Robert Blum: Sure. And thank you for the question. I’ve read some of the research that you guys have published relating to this matter and maybe I could clarify how we think about it. We’re looking at data from SEQUOIA-HCM with already having discussed with FDA in the design of SEQUOIA-HCM a protocol that’s permitting of down titrations when EF falls below 50% as opposed to dose interruption or dose termination. The consequences of down-titration being well within the norm of cardiology group practices in this area. So we approach the data when it will be available from SEQUOIA-HCM with those same optics, meaning I don’t think it’s really a question of its 3% or 6% or any number within that range. But how does that really affect patients and physicians?
And how likely would FDA feel about what would be the consequence if EF does fall. We’re feeling emboldened by the fact that aficamten has a half-life that’s enabling of a relatively rapid return to normalcy with an EF such that if EF does drop it may be inconsequential. And in that way a simple down titration would be acceptable by physicians without any concerns and worry. We believe that could be very important for ultimately the profile of aficamten. So I wouldn’t dwell on the number. Even though as Fady reported, we’ve had quite a low number of EF excursions and 99.5% of echos have not resulted in any adjustment to dose but for the fact that these down titrations might occur occasionally, I would think that that will go a long way to be providing hopefully if the data in SEQUOIA bear out like we’ve seen in FOREST, a profile that will be deemed next in class.
Fady anything you want to add to that?
Fady Malik: I just might add that cardiologists are really quite adapt at managing drugs that have to be monitored. And if you think about for instance heart failure therapies like mineralocorticoid receptor antagonist – these drugs have long been known to cause rises in potassium even life threatening increases in potassium. And if you read the label of eplerenone for instance in 1% to 4% patients that receive these drugs. And it’s not – cardiologist no stranger to drugs that need to be monitored. So I don’t think it’s ultimately as one becomes familiar with a class that it’s not surprising that one begins to see monitoring become changing over time and it becomes as part of standard practice. So I think as Robert said what we’ve seen to date with aficamten coupled with familiarity with the class would hopefully lead to something that’s both reasonable for patients and physicians to execute and maintain patient safety.
Unidentified Analyst: Appreciate the color. Thank you.
Fady Malik: Thank you.
Operator: Thank you. Our next question comes from Serge Belanger from Needham. Your line is open.
Robert Blum: Good afternoon, Serge.
Serge Belanger: Good afternoon, Robert. A follow-up on a prior question regarding the data disclosure that we’re expecting in late December. ACC has historically been pretty restrictive and what can be disclosed ahead of the late-breaking clinical trial presentation at their meeting. So in some cases we heard nothing more than whether at a primary endpoint. So, just curious if you’re confident that you will be allowed to provide more data than that on both the efficacy and the safety side of the trial? Thanks.
Robert Blum: Thank you. Again, not having the data it’s difficult to be as clear as you might ultimately want. But yes, I’m confident. I think we can communicate what we need to communicate to be satisfying both our objectives to be disclosing that which is deemed material for the benefit of shareholders and ultimately also enabling of a proper presentation at the ACC when it comes. We’ve been down this path before. Others have to. And I think this is something that can be accomplished. Next?
Operator: Thank you. Our next question will come from Ashwani Verma from UBS. Your line is open.
Robert Blum: Good afternoon.
Unidentified Analyst: Hi. Good afternoon. Thanks for taking our question. Fatima here on behalf of Ash Verma from UBS. Just two quick ones here. We understand that you have low beta blocker use in your study from the baseline characteristics. And that can help tease out the effect size for aficamten. But since data blocker usage is really high in the real world with aficamten effect size in real world potentially be lower than what you will show in the SEQUOIA study. I mean just a second quick one. We want to get your views on what is the relationship between LVOT. It was great in reduction and peak VO2. We have some studies like one from KEMZYO that shows correlation but there are other studies from beta blockers that show that there is no correlation. So what do you see as the posality or the correlation between these two end points when it comes to aficamten?
Robert Blum: Sure. So I’ll just start and then ask Fady to speak to your questions. We designed and conducted a study SEQUOIA-HCM that we believe is very representative of the population that we hope ultimately aficamten will be available to treat. So it’s not an artificial construct. It’s not a manufactured population. It’s in fact real world. And in that way, we went to great pains to ensure that this was a study that was enabling of physicians ultimately upon the availability of data to apply these results to their own practices. And with that, I’ll turn it to Fady.
Fady Malik: Yes. Let me remind you that I said 61% of the majority of patients are taking beta blockers. It’s not out of line with what it’s seen in the real world. Additionally, you look at the use of calcium channel blockers, the allowance for combination therapy of calcium channel blockers and beta blockers or beta blockers and dicoparamide. I would argue that SEQUOIA-HCM provides a very relevant real world experience in terms of aficamten’s effectiveness when we have those data. So I think that question is really answered by the baseline characteristics. It showed that there’s a high degree of background medical therapy that’s employed. I think the second point as we pointed out is that background therapy may not be optimal for these patients.
Ultimately some of these background therapies may be holding them back and beta blockers being an example. One of the reasons you see less good correlations between LVOT gradient reduction and peak VO2 is because beta blockers disrupt that correlation in the absence of being able to increase your heart rate during exercise even as you’ve gotten rid of the gradient you can increase your exercise performance because you can increase your heart rate. And so it’s more complicated unfortunately than a clean scientific experiment where you change one variable and measure another variable. But roughly there is a good correlation, reducing the gradient has always been the target of both medical and surgical therapy. And obviously there’s precedent in the class that reducing the gradient improves PVO2.
Unidentified Analyst: Great. Thanks for taking the question.
Robert Blum: Thank you.
Operator: Thank you. And our next question will come from Jason Butler from JMP Securities. Your line is open.
Robert Blum: Hey, Jason.
Jason Butler: Hi. Thanks for taking the question. Hi, Robert. Just wondering, if you could comment on from a commercial planning perspective, how feedback from FDA assuming positive data from SEQUOIA and you meet with FDA in 1Q 2024. How that feedback on a REMS program will impact your commercial planning and scenario there the REMS could be similar to mavacamten or less burdensome the mavacamten? Thanks.
Robert Blum: So I just want to make sure I captured your question properly. Could you repeat the first part?
Jason Butler: Yeah. Just when you get feedback from FDA on potential of what a REMS program may look like, how that would impact your commercial planning in scenarios where the REMS was similar to mavacamten or less burdensome the mavacamten?
