

It seemed very small with Baxter sat and really nice to see especially in patients taking multiple antihypertensive. So any comments you can share from a biological perspective on the overall rates and how quickly you would be great. Thank you.

was focusing attention on it until there were approved drugs that were available, and then pulmonary hypertension is popping up all over the place. The same sort of thing with amyloid once there were effective therapies that were FDA approved for it. So I see the same thing playing out here, though perhaps to a much larger scale than those more niche disease areas that I just alluded to because there's a lot of resistant hypertension out there, especially once you kind of relax the definition as I think would happen in real life to not just the very rigid sort of guideline.

Yes, I think things are terrific questions and points that you raised in the questions. So just starting with the blood pressure I mean, these are large blood pressure reductions for sure.

We are.

Again in real life, a physician or a patient would see the actual blood pressure reduction there won't be a placebo corrected reduction of course, so having a 20 millimeter reduction with the two milligram or 17 ish millimeter of Mercury reduction with the one milligram dose or large reductions by anyone's sort of estimation.

recommendation but the more common sense recommendation that you've got a patient maxed out on drugs whether it's three But it might be less than three in terms of what they can tolerate and you know their blood pressure is still not a target What are you going to do with them in real life then you've already maxed out on whatever generic drugs are available that they can tolerate So I think those sorts of patients

And having the.

At least with the higher dose the diastolic blood pressure reduction thats, even significant placebo corrected. So the results you know in many respects I think.

Speak for themselves and are very strong and I think physicians would view them that way.

You know, just based on these types of data would be where the drug would be used. And if, you know, trials like Halo are also positive that would further expand, you know, the potential patients that could benefit. And, you know, I can't pick what Halo is gonna show. I think Mason did a nice job sort of weighing out what the possibilities were, you know, one might expect that there'd be blood pressure reductions of this sort of magnitude when...

Firstly, I think even single digit blood pressure reductions when there are significant are important to the large observational studies that have been done show that even a few millimeters of mercury reduction in blood pressure can translate into significant reductions in heart attack stroke heart failure kidney failure.

If.

Suncor did the calculations.

There's less medicines on board. Alternatively, one could predict there might be less in a population that doesn't have just such a resistant hypertension, so to speak. But I think what we can say from the study and the data in front of us right now is the fact that there seem to be a consistent benefit in the different subgroups that have been analyzed, though not detailed here, to me is encouraging that this mechanism action isn't just for specific, very targeted subpopulation of folks about a control hypertension, but likely.

Scrap weighed out to a pretty substantial reductions in cardiovascular risk based on again observational data so.

The results really are quite large and impressive.

And if you think about renal denervation for example, obviously that's a device not a drug my hope is that will also ultimately get FDA approved.

Got some data in the resistant hypertension space, but we're not really seeing to date and sham controlled studies at least blood pressure reduction et cetera.

Quite this large yes, I think that therapy will still get approved so here to have.

applies very broadly. So, Deepak, I know we're running out of time, but I think the second part of this question was also, other subpopulations, maybe, particularly, we're thinking about heart failure or people with CKD, for which we have no data, but do you think there could be a role in those disorders? Oh, okay. Sure. No, no. It was a 30,000-foot-view question. I didn't hear it in its entirety. I know that's a really great point. I mean, obviously, I'm very excited about many other things about this drug and mechanism of action.

Something that we.

A pill can can provide such incremental blood pressure reduction over and above it.

Lisa III pretenses, I think physicians will unequivocally view this as a major advance and I think theres a lot of exciting stuff happening in the resistant hypertension space.

Parenthetically mentioned a device based approach with renal denervation.

That again, assuming that technologies after approval further sort of grow this resistant hypertension.

The resistant hypertension looks like that question has been scientifically answered here. But just other sorts of adjacent populations of hypertension as such as being studied in HALO. But then beyond that, I think for heart failure, lots of promise here for this approach. For a CKD, again, lots of promise for this approach. There's already good data suggesting that the aldosterone axis is very important.

Market so to speak.

So I think that even without seeing what halo shows someone had asked about that before this is actually a pretty large number of patients with resistant hypertension or just totally out of control hypertension. Despite.

Taking multiple.

Medicines, even if it doesn't meet the classic definition.

A lot of these folks out there so and sufficient don't know what to do with them right now and a lot of times. They are landing in an emergency room or something because of blood pressures really high they called their primary care physician primary care physician here is this high number that gets sent to the emergency department. So it's not just.

and antagonizing that axis is very important in terms of reducing fibrosis in the heart, so potentially benefits not just in heart failure with reduced ejection fraction, but heart failure with preserved ejection fraction, which appears to be at least as prevalent with heart failure with reduced ejection fraction. That's an area that's really going to grow, given the SGLT2 inhibitors, and their effectiveness in that disease state there's going to be now a greater reason to identify patients with heart failure with preserved ejection fraction.

Cardiovascular risks associated without a control resistant hypertension. It's also the healthcare resource utilization, which tends to be high so I think physicians.

Again, assuming the drugs approved for this indication would really welcome it and embrace it is just what I would predict and as far as the hyperkalemia that part of your question. There I think this is at least what we can see in the context of this phase II trial. It seems to be a really manageable low level of hyperkalemia initial users of this medicine.

to have additional therapies there, I think this seems like it could be really promising for HEPPF as well as HEPPF and CKD as well. Obviously there needs to be more study in CKD and patients which are lower than the ones that were included in this particular trial. There was a cut off here, 45, but once those data are available, I think there's good reason to be optimistic as well. So yeah, I'm very excited about the potential beyond what's been listed on the final.

I mean prescribers by users are going to likely be physicians that are particularly expert in hypertension and for them. This degree of hyperkalemia is even better.

Just are on their radar of concerns same course already sort of chatted with many of the leading hypertension experts to get their pulse co <unk>.

At least the folks that ive heard opine on it.

Private to same core havent found this to be an issue obviously there needs to be.

Larger phase III trial, more data is coming with payroll and other.

Planned studies, but what we can see her to date to me looks really encouraging and some in terms of something that is highly effective for lowering blood pressure and also appears to be quite safe.

from study. So I think really lots of reasons to be excited about this drug and its mechanism of action that go beyond what was just studied and presented here.

Okay. Thanks, Victor that so it will take probably the next question I know we are writing.

Behind them.

Okay, thanks Dr. Bath. So we have two analysts who are still want to ask maybe one question. So can we go operator to those, but we'll ask just one question because we're always here running out of time and thanks again for all your participation. Okay, thank you. The next question comes from your, yes, me and Rahimi from Piper Sardila, please proceed. Good morning team and congratulations to the stellar data and Dr. Bath, wonderful to have you on the phone and being able to ask your question.

Thank you. The next question comes from Jeff <unk> from Morgan Stanley . Please proceed with your question James.

Gratulation is on the update and thanks for taking my questions. Firstly, I guess, how high did the potassium levels go into three patients who had potassium above six and then for doctor, but for this patient population just to clarify.

Can you talk about the patients who you think might be better treated with Baxter stat and are there any subgroups of patients who might not be as good candidates for treatment. Thank you.

Thanks, I'll take the first one the highest potassium in the.

Those three patients was six three.

And one of them.

Yes.

Others were lower than that.

Okay.

Tibet is can you comment on the.

The sub population.

To comment on which subpopulation.

Well the drug to be perpetually.

In theory, one might expect measuring baseline aldosterone levels would be a great way to target this drug. I think that's what a lot of hardcore hypertension experts would have postulated, that is measure aldosterone levels. Those are the patients with elevated aldosterone that would really be the ones that benefit. Myself, I actually didn't necessarily believe that that would be the case because the fact of the matter is a lot of patients who have...

Keith.

Let's face it.

Well, we got you.

Where it could be what could you repeat that it sort of cut out there for a minute.

Hi, Charles.

Yes, Deepak just looking for whether there is any reason to believe that there might be sub populations that would be particularly benefited by this drug that you could oh, yes, that's a terrific question.

So first of all I think the population as it was defined here of resistant hypertension meets the Richard official definitions and I would say that population is a pretty large population and it seems like a sort of a.

quote unquote, resistant hypertension, do have elevated endostom levels, not all of them, but a lot of them do. So I think it's a double edged sword on the one hand. It can be nice having a biomarker to target a few branded therapies. On the other hand, it limits the potential number of patients that can benefit or from your perspective, the market size. But before I comment more specifically, the data weren't shown here, so I don't know if I am going to be able to opine or not, but from a synchor perspective, I mean, I've seen those data.

Slam dunk to consider use of the drug again, if approved in that population. So that would be the one there are a lot of those folks out there I think that will be a growing pie actually based on the fact that there are other people might be renal denervation device folks that are going to.

They have an incentive to raise awareness of resistant hypertension is a consequence of that as well there'll be.

Increasing our centers are focused on treating resistant hypertension once there are.

Active approved therapies that tends to lead to more awareness of disease states among.

Sessions, among hospitals, starting thinking starting programs among patients themselves, but I think the potential convergence of a drug that may get approved for resistant hypertension and devices that may get approved for resistant hypertension will lead to a lot more attention to this therapeutic area. I mean, it's what happens do you think about <unk>.

decision, but then in real life doctors just want to be able to write a script and not have to think about it too much.

Mary Hypertension for example, it's been around forever, it's been a big problem for ever but nobody really was focusing attention on it until they were approved drugs that were available in them.

Great. Thank you so much, Dr. Bob, for your top point on there. Oh, yeah. Thank you.

So we'll take the next question.

Yes, the next question comes from Rami Katkuda from Lifesight Capital. Please proceed with your question.

Hypertension is popping up all over the place the same sort of thing with amyloid ones. So there were effective therapies that were FDA approved for it. So I see the same thing playing out here, although perhaps to a much larger scale than those more niche disease areas that I just alluded to because there's water resistant hypertension out there, especially once you kind of relax the definition.

Hey guys, I wanted to add my congratulations on the data and thanks for taking my questions. Thank you.

I guess, do you expect mean serum potassium levels to continue to increase over time or kind of plateau in patients treated with bactrostat? And how may that compare to the kinetics of potassium increases with spironolactone?

As I think what happened in real life to not just the very rigid sort of guideline.

mesason.

<unk>, but the more common sense recommendation that you got a patient maxed out on drugs, whether its three but it might be less than three in terms of what they can tolerate and their blood pressure is still not a target what are you going to do with them in real life.

That is a terrific question. What we are actually observing in this study is that...

That's majority of cases of an elevated potassium happened within the first six weeks of patients being in the trial. So my interpretation of that, and this is a scientifically informed but not fully proven hypothesis. The one you're seeing is that with the reduction in aldosterone and the potassium retention and the sodium excretion, there is a reduction in blood pressure that takes place over the first two to four weeks. And then we...

We're already maxed out on whatever generic drugs are available that they can tolerate so I think those sorts of patients.

Based on these types of data would be where the drug would be used.

Miles by Kalo are also positive that would further expand the potential patients that could benefit and.

I can't pick what Halo is going to show I think makes it did a nice job sort of laying out what the possibilities were one might expect that there'll be blood pressure reductions.

basically hit a nadir, and then you reestablish a homeostatic balance, meaning you're not having the large amount of sodium excretion and potassium retention thereafter, and the patient re-equilibrates. So I think the best answer I can give to your question today is I think any increase in potassium is likely to be observed in the first four to six weeks of use of the drug, and I think patients establish an equilibrium that would allow you not to monitor the potassium at anywhere.

Sort of magnitude when theres less medicines onboard Alternatively, one could predict there might be less in a population that doesn't have just such.

Resistant hypertension, so to speak but I think what we can say from the study and the data in front of US right. Now is the fact that there seem to be a consistent benefit.

And the different subgroups that have been analyzed do not detailed here to me is encouraging that this mechanism action isn't just for specific very targeted subpopulation of folks without a control hypertension, but likely applies very broadly.

So Deepak I know, we're running on time, but I think the second part of his question was also other subpopulations, maybe particularly I was thinking about heart failure or people with CK deed for which we have no data, but do you think there could be a role in those disorders.

Okay sure.

30000 foot view question I didn't hear it in its entirety I know that's a really great point I mean, obviously I'm very excited about many other things about this drug and mechanism of action.

might also show this early rise that's been Plato's and people reaching new equilibrium that makes you not so worried about it.

Yeah, that's correct.

The resistant hypertension looks like on that.

The other point I would make though is that also, unlike, for example, a vasodilator blood pressure medicine, say an old one like hydrolazine or any new one who's prominently working on just relaxing a blood vessel, which can occur very quickly, one of the advantages of using a drug that requires these physiologic changes, salt and water retention, is I think the blood pressure response is likely to be a little more gradual, which to my mind, gives you a little bit more of a safety buffer in introducing it into more elderly people.

<unk> been scientifically answered here.

Yeah.

Is it just other sorts of adjacent populations of hypertension as such is being studied in Halo, but then beyond that I think for heart failure lots of promise here for this approach for our.

CK D again lots of promise for this approach there is already good.

Data, suggesting that the aldosterone axis is very important.

We're antagonizing that access is very important in terms of reducing fibrosis in the heart so potentially benefits not just in heart failure with reduced ejection fraction heart failure with preserved ejection fraction, which appears to be at least as prevalent as with heart failure with reduced ejection fraction. That's an area, that's really going to grow given the <unk>.

<unk> inhibitors and their effectiveness in that disease state theres going to be now great.

Greater reason tidende of five patients with heart failure with preserved ejection fraction. So to have additional therapies. They are I think this seems like it could be really.

Same for test pass as well as have breadth and CK Dias will obviously there needs to be more study <unk> in patients with GFR are lower than the ones that were included in this particular trial as you know there was a cut off here a 45, but.

So we weren't having those. And I think that's due to the mechanism by which this rub works. And I think that's due to the mechanism by which this rub works.

Okay, so great. So thanks for all your contributions. So I think we're going to close now our conference call. Thanks so much again for listening to us. Again, I'd like to reiterate the excitement around the data and I think more importantly for the needs of patients, we need an alternative drive to those already existing in hypertension. So thank you very much. And again, we'd be in touch with Terry Corrito, our CFO for any further questions.

all your contributions. So I think we're going to close now our conference call. Thanks so much again for listening to us. Again, I'd like to reiterate the excitement around the data. And I think more importantly for the millions of patients who need an alternative drug to those already existing in hypertension. So thank you very much. And again, you'd be in touch with Terry Corrado, our CFO , for any further questions. Bye bye.

But once those data are available I think there's good reason to be optimistic as well. So I'm very excited about the potential beyond what's been listed on the final slides here for study in heart failure and advanced kidney disease.

And also I'll just throw in there is a drug to reduce cardiovascular risk generally speaking that is getting these sorts of reductions in systolic and diastolic blood pressure you would expect reductions in heart failure and kidney events, but also in myocardial infarction that his heart attack.

Thank you. Take care. Bye. Thank you. Thank you. Thank you. Ladies and gentlemen, this does conclude today's call. You may disconnect your lines at this time and thank you for your participation.

And ultimately even in cardiovascular death, if one.

Large enough long term study so I think really lots of reasons to be excited about this drug and its mechanism of action that go beyond what was just studies presented here.

Okay. Thanks, a lot of that so we have to add.

I just.

I want to ask maybe one question. So okay can we go operator to those but will ask just one question, because obviously youre running off assignment and thanks again for your participation.

Okay. Thank you. The next question comes from Yes, Yes mean rahimi from Piper Sandler. Please proceed.

Good morning team and congratulations so that's all our data and Dr. Bhatt wonderful to have you on the phone and being able to ask you a question about given that the data that you've seen in also known mechanism.

Do you have any views any biomarkers that could be used to maybe enriched population potentially for a larger phase III study or maybe some thoughts around what you enriched population based on all the Austrian levels and thank you again for taking my questions.

Yes, that's a really terrific question and.

In theory, one might expect measuring baseline aldosterone levels would be a great way.

To target.

This drug I think that's what a lot of hardcore hypertension experts.

Postulated that is measure aldosterone levels and those are the patients with elevated thoughts around that.

That would.

Be the ones that benefit myself I actually don't necessarily believe that that would be the case because.

The fact of the matters a lot of patients who have quote unquote resistant hypertension do have elevated aldosterone, but not all of them, but a lot of do.

So.

I think it's a double edged sword on the one hand, it can be nice having a biomarker to targets.

Dual branded therapies on the other hand, it limits the potential number of patients that can benefit from your perspective, the market size, but.

Before I comment more specifically the data warrant shown here so I don't know if.

I am.

Going to be able to opine or not but from a syncor perspective, I mean I've seen those data obviously are those data to be discussed on this call are not no no.

Okay.

Sure.

Okay. Good so I won't opine beyond what I said, but in general I think physicians always want a biomarker when drugs are being developed and then once they are approved and released they never want a biomarker.

<unk> repeatedly.

Drug development, where there is always a claim for a desire for scientific precision railroad doctors just want to be able to write a script and not have to think about it too much.

Great. Thank you so much talked about quite a tough plans there.

Thanks.

So it will take the next question.

The next question comes from Remy cut could have some lifestyle capital. Please proceed with your question.

Hey, guys wanted to add my congratulations on the data and thanks for taking my questions. I guess do you expect mean serum potassium levels to continue to increase over time or kind of plateau in patients treated with <unk> and how that compares to the kinetics of potassium increases with spirit in the Latam.

Mesa.

Yeah.

It's a terrific question, what we're actually observing in this study is that.

The vast majority of cases of an elevated potassium happened within the first six weeks of patients being in the trial. So my interpretation of that and this is a scientifically informed but not fully.

Proven hypothesis is that what youre seeing is that with the reduction in aldosterone and the potassium retention in the sodium excretion. There was a reduction in blood pressure that takes place over the first two to four weeks and then we basically hit a nadir and then you reestablish.

Homeostatic balance, meaning youre, not having the large amount of sodium excretion and potassium retention thereafter, and the patient re equilibrate. So.

The best answer I can give to your question today as I think.

Increase in potassium is likely to be observed in the first four.

Four to six weeks of use of the drug and then I think patients establishing an equilibrium that would allow you not to monitor the potassium at anywhere near the frequency that you might wish to in the first month, which might make one.

Measurement or at most two but I don't think you'd have to do that.

Following it based on what we're seeing today and I don't think the <unk> data, but I am less familiar so I don't want to comment is if I know this exactly but I suspect the.

There's been a lot count.

Data would look somewhat similar because the effect on aldosterone and something absolutely retention might also show this early rise.

Then plateaus and people reached a new.

Equally been that makes you not so worried about it.

Yeah, that's correct.

The other point I was making.

The other point I'd make though is it also unlike for example, a vasodilator blood pressure medicines and also unlike hydrology in or any new one whose prominently working on just relaxing a blood test, which can occur very quickly one of the advantages of using a drug that requires these physiologic changes saltwater retention is I think the <unk>.

Pressure responses likely to be a little more gradual which to my mind. It gives you a little bit more of a safety buffer and introducing it into more elderly patients for whom a sudden prominent droplet of blood pressure might create some dizziness or even some potential.

Potential to even saying so I think our we had one case of hypertension in the entire study and all of the experts that we've talked to are extraordinarily surprised if that is and that patient was treated as an outpatient it didn't require hospitalization, but they were very impressed at how little of.

Acute severe blood pressure drops that might have led to some medical issues. So we weren't having dose and I think that's due to the mechanism by which this drug works.

Okay, great. So thanks for all your contribution so I think we're going to close now.

Paul Thanks, so much again for listening to me to US again, I'd like to reiterate the excitement around.

The data and I think more importantly for the millions of patients we need to.

If you drive to those already existing potential. So thank you very much and again you'd be in touch with Terry how are you.

Our CFO fall any further question.

Bye bye.

Thank you take care bye. Thank you.

And ladies and gentlemen, this does conclude today's call you may disconnect. Your lines at this time and thank you for your participation.

[music].

Uh huh.