Thank you for standing by. Welcome to the American College of Cardiology Investor event at acc-dot two three/wcc. At this time, all participants are in a listen-only mode until the question and answer session of today's conference. At that time, to ask the question, press star one on your phone and record your name at the prompt. This call is being recorded. If you have any objections, please disconnect at this time. I would like to turn the meeting over to Mr. Peter Dannenbaum, Vice President, Investor Relations. Sir, you may begin.
Thank you very much. Good evening, everyone. Welcome to Merck's Investor event here at the American College of Cardiology, in conjunction with the World Congress of Cardiology. Thank you to all of you in the room here who've made the effort to be with us here in New Orleans. Thanks to everyone that's listening in on the webcast. We're very excited to have this opportunity to speak to you about the significant data that we presented today. During today's call, a slide presentation will accompany our speakers' prepared remarks, and that presentation has been posted to our website. Before we get started, we would like to remind you that some of the statements that we make during today's call may be considered forward-looking statements within the meaning of the Safe Harbor provision of the U.S. Private Securities Litigation Reform Act of 1995.
Such statements are made based on the current beliefs of Merck's management and are subject to significant risks and uncertainties. If our underlying assumptions prove inaccurate or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Our SEC filings, including Item 1A in our Form 10-K for the year ended December 31, 2022, identify certain risk factors and cautionary statements that could cause the company's actual results to differ materially from those projected in any of our forward-looking statements made this evening. Merck undertakes no obligation to update any forward-looking statements. Our presenters today will be Dr. Dean Li, President, Merck Research Laboratories, Dr. Joerg Koglin, Vice President, Global Clinical Development, Cardiovascular and Respiratory, and Dr. Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer. Dean will kick off our presentation with a few opening comments.
Joerg will follow with data highlights. Eliav will wrap up with some closing remarks. Following prepared remarks, we'll take your Q&A. We'll also include Chirfi Guindo, Chief Marketing Officer, Human Health, and Jannie Oosthuizen, President, Human Health, U.S. I will now turn the stage over to Dean.
Thank you, Peter. It's a privilege to share the stage with my clinical colleagues and my commercial colleagues as we share the work of our teams. A year ago, I spoke to many of you about our cardiovascular pipeline as it progressed into the later stages of clinical development. Our aspiration then and now is to meaningfully address great unmet needs such as heart failure, thrombosis, atherosclerotic cardiovascular disease, and pulmonary arterial hypertension. We have made important progress throughout our portfolio. In heart failure, we've made progress in our vericiguat and VICTOR trials. In our thrombosis efforts, we've made inroads in our MK-2060 late-stage clinical development program.
The focal point of this event and our time at ACC is on pulmonary hypertension, and it's the sotatercept, the activin signaling inhibitor, which is interdicting with a pathway identified by human genetics as a cause for PAH. We will also have a brief discussion on MK-5475 as well. In terms of atherosclerotic cardiovascular disease, we will be talking about PCSK9, a proven molecular mechanism for lowering LDL cholesterol. Let me just get to the top-line results that were presented today at ACC, and Joerg will give a more detailed description. The top line for sotatercept is we have a six-minute walking distance improvement of greater than 40 m. We have reductions in pulmonary vascular resistance shown here. We have reductions in important biomarkers such as proBNP.
Very importantly, we have substantial reduction in time to clinical worsening or death of an 84% risk reduction. You know, these trial met primary and eight out of nine of the secondary endpoints. I know that Joerg will give additional color. I think some of the comments that were made by others today during the session and also during the follow-up session, is the possibility that this could be a potentially transformative option for patients in this, as it was quoted, a landmark trial. In relationship to MK-0616, our PCSK9 inhibitor that is oral and daily, there was a reduction of LDL cholesterol up to 60%, 60.9%. We had reductions in ApoB and non-HDL-C and the ability to reach LDL goal.
We are transitioned this program from phase I to phase III in less than 18 months. Let me just turn the stage over to Joerg as he goes in more detail, especially for many of the people who might have missed the presentation at ACC. Joerg?
Thank you, Dean. Hello, good evening from New Orleans. Thanks for being here. Having attended ACC for 30 years as a cardiologist, this year's meeting might be the most exciting one for me. Results from two of our development programs, both as late-breaking trial presentations and those with the promise that they might not only improve but could potentially transform the way patients are treated, that is as exciting as it gets. Over the next few minutes, I will summarize key findings from these two studies. The results are also available through simultaneous publications in today's New England Journal of Medicine for the sotatercept activin inhibitor program, and in the Journal of the American College of Cardiology for MK-0616, our PCSK9 inhibitor. Let's start with sotatercept and the STELLAR study.
Primary pulmonary arterial hypertension is a rapidly progressive and fatal disease. It often affects women in their prime of life. In the U.S. alone, PH is estimated or is diagnosed in roughly 40,000 patients. Current treatment options consist of combinations of various vasodilators. These therapies are good in reducing symptoms and improving exercise capacity. Beyond that, the circling mortality has really not changed over the last two decades. PH is a disease of vessels that transport blood from the right side of the heart to the lung in order to get oxygenated. In PH, these blood vessels become thickened and narrowed, limiting the blood flow. This abnormal narrowing of these vessels is caused by an imbalance in factors that controls growth of smooth muscle cells in the pulmonary vessel wall.
Sotatercept is the first of a new class of activin signaling inhibitors that's proposed to rebalance these factors by trapping signaling molecules that otherwise would lead to the overgrowth of these narrowing vessels. Sotatercept directly targets the underlying cellular mechanisms that contribute to the narrowing of the lungs' blood vessels in PH patients. In the phase II study, PULSAR, which was also published in the New England Journal in 2023, sotatercept resulted in a very profound reduction in PVR. Based on these results, we embarked on multiple phase III studies. The first of these studies, STELLAR, was presented earlier today by Professor Hoeper. STELLAR enrolled 323 patients to receive either placebo or sotatercept, titrated from 0.3 mg- 0.7 mg/ kg body weight and administered every three weeks through a subcutaneous injection.
The study enrolled a broad, fairly advanced patient population. Half of the patients were all functional class three. That means they experienced severe limitations even with normal daily chores. Patients were very well treated. Over 60% of those patients were on triple PH background therapy. This is typically a patient population that is very hard to further improve. This slide shows the results for the primary endpoint, change in six-minute walk distance. Six-minute walk distance is a well-established and widely accepted registrational endpoint in PH patients. It assesses exercise capacity. It's also used by physicians to follow individual patients and in their treatment progress. The control group is in gray. The treatment group is in green. The X-axis shows time from baseline to week 24. The Y-axis shows the change in six-minute walk distance.
The observed mean change for placebo over this time period was a reduction in six-minute walk distance by 1.4 m. The observed mean change for sotatercept was an increase of 40.2 m. To correct for outliers, we used the Hodges-Lehmann method as an established approach to compare the six-minute walk change between groups. The modeled improvement of sotatercept over placebo was 40.8 m, a result that's both statistically and clinically very meaningful. The study also met the next eight out of nine pre-specified secondary endpoints. These endpoints were tested in a hierarchical manner. These endpoints were chosen to assess the impact of sotatercept on disease hemodynamics, on disease severity and outcomes, on biomarkers that correlate with the prognosis of the disease, and on patient-reported outcomes. I will talk about four of those endpoints in a little bit more detail.
Until now, the best that existing therapies could do is to delay the progression of the disease. Sotatercept is the first investigational drug that actually showed an improvement in a substantial subset of patients. The multi-component improvement endpoint counts the number of patients that need all three of the following clinically very relevant param. These patients have to meet, have to show an improvement in six-minute walk distance by at least 30 m. They have to show a reduction in NT-proBNP, a prognostically relevant marker for right heart strain, by at least 30%. They have to show an improvement in functional class.
38.9% of all patients, four out of 10 patients, showed this level of improvement in the sotatercept group. That compared to only 10.1% in the placebo group. Pulmonary vascular resistance, or the resistance by the pulmonary circulation to blood flow, remained essentially unchanged, a slight numerical increase in the placebo group. Sotatercept resulted, similar to phase II, in a profound reduction in PVR. The chronic increase in strain on the right heart, so increasing difficulty to pump blood through the ever-narrowing pulmonary circulation, in the end, leads to right heart failure. Right heart failure is the leading cause of death in PH. NT-proBNP is a circulating biomarker for cardiac wall strain. We assessed the impact of sotatercept or placebo on NT-proBNP.
What we showed was a slight increase in NT-proBNP in the placebo group and a very profound reduction in NT-proBNP in the sotatercept group, suggesting substantial unloading of the right ventricle. Perhaps most profound were the findings for time to clinical worsening, which includes death. Shown here are the Kaplan-Meier curves. We see placebo group again in gray, the treatment group in green, and the X-axis is again the time course. What you see here is these Kaplan-Meier curves separate early, separation increases, and then is maintained over time. With a median follow-up of 32.7 weeks, the hazard ratio of only 0.16 equates to a reduction in the risk for death and worsening by 84%. This is an effect size that has not been observed with any other PH study.
This result, is further supported when looking at the individual components of this endpoint. The difference in time to death or the non, adverse non-fatal clinical worsening event was really supported by each of the, components. A reduction in deaths, a reduction numerically in patients that were hospitalized for PH, a reduction in deterioration of PH, and a reduction in the need, for additional rescue therapy. On the safety side, sotatercept was well-tolerated, with numerically lower levels of discontinuations due to treatment, emergent, adverse events, and a lower rate numerically of serious AEs. The overall AE profile was consistent with previous studies, with adverse events that were generally mild and manageable without the need to discontinue, therapy.
Over 99% of the patients, 162 out of the 163 patients in the sotatercept, were able to reach the maximal dose of 0.7 mg/kg body weight. Proactively monitored as mechanism-based AEs of special interest, we observed an increased incidence in typically minor bleedings. These were typically minor nose or gum bleeds. We were able to see a slightly higher rate of telangiectasia, or spider veins. These are thin, widened vessels in the skin. We saw changes in red blood cell and thrombocyte counts. These changes typically didn't require any medical interaction. Only in six cases did these changes trigger an only intermittent reduction in dose, these changes did not lead to any treatment discontinuation in our study.
In summary, the therapy with sotatercept resulted in an improvement in six-minute walk distance by 40.8 m. It resulted in a reduction of PVR by 26.7%. It resulted in a reduction in NT-proBNP by 62.6%, and it resulted in a reduction in the risk for death or a clinical worsening event by 84%. These data suggest that sotatercept, on top of stable background therapy, may provide a potentially transformational treatment option in PH. We are now working with agents, with urgency to get these results formally presented to regulatory agencies. Let me switch to our PCSK9 program. Today's presentation by Professor Ballantyne reviewed the results of the phase II dose-finding study for MK-0616, our novel oral PCSK9 inhibitor developed in patients with hypercholesterolemia. What is the context of this development program?
Cardiovascular death remains the leading cause of death worldwide. The majority of these death events is caused by atherosclerotic events, such as myocardial infarctions and stroke. Elevations in LDL remains a leading risk factor for atherosclerotic events. While existing antilipid therapy has shown a solid reduction in cardiovascular risk in well-controlled clinical studies to up to 30%, enormous residual cardiovascular risk remains. At the same point of time with existing therapy, only a minority of patients reaches these treatment goals. Inhibition of PCSK9 has been identified as the most effective drug intervention to reduce LDL cholesterol. To date, three injectable PCSK9 inhibitors are available. Nevertheless, high priceAccess barriers and the need for repeated injections, often by a healthcare provider, have limited the real-world use.
The availability of an all PCSK9 inhibitor would have the potential to reduce access barriers for this mechanism. However, to date, there are no all PCSK9 inhibitors available. Using our novel macrocyclic peptide platform, our discovery team was able to develop MK-0616, a cyclic peptide with antibody-like potency and selectivity at a hundredth of the size of an antibody. Given together with a naturally occurring permeation enhancer, all MK-0616, one tablet per day, is able to reach exposures that reduce PCSK9 by over 90%. The goal of this program is to develop the most potent LDL-lowering pill that could be accessed by a broad patient population, which may allow substantially more patients to reach their treatment goals and thereby help to reduce the global burden of atherosclerotic disease. The study was designed to define the optimal dose for future Phase III development.
381 patients were enrolled into one of four dose groups or placebo. The study included treatment-naive patients, as well as patients with intermediate and high doses of statin background therapy. The primary endpoint was the percentage change in LDL from baseline to week eight compared to placebo. The graph on the left shows the placebo-corrected result for the four treatment groups with a clear dose response. Each group showed a significant reduction over placebo, not shown here, but shown in the manuscript. Near complete efficacy was already accomplished by around week two. That was the first treatment visit after drug initiation and was maintained over the entire eight-week treatment period. The observed LDL reduction was up to 60.9%, with a suggested plateau somewhere between 18 mg and 30 mg. The results were generally consistent across all pre-specified subgroups.
The effect size appears to compare well with the efficacy of injectable PCSK9 inhibitors. The secondary endpoint, mean change in apolipoprotein B and the mean change in non-HDL-C, represented additional markers of atherosclerotic risk. The dose-dependent reduction in these measures further supports the findings for the primary endpoint. The percent reduction from baseline for ApoB was up to 51.8%. The mean reduction for non-HDL-C was up to 55.8%. The study also looked at the proportion of patients in each treatment arm who achieved protocol pre-specified LDL-C goals. Looking at treatment guidelines at the time of study design, these goals were set based on the presence of, or the risk for atherosclerotic cardiovascular disease.
Only 9.3% of the patients in the placebo group, and remember, most of these patients were on statin background therapy, reached these goals. Goal attainment was achieved in up to 90.8% of the patients in the MK-0616 groups. On the safety side, the PCSK9 inhibitor was generally well-tolerated. An overall low rate of AEs, discontinuation due to AEs or serious AEs. There was for none of those categories, any dose response. When looking at the serious adverse events, there was no clear trend across treatment arms or towards specific organ classes. None of these serious adverse events was deemed related to study drug by the investigator. The one death was unfortunately due to a motor vehicle accident. There was no AEs that increased in a dose-dependent manner. The most common AE in the study was COVID-19 infections.
The study was run during the pandemic. The gastrointestinal AEs here, again, without any dose response, were all non-serious, generally well-tolerated, and typically did not lead to discontinuation of the drug. In summary, all inhibition of PCSK9 with MK-0616 at doses from 6 mg- 30 mg provided significant and clinically very meaningful reductions in LDL cholesterol with an effect size and a risk-benefit profile that's well comparable to injectable PCSK9 inhibitors. These results strongly support further development of MK-0616, which could widen access to effective oral LDL lowering and help improve attainment of guideline-recommended LDL goals as a mean to reduce cardiovascular risk. With that, I would hand it over to Dr. Eliav Barr, our Chief Medical Officer.
Thanks, Joerg. Again, thank you for coming to New Orleans and for being on the phone. What I'm gonna do is I'm gonna summarize Joerg's review of the data on sotatercept and MK-0616, then bring it forward to what the future is gonna be for our clinical programs in the pipeline. As Joerg mentioned, sotatercept has the potential to profoundly change the treatments for PAH. It's a first-in-class activin signaling inhibitor. It's the first of a potential new drug, new class of therapies that target the underlying pathophysiology of PAH. You know, I think that it's fair to say that the efficacy findings in the STELLAR trial were robust, actually pretty stellar.
Compared to placebo, you've heard this before, but it's just worth mentioning, patients who receive sotatercept experienced substantial improvements in six-minute walking distance, markedly reduced risk of clinical worsening or death, and substantial improvement in measures of right ventricular stress. This is important because most patients die with PAH die from right heart failure. Clinical benefit was observed in the primary endpoint and the other measures, regardless of background therapy or disease severity. Therapy was generally well-tolerated with the safety profile consistent with prior studies. Now, we intend to build on the results of the STELLAR study to expand our understanding of how sotatercept may help patients with a broader range of pulmonary hypertension. For sotatercept, we've already initiated two additional phase III trials, the HYPERION trial, which evaluates sotatercept in newly diagnosed intermediate and high-risk PAH patients.
The ZENITH trial, which evaluates sotatercept in patients with advanced PAH at high risk of death. We're trying to pull them up away from the abyss that they're facing with advanced disease. We're also expanding the studies of the drug in different kinds of pulmonary hypertension, especially that pulmonary hypertension associated with left heart disease. Our efforts aren't just limited to sotatercept. They include MK-5475, which is our inhaled soluble guanylate cyclase stimulator. This drug has the potential to be a first-in-class pulmonary selective vasodilator. As you know, currently available vasodilators for pulmonary hypertension can dilate the pulmonary vessels, but they have a dose-limiting toxicity of also dilating the systemic circulation, so it causes low blood pressure, and patients feel very faint.
That impacts the ability of the drug to actually do anything from a symptom relief point of view. Inhaled delivery of MK-5475 is different because it's got the potential to deliver the right doses of inhaled vasodilator right to the pulmonary vasculature that needs to be dilated. The relative concentration of the drug in the lungs is much higher than the circulation. Therefore, you can really get high levels of vasodilation without impacting systemic blood pressure and hypertension. Oops, sorry. We've initiated two trials of MK-1675. The first is in pulmonary arterial hypertension, so in a population not terribly dissimilar from what we reported today.
The second in patients who have pulmonary hypertension in the context of chronic obstructive pulmonary disease, a very important set of patients for whom there's really nothing available. Now, shifting over to atherosclerotic cardiovascular disease in MK-0616. I think the data that were presented at ACC and so nicely by Joerg today, show the really strong potential of MK-0616 as a new way to improve LDL cholesterol reduction and a means to democratize access to this important class of disease. MK-0616 is potentially the first oral PCSK9 inhibitor. That's an important innovation because it will reduce the access that patients have, and the market has shown us, occurs when patients try to access PCSK9 inhibition.
The phase II data that we saw today really demonstrates that MK-0616 therapy is quite effective in reducing lipids to the levels that are consistent with those observed with the various injectables. The safety profile was favorable across the different doses of MK-0616. Based on the phase II-B results, we anticipate looking at a very large clinical program, which we'll initiate in the second half of 2023. We plan on three kinds of studies. The first are gonna be lipid-lowering trials. These are the traditional trials that look at high risk primary prevention and secondary prevention patients and examine the effect of the drug on LDL cholesterol levels over a period of time.
They're designed to look at efficacy with respect to LDL cholesterol reduction and other measures of lipids, and also safety and tolerability. The second kind of study that we'll do is the cardiovascular outcomes trial. Although this mechanism of action is really very, very well-validated and has been repeatedly demonstrated to improve outcomes, we also wanna be able to look at our own trial, our own drug, and to examine the effect of the drug on outcomes both in high-risk primary prevention patients as well as in secondary prevention patients. Finally, we're gonna have a set of supportive studies that in aggregate will seek to look at MK-0616 in specific subgroup of patients and also in combination with other drugs that are used for cholesterol lowering.
I wanna just finish by saying that from a broader point of view, the today's presentations really represent an acceleration of our cardiovascular efforts, and we've made great progress towards our goal of creating meaningful medicines that will transform and improve the outcomes of patients with a variety of cardiovascular disease. Our cardiovascular portfolio is growing and advancing with the potential of about eight approvals by 2030. As we noted, we anticipate that this pipeline will provide over $10 billion in revenue by the mid 2030s. We're really excited about being back in cardiovascular medicine and really making contributions to patients. With that, I'll turn it over to Peter for your comments.
Thank you, Eliav. We're ready to get started with the Q&A. We're gonna take questions here in the room first. Steve and Dominic have mics, so please wait for a mic and announce your name and firm, when you get the mic. In a few minutes, we'll go to questions on the webcast. Chris Shibutani.
Thank you very much, and thank you for hosting this event. Very comprehensive and the data, obviously, congratulations. Chris Shibutani from Goldman Sachs. On sotatercept, I think as we think about the time to clinical worsening endpoint, can you help us decode it to any extent possible so that we can attempt in our efforts to extrapolate the potential results for both HYPERION and ZENITH? When we think about those primary endpoints, they really center on time to clinical worsening. In particular, the ZENITH study, it seems to have the primary endpoint of time to all-cause death and PAH related hospitalization with the more severe patients, whereas in HYPERION it's more broad. If we are trying to assess the potential future based upon this data set, any granular insights would be really helpful.
Take a first shot at that. You can make some more comments, and I may add something on top. Joerg?
Good. you'll appreciate that, the patient population in Zenith and the patient population in HYPERION is overlapping but still different from what we studied in STELLAR. STELLAR went for the broad overall PAH patient population. In ZENITH, these are really patients with really high risk score. Many of those patients are already on a transplant waiting list. This is going to be a hard outcome study. it's time to death and PAH hospitalization. In STELLAR, when you look at the overall results with just the 32.7-week follow-up, you saw 6 versus 2 and 7 versus 0.
Of course, we went in there and we're trying to squeeze out in that small sample size. How did the patients in the higher risk group do? That I think further supports our assumptions of, yes, in Zenith, we should have a chance to detect that in a reasonable time period. Time to clinical worsening in Hyperion, there, the objective is a different one. The objective is to figure out in how early in a patient journey should you actually start Sotatercept. Remember, in STELLAR, the median time from diagnosis to the patient ends up in the study was eight to nine years. These are well-treated patients. Typically, they've tried everything else. Now, the question is, if it works there, how early should you actually start it in a patient population?
In HYPERION, all patients are just diagnosed within the last 12 months. We still mandate that they start with the guideline required combination therapy of vasodilators. Time to clinical worsening there will be more driven through the components of need for rescue therapy or deterioration of PAH. This is a much lower risk patient population. Again, when we look at the STELLAR results, when we tease out the patients with lower risk, when we look at those components, we believe, yep, that's a study that has a very reasonable probability of success.
I would just add one, just a couple of things, having to do with the time to clinical worsening on HYPERION, because really ZENITH is a hard endpoint trial. It's going to be, whether we can salvage patients who are, really heading towards lung transplant. You know, the expectation was that, HYPERION would be necessary to show benefit in time to clinical worsening.
Mm-hmm.
We just didn't realize how incredibly effective sotatercept was. The data here are just, you know, pretty extraordinary and I think unequivocal. The question that I've heard a lot of key scientific leaders talk about is whether earlier intervention might actually be even further beneficial. The reason for that is that perhaps at an earlier stage of the disease, the disease is more dynamic. There's more activity going on and less, let's say, fibrosis and kind of end-stage vessel behavior. It may very well be the case that in earlier trials, the earlier patients, we might get an even further improvement in time to clinical worsening. Time will tell, but we're really enthusiastic about the trial. We can take another question.
All right. Yeah. Good. Thanks.
Next question. Chris Schott.
Great. Maybe just following up on sotatercept. Can you talk about the logistic of 40,000 patients in the U.S.? How many of those are you able to go after post STELLAR? I mean, it seems like we saw a very strong signal, kind of whether you're on dual or triple. I guess just with the, kind of, not so great standard of care currently, do we need to wait for HYPERION to get access to that? Or can we go after a majority of the patients just with what you have currently? Then maybe just a quick follow-up on PCSK9. Can you talk about the food effect seen with the drug and how you're kind of managing through that?
It seems like at least in the diabetes setting with the GLP-1s, the food effect was a pretty big hurdle to get some patients off injectables onto orals. I'm just wondering, is it different in this situation or how do you, how do you kind of manage through that? Thank you.
Why don't we have Jannie take your first question, and then I'll have Joerg speak about the food effect, and I may make some comments.
Jannie?
Yeah. Thanks, Chris. That's a good question. In terms of if you think about how PAH is treated in the U.S., it's a very concentrated treatment setup in terms of a few, you know, less than 150 specialized centers around PAH where most of these patients are treated. I mean, this is a tight community of experts, you know, specialists, mostly consisting of pulmonologists, but also cardiologists with a specific focus on PAH. I think the ability to get to the majority of these patients is gonna be fairly efficient. You know, through a few centers in a highly, you know, connected treatment community that obviously is very much aware of the data that played out today already.
I think the other thing is, if you look at the patient population within STELLAR, it is pretty much the patient population that exists out there, right? I think it's gonna be the discussion over the next few weeks and months to see exactly how thought leaders and general treatment physicians are thinking or the treatment healthcare professionals are thinking about where to use sotatercept in the context of the patients that they have today.
Joerg, did you wanna take the-?
Sure.
MK-0616 question?
We're pretty advanced with our clinical pharmacology program, and we learned, given with the permeation enhancers, that absorption is better if you put 30 minutes between taking the drug in the morning and then taking in foods. That was the recommendation that was used in phase II. Those are the results that you've seen here. I think that will be the recommendation as we take this into late-stage development into phase III.
I'll just make some really quick questions, comments. You know, the sotatercept data will potentially change how people think about PAH. They may actually change how people diagnose as well. One of the things that I wonder is oftentimes you have 40,000 patients if that's what you think, and all of a sudden you have a medicine that substantially changes the course, and it might change how people think about how, for example, a woman who comes in with no known coronary artery disease sort of risk factors, with no asthma, comes in and short of breath, and how fast people will start trying to drive to diagnosis.
What I would say at this point is the time to diagnosis is something that could be substantially improved, and we are hoping that the excitement around sotatercept may catalyze that. The second issue that I would say in relationship to MK-0616 is at least from my practice, when I used to practice, you know, the patient population often has other oral daily drugs that they're taking. You know, this is a patient population that may be taking a baby aspirin a day, may be taking a statin, may be taking a beta blocker, an ACE inhibitors and all of this. At least, you know, limited time that I was on the wards, one of the things that we often did is we would have it once a day, but you take 1 set at night and 1 set in the morning.
Those drugs that change your hemodynamic status, you would take in the morning. Things like aspirin or maybe a PCSK9 you would take at night. At least in my mind, when you look at the adverse effects, I don't know that it has a big impact. You can do it 30 minutes. The way that you pace a patient through reality, I think this will be something that can easily be handled through the practice of medicine.
Great. Thank you. Next question. One more from this side, then we'll go to the other side. Daina.
I wonder if you could talk about how AEs, dose alterations, and compliance events fell across the treatment period in STELLAR. From that study and anything you see in the open label extension, whether there are certain events that you think may be more important as we get to more chronic dosing. I'll take that. Thank you.
Joerg?
I can get started. The mechanism. One observation, expected mechanism-based, is the increase in red blood cell counts. We see that developing over the first few weeks, and when patients are stable. The mean increase in hemoglobin that we observed in the study was 1.3 m g/dl. As I pointed out, there was an increase in this patient population. Remember, hemoglobin increases the oxygen carrying capacity in patients that don't have enough of that. That was generally well acceptable. Our protocol-defined intervention rules, I mentioned that a few patients had to be down titrated, were much more conservative than what most of our PAH sites would use in clinical practice. The same is true for thrombocyte changes. If they develop, you see them early.
With respect to telangiectasia, I think we're still learning. In PULSAR, see, initially, we didn't see any telangiectasia. Only once we went out to sites and said, "Mechanism-based, please look for that," we started to report those. All the patients in PULSAR, now the patients in STELLAR get enrolled over in a long-term extension. I think that will help us to understand, are telangiectasia occurring more over time? Are they stable after a certain time period? I hope that answers your question.
Next question, Carter.
Great. Carter Gould, Barclays. Iliad, your characterization of the CVOT for 0616, seem pretty, I'm not gonna say aggressive, but ambitious. Certainly seems as though you're looking to differentiate not just on the oral nature, but also not run 48 2.0 or ODYSSEY 2.0. I think I heard you say going into primary prevention too. Can you just expand how you think about differentiating versus those? What I didn't hear is something Merck used to be known really well for is fixed-dose combinations in CV studies. Can you talk about Merck's interest there?
Sure. So first and foremost, the design of our cardiovascular outcomes trial is still in discussion with internally and with FDA. We see this drug as being a very important drug across a broad range of patients. This isn't a salvage drug. It's not a drug for just for people who don't tolerate statins, none of that. It's for people. Our interest is to broaden and democratize PCSK9 inhibition as a tool for obtaining for patients obtaining their LDL cholesterol goals. That means not just secondary prevention, but also primary prevention in high-risk patients, obviously, at the beginning. You know, we think this is a really important drug so that patients reach their goal regardless of whether they're, they've had an MI or other event or not.
In terms of fixed-dose combinations, you know, we'll take a look at that. you know, the important thing for us first and foremost is to be able to see how we do on top of a variety of standards of care. In other words, not to just say only one statin or only one intervention, but a broad range. The future will take us, I'm sure, to different places.
Great. Thank you. Next question. Vamil?
Thanks. Vamil Divan from Guggenheim. Two questions if I could. One, following up on the hemoglobin. I noticed the rate was much lower than we saw in phase II, I think 5% versus-.
Mm-hmm.
17%. I was just wondering, was there something different
Mm-hmm.
patients were monitored or how it's defined or anything along those lines? Then the second one, we talked about this briefly before, but just on the commercial preparation, since it is a weight-based, dose, subcutaneous, I guess people would be giving it to themselves. Are you thinking about sort of how you'd, provide that commercial?
Why don't we go to Joerg Chirfi? You wanna take the other question? Joerg first and then Chirfi.
The protocol criteria and then exclusion criteria, the way how hemoglobin was managed, monitored, how the protocol responded to hemoglobin changes was identical to PULSAR. One difference is in PULSAR, remember, patients either received 0.3 mg or 0.7 mg. What we did in this study is we uptitrated from 0.2 mg-0.7 mg. One can speculate perhaps that helps patients to accommodate a little bit better. I think it's the only difference that I could come up with. Yep.
As far as commercial, I mean, these patients are used to taking, medicines, you know, that are, fairly complicated to administer. This will not be the more complicated, of the medicines that they take, but certainly we continue to work on pre-preparing the environment so that, patients or physicians, if it had to be physician administered, are able to administer this drug in a way that's safe, in a way that is, simple, as simple as possible going forward.
I would just add 1 more comment on top of Chirfi's. It is weight-based, and Chirfi's told us, told you we're very confident in our ability to get this medicine, especially in this patient population. Your question also points out that further innovation on our part as to how we think about delivery systems and the such should be something that we intensely think about, especially if we wanna make this broadly available. I just wanna reemphasize, the most striking part of this story for me is what Eliav spoke about. If you talk about good remodeling or the field of regeneration, it is generally when you take those signaling cascades, you generally do not apply them 9 years after the diagnosis because there's all this negative remodeling going on.
The fact that we had such a profound impact despite starting that late, I think is really interesting. In one of the commentary that was afterwards, there was a clear appetite of physicians to really ask the question, should we really be waiting five, seven, nine years afterwards, and how soon can we put it? I just wanna emphasize that point, and if that's how we're going to sort of bring that up in relationship of how much earlier from the time of diagnosis and the start of other medicines, I think we need to think carefully about further innovation that will make this drug extremely easy to access wherever you are in the world that you have this disease.
Okay. We'll take one more from the room and then, maybe front row here, and then we'll take a few from the phone line. I know there's a lot of questions, and we'll go past the hour because I wanna try to get to everybody.
Good evening. This is Hao, for Geoff Meacham, Bank of America. First of all, congratulations on the great data from sotatercept and the MK-0616. My question about the oral PCSK9 trial. In 40% of patients is not on statin, only 25% of patients was on high-intensity statin. Just curious, like, are those patients just running out of options or are they on maybe PCSK9 injectables? A quick follow-up on sotatercept. Are those bleeding event has any correlations with thrombocytopenia or hemoglobin increase? Thank you.
I'll have Joerg, you take both of them.
I can start with both of them. Yep. First question was around 616. Help me again.
The intensity
Intensity.
Background statin.
Background statin versus-
In the phase II study, it was important for us to just get essentially equal subpopulation. We intentionally looked for 30%. We wanted to end up with a third, a third and third, and I think we got pretty close to that. When you look at the Journal of the American College of Cardiology publication, you also see the subgroup analysis. In general, our PCSK9 inhibition led to LDL reductions that was pretty comparable between subgroups. We observed the same distribution that you would observe with an injectable. In terms of bleeding events with sotatercept, thrombocyte reductions were actually fairly mild. We had two patients that very briefly dropped below 50,000 thrombocytes. Nobody required platelet infusions, and we didn't have any bleedings associated with that.
Thrombocytes did not trigger any change in dosing in this study. No, I think there was also no correlation with patients that had higher hemoglobin. I think pathophysiologically, that would be also a lesser concern to start with.
I'll just add a comment. I mean, just to reset, we are trying to make the most potent LDL-lowering cholesterol medicine, period. At the same time that is happening, the guidelines appropriately is reducing the level of LDL. We're trying to chase both at the same time. We're trying to make the most potent pills at the same time that the level of LDL has gone, I don't know, you have to remind me, 130 to 110...
Yep.
-to 90 to 70 to 55.
Mm-hmm.
That's what we're trying to do. In some patients, we wonder whether the most potent LDL lowering cholesterol pill might be enough. In other situations, you may need to combine it with others. That possibility has not eluded us and the possibility laid out by the other gentleman and there's question about fixed-dose combination. As we learn more about how we look at those populations in phase III, that may inform us in relationship to the other question that was asked.
Great. That gets all your questions out? Yeah, good. Okay, Calvin, can we take a few from the phone line, please?
Our next question comes from Tim Anderson, Wolfe Research. Your line is open.
Couple of questions. If you think forward many years from now, peak for these products, I'm hoping you could say which product you think would be bigger? The major focus, I think, at least using sotatercept and the data is fantastic, but that's a rare disease. Obviously, the size of the market for cholesterol is much bigger, but there's commercial dynamics to contemplate. I'm guessing consensus thinks that sotatercept will be bigger, but I'd appreciate any thoughts, even if directional from you on that question? The second question-
That's great.
On the adverse events for, STELLAR. The impact on TTCW, you know, it's great. Does that completely eliminate any concerns about some of these treatment emergent adverse events? Do you think there could be some residual concerns by prescribers about patients on this therapy when they've been on it for maybe two or three years? Thank you.
Why don't we do this? Why don't we have the second question go first. Joerg, you answered that. The first question about rolling the dice and saying what the commercial sort of thing, I'll leave it to Chirfi. I may make some broader comments after that. Joerg?
Thanks for the question. I think the context PH is a context where the current standard of care, all those drugs are essentially based by safety. Are dosed by safety. You up titrate them until they are not tolerated anymore. They are not dosed by efficacy. All those drugs have safety profiles that are pretty profound. I mean, take Prostacyclins, take ERAs. In that context, I think the safety profile that we observed with sotatercept is deemed by treating physicians and patients as typically well acceptable. You contrast that with the efficacy signal that we observe. We believe there is a very strong risk-benefit profile that the AE profile is typically well manageable.
Doesn't typically require any changes in the way how the drug is dosed, and I think supports use in this patient populations.
Chirfi?
In terms of... I love the question, obviously. We believe that both have a multi-billion dollar potential. The reason for that, obviously, is that they are both in their own way, pretty transformative. I mean, you heard, the enthusiasm by the scientific community today at ACC. If you think about sotatercept, you know, Jannie mentioned 40,000 patients in the U.S. You add Europe to that, you add Japan, you're talking 90,000 patients plus. Then the rest of the world will be obviously even more patients who are desperate for an option to treat their PH. Despite the fact that you have many drugs available, you still have a high mortality in this space. 43%, you saw that. These are young women, typically, the prime of their age.
You know, they have their professionals, they have families. We believe that sotatercept, given its transformative nature, will really have a rapid uptake and achieve multi-billion dollar potential as the years to come. Turn to MK-0616. As you heard from my colleagues, this is the opportunity that we have to really democratize access to PCSK9. Right. You provide the same efficacy, similar efficacy to the injectables in a way that is simple, in a way that is acceptable around the world, right? Global access. There are 40 million patients just in the U.S., Europe and Japan that are living with atherosclerosis secondary prevention. Initially, those are the patients that we're going to be targeting, right?
Over time, as we get the cardiovascular outcome data, we will have the opportunity for additional upside if you think about the primary prevention. Again, significant patient population. Of course, the price points are not going to be the same, but both innovations, both compounds we believe have multi-billion dollar potential.
I just want to make a comment. Eliav, who's a cardiologist, and myself, who's a cardiologist, you're asking us which child do we think is more important. That is a very difficult question to answer. I'll just remind you that you trained at Michigan and University of Chicago. I trained at WashU. PAH is a rare disease, but it's not so rare that a regular cardiology fellow that sees these patients. I just want to make sure everyone understands it. The second thing is, when they come in, I mean, you're talking about generally women who are suffocating to death. I don't know how to explain that better than they are suffocating to death. The fact that you see this type of data can have such a meaningful impact.
I would also remind you of the other comment that I made, which is I'm very surprised at how good the data is, because from a basic science standpoint, you would not imagine that you could positively remodel the heart after nine years. It'll be very interesting to see what happens as we look at other diseases that have right heart strain. Although it's in PAH, I would be a little bit, you know, we have to see what the data is from CADENCE to understand how big of an impact. You know, anyone who's been doing cardiology recognizes that the number of patients that have reached their goal when they have risk factors of an LDL less than 55 is shockingly low. We just sit there and go, from a global standpoint, there is, you know, whether you like that or not.
With that, the scourge of cardiovascular disease has increased. The ability to make a meaningful impact, not just in the U.S., but globally, is something that I think the three of us think is just really important. We love both our children.
There you go. Thank you, Tim. Calvin, another question, please.
Our next question comes from Colin Bristow, UBS. Your line is open.
Hey, good evening, and congrats on the really impressive data today. A couple follow on from sotatercept. Can you give us a little more color on the bleeding events and telangiectasia, both in terms of the severity and when these events were typically observed during the treatment course? More the point of curiosity, do you have any information on whether there is a correlation between the hemoglobin increases and the six-minute walk improvement you saw during the trial? Thank you.
Joerg and then Eliav make some comments about that.
Sure. Um- I start with bleeding events. We have detailed AE tables in The New England Journal in the supplement. What you see there is really the bleeding events that we observed here were minor bleeding events. These are epistaxis, nose bleeds, gum bleeds. We're not talking about big gastrointestinal bleeding events or intracranial bleeding events. That's not what we observed in this study. Telangiectasia, we'll have to learn a little bit more about that. I think in principle, those spider veins are not a clinical concern. Many of those patients often are not even aware that they have those spider veins. When you proactively look for those, physicians start to detect them. What you want to exclude is that those telangiectasia come with any other concomitant risk.
There is a disease that's different from what we observe in this study, where telangiectasia go hand in hand with arteriovenous, which means blood vessel malformations. We haven't observed this in this program. Then we'll learn more through the SOTERIA study and through the other studies that we do. Hemoglobin. In principle, it's correct. Having a little bit more hemoglobin is not a bad thing for a patient with PH. Actually, PH physicians often supplement iron to increase the hemoglobin. The hemoglobin is not driving the benefit that you observe here on six-minute walk distance. What we've done in the PULSAR study is we actually used exposure models to try to figure out how much of that six-minute walk distance. This is a theoretical exercise. It's driven by hemoglobin.
We came up with something that would be around 4 m. You contrast that to the 40.8 m that we observed in this study. The increase in hemoglobin drives not the six-minute walk distance. Actually, by the way, it would work against your PVR. Higher hemoglobin gives you more PVR, not less, and we saw this impressive PVR effects.
Right. I just to amplify on that, I think that the hemoglobin increase that we saw was there for sure. I think where the dramatic results were in the decreases in right ventricular strain and the pulmonary vascular resistance. I think that's a really important.
... point that helps us to understand that this is really a meaningful benefit at the vessel wall and at the circulation itself. You know, in terms of bleeding, again, minor bleeding, and time will be an important component. We'll be looking at how well people do over the course of the year. SOTERIA, which is the open label study, has been really instructive in that in that regard. We see the patients have been on drug for quite some time now, and we'll continue to increase patients under observation. I think that that's going to turn out in patients to be a nuisance more than a major event.
Thank you, Colin. Back to the room. Question back here.
Hi, Jennifer for Louise Chen at Cantor Fitzgerald. Thanks for taking my questions. Maybe to start off with sotatercept. Are you going into your conversations with regulators, possibly with the consideration of allowing a label that enables earlier intervention in patients? If not, for HYPERION, is there an opportunity for an interim analysis or an earlier readout ahead of 2028? For the oral PCSK9, Dean, you were talking about delivery being important. You've talked about the macrocyclic peptide technology. Are there other targets that you're actively looking at? I guess, what are the most important or attractive opportunities? Thanks.
I'm going to have Joerg and Eliav answer the sotatercept question, and then I'll take the PCSK9 question.
Yeah. I think, just to follow up on the question about FDA and early intervention. You know, we're going to work with the FDA to determine what the best path forward for sotatercept will be. The STELLAR trial obviously is the centerpiece of the regulatory submission. I think that that's gonna be the centerpiece of what the product circular will look like, although FDA, of course, is the final arbiter of that. In terms of HYPERION, we always have interim analyses in our trials. HYPERION was designed also in the context of our old thinking about time to clinical worsening. That said, right now the PCB date is in 28 and protocol completion date, primary completion date.
That's probably the best date for planning. As I said, you know, this drug surprises us a lot in a good way. We look forward to seeing what the results of that study will show us. Dean.
Yeah. I just wanna just step back and just sort of emphasize what the design principles for PCSK9 was and is. In 2018, we sat there and said, "How are we going to do this?" What we recognized is the monoclonal antibodies interdict between the LDL receptor and the PCSK9 at a very specific place. The design principle is why change that? The design principle was to make a small molecule that could do precisely. When I mean precisely, I mean not just block, not just turn down PCSK9, but interdict where the monoclonal antibody goes interdict. The other issue was you need to take something that's 150,000 daltons, and you need to make it smaller by 150, 100-fold more, right? You have to.
If you can't do that, there's no chance of making it oral. That's what the teams were able to do. It allows you to make an oral, it allows you to make a daily, and it allows you to make it in a way that you don't require cold chain, which is absolutely required in my mind to make it have a global reach. One of the issues that comes up is you can invent these molecules, and that's all nice, and you can get a science or a nature paper about it. If we want global access, we need to be able to synthesize it at scale, such that my colleagues down the line can offer it at an accessing value price point similar to other oral small molecules. Those were critical issues.
We invented it, and we knew that we could do that. Given what I've just told you, that means that, you know, in phase I, we already knew where we stood, right? You can just sit there, and you can just take biomarkers, and you know where you are. We were not going to start a phase II-B unless we knew that we could synthesize it in a way such that the access that we think is required for this is possible, such that Jannie and Chirfi are in a position that when we talk about global access, we mean it. What I can tell everyone is that we were not gonna start a phase II-B unless we knew that.
The problem is, if we don't know that and we get a phase II-B, it's a little bit like the forbidden fruit in the Garden of Eden, right? We know that we can make this and deliver this. You asked another question, which is, will you see other molecules coming through our pipeline in the coming years? The answer is yes. If you have suggestions of molecules you would like us to make. Dean.lee@merck.com.
All right. Thank you, Jennifer. Next question, maybe back in the back corner.
Hey, this is Malcolm Hoffman on for Evan Seigerman at BMO Capital Markets. The question we have is, when we think about the phase III program for MK-0616, how will you approach the need for outcomes trials?
These were critical for injectable medications, but took a long time with reimbursement for very limited ahead of these data. How do you envision MK-0616 coexisting with other cholesterol-lowering non-statin therapeutics?
Hmm. Do you want to take that?
I can give a shot.
Chirfi?
Yeah.
Chirfi and Jannie.
Yeah.
Then I'll just make a final point related to the mechanism of action.
Yeah.
Chirfi and Jannie.
You believe-- You know, I gave you the epi for the secondary prevention of 40,000 in the U.S., Japan, and in Europe, and obviously a lot more around the world. 70% of those patients who are treated, this is secondary prevention patients who've had an event already and who have high cholesterol. 70% of them treated with a statin, including high-dose statin, are not a goal. Right? We believe that there's an opportunity to provide access to those patients in the first instance, right? Later on, as we get into the cardiovascular, you know, CVOT data, then we can move into primary prevention. This is kind of how we are planning forward for MK-0616.
Yeah. I mean, I was gonna say. I mean, I think there's a compelling case to be made, right? If you look at 85% of cardiovascular deaths is all driven by atherosclerotic cardiovascular disease, right? Less than 5% of patients today are getting an injectable PCSK9. As Chirfi said, 70%, you know, virus patients are not at goal. I think there's a compelling argument. No doubt they have some policy work to do and guideline shifts that need to happen. That's where the work is gonna be, it's gonna be focused in order to prepare this environment within which these therapies are broadly accessed by more patients.
There's clearly an access issue today with injectable PCSK9 in terms of the treatment setting as well as the price point, and how it's being managed. I think we have significant opportunity to open that up in the U.S., and then as being said, you know, earlier I kicked it off with democratized access to PCSK9. That is really the aspiration for Merck or MSD throughout the world.
I'll just remind the previous comments that I made. When you have a new molecule or a new mechanism, there's always this question of how do you extrapolate what you see from a biomarker to outcome, right? That's always a question that occurs. When the PCSK9 antibodies came out, there was no evidence that lowering LDL by interdicting with PCSK9. Everyone knew it could affect LDL, but they didn't know that it could affect outcome. That's been proven, right? That's been proven, and it's beautiful work by other companies who've done that, and we applaud that. I'll just recount. Our molecule will lower LDL. Our molecule interdicts with the PCSK pathway. It doesn't just interdict with the PCSK9 pathway. It interdicts in the same biochemical mean by which the antibodies work, right?
This is not, "I'm going to do some other mechanism in relationship to PCSK9." At the biophysical and the biochemical level, we are doing what the antibodies. We have simply taken 150,000 antibody and we've gone, poof, made it 1,500. When one thinks about what is the probability that this might be able to replicate the outcomes trial, I think if people think through that, I think that would be a reasonable way to think about it. I should also remind is that the access requires no cold chain. This is something that can be mailed to you. This is something that you can go to your local Walgreens or CVS or something like this. This will be that easy to get.
In order to get that global access, we need to make it such that a price point that makes it accessible is possible. You're right, but when we designed the principles in 2017, 2018, this is what we laid out.
Next question.
Hi, this is Cerena. I'm from Mohit Bansal, Wells Fargo. I have two questions on sotatercept. One is on the AEs. Given the rate of certain visible AEs like epistaxis and the telangiectasia. Sorry about that.
Yes.
What do you think about the potential for an unblinding effect with the AEs? The second question is on the potential remodeling effect of sotatercept. When would we see the CT scan or vascular imaging data that would support this effect? How would this data impact how early sotatercept is used in the treatment paradigm? Thank you.
I'll let Joerg take the first two, but also this question of unblinding and all of this sort of thing. I'll let Eliot also speak to that as well.
What we do in clinical studies, for example, we blind the study personnel, the investigator to hemoglobin. Precisely avoids that there would be some intentional or unintentional unblinding of individual patients. With respect to telangiectasia, I mean, you saw we had a 3.5% telangiectasia AE rate also in the placebo groups. We see the same treatment effect in PULSAR at a time where we didn't look for a telangiectasia. They were not detected, same treatment effect. I think that makes me a little bit more comfortable that what I observe is not confounded by any of those AEs.
Do you wanna speak, Eliav? I mean, just the profound and how many patients are being affected-
Yeah.
versus us searching for telangiectasia and what % that is.
Right. I think that the, you know, obviously adverse experiences that are imbalanced between the treatment groups, are, you know, are things that we see sometimes, with drugs based on their mechanisms of action. The event rates for those events were really pretty small.
What's also important and striking is that the actual measurements that we do, the values that we measure are objective measures.
Mm-hmm.
In other words, it's not about us saying, we're gonna do some sort of score. It's really more about how much people can walk.
Mm-hmm.
What is the pulmonary vascular resistance as measured in a cath lab? The NT-proBNP is simply a blood test. I don't believe that there was any cases where there might have been sort of this systematic potential for bias. The other thing is that epistaxis are pretty rare. I remember these folks are also getting a lot of O2, you know, nasal O2. They have in usual course of practice, have a little bit of nosebleeds. You know, I think that the doctors were not looking at that as a mechanism-based thing.
In terms of trying to be able to tease out the mechanistic underpinnings of the drug in patients, you know, I think that none of these tools is validated, frankly. The best way to do this, and you know, it's not exactly the same as in preclinical models. In that, in those models, which are pretty predictive, there was pretty substantial remodeling in the right way. In other words, reversal of fibrosis and I'm sorry, reversal of thickening and then a return to normal biology. You know, at the end of the day, time will tell. The most important thing is what the time to clinical worsening is.
You know, when you, when you think about it, hard endpoints was already, were already improved, with a 300 somewhat patient trial. I mean, it's pretty impressive. I think that that will be the ultimate demonstration, that the drug is doing something more than just simply dilating blood vessels.
Great. Maybe last question here in the room.
Hi. Nishant Gandhi on for Robin from Truist Securities. Thanks, and congratulations on all the great data today. I have two questions with the MK-0616. First, just wondering in terms of GI side effects, whether you think these effects are mostly related to the oral drug, and if they are like a class side effect in terms of PCSK9 in general. The second one is in 1 of the recently presented outcomes trial for LDLC, over a period of time, we saw the placebo group started curving upwards over a period of time in one of the trial. Whether you think if that is an issue in your trial and if this needs addressing. Thank you.
I'll start with the placebo question. As a clinical trialist, it is important to do everything you can do that your placebo group essentially is constant. You do that by mandating that patients are on background therapy for a longer time frame. Sometimes you do a run, and we didn't do this here. We had a good experiment. There was no real change in placebo LDL, so just is on in a really stable patient population. The second question, please help me again. Or the first.
This was about.
GI side effects
-side effects what was the mechanism of action for that. Yes.
Yep. We'll have to learn more about those GI side effects. The good news is they were rare, and they were mild. When you look through the table, there is no real dose response. I think we'll need more than 381 patients observed over eight weeks and then eight weeks of safety follow-up. That will be a focus of our phase III program. It is not a PCSK9 mechanism-based side effect. I mean, the side effects that you see with injectables very often have to do with the injection itself and with the way how the drug is given. That's not our problem with the tablet. PCSK9 inhibition doesn't mechanistically cause GI side effects.
Yeah.
Thank you very much, everybody for attending, making the trip down here to New Orleans. Really appreciate it. Great questions. Let me turn it to Dean for any final comments.
Thank you all for making it all the way to New Orleans to speak to us. This has been an important day for us, and I just wanna make sure that we thank the patients and the investigators. I also wanna specifically call out for the sotatercept program. I really wanna thank our colleagues at Acceleron, who really did, you know, were remarkable in the work that they've done prior to the merger acquisition, during the merger acquisition, and many of them have become Merck colleagues, and without that smooth transition, I'm not so sure this day would come for patients with PAH. For people who have seen patients with PAH, I mean, it is, it is a horrible disease, and the fact that we might be able to change the treatment paradigm is something that has all of us absolutely thrilled.
For the PCSK9 program, I do, again, wanna thank the sites and the investigators and the patients, but we're all here in our suits, but I just also wanna highlight those of us who are at Merck who are in the engine room of the Starship Merck, and in that engine room are people who have done what I believe has been... People have thought of making an oral PCSK9 for decades, and to be able to do that and to be able to create it and to be able to make a molecule that has the possibility of having that accessibility is just remarkable.
I thank Eliav's teams and Joerg's teams and the product development team leaders for this, but I just wanna make sure that I made a call-out for all of our colleagues from Acceleron and all of our colleagues in the engine room of Merck. Thank you very much.