Tourmaline Bio, Inc. (TRML) Earnings Call Transcript & Summary

Good morning, and welcome to today's presentation of top line data from Tourmaline Bio's Phase II TRANQUILITY Trial. Thank you for joining us. We'll be recording today's event which can be accessed later on the Events page of Tourmaline's website at www.tourmalinebio.com. [Operator Instructions] I would now like to introduce Tourmaline's Co-Founder and CEO, Dr. Sandeep Kulkarni. Please go ahead, doctor.

Good morning, everyone. Thank you for joining us. On behalf of the entire team at Tourmaline, we are thrilled to share with you the top line data from our Phase II TRANQUILITY trial of pacibekitug. I'm joined today by Dr. Emil deGoma, our Senior Vice President of Medical Research and a Board-certified Cardiologist and Dr. Deepak Bhatt, Director of the Mount Sinai Fuster Heart Hospital and Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai in New York City. Dr. Bhatt also serves as the Chair of Tourmaline's Cardiovascular Scientific Advisory Board. Today represents the first clinical trial readout for us at Tourmaline, and we are pleased to share these exciting top line data with you all. Getting to this point, however, was a collaborative effort. We want to extend our heartfelt of thanks to all of the study participants, site investigators, Tourmaline employees and advisers who have made and are continuing to make this trial possible. Before we dive into the data presentation, I want to quickly address some housekeeping items. During today's event, we may make certain forward-looking statements. These statements reflect our beliefs and expectations as of today, and they are subject to various risks and uncertainties that could cause actual results to differ materially from those discussed today. I encourage everyone to review our filings with the SEC for more details on these risks. We undertake no obligation to update or revise any forward-looking statement for any reason. At the outset of the Phase II TRANQUILITY trial, we set out to accomplish 3 main objectives. First, to test for the first time for this class, whether an IL-6 inhibitor could be administered quarterly and achieve rapid, deep and durable reductions in high-sensitivity C-reactive protein, or hsCRP, an important biomarker of inflammation-driven cardiovascular risk. Second, to gather sufficient safety exposure data to proceed into Phase III development. And third, to confirm the selection of the dose to take forward into future cardiovascular disease studies. The top line results we are presenting today have exceeded our expectations, delivering a remarkably consistent signal across all arms and all endpoints that we tested. We believe we have decisively demonstrated the first of our objectives and are on track to achieve the remaining 2 over the coming months in close collaboration with our world-class Cardiovascular Scientific Advisory Board, other advisers and regulatory authorities. Rapid, deep, durable and highly statistically significant reductions in hsCRP were seen across all quarterly and monthly drug arms as compared to placebo, statistically significant percentage of patients in all quarterly and monthly drug arms achieved hsCRP below 2 milligrams per liter, a key threshold for defining residual inflammatory risk and pacibekitug was generally well tolerated with overall rates of adverse events and serious adverse events that were comparable to placebo. We believe the data observed in the quarterly dosing arms is particularly remarkable given that at the time of the primary analysis, participants had only received a single dose of study drug. We believe that these results bolster pacibekitug's best-in-class potential especially now that we have human clinical data demonstrating rapid, deep, and durable suppression of inflammation with quarterly administer. Before we get into the detailed interim trial results, it is important to put this study into its proper context, namely the significant unmet need that persists within cardiovascular disease as well as a substantial evidence supporting the potential for IL-6 inhibition to address gaps in existing care for potentially millions of patients. As seen here and likely no surprise to this audience, cardiovascular disease in its many forms affects tens of millions of people in the U.S. alone with multiple more affected worldwide. In particular, cardio -- atherosclerotic cardiovascular disease, or ASCVD, continues to be the world's big killer as described by the World Health Organization. Despite available and emerging therapies, risk related to low-grade chronic inflammation continues to drive morbidity and mortality and is not well addressed with currently approved treatment options. Large population studies suggest that roughly 50% of patients with cardiovascular diseases have evidence of inflammation as measured by an hsCRP greater than 2 milligrams per liter. We believe these populations may benefit from treatment with a targeted anti-inflammatory, in particular, an IL-6 inhibitor like pacibekitug. We believe the clinical evidence supporting IL-6 as a causal driver of cardiovascular inflammation is already strong and continues to expand. This evidence comes in 3 forms: human genetics, epidemiological and evidence from clinical trials. Taken together, these lines of evidence yield a converging story of IL-6 as a critical risk factor in cardiovascular disease and, more importantly, as a modifiable risk factor that may addressed with an IL-6 inhibitor such as pacibekitug. With that context as background, I will now turn it over to Emil to walk through the top line results from the ongoing TRANQUILITY study in detail. Emil?

Thank you, Sandy. The TRANQUILITY study is an ongoing, randomized, double-blind, placebo-controlled, dose-ranging pharmacodynamic study, testing both quarterly and monthly administration of pacibekitug. Key eligibility criteria included elevated HsCRP and moderate to severe chronic kidney disease or CKD. CKD was used as an inclusion criterion to enrich for high-risk patients more likely to have elevated hsCRP. Participants in TRANQUILITY were stratified by CKD stage and randomized to receive subcutaneously administered pacibekitug 25 milligrams quarterly, 50 milligrams quarterly, 15 milligrams monthly or placebo and are treated for 6 months and then followed for an additional 6 months. As shown in the figure by the shaded triangles, participants in the quarterly dosing arms received active drug on day-1 and day-90, while participants in the monthly dosing arm received active drug on days 1, 30, 60, 90, 120 and 150. After the treatment period, participants are followed for an additional 6 months. The primary evaluation period is through day-90, denoted by the vertical dotted line, which captures the observed effect of a single dose of quarterly pacibekitug or 3 doses of monthly pacibekitug. The primary endpoint of the TRANQUILITY study is median time average percent change from baseline in hsCRP through day-90. Time average assessment of cardiovascular biomarkers has increasingly become the standard approach for therapies with prolonged duration of effect for medical and statistical reasons. From a medical standpoint, cardiovascular risk is better reflected by cumulative exposure over time rather than at a single time point. Secondary end points being presented today include a median percent reduction at day 90, a single time point analysis. Percentage of participants who achieved hsCRP levels below 2 milligrams per liter, the usual threshold to define residual inflammatory risk through day-90, the percentage who achieved HSC reductions of 50% or greater and available HSC levels through day-90, the total treatment period. The TRANQUILITY trial began enrolling in May 2024 with a target enrollment of 120 participants. We completed over-enrollment of 143 participants across 49 U.S. sites in December 2024. We believe this rapid over-enrollment reflects the enthusiasm among physicians and patients to finally address a critical risk factor for which to date, there are limited treatment options. Today, we are reporting topline data for participants in the primary pharmacodynamic analysis population through day-90 of treatment, the time point corresponding to the trial's primary endpoint. We anticipate study completion in December 2025, at which time, all remaining participants are expected to have completed day-180 of the treatment period and to have completed the full 6-month safety follow-up period. Please note that today's data reflect the data extract date of April 23, 2025. This database continues to be updated with additional data as they are collected, and our analysis of these data is ongoing. A total of 143 participants were enrolled and 141 were dosed. 126 participants constitute the prespecified primary analysis population. The prespecified primary analysis population is a modified intention-to-treat population, a common approach for Phase II biomarker trials. A key objective of the TRANQUILITY trial is to guide pacibekitug dose selection for future studies. With that in mind, we focused the prespecified primary analysis population on participants who had most informed the effect of pacibekitug on hsCRP. The primary analysis population is defined as participants who, number one, had a baseline hsCRP of at least 1.9 milligrams per liter. Baseline is defined by convention at the average of 2 pre-dose values from the screening and day-1 visits. Number two, had at least one post baseline hsCRP and number three, received all planned study drug doses during the primary evaluation period. Now turning to the baseline characteristics of participants enrolled in the TRANQUILITY trial. The median age of participants in the primary analysis population of the TRANQUILITY trial was 71 years and 62% for women. Median baseline body mass index was 33.3 kilograms per meter squared. Atherosclerotic cardiovascular disease was reported at baseline in 46% of participants and diabetes in 60% of participants. Median baseline eGFR was 42.5 and median baseline hsCRP was 4.45 milligrams per liter. Overall, these baseline characteristics are in line with our expectation for a Stage 3 to 4 chronic kidney disease population with the exception that the majority enrolled were women, we feel fortunate that we have good representation here. Baseline characteristics were generally balanced between groups with the exception of a lower prevalence of baseline ASCVD in the 15 milligram monthly arm. In addition, the median baseline hsCRP in the placebo group was numerically lower than other groups. Now getting into the top line results from the ongoing TRANQUILITY trial. As Sandeep mentioned at the beginning of this presentation, we are thrilled to report that all active drug arms of pacibekitug achieved deep and statistically significant median time average reductions in hsCRP through day-90. This represents the primary endpoint of the TRANQUILITY study shown on the left. For the 25-milligram quarterly arm, participants achieved a median time average reduction from baseline of 75%. For the 50-milligram quarterly arm, participants achieved a median time average reduction from baseline of 86%. For the 15-milligram monthly arm, participants achieved a median time average reduction from baseline of 85%. And finally, participants in placebo arm achieved a median time average reduction from baseline of 15%. All comparisons to placebo were highly statistically significant with p-values less than 0.0001. As expected from the previous PK/PD modeling, dose-dependent reductions in hsCRP were observed between the lower dose 25-milligram quarterly group and the higher dose groups of 50-milligram quarterly and 15 milligrams monthly. On the right, we also have presented median reductions in hsCRP at day-90 representing a point-in-time measurement as opposed to time average measurements. Importantly, data are consistent whether time average analysis or single time point day-90 analysis is used. At day-90, participants in the 25-milligram quarterly arm, 50-milligram quarterly arm and 15-milligram monthly arm achieved median reductions from placebo of 70%, 85% and 89%, respectively, as compared to 12% for the placebo group. As a sensitivity analysis to pressure test the robustness of the results here, we also examined hsCRP reductions using the intention to treat population or ITT in post-hoc analyses, including all randomized participants. The results of the ITT analysis were highly consistent with the results from the primary analysis population. Rapid, deep and durable reductions in hsCRP were observed with pacibekitug across all dosing arms, as shown in these figures of hsCRP values over time. Deep reductions were observed by the first dose time point at day-30 and remained significant through day-90. Median levels of hsCRP are shown by visit on the left. Median hsCRP levels in the 50-milligram quarterly arm and the 15-milligram monthly arm overlap between day-60 and day-90, which is why the dark blue line corresponding to the 50 milligrams isn't visible here. Median percent change in hsCRP by visit is shown on the right. Additionally, we are highlighting here a key secondary endpoint, the percentage of participants achieving hsCRP levels below 2 milligrams per liter. For context, 2 milligrams per liter is widely emerging as the critical threshold for determining residual inflammatory risk. Published clinical trials of other drugs as well as epidemiological studies have shown lower cardiovascular risk among patients with an hsCRP below 2 milligrams per liter. As you can see in the chart presented on the left, 81% of participants in the 25-milligram quarterly arm, 80% of participants in the 50-milligram quarterly arm, and 88% of participants in the 15-milligram monthly arm achieved time-average hsCRP of less than 2 milligrams per liter through day-90. This compares to 26% of participants in the placebo arm achieving this threshold. All comparisons to placebo were highly statistically significant with a p-value less than 0.0001. Similarly, we have presented the same responder analysis using measurements at day 90 on the right. Results are again consistent with the time average data. At day-90, 77% of participants in the 25-milligram quarterly arm, 83% of participants in the 50-milligram quarterly arm, and 88% of participants in the 15-milligram monthly arm achieved hsCRP of less than 2 milligrams per liter. This compares to 13% of participants in the placebo arm achieving an hsCRP of below 2 milligrams per liter at day-90. These results compare very favorably with previous studies of IL-6 inhibitors that have measured hsCRP reductions, again, noting that this is the first time that quarterly dosing of an IL-6 inhibitor has been tested. Large reductions in hsCRP were consistently observed with pacibekitug with the vast majority of participants achieving at least a 50% reduction in hsCRP through day-90. On the left is the time average analysis, 81% of participants in the 25-milligram quarterly arm, 87% of participants in the 50-milligram quarterly arm, and 94% of participants in the 15-milligram monthly arm achieved time average hsCRP reductions of 50% or greater. This compares to 19% of participants in the placebo arm achieving this threshold reduction. Results, again, are similar, whether time average analysis or point-in-time day-90 analysis is used as shown on the right. Consistency of hsCRP reduction is also shown in the waterfall plots of percent reduction through day-90. The waterfall plot on the left showed time average percent reduction in hsCRP through day-90. Each bar represents a unique individual participant. The top left panel illustrates the placebo group. The top right panel 25 milligrams quarterly, the bottom left 50 milligrams quarterly, and the bottom right panel, 15 milligrams monthly. Deep reductions in hsCRP were observed in almost all pacibekitug-treated participants. The waterfall plot on the right shows percent reduction in hsCRP at day-90, the single time point analysis. These results are again consistent with the time average results. Now we are presenting here something that we think is particularly interesting. As of the data extract date, a total of 47 participants had completed their day-180 visit, the end of the treatment period. The hsCRP results among this subgroup of participants who completed day-180 are shown here. As you can see in the figure of hsCRP levels over time on the left, and percent reduction on the right, available hsCRP data beyond day-90 through day-180 show the reductions in hsCRP are consistent with hsCRP results through day-90. This analysis is preliminary and only reflects a partial subset of the primary analysis population. The findings here are subject to change as additional data are collected through the ongoing trial. However, we find these data to be promising as they relate to sustained hsCRP reductions over time and further illustrate the viability of quarterly dosing with pacibekitug. An additional key point that is illustrated here is the variability of hsCRP levels in the placebo group at any given time point. As shown in the figure on the right, hsCRP increased in the placebo group from baseline at days 150 and 180. Note the median percent change along with the wide error bars. Variability in hsCRP in the placebo group has been a characteristic of other published trials of IL-6 inhibitors in which median percent reductions from baseline in the placebo group of 20% or greater at different time points and even median percent increases have been observed, consistent with what we are observing here in TRANQUILITY. Turning to safety. We are pleased to report that pacibekitug demonstrated overall incidence rates of adverse events and serious adverse events comparable to placebo in the ongoing TRANQUILITY trial. The vast majority of adverse events were isolated events, including all of the serious address events across pacibekitug-treated groups, which were single occurrences in individual participants. To preserve the integrity of the blind in an ongoing study, we are limited in our ability to provide further details on such individual cases until the study is completed. The cumulative incidence of rates of adverse events are summarized in the table. These data reflect the data extract date from the ongoing trial. Given the low incidence of adverse events as well as the robustness of hsCRP reduction across all pacibekitug doses, we pulled adverse events in all pacibekitug-treated participants in addition to presenting data by pacibekitug dose group. The incidence rates of adverse events, serious adverse events, AEs leading to study drug discontinuation, infections and serious infections in pacibekitug groups were all comparable to placebo. There was no association between the incidence of adverse events and higher pacibekitug dose. There was one death in the lowest active dosing arm, a fatal case of COVID-19. Regarding this case, this participant had multiple known risk factors for severe COVID-19, including older age and chronic kidney disease. Importantly, multiple studies of other IL-6 inhibitors have shown a benefit of IL-6 pathway inhibition in hospitalized patients with severe COVID-19. Tocilizumab, an anti-IL-6 receptor monoclonal antibody was approved by the FDA for the treatment of severe COVID-19. There were 2 participants with AEs that led to study drug discontinuation. Both were unrelated to study drug. There were no injection site reactions grade 2 or higher. There were no cases of confirmed grade 3 or higher neutropenia and no cases of confirmed grade 2 or higher thrombocytopenia. Regarding cholesterol and triglycerides, no clinically meaningful median percent changes in atherogenic lipid or lipoprotein measures were observed in pacibekitug arms compared to placebo. As shown in the top row figures with regard to atherogenic lipids or lipoprotein measures, there was no increase in LDL cholesterol, triglycerides, total cholesterol to HDL cholesterol ratio, apolipoprotein B or apolipoprotein B to apolipoprotein A-1 ratio compared to placebo. With regard to measures of non-atherogenic lipids, as shown in the bottom row of figures, there were statistically significant increases in HCL cholesterol and apolipoprotein A1 in several treatment arms compared to placebo. Epidemiological studies have shown that higher levels of HDL cholesterol and apolipoprotein A-1 are associated with lower cardiovascular risk. We have collected data for additional pharmacodynamic endpoints such as fibrinogen, lipoprotein(a) and serum amyloid A. The results of these analysis were consistent with the known impact of IL-6 inhibition. We plan to present these endpoints in upcoming medical meeting. Now it is my pleasure to introduce Dr. Deepak Bhatt. Dr. Bhatt is Director of the Mount Sinai Fuster Heart Hospital and the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai in New York City. Dr. Bhatt is a preeminent clinical trialist, having led numerous landmark cardiovascular studies across multiple indications and therapeutic mechanisms. He was the PI for CHARISMA, CRESCENDO, COGENT, REDUCE-IT, SOLOIST, SCORED, and ENTRIGUE and co-PI of the three CHAMPION trials, STAMPEDE, SAVOR-TIMI 53, SYMPLICITY HTN-3, THEMIS, and the REACH registry. In 2014, he was listed in the American Heart Association/American Stroke Association top advances in heart disease and stroke research for STAMPEDE and SYMPLICITY, REDUCE-IT was listed and also named the top cardiology trial by The New England Journal of Medicine. In 2020 and again in 2021, SOLOIST and SCORED were listed by the The New England Journal of Medicine. We are fortunate to have Dr. Bhatt serving as the Chair of our Cardiovascular Scientific Advisory Board and to have him here today. Dr. Bhatt?

Thank you, Dr. deGoma for that kind introduction and also that very clear presentation. Strong data from basic science, genetic, epidemiologic and clinical studies over the past 3 decades or more have established inflammation as central to atherosclerotic processes, for example, heart attacks, stent and bypass graft renarrowing, strokes, amputations and aneurysm growth among many others. As therapies such as cholesterol lowering have matured, the concept of residual cardiovascular risk has emerged. What can we do to reduce cardiovascular risk beyond telling patients to stop smoking, lose weight, lower cholesterol and so forth. And in that context, targeting inflammation has emerged as a scientifically promising strategy to address this so-called residual cardiovascular risk. Among markers of cardiovascular inflammation, high-sensitivity C-reactive protein, or hsCRP has emerged as the most practical and commonly available measurement of inflammation and is already in common clinical use with multiple studies showing a strong association between elevated levels of hsCRP and worse cardiovascular outcomes. HsCRP is essentially a downstream marker of interleukin-6 or IL-6 activity with several studies showing a strong association between elevated IL-6 levels and greater cardiovascular risk. In this context, we now hear about the top line TRANQUILITY data. This Phase II trial showed large and statistically significant reductions in hsCRP levels with over 80% reductions with different dosing regimens. In particular, the promising results with the quarterly dosing could be an advantage on 2 fronts. First, from a future clinical trial perspective, the follow-up visit schedule would be easier and less cumbersome, that is you would only need to bring in trial participants in every quarter instead of every month. Second, if approved, quarterly dosing would be a useful feature clinically because patients would need to be dosed less frequently. Regarding the other main aspect of a Phase II trial within the context of the sample size study, safety was demonstrated versus placebo, and this is on a larger background of known safety of inhibiting this particular pathway. I believe the TRANQUILITY trial results provide a very strong rationale to proceed with Phase III cardiovascular trials. Potential modest sized and modest duration trials include study of this drug in abdominal aortic aneurysms and of course, also interesting would be larger longer-term trials examining endpoints such as heart attack, stenting, coronary bypass procedures and strokes in high-risk patients with known established coronary artery disease, cerebrovascular disease, peripheral artery disease. So a potentially large number of possible indications where this promising drug could be studied with options for trials that are relatively smaller and quicker such as aneurysms or larger ones that I mentioned. So a very exciting time given these Phase II data. Let me now turn things back to Dr. Kulkarni.

Thank you, Dr. Bhatt. We appreciate your insights and your years of tireless work to advance the field's understanding of cardiovascular disease and cardiovascular inflammation. As we look to the future, our approach to differentiation is three-pronged, and I'm very excited that the TRANQUILITY results now confirm the viability of quarterly dosing our first prong. We believe that quarterly dosing as evaluated for pacibekitug in TRANQUILITY as opposed to monthly dosing as evaluated in ziltivekimab's trials has the opportunity to be a real game changer, one that further bolsters pacibekitug's best-in-class potential. Second, we intend to further differentiate through our development strategy. There are several high-risk patient populations within our lead indication, ASCVD, that we are currently assessing for pacibekitug and where others are not presently conducting clinical trials with this mechanism. Moreover, abdominal aortic aneurysm or AAA is a very high-risk patient population where if our planned Phase II proof-of-concept trial is successful, pacibekitug could even be first in disease. Finally, being second to market could offer us tremendous opportunities to learn fast, generate critical insights and act upon them. Learnings from external CV outcomes trials may guide us to additional points of differentiation. Now with positive TRANQUILITY top line results in hand, we'd like to turn our focus to what comes next. First, we will be working with our world-class Cardiovascular Scientific Advisory Board, other advisers and the regulatory authorities over the coming months to confirm the dose we intend to advance and finalize our clinical development strategy. Second, we expect to meet with the FDA by end of year on the design of a potential Phase III cardiovascular outcomes trial in ASCVD. Finally, we expect to initiate a Phase II proof-of-concept study in AAA in the second half of this year after we have selected a dose to advance. And with that, we'd like to open the floor to your questions. Operator?

[Operator Instructions] Our first question today is coming from Yasmeen Rahimi from Piper Sandler.

Congrats to the data. I guess the first question is direct to Dr. Bhatt. So Dr. Bhatt, I think one of the questions that many investors have given this data this morning is how do we put it into context of IL-6 in risk prevention given that we have not seen any outcome studies yet. So I would love maybe if you could share some color around the data supporting IL-6, obviously, this is expected in 2026. So this data into the context of risk prevention given that event rates have not been measured? Second question is just a clarification question for the management team. When you shared the ITT analysis, did you say that the ITT analysis includes patients with high CRP reduction? I guess, just define what that ITT definition was? Very helpful and I respect your wishes of one question, and I'll jump back into the queue.

Well, great hearing from you, first of all. A terrific question. So there's lots of data from basic science, genetic sources, epidemiologic studies, observational studies showing associations between IL-6 levels, IL-6 activity and worse cardiovascular outcomes. That set of data, very robust. What hasn't happened yet is a clinical trial, cardiovascular outcome trial that has yet demonstrated that reductions in IL-6 actually translate into cardiovascular outcomes. And you're right, I mean, the only way to know that would be to do Phase III trials. And as you're aware, some are already ongoing with other compounds. I think the data for this particular compound certainly look good and justified proceeding into Phase III trials. But that is a big question in cardiovascular medicine. Does tackling this pathway of inflammation reduce cardiovascular events? That's in part what makes it so exciting. We know, for example, pathways such as LDL cholesterol reduction regardless of how you get there, assuming there's no offsetting toxicity, reduce cardiovascular events. That's pretty sacrosanct now. Is the same true of inflammation? I think it's a bit of a different paradigm. There, I think how you lower inflammation probably does matter because there have certainly been trials of other pathways of reducing inflammation that haven't been effective. Methotrexate is one example. On the other hand, trials such as CANTOS, an adjacent anti-inflammatory pathway study there did show a significant reduction in cardiovascular events. So I do think targeting inflammation conceptually has been proven by the CANTOS trial. And even though in that circumstance, the particular drug studied ended up not getting an indication for cardiovascular purposes. That opened the door for other drugs targeting inflammation and pathways like IL-6 to be test. So yes, you're right that final step in the causal pathway still needs to occur and others need to prove that IL-6 targeting actually lowers cardiovascular events, but all signals up to this point do seem promising.

Great. Thank you. Emil, do you want to take the second question about the ITT?

Absolutely. And thanks, Yas, for your question. So to review the prespecified primary analysis population is a modified intention-to-treat population and this is a common approach in Phase II biomarker studies. So we're -- in order to help guide dose selection for pacibekitug, we focused this in a prespecified manner, primary analysis population on those who might -- those participants who might best inform the effect of pacibekitug on hsCRP levels. And so we did this in a prespecified manner prior to unblinding and defined this group as participants who had at least one post-baseline hsCRP measurement, had a baseline hsCRP of at least 1.9 milligrams per liter and received all scheduled study drug doses. And those were for the primary analysis population. Importantly, as I mentioned, we did a sensitivity analysis using all randomized participants. So that would be an intention to treat analysis. And those results were very similar to the primary analysis population.

So Yas, just to confirm, like that ITT analysis included all 143 participants who were randomized, including those who received no study drug and the results are highly, highly consistent with what we are reporting for the primary analysis.

Next question today is coming from Roger Song from Jefferies.

Excellent. Congrats for the impressive data. Maybe I will keep my question to one. For the upcoming FDA discussion, can you give us a little bit of color what are the key topics? And then it seems you want to select the dose before the FDA decision and then what will be the key data points you want to be looking at before you make the dose selection because it's pretty clear that quarterly has the advantage and also supporting by the data we see today?

Great. Thank you, Roger, for that question. Maybe I'll take the first part and then hand off to Emil to cover what happens next in terms of selecting a dose. So in terms of the FDA interaction, we're planning for an end of Phase II meeting by end of this year to talk to our plans in ASCVD. And so in that discussion, certainly, we'll want to present more of the data from TRANQUILITY with regulators along with our justification rationale for what dose we'd like to advance along with our clinical trial plans for Phase III. As I know we've talked with you many of the folks on this call about, there are a lot of trial options within ASCVD here. We are excited that there's ample white space for us to pursue and go after high-risk populations who do have residual inflammatory risk, and we're lucky to have a world-class CV SAB helping guide and inform those discussions here. Luckily, in the context of cardiovascular disease outcomes trials, there's a lot of precedence for us to look at. So we are excited to have that discussion and be able to move to the next phase. Emil, do you want to talk through our dose selection plans?

Yes. Thanks, Roger, for the question. So as far as finalizing dose selection, we agree we find the data that we have through the primary evaluation period and the data set beyond to be very encouraging and supportive in validating the quarterly dosing. As far as next steps in order to be rigorous would be to leverage the existing PK/PD model to further establish the optimal dose for subsequent studies. The PK/PD model that we use to inform dosing in this trial has been very helpful and a rigorous approach in order to establish and finalize dose selection for subsequent studies would be to use that model as well.

Our next question today is coming from Kripa Devarakonda from Truist Securities.

Congrats on the data. I just want to maybe dig a little deeper into the placebo response here. I know Emil talked about the variation in placebo rates. But just wanted -- is this a factor of small numbers of patients? Was there anything in the baseline characteristics that made the patients respond? And Dr. Bhatt, maybe I can ask you, how important do you think it is to look at placebo-adjusted responses versus the absolute response rate?

Kripa, thank you for that question. Let me start off and then hand off to Dr. Bhatt for his commentary. So first of all, the placebo in the study looks comparable to placebo arms in other IL-6 trials. RESCUE, for example, had a placebo hsCRP reduction that fluctuated between minus 4 and minus 20 depending on the time point with wide error bars, which reflects the inter-quartile range that goes anywhere from minus 50 to plus 50, again, depending on the time point. So looking at our data through day-90, we see a similar pattern in RESCUE with lines that crisscross if you were to plot the placebo lines on the same set of axes. And then we also presented data from our study out to day-180. And so if you look there, the placebo hsCRP reduction, that trend reverses and actually goes above baseline whether looking at the medians over time as well as the medians for the pairwise percent change. And I think this very nicely illustrates the variability that's been seen in placebo arms across various studies. I also just want to make sure we don't lose sight that when we compare -- when we look at the placebo response from the drug arm, we see very deep reductions in the active arms of the study with very tight error bars. So it's really hard to -- for us to believe that the sheer magnitude of these dramatic reductions could be related to a placebo effect. Dr. Bhatt, maybe you can comment on how to contextualize placebo.

Yes. No, it's a great question. I've given lots of thought to placebo responses in a variety of different disease states. Certainly, hsCRP, there's a certain amount of variability to it in placebo arms that's been seen in prior trials. Same could be said about LDL, maybe less so. Triglycerides can be quite variable in different placebo arms, same with blood pressure. So this idea of having placebo responses isn't really specific to this trial. It's always something that goes on in the background of trials, especially Phase II trials with obviously a relatively modest sample size compared to very large Phase III trials. So in that context, what I see on the placebo arm, nothing looks particularly surprising or out of the ordinary. And I think even when one is looking at placebo-adjusted comparisons, they look pretty robust to me across the dosing arms, including the one that I think is most promising, which is quarterly dosing. So I do think, in general, the answer to your question, yes, I do, in general, look at placebo, correct the responses for things. But again, this is a Phase II trial. We wanted to make sure that the drug was having a significant effect on hsCRP. And it's a significant effect with a significant magnitude of effect no matter how you sort of slice the data. So I'm really quite reassured that the drug does what it's supposed to with respect to CRP and ultimately IL-6, and the safety profile as well looks to be very good. So that combination of findings tells me, yes, definitely worthwhile to proceed to Phase III testing. And the variability in placebo that was seen here and it's been seen in all the trials that have looked at hsCRP, in fact, some of the trials -- other trials have found even greater variability in hsCRP levels. So to me, I think the class of medication studied to date seem to be reducing hsCRP significantly and I don't think I see anything here that makes me think, oh, this is an outlier with less or for that matter, with more effect, but really, the differentiator seems to be the potential for quarterly dosing.

Your next question today is coming from Thomas Smith from Leerink Partners.

Let me add my congrats on the data. Just with respect to the dosing, the data from the 50 mg quarterly dose look great and really consistent, especially the early day-180 data. Can you just elaborate a little bit on how you're thinking about the dose selection going forward and some of the modeling work? And is there an opportunity to maybe look at even less frequent dosing given the consistency that you're seeing so far? And just a follow-up to that. If you were to evaluate other dosing intervals, is that something you'd look to do perhaps in the planned Phase III? Or is that something we could see in a separate Phase II dose-ranging setting?

Yes. Thanks, Tom, for that question. Let me start off and then hand off to Emil and Dr. Bhatt if you have additional comments. So we find the data through 180 to be highly encouraging. I realized this is only a subset of the patients who've completed day-180 at this point. But if you look at those curves carefully, what we see is a potential sign that the responses may even deepen between day-90 and day-180. Again, early data here, but overall, we think that is encouraging. We're still digesting the PK/PD -- PK data from the trial. We will incorporate that into our model and be able to explore that exact questionnaire. In fact, we've had some comments from our SAB members that's been consistent with that, whether we might even think about pushing to every 6-month dosing potentially with a loading period upfront. So we think we have a lot of options here. We will explore that in the context of the modeling. But overall, I think the data here that we're seeing either for day-90 as well as day-180 speak to the viability of quarterly dosing with potential to go even longer than that. Emil, anything you would add?

Yes. So here, I think as Sandeep mentioned, very encouraged by the data validating quarterly dosing here. Again, the published PK/PD model has served us well in informing dosing for the Phase II study we did collect a number of -- at a number of time points, drug concentrations and hsCRP values throughout the study. And these then will help further sort of assess different dosing regimens and quarterly in particular. But also as Sandeep mentioned, the ability for the PK/PD model to help inform perhaps potentially less frequent dosing is something that we can explore as well. So those activities are ongoing from a modeling standpoint.

Yes, I'm not sure I have much to add to those nice responses. I think the quarterly dosing is definitely a win and in the next few months, we should be able to sort out whether the dosing interval could be even longer. I certainly wouldn't be unhappy if it were a dosing interval, say, over every 6 months, but on the other hand, quarterly is pretty good and a differentiator as is. But yes, so I guess I'd say, stay tuned for the further longer-term effect data and the full data set.

Your next question today is coming from Yatin Suneja from Guggenheim.

Very nice results. Just one quick question from me. So as you think about the dose selection or the Phase III dose, conceptually, are you just looking at one dose or there is a potential for you to test either multiple dose or strategy in that Phase III program as you conduct it could be an induction plus maintenance? Just curious like how you are conceptually thinking about whether it's just one dose or two doses or regimens?

Yatin, thanks for the question. Emil, can you take that?

Thank you for the question. For a Phase III study design and for cardiovascular outcome trial, in particular, we would plan to select a single dose, and that would help support the efficiency of the study. And so that's one of the key reasons why selecting a dose is so critical for us and why we're going as well through -- the rigorous PK/PD modeling exercise is to firmly justify what we believe is the optimal dose to take forward into Phase III cardiovascular outcome study. While Phase III cardiovascular outcome trials can be done with multiple doses, that certainly adds an additional level of complexity. And so the goal through our Phase study and with the PK/PD modeling as well and discussions with our Cardiovascular Scientific Advisory Board is to select a single dose to proceed in a Phase III study.

Yes. And I would just add that, I mean, the precedent has been set here for other IL-6 inhibitors in cardiovascular outcomes trials where the results of Phase II PK/PD studies that were comparable to TRANQUILITY have informed selection of a single dose to advance into those outcomes trials. So there is precedent here that we're able to follow.

Our next question today is coming from Laura Chico from Wedbush Securities.

Just with respect to the day-180 data, I'm trying to understand, Emil, would there be potential for a deepening response when you get the full roster of patients through that day-180 time point? And then kind of related to that, when should we anticipate having visibility into the day-180 data?

Hi, Laura, thanks for the question. Emil, can you take that?

Yes, absolutely. No, thanks for the question. So I think that the -- as you noted on the figure looking at hsCRP levels through day-180, among the subset of completers and right now, we have 47. With that partial data set, we do find it quite encouraging as far as hsCRP levels being sustained and the potential, as Sandeep mentioned, for deepening responses after a second dose of the quarterly dosing regimens at day-90. That said, still ongoing data, we're collecting more data, but the initial information that we have is certainly quite encouraging for quarterly dosing and the potential for deepening over time.

Our next question today is coming from Rami Katkhuda from LifeSci Capital.

Congrats on the update. I guess were there any notable differences in baseline characteristics between IL-6 responders versus nonresponders or those who had maximal hsCRP reductions with pacibekitug? Or more broadly, is it known why some patients do not respond to IL-6 inhibitor treatment in general?

Rami, thanks for the question. Emil, can you take that?

Thanks for the question, Rami. So we conducted a number of prespecified subgroup analyses by various baseline characteristics. And what's quite remarkable is the consistency of the reduction across these prespecified subgroups, which we're hoping to share and submit for a medical conference later this year. That said, what you're getting at, so the individual responders, that's data that we'll continue to probe and digest or this is not uncommon in the context of these studies. As with other IL-6 inhibitor trials, there are a handful of participants who don't appear to have robust reductions. And so we'll continue to explore that as we look through beyond the top line data analysis. But again, for the major subgroups that we had prespecified, we saw robust reductions in hsCRP in all of the subgroups that we've looked at to date.

Yes. This is part of the reason why we included the waterfall plot to really illustrate just how infrequent it is that someone is -- does not have a deep reduction in hsCRP. So as Emil noted, these sort of look to be noted in other studies, we will explore to see if there are any reasons that might explain it. But overall, we're fortunate that the vast majority of patients have deep meaningful responses on hsCRP.

Your next question today is coming from Kostas Billiouris from BMO Capital Markets.

This is [Yuri] on for Kostas. Congrats on a really strong data. So as you may be aware, over the past year, we've seen an increasing number of licensing deals for cardiovascular assets coming out of China that potentially offer strong durability. And then although we haven't seen such deals in IL-6 space, can you point to specific or unique features of pacibekitug that make it hard for other assets to replicate the observed best-in-class profile?

Sure. Yuri, I'm happy to take that question. So we find compelling about pacibekitug is even before today, we already had 450 patients worth of data from the previous Pfizer data set to inform what the drug does, like how it behaves, right? So most of that experience was using every 8-week subcu administration. As we've said before, we thought we could get to every quarter. And thankfully, with the data today, I think we've shown that, that is possible. We're not aware of any other IL-6 inhibitor that has generated data with even every 8-week administration, let alone every quarter administration. So we are alone in that respect. Now in terms of competition from other programs, we think we're in a fortunate position that this field could rapidly change, and we have an asset that has already declared itself to have very strong properties and would be Phase III ready, again, pending some of the upcoming work as well as discussions with regulators here. So that presents a head start that unless someone has something that's even stronger than the profile we're seeing, we think we're in a really good position.

We've reached the end of our question-and-answer session. I'd like to turn the floor back over to Dr. Kulkarni for any further closing comments.

Thank you. As we wrap up today, on behalf of the entire Tourmaline team, I want to extend a sincere thank you for attending today's TRANQUILITY top line data presentation. I also want to thank again the study participants, site investigators and advisers who make this trial possible. Finally, I would like to thank Dr. Bhatt for his time and for sharing his valuable insights into the need to directly address inflammation as a driver of cardiovascular disease. With positive results from the Phase II TRANQUILITY trial now in hand, we believe that we are well positioned to further advance our pacibekitug clinical development efforts within cardiovascular inflammation. Operator, you may now end the call.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.