Michael DiFiore: Great. Very helpful. Thanks again.
David Rodman: Thanks, Mike.
Operator: [Operator Instructions] Your next question comes from Rami Katkhuda from LifeSci Capital. Your line is now open.
Rami Katkhuda: Hi, guys. Thanks for taking my questions as well. I guess first, is there any risk that the three-week run-in period in Advance-HTN is not long enough to have patients get to stable blood pressure on the standardized background regimen?
David Rodman: So good question. Many of the people who come in will already be on most or not all components of that given the type of patients we’re screening for and screening out. And so I think the risk is relatively modest. It’s taken care of, though, in the design because the placebo group stays on that regimen. So let’s just say over 12 weeks in the run-in period, let’s just say their blood pressure dropped by 8 millimeters of mercury, but it drops another 3 from the regimen over those 12 weeks. That will then be in the placebo effect, but it will also be in the treatment arms and it will just get subtracted out. So in the placebo adjusted, there is no risk.
Rami Katkhuda: Got it. That makes a lot of sense. And then I guess with BI’s ASI, it was recently shown to have a cell activity of 250 to 1, but they still saw a number of cases of adrenal insufficiency in their CKD study. I guess, does this change your view at all on the selectivity threshold that’s needed to kind of avoid the off-target suppression of cortisol?
David Rodman: Well, it’s a really good question. I’m going to point out that – when we had LCI 699 at Novartis, when I was there, that’s essentially what killed the drug, and that’s why it actually is sold now as a treatment for hypercortisolism, not hyperaldosteronism. So the regulators are extremely, if not super sensitive about this issue. When we do those selectivities, what we do is we take recombinant human enzyme and test it. But once you’re in a patient there are other variables, so I don’t think I can answer your question and say we know an exact cutoff in vitro. Proof is in humans. We haven’t seen this so far, and it hasn’t been a close call for us. But we’re continuing to look at that. Why BI saw it, I can’t say.
We’re very careful about not including people who’ve been using high-strength steroid creams or taking inhalers for asthma and things like that and confounding the data. We will look at that in profiling later because the real world is people do that. So it’s possible they’re taking people who are predisposed and showing that their drug can suppress them. We’re going to take that more carefully in our development programs, so that when we eventually have guidance for physicians, they know exactly what our drug does and doesn’t do.
Rami Katkhuda: Got it. Thanks so much.
Operator: Your next question comes from Rich Law from Goldman Sachs. Your line is now open.
Rich Law: Hi, guys. Good to be back and congrats on the progress so far. For Advance-HTN, can you discuss how the patients are enrolled and randomized 2 to 3 week background standardizing period? Since you’re taking patients off to 2 to 5 meds and then putting them on the background of 2 to 3, how do you think that change in treatment from the sanitization could affect the results in the study? And then how do you mitigate against that?
Jon Congleton: Yes. Rich, the way Advance has built is really to address the question of, is somebody truly uncontrolled or truly resistant. And we really have four main vectors that we address that during that run-in period before subjects ever get randomized to either placebo or active. And the first is following AHA prescribed guidelines for what subjects should be on. So if patients are on two meds coming into the trial, we take them off of those two meds and put them on olmesartan, an ARB and a diuretic. If they’re on 3, 4, 5 meds, we put them on olmesartan, a diuretic and amlodipine, a calcium channel blocker. So we’re putting them on the right drugs according to the AHA guidelines. Secondly, we ensure that they’re on the proper dose of those medications.
So in the case of olmesartan, it’s 40 milligrams. In the case of the diuretic, it’s in depth mine it’s 2.5 milligrams. If it’s HCTZ, it’s 25, and amlodipine 10 milligrams. So now we’ve got the right drugs at the right dose. The third piece that we do is we ensure compliance. We know compliance is a factor in patients’ inability to get to goal. We’re working with a firm called AiCure that’s done, I think, up to 300 different registrational studies with this technology. And its smartphone technology that captures their consumption of that – these standardized medications during the run-in and then we use it during the randomization period as well for background meds as well as placebo and active. But during that run-in period, this allows us to have daily confirmation that subjects have taken their medications.
This is Bluetooth, cloud-enabled. So we get daily feedback are subjects being compliant or not. It goes to the site. It goes to our CRO and it comes to us as far as that information. And we’re able to actively reach out to these subjects if they’re missing doses and reinforce the importance of taking the study drug. So now we have them on the right drug at the right dose and we’re ensuring they’re compliant. And then at the end of that three-week period, which as you heard Dave said, when it is sufficient to get subjects to peak plasma and probably maximal effect with that background regimen, we do 24-hour ambulatory blood pressure measurement. That’s the gold standard measurement. As you heard Dave say earlier, it has a very de minimis placebo response, takes out a lot of noise in what can sometimes be a noisy measurement in the office.
If after that measurement they continue to be hypertensive, so they have not achieved goal, then we randomize. If they do achieve goal, we don’t randomize them and they’re not included in the study.
Rich Law: Great. And then for patients who are treatment resistant on 4 or 5 med coming into the trial and you take them down 3 background med and then adding lorundrostat. Do you think these patients are more difficult to treat compared to others since they are already treatment resistant on 4 or 5 and then you take them back down to 4?
David Rodman: Yes. So this is Dave Rodman. So traditionally, the definition of resistant is having not reached goal on 3 medications, an ACE or an ARB, a thiazide ot a thiazide-like diretic and then either a beta blocker or a calcium channel blocker. And so they may be on 4 or 5 drugs. But once you get to 3, without a drug like ours, you can expect maybe a 3- or 4- or maybe at best case 5-millimeter mercury fall, with adding any one of those as a fourth drug. But once you – the more you add, the less the benefit generally. And the reason for that is you’re not going after the main reason that they have this problem. That’s the reason why guidelines say, go after aldosterone as your fourth line. The problem is there isn’t a great drug to do that.
Eplerenone just simply is too weak. Spironolactone, you can’t dose up to the maximum efficacious dose of 100 to 200 milligrams without running into problems. And so the reason why we think we’re actually going to be very effective in that population where we cut them down to 3, is that we’re going to be the first drug that really can go after that guideline of going after aldo as fourth line because we can dose up to maximum efficacious dose with our drug and get a robust blood pressure response. So I don’t think it’s a bug. I think it’s a feature of cutting them down to 3 and then giving them the drug they really need, which is what we anticipate we’re going to see.
Rich Law: I see. And then one more question from me. So looking at the data you guys presented at ASN last year where you show BMI versus the SBP reduction. And we see around like 20% of patients who did not respond to treatment across the BMI spectrum, meaning that the SBP trajectory went up in the study. Have you characterized these patients further on why they did not respond? And was there any difference of nonresponder rate between the 50 mg and 100 mg dose in Target-HTN? And going forward, what do you expect is the nonresponder rate for your pivotal studies? Thanks.
David Rodman: So that’s a really good question. What we actually – and I’m going to – hopefully I don’t give you a wonky answer because I’m a wonky guy. But when we do a frequency histogram and ask the question, what’s the distribution. On the right side of no response, it’s a perfect – it’s nearly a perfect normal distribution. In other words, it’s just statistics. They didn’t respond on that day but they might respond a similar amount on the next time they’re measured. It’s just noise in the measurement when you do AOBP. On the left-hand side, it’s a left skew distribution, meaning we see responders and we see super responders. And so we really don’t think it’s a confounder. Sure, there will be people in a general population that don’t respond to our drug more than an average drug.
But it’s not really responder, non-responder. It’s really the normal distribution on the right-hand side, and this really interesting left skew distribution where we see people with 30-millimeter mercury falls in blood pressure. The higher the blood pressure, the bigger the fall essentially and that’s because they’re aldosterone dependent. So it’s a really good question. It’s easily controlled in our placebo-controlled design and the use of our statistics. So it doesn’t introduce any kind of a confounder.
Jon Congleton: And Rich, I’ll just add, and you’re well aware of this. Our whole intent is to really identify those positive and negative predictors for response to lorundrostat. BMI clearly was a prespecified analysis that we did in Target-HTN. We saw a very tight correlation as far as response magnitude relative to BMI. That’s something that we’re going to continue to analyze in Advance and Launch-HTN. But as I noted in my opening comments, we’re partnering with an AI firm to continue to really identify those predictive values that would say this is the type of patient that’s going to respond to lorundrostat very exquisitely. Dave made the point, the data is out there that as you get into that resistant state, we are on 3 or more background meds.
There is an enrichment of an aldosterone-dependent form of hypertension in that population because fundamentally, those patients aren’t being addressed with an aldosterone-directed therapeutic. And so all of those, I think, are really going to enable us in this development program to come forward with a really clear toolkit of who should be on lorundrostat and the kind of benefits that they can derive from it.
Rich Law: Got it. And then just following up based on what you guys said. Is there like a certain percentage of patients who are just not aldo driven in that fourth – that third and fourth line? Have you guys thought about there could be other drivers of hypertension?
Jon Congleton: I think the literature would say that there are going to be other drivers. Our interest has always been on where aldosterone is driving it. Hypertension is a multifactorial disease. We’re not developing lorundrostat as a monotherapy. We actually think an ideal combination would probably be an ARB, a diuretic and lorundrostat for those patients who have aldosterone-dependent hypertension. So there are definitely other factors driving this condition, but that’s where frankly, we’re taking the vantage point of let’s bring a level of precision on the treatment of hypertension and acknowledge those different variables and in our case, very specifically, let’s identify those subjects that have dysregulated aldosterone and will benefit extremely well from lorundrostat.
Rich Law: Great, that makes sense. And then just another final follow-up. And are you able to quantify how much of those patients are just not aldo driven at that point and may not respond to an ASI?
David Rodman: So it’s a great question. Just to embellish one statement that we’ve made. If you look at the classical teaching, the most common cause of hypertension beyond what we used to call essential hypertension or primary hypertension is too much aldosterone. Previously, that was called hyperaldosteronism and it had a very specific and complex way of diagnosing it. We now call it inappropriate aldosterone. The field recognizes that you can have a low aldosterone but be aldosterone dependent. And so while we will be measuring blood aldosterone, urinary aldosterone, at the end of the day, the gold standard is does your blood pressure go down when you reduce that aldosterone. And so we’ll be looking at that and saying, do we have people who didn’t reduce their aldosterone and is that why they didn’t respond.
And if that’s the case, we will see that in the 50 to 100 dose escalation arm of the trials. Or are they truly, truly, truly resistant? Aldo doesn’t go down, blood pressure – aldo does down, blood pressure doesn’t. And then we’ll be able to answer your question with data, and we’ll have those data.
Rich Law: Great. Thank you so much.
Jon Congleton: Thanks, Rich.
Operator: Your last question comes from Mohit Bansal from Wells Fargo. Your line is now open.
Mohit Bansal: Great. Thank you very much for taking my question. [Technical Difficulty]
Jon Congleton: Mohit?
Mohit Bansal: Can you hear me?
Jon Congleton: It was a little bit difficult to hear you. I just wonder if you could reorient the phone.
Mohit Bansal: Can you hear me better now?
Jon Congleton: Yes, thank you.
Mohit Bansal: Yes. So I just wanted to ask – yes, sorry. Can you hear me?
