Good day, and thank you for standing by. Welcome to the Quad AI SUMMIT Part 1B Update Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To address your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Christi Waarich, Senior Director, Investor Relations. Please go ahead.
Thank you, Operator. Before we get started, please be reminded that remarks made during this call may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our future expectations and plans, clinical development and regulatory plans and timelines, including anticipated timelines for top-line results across all three of our active studies and our anticipated cash runway. While these forward-looking statements represent our views as of today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on an obligation to do so. Please refer to our most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with our business.
With that, it's my pleasure to turn the call over to Andrew Robbins, President and Chief Executive Officer. Andy?
Thanks, Christie. Thanks to everyone who has dialed in today to listen to our update. My name, as Christie mentioned, is Andy Robbins, and I'm CEO of Cogent Biosciences. I'm pleased today to have Dr. Frank Siebenhaar back with us, as he has graciously agreed to help us present our SUMMIT Part 1b data, which will be shown this weekend at the 2024 annual conference of the American Academy of Allergy, Asthma, and Immunology. In addition, our Chief Medical Officer, Dr. Jessica Sachs, will be with us today for Q&A. Slide 4 here serves as a reminder that we at Cogent Biosciences are focused on the research, development, and ultimately commercialization of targeted therapies for rare, mutationally driven diseases.
Our lead program, bezuclastinib, is a selective and potent KIT mutant inhibitor, now actively enrolling three registration-directed clinical trials: APEX Part 2 in advanced systemic mastocytosis patients, SUMMIT Part 2 in non-advanced systemic mastocytosis patients, and PEAK Part 2 in combination with sunitinib for second-line gastrointestinal stromal tumor patients. Each of these studies is on track to deliver top-line results by the end of 2025. In addition, we have an exciting and growing portfolio of novel research programs focused on creating best-in-class medicines for patient populations with significant unmet medical need. Finally, as we announced last week, we recently raised $225 million, which bolsters our balance sheet and extends our cash runway into 2027, significantly past all three bezuclastinib clinical trial readouts. Here on Slide five, we lay out the objectives of our call today. First and most importantly, we are looking forward to hearing from Dr.
Frank Siebenhaar, who will walk us through the clinical data we're presenting at Quad AI this weekend. We're very excited to share that based on the exceptional data from SUMMIT Part 1, we have selected once daily 100 mg bezuclastinib as the recommended phase II dose for patients with non-advanced systemic mastocytosis. In addition to a very clean safety profile and robust pharmacodynamic effects, the 100 mg dose of bezuclastinib demonstrated a 51% mean change in total symptom score at 12 weeks, along with a 49% mean improvement in quality of life at the same time point. Maybe most impressively, 70% of patients receiving 100 mg of bezuclastinib reported at least a 50% reduction in symptoms at week 12. This depth and speed of benefit exceeded even our expectations for bezuclastinib's performance. In addition to Dr.
Frank Siebenhaar's data review, I'll also provide some background on the development of our MS2D2 novel PRO measure, as well as do my best to put the SUMMIT Part 1b results in context of other datasets that have been presented from non-advanced SM clinical trials. Now turning to Slide six, non-advanced systemic mastocytosis is a serious disease caused by proliferating and overactive mast cells, driven by the KIT D816V mutation. Patients fighting this disease experience a multitude of disabling and severe symptoms and are in search of new treatments that can effectively target the biological cause of their disease without delivering side effects in place of their symptoms.
While the focus of the presentation today will be on the SUMMIT Part 1b clinical data, here on Slide seven, we report results from a recently completed non-clinical experiment looking at the effects of bezuclastanib and avapritinib in mice within grafted ROSA KIT D816V cells, a well-known animal model for mastocytosis. As you can see in the table, we delivered 8-week daily doses matching clinical exposures for bezuclastanib from SUMMIT Part 1b and clinical exposures for avapritinib from Pioneer Part 2, notably showing bezuclastanib at more than 10 times the exposure of avapritinib. From the bar chart shown here, you can see at these exposures, bezuclastanib is very effective at targeting the mutant cells in mice at a level statistically significant when compared to either placebo or avapritinib. We believe this illustrates that achieving robust levels of KIT D816V target engagement is necessary to eliminating mutant mast cells.
Now, before I hand the call over to Dr. Frank Siebenhaar, I would like to spend a few moments on Slide eight and describe Cogent's novel MS2D2 patient-reported outcomes measure. As we've described before, the development of a PRO measure is a rigorous process, and we are working closely with an outside firm with deep expertise in this field. Before starting this effort, Cogent met with the FDA and aligned on a process to determine the most frequent, consistent, and impactful symptoms that non-advanced SM patients experience, using literature review, patient and physician interviews, and culminating with a quantitative psychometric analysis of SUMMIT Part 1 data, a trial which was conducted with a robust number of patients in a randomized, blinded, placebo-controlled fashion.
As you see here in the middle column, a total symptom score for MS2D2 has been developed as an output of our work focused on the 11 most frequent and impactful symptoms reported by non-advanced SM patients. In comparison to older PRO measures used in previous studies, the addition of skin redness, difficulty concentrating, and difficulty remembering arose from our process as three of the most frequent and bothersome symptoms for patients. Conversely, based on the limited spontaneous patient reporting, along with helpful feedback from the FDA, we've excluded dizziness, diarrhea severity, and brain fog from the MS2D2 total symptom score. It is important to note that while not components of TSS, Cogent will continue to measure these three symptoms if they arise using the broad MS2D2 measure administered to all patients in SUMMIT Part 2. With that, I'd like to welcome and thank Dr.
Frank Siebenhaar for joining our call to present the SUMMIT Part 1b results. Frank?
Yeah, thank you, Andy. Good morning to everyone. My name is Frank Siebenhaar. Great pleasure to be here with you this morning, and also a pleasure to walk you through the SUMMIT Part 1 results. On your slide nine, you can see the title slide as the study is being presented at the Quad AI this week. I briefly want to introduce these initial results from the SUMMIT, which is an ongoing three-part multi-center randomized double-blind placebo-controlled phase II clinical study of bezuclastinib in adult patients with non-advanced systemic mastocytosis. On slide number 10, you see again the study design.
Patients with non-advanced systemic mastocytosis diagnosed with either indolent systemic or smoldering systemic mastocytosis based on the WHO classification from 2016 were eligible for being enrolled in the study once they had moderate to severe symptoms on at least two anti-mediator therapies that were not sufficient in controlling their symptoms. In the Part 1, we had Part 1a and Part 1b, two cohorts, one with the original formulation treating with bezuclastinib 100 mg once daily plus best supportive care and 200 mg compared to placebo, and a Part 1b with optimized formulation 100 mg bezuclastinib and 150 mg bezuclastinib both plus best supportive care medication compared to placebo and best supportive care medication.
Primary endpoints at week 12 were safety, pharmacokinetic biomarker symptom assessment in terms of symptom improvement measured by the MS2D2, and quality of life measures, and all patients then going to be rolled over in a Part 2 expansion phase. On 11, you see the demographics of the patients enrolled in both parts of the study. So a bit more females than males, mean age about 50 years in both. So you see there are comparable 90% of patients about in both parts had indolent systemic mastocytosis, a minor part smoldering systemic mastocytosis, which is fine because smoldering systemic mastocytosis is much less frequent than indolent, which is the most common form. Most of the patients who were D816V positive had a high tryptase and had a high mast cell burden in their bone marrow, as those also reflect the diagnostic criteria for the disease.
On the right-hand side, you see the best supportive care medications. Most patients were on H1 blockers and H2 blockers, also some on leukotriene antagonists, proton pump inhibitors, cromolyn sodium, omalizumab, and very minor on corticosteroids. If you then look at that, basically all patients in the study are still on the study. 20 patients completed Part 1a and 34 patients completed Part 1b. On the study cutoff, 90% and 97.1% were still on the study, only minor discontinuations and only one due to an adverse event and one by a patient decision. We're now going further with the data obtained from the bezuclastinib 100 mg in the optimized formulation, which was detected, and look first into the safety. The safety looks very well. It's very encouraging on Slide 13.
You see that the majority of treatment emergent adverse events were low-grade and were reversible without any need of dose modifications. Most importantly, no bleeding or no cognitive impairment events were reported across the bezuclastinib cohorts. No dose reductions at 100 mg cohort were needed, and only one in the 150 mg dose to a Grade 1 liver enzyme elevation and a Grade 2 abdominal pain. Also, only one serious adverse event was reported in the 150 mg cohort, also due to a liver enzyme increase that led to this single discontinuation. On Slide 14, you see that there's a dose-dependent but very well-maintained mean steady state exposure by the drug in the low dose and in the high dose cohort, as this is expected. Now on Slide 15, the most important part.
Here you see at the endpoint, week 12, the reduction of markers for mast cell burden, namely serum tryptase, KIT mutation allele frequency in the peripheral blood, and the number of mast cells in the bone marrow. When we look at patients that had baseline tryptase over 20 ng/mL, nearly all patients treated with bezuclastinib achieved improvement and decrease of their tryptase below 20 ng. This counts for 100% of patients in the 100 mg dose and 89% of patients in the 150 mg dose and for 0% in the placebo group. Overall, mean time to tryptase decreased below 20 was 4.5 weeks, which was even quite early and much earlier before the measured endpoint for patients treated with bezuclastinib. We also looked at patients where baseline tryptase levels were above 11.4, which is the lab cutoff.
And also here, 70% of patients on 100 mg and 90% of patients on 150 mg , but zero on placebo, achieved reduction of tryptase below the lab cutoff 11.4. Same was true for the decrease of the KIT D816V mutation allele burden in the peripheral blood. 100% of patients on 100 mg and 89% on 150 mg and zero in placebo achieved at least a 50% reduction or even a KIT D816V mutation burden that was below the detection limit at week 12. And when looking into the bone marrow among patients that had evaluable bone marrow investigations, 86% on 100 mg and 78% on 150 and 40% on placebo achieved at least 50% reduction in bone marrow mast cells at week 12.
So the mean % change from baseline in bone marrow mast cells at week 12 for patients treated with bezuclastinib with 100 mg was -70% versus 30% on placebo. Okay, let's go further and look into the symptoms. On Slide 16, you see the improvement of symptom severity measured by the MS2D2, which is very impressive. So as already mentioned by Andy, 51% mean improvement in overall symptom severity from baseline to week 12 for patients receiving 100 mg bezuclastinib versus only 80% improvement for the patients on the placebo arm. Patients treated with the 100 mg bezuclastinib reported a significant reduction in the total symptom severity versus placebo. So also the absolute numbers were -22.78 versus only 9.03 in placebo, which was highly statistically significant.
70% of patients treated with 100 mg bezuclastanib achieved a higher than 50% reduction in the MS2D2 total score at week 12 versus only 8% patients in the placebo arm, which is a quite impressive result. Also when we look on the quality of life measurements, then you see that 49% mean improvement in quality of life as measured by the Mastocytosis Quality of Life Questionnaire, which is a disease-specific quality of life measuring tool, from baseline at week 12 in the 100 mg group versus 24% on placebo. Patients reported a significant improvement in quality of life after week 12 of bezuclastanib 100 mg once daily treatment compared to placebo, which was -24.86 versus 12.39, also highly statistically resolved. On Slide 18, you see the demonstrated improvement compared to placebo across the different symptoms that were measured by the MS2D2.
On the left-hand side, placebo, on the right-hand side, the bezuclastinib on the spiderweb plots, you see that all the measured symptoms improve very nicely. And on the bottom, you also see improvement across the different domains measured by the quality of life tool. And you see that there is major improvement of quality of life related to symptoms, to social life and functional, also to emotions and skin. There's probably room for improvement, which is the quite early time point because emotions mostly measure how patients live with the disease. And this takes a bit of time until patients get used to a lower symptom burden. Same skin. We already see fading of skin lesions and major reduction in skin symptoms. But also the appearance of skin lesions is what is picked up by the quality of life.
We see initial improvement, but we have experienced that this takes a bit longer for the skin lesions to fade completely, which will happen, but which will happen probably to a bit later time point. We are excited to see later time points as well in the study. On Slide 19, you see again symptom measured this time with the Mastocytosis Activity Score, another symptom assessment tool, which is used for inclusion. You see that also here there's a nice response compared to bezuclastinib 100 mg to placebo. By using this tool, 41% mean improvement from baseline at week 12 was measured in patients receiving 100 mg bezuclastinib versus 21% improvement in the placebo arm. 50% of patients treated with 100 mg achieved at least 50% improvement in the Mastocytosis Activity Score at week 12 versus 0% in placebo. Also this readout shows great efficacy.
So let me come to the conclusion. Overall, we see that bezuclastinib was very well tolerated by patients, and the 100 mg as chosen for best supportive optimal dose, sorry, for bezuclastinib showed good safety and tolerability profiles. Again, most importantly, no bleeding, no cognitive impairment, no edema adverse events were reported, and no dose reductions or discontinuations due to adverse events were reported. Also, a rapid reduction across all markers of mast cell burden, including tryptase, KIT mutation burden, and bone marrow mast cell numbers were recorded. Significant improvement versus placebo at week 12 in both symptom severity and quality of life. And again, 51% reduction in symptom severity as measured by the MS2D2, 49% improvement in health-related quality of life as measured by the Mastocytosis Quality of Life Questionnaire.
Overall, 70% of patients achieving more than 50% improvement in their symptom severity versus only 8% on placebo as measured by the MS2D2. With this, Andy, I hand back to you.
Great. Thank you again, Dr. Siebenhaar, for an excellent presentation and for staying with us when we open up for Q&A in a little bit. But before that, I'd like to share a few thoughts about the SUMMIT Part 1b data and why we at Cogent are so encouraged with the performance of bezuclastinib. Here on Slide 22, we've collected symptomatic severity data from the four clinical datasets presented so far in non-advanced systemic mastocytosis. When reviewing this slide, please remember the caveat that each of these four studies was run independently at different times. On the left side here in blue bars, you can see the results from PIONEER Part 1 and PIONEER Part 2 using the recommended phase II dose of 25 mg of avapritinib.
In the middle in green, you can see the results of the SUMMIT Part 1b trial using our recommended phase II dose of bezuclastinib. And then finally, on the right in yellow, you'll see the results from the HARBOR Part 1 study across different doses of elenestinib, for which an RP2D has not yet been declared. The first point to note is that while different PRO measures were used to estimate the benefit on symptomatic improvement across these trials, the placebo effect appears highly consistent between PIONEER Part 2, SUMMIT Part 1, and HARBOR Part 1. It's worth noting that in PIONEER Part 1, patients were not blinded to their laboratory values, meaning that they may have been aware of their serum tryptase levels during the study, effectively unblinding those patients in the study, making it difficult to interpret the placebo effect in PIONEER Part 1.
We do recognize that the PIONEER Part 2 protocol was amended to ensure that this did not occur during the pivotal portion of that trial. Second, whether looking at the magnitude of the active arms alone or at the placebo-adjusted effect across the three blinded trials, the depth and rapidity of symptomatic improvement associated with bezuclastinib is quite impressive. Third, and potentially most important to non-advanced systemic mastocytosis patients and caregivers, is the frequency at which patients receiving bezuclastinib achieve at least a 50% reduction in their symptoms by week 12. With the current approved standard of care delivering this level of clinical benefits for less than one out of five patients at week 12, a 70% rate of response at week 12 is quite dramatic. Flipping now to Slide 23, we have been asked several questions about the MS2D2 results, so we put this slide together to help.
In that first column on the left, you'll see the familiar SUMMIT Part 1b, 51% week 12 mean change TSS. Moving to the second bar, we show that patients receiving 100 mg in SUMMIT Part 1a had a similar MS2D2 week 12 mean change of 47%. Pooled together, these 17 patients demonstrate just under a 50% week 12 mean change in TSS. Then in that fourth column, while we are prevented from using the actual ISM SAF PRO measure in clinical practice, we can construct an ISM SAF-like score by using the same 11 items that comprise that measure. When we look at the results of SUMMIT Part 1b through that lens, we see a 49% week 12 mean change in TSS. We remember earlier that Dr. Siebenhaar presented the MS2D2 radar plot demonstrating a broad and consistent effect across items and domains.
We now see the magnitude of effect from Part 1b is highly consistent with the performance of patients at a similar exposure from SUMMIT Part 1b. Even when using other measures of symptomatic severity, these results hold. Unsurprisingly, the clinical benefit associated with bezuclastinib is not simply a function of a new test in a single dataset. Regardless of how you measure its performance, the emerging story is that bezuclastinib can provide meaningful clinical benefit to patients. Finally, we've heard many questions about why does the higher dose of bezuclastinib have a lower TSS score in SUMMIT Part 1b? In order to understand this, it is important to realize that patient-reported outcome measures are inherently a mixed measure of efficacy and safety.
Increasing the exposure of a potent kit inhibitor will serve to eliminate proliferating and degranulating mast cells, but above a certain point, any interventional therapy will inevitably increase the rate of off-target adverse events. The optimized dose of a novel therapeutic for non-advanced SM should balance these two variables, which is what we've demonstrated at the 100 mg dose. Here on Slide 24, you can see a case study describing one of our Part 1b patients who received the 150 mg bezuclastinib dose. This patient had rapid, dramatic resolution of serum tryptase moving from baseline 7.1 ng per mL down to 8.6 ng per mL by week 12 and showed corresponding drops in skin symptomology, essentially eliminating all redness and flushing by week 12.
Although this patient achieved a 100% improvement in their MS2D2 dermatologic symptoms, their TSS at week 12 shown in the black line was only a 37% improvement. This was directly due to low scores on their abdominal pain in yellow and tiredness in red, which were symptoms associated with grade 2 abdominal pain and grade 1 fatigue adverse events. Interestingly, a decision was made at week 20 to reduce the dose of bezuclastinib to 100 mg, and immediately thereafter, the patient's abdominal pain resolved, leading to a corresponding improvement in their tiredness and resulting in a week 24 change in TSS of 73%. We've seen a similar dynamic in other SUMMIT Part 1 high-dose patients with low-grade adverse events clearly compromising the ability to achieve larger improvements in TSS scores.
We are confident that the 150 mg bezuclastinib dose is hammering the KIT mutant target, but we have chosen to move forward with the 100 mg dose, which delivers a very consistent PD effect, but with an improved safety and tolerability profile that drives noticeably better outcomes for patients as measured by TSS. Now to wrap up on Slide 26, I'd just like to remind investors about the Cogent setup. We have delivered clinical data in both ASM and non-advanced SM that provides a believable, clear path to differentiation in market leadership with ongoing registration-directed trials set to read out by the end of 2025. In addition to our exciting bezuclastinib position in mastocytosis, we are running a parallel global phase III registration trial in second-line gastrointestinal stromal tumor patients, which is also on track to deliver top-line results by the end of 2025.
Taken together, these three indications with very limited competition represent an annual total available market potential of $2.5 billion in the U.S. alone. With our successful financing last week, we're in a very strong financial position to complete these three trials and begin positioning Cogent for commercial success. Before I turn the call over for Q&A, I would like to sincerely thank the patients, their families, and the investigators for participating in the bezuclastinib trials. It is with their help that we are on our way to creating a new medicine for thousands of people waiting for its benefits. With that, operator, we are ready for questions.
Thank you. As a reminder, to ask your question, you'll need to press star 11 on your telephone. To withdraw your question, please press star 11 again. Please wait for your name to be announced. Please stand by while we compile the Q&A roster. One moment for our first question, please. Our first question comes from the line of Chris Raymond with Piper Sandler. Your line is now open.
Thanks for taking the question. Maybe first for Dr. Siebenhaar, I just wanted to get a sense from a real-world perspective. And let's just assume that the pivotal trial recapitulates these data and bezuclastinib is approved in ISM. We'll have essentially two approved drugs in the same indication with dueling scoring systems. Maybe give us some perspective. How do you think this information will inform your treatment decisions, assuming, again, that both drugs are available? I guess maybe the broader question is, is there a segmentation of patients that might benefit from one or the other, or do you think this is more of a clear-cut winner-take-all kind of a scenario? And then I have a follow-up.
So, Andy, if you allow, I go into the answer. Yeah, so thank you for this question. I mean, it's exciting times for us now because we're just starting getting any kind of effective treatment options in mastocytosis. But it's not an exception that we have more than just one drug targeting the same target, but still, anyways, there's differences. I mean, we're going to learn in the future what's about the efficacy by head-to-head under real-life conditions, what's the tolerability. But in the end, I think it doesn't make such a big difference if you choose one or the other. But what is one or the other good for? And we're not knowing yet what will be the label in the future for bezuclastanib, but we know the label for avapritinib, and this is, for now, restricted to Indolent Systemic Mastocytosis.
Bezuclastanib has a bit wider range because it looks at all the non-advanced, including the SSM. And we also see some patients that are not effective on the avapritinib dose. So I see the advantage that bezuclastanib may be more effective in patients that need probably a higher target engagement of their KIT D816V mutation, which we see in the SUMMIT trial, as Andy showed you. And this may be the difference in the end. And we're looking very much forward to seeing more additional study results coming up. It's very hard to predict now what will be the real-world evidence, but I can tell you that we already see some differences in the performance and in the efficacy of these two drugs. So I think in the end, there will be a clear-cut decision what patient to put on what drug. But we need to learn more about that.
But the indicators are already there that patients that need a higher engagement of their target may be even better being treated with bezuclastinib in the future when available.
Thanks. That's helpful. And then maybe it's the follow-up. I know you're still early days. I think you're just 12 weeks out with these patients. But is there sort of anything you guys can say at this point around the polypharmacy benefit potential, the ability to sort of transition patients off other meds? And will this be looked at, and how will it be looked at during Part 2 of the study? Thanks.
Yeah. Thanks for the question, Chris. It's a great point and something that we're very interested in. What we can say is during the blinded portion of both Part 1 and Part 2, the instructions are not to change the concomitant or polypharmacy medications so that it doesn't confound essentially the effect of the trial looking at bezuclastinib versus placebo. But once the patients are unblinded or cross over from placebo to active, we will absolutely be looking about the opportunity to reduce some of the polypharmacy. So we call it the open label extension. Patients who complete the 12 weeks in Part 1 and the 24 weeks in Part 2 are given the opportunity to continue taking bezuclastinib for as long as they benefit.
In that portion of the trial, we absolutely will be looking at the opportunity to reduce some of those concomitant meds as sort of a real-world inpatient-directed benefit of the therapy. Based on how fast Part 1b enrolled, we simply don't have really any robust follow-up from these patients at this point in the open label extension. Later in 2024, this year, we will be looking for an opportunity to come back and present longer-duration follow-up from an open label extension cohort of Part 1.
Great. Thanks so much.
Thank you. One moment for our next question, please. Our next question comes from the line of Anupam Rama with J.P. Morgan. Your line is now open.
Hey, guys. Thanks so much for taking the question. What are the timelines and sort of one for the company. What are the timelines and the gating factors to getting that FDA feedback and approval on the MS2D2 patient-reported outcome as being the primary endpoint in Part 2? And then as a follow-up to the prior question for the KOL on the line, Dr. Siebenhaar, so based on the totality of the data that you see today, if you had to point to the one or two differentiating features for bezuclastinib versus, say, marketed or investigational products, what would it be? Thanks so much.
Great. Thanks, Anupam. I appreciate the question. And Dr. Siebenhaar, I'll take the first one, and then I'll hand it over to you. So from a timelines perspective, as we mentioned, we've initiated SUMMIT Part 2, the registration-directed trial. We are measuring MS2D2 in all patients. And now that we've collected the data, we're in the process of submitting a request to the FDA based on the process that the FDA has for a meeting to discuss the results of our MS2D2 TSS. We expect that that will occur in Q2 this year, just based on the timelines of how you set up meetings with the FDA. And what we're looking for there is alignment on the process and the result that has come out of the process that we've taken to create a novel PRO.
I think, as folks know, it's unlikely the FDA will say, "We agree with you." It's much more likely that they will say, "Our decision in the future after SUMMIT Part 2 will be based on the totality of the evidence, but something like, 'We don't disagree with your approach.'" So that's the type of alignment we're looking for with the agency. The nice part, and I tried to make the point before, but let me reiterate it, is MS2D2 is a patient-reported outcomes measure that includes many more questions than are represented in the Total Symptom Score-focused measure.
So even if we were to need to change, to tweak, to add, to replace items in a discussion with the FDA, we have that opportunity even with the patients that are screening and enrolling today because they are being administered a much broader questionnaire than is just for the total symptom score. So we've set up the trial to allow for potential changes in the future, but we're confident that the process we've followed will deliver a tool and a measure that is valid and fit for purpose and will become the new standard of care in measuring performance in non-advanced systemic mastocytosis. So hopefully, that helps, Anupam. And maybe if you want to cover your thoughts about the top two, three most differentiating aspects of bezuclastinib in SUMMIT Part 1.
Yeah, sure. So I mean, from my personal perspective, I find it very, very, yeah, engaging and very nice to see how fast and how rapidly and how intense we see a good reduction in the markers for mast cell burden. So it's really quick how tryptase goes down, how skin lesions start to fade, which is really one of the major impacts of the disease for patients that have skin lesions, how the KIT mutation in the peripheral blood goes down, how bone marrow mast cells disappear, and how symptoms improve. I must say, from the quite low number yet of patients we have seen in the trial, that is very impressive. This looks even, yeah, better and even more effective than we have seen in other clinical trials.
This may be that the dose is adjusted, that the avapritinib is 25 mg and 50 mg , bezuclastinib is 100 mg . And even if you equalize this to the molecular weights, it seems like that there is better, let's say, from the perspective now, an even better target engagement and better efficacy of bezuclastinib. I hope this will hold true for the future, but for now, it looks very good, and especially for the patients that have a high mast cell burden. And many patients have a high mast cell burden. We have indolent systemic mastocytosis patients with tryptase over 100 with mutation burden in the peripheral blood in the two-digit range. And it's good for them to have a rapid and very effective and early suppressive target engagement in their first week of treatment.
Thanks so much for taking our questions.
Thank you. One moment for our next question, please. Our next question comes from the line of Sam Slutsky with LifeSci Capital. Your line is now open.
Hey, good morning, everyone. Thanks for the questions. Got two for Dr. Siebenhaar. I guess first, just when considering potential treatments for ISM patients in the future, how do you weigh the importance of pharmacodynamic effects on things like tryptase, mast cell burden, mutant nuclear fraction versus actual patient-reported outcome symptom data? Essentially, what I'm asking is, what are the ultimate goals of treatment as a physician?
Yeah. So this is a very good question, and it's not so easy to answer because if you would have asked me three years ago, my answer would have been, "I don't care about the mast cell burden markers so much because if you look at baseline, you see that there's, interestingly, not a very good correlation of how high your tryptase is, how high your mutation burden is compared to how you're affected by symptoms or how much your quality of life is impaired." What I want to say in the end, in other words, both is important. I mean, tryptase needs to go down, mast cell burden needs to go down, skin lesions need to fade because those are the major clinical signs of the disease. And this is the disease burden.
And don't forget, not a high number, but a small number of patients with ISM also have a risk to progress. And this, so to a higher category of the disease. And this we only prevent by hammering the mast cells down. And this we can nicely follow by seeing tryptase decrease, seeing mutation burden decrease, and so on. Of course, most important for the quality of life and for the patient and for patients' perception is the control of their symptoms. This is what treatment of ISM mostly is about. And let's say one does not work without the other. And we now see that the reduction of symptoms goes very well along with the reduction of markers for mast cell burden. So it stays important to say, in other words, that it's important to measure both.
In the end, our endpoints should be on the patient's side, should be the reduction of symptoms, and should be the improvement of quality of life. Target engagement, we measure with decrease of tryptase and on the mast cell burden markers. One cannot accept the other. It's good to have positive signals in both.
Okay. That's helpful. And then just second question for you. Just as a physician, could you walk through how you think about the different PROs that are used for ISM? There's obviously MC-QoL, MS2D2, ISM-SAF. And is it reasonable to kind of compare the data across them?
Okay. So let's say making PROs in mastocytosis is not an easy task, as you have heard, because there's such a high heterogeneity and variability in symptoms. So first of all, there's a lot of symptoms patients are affected by. For some symptoms, the connection to mast cell activation and release of mediators is clear, for example, in itch, in gastrointestinal symptoms, in flushing, in wheeling, in skin redness. But in others, it's not so clear. We don't actually really know if tiredness, concentration difficulties, brain fog, all these symptoms that have a very high burden for patients with mastocytosis are a direct consequence of mast cell activation and mediator release or more a long-term effect of suffering from mastocytosis for a long time. So once we started developing PROs a couple of years ago, we had no clue on the responsiveness of symptoms by effective treatment options like bezuclastinib.
Saying that, there's an evolution of the PROs because they're all based on, of course, patient perceptions, but also based on our experience. They become better and better. This is the reason why these tools are a bit slightly different because they evolve. This is good because since we've learned about the responsiveness of symptoms, making better connections of symptoms to mast cell activation, short-term, long-term effects, we can also build and develop and validate better tools that not only mirror the perspective and perception of patients, but also mirror basically the connection of symptoms to the disease and connection of symptoms associated to the disease.
Okay. And then just to a second part of the question, just comparing across PROs, is it reasonable to sit there and say, "One had this reduction, this one had this one"? Just how do you think about cross-comparing data?
Yeah. This is difficult to do unless we have really head-to-head studies. I mean, since these tools are a bit different, it is so all of them in future will have a defined minimal important difference. So you can know what is the distance of improvement you need to measure by a tool, by this or that tool, to have clinical meaningful improvement. I also expect, but it hasn't yet been compared, that in the range of what is mild, moderate, severe, very severe symptoms will be similar by the tools, but the response may be different. So if you have a reduction of symptoms measured by one tool, maybe not able to translate one-by-one to a symptom improvement measured by another tool. But who knows? I mean, in future, we will follow our patients in real-world evidence.
Hopefully, we can apply several of the tools to our patients under real-world conditions, and then we will learn how these tools and the responsiveness of the tools compare to each other.
So let me just add one thing that could be helpful as folks think through this very important question, Sam. And this is informed by other diseases that also use patient-reported outcomes to measure effect size. And what I think I've seen effectively interpreted in other settings is that when looking at across trials with potentially similar but not identical endpoints, if the trials are placebo-controlled and the placebo arms perform very similarly, it helps people get more comfortable that the active arms are similar as well. So that's something that we'll certainly be looking forward to in SUMMIT Part 2. If we can deliver a placebo effect that looks very similar to placebo effects in other studies, then it's probably harder to ignore dramatic effects of the active arm.
Got it. Thanks for that.
Thank you. One moment for our next question, please. Our next question comes from the line of Kelsey Goodwin with Guggenheim Partners. Your line is now open.
Oh, hey. Good morning. Thanks for taking my question. I guess for the company, I know you touched on it, but could you just provide more color on the tool and specifically why the three new symptoms were added in and the other three were removed? And then for Dr. Siebenhaar, I guess, could you comment on your thoughts on those six specific symptoms and your thoughts on kind of taking out the brain fog, dizziness, and diarrhea, and adding in the skin redness and the difficulty concentrating and remembering? Thank you.
Sure. Thanks for the question. So just a little bit to kind of go back to the presentation, the addition of the three new items into the MS2D2 is really based on the process that we've followed of meeting and asking questions from patients and physicians and then conducting the SUMMIT Part 1 study, enrolling the 54 patients, and measuring the symptoms that they reported at place as being most frequent and bothersome and impactful to their lives. And so an unofficial cutoff in the creation of patient-reported outcomes is looking for symptoms or items in which more than 50% of the patients that you speak with or interview report as impactful to their lives. And so these three new items that we've added certainly met the spirit of impactfulness, frequency, spontaneous mention by patients.
And so that's why we feel strongly they belong in a composite endpoint that measures the improvement of symptoms for these patients. And as I mentioned before, the three items that are not in our total symptom score but do show up in older versions of patient-reported outcomes that measure symptomatic severity are done so on purpose, both from the process that we've followed about the much lower frequency of spontaneous reporting from patients as well as direct feedback from the FDA, both A, to us, and B, I would encourage people to read the summary basis of approval for Ayvakit where the FDA provided the very similar guidance about the lower impact of those items on the Ayvakit in the PIONEER trial, PIONEER Part 2.
So it's a combination of what we witnessed, experienced, and assessed, meeting all of these patients in our journey, as well as direct feedback from the FDA of how we've constructed our test.
Yep. Let me add on to this. I think there's two major considerations in the concept in developing these tools. As Andy said, it's all due to the rules. It's all what patients report to us. But then in the end, it is a matter of how we translate this in expert review to have it in a good understandability and also in the best way of reflect what symptoms mean. I'm a total fan, completely a fan of exchanging brain fog, which is not a very well-defined term. We realized in cognitive debriefings that it's a very common term for U.S. patients. It's not so a common term outside the U.S. Even within the U.S. population, if you do cognitive debrief and ask patients, "What do you understand if you say brain fog?" then you understand that it's different.
There's a different perception what patients understand and what they rate being severe when they talk about brain fog. So it's much more precise because this is part of it to ask, "Do you have difficulty concentrating? Do you have difficulty remembering things?" because it's much more precise, and the ratings are much more homogeneous. Also, it's good to have symptoms that if they occur, they are better on a daily basis than being only reflected by attacks. For example, diarrhea severity, I may have gastrointestinal symptoms all day or every day, but I may not have severe diarrhea every day. Doesn't mean that my symptoms are better, but I may score differently in the severity because my understanding of severe diarrhea is different, for example, from other gastrointestinal complaints that go along with that, like abdominal pain and nausea.
So this is a very typical thing of refining tools because it's not only that we ask patients, "What are your symptoms?" and make the best terms of this, but also how patients then, in a broader way, understand and translate the terms we provide in the tools to their symptoms. And this is why I think it was a very good idea to exchange this because it will lead to a better harmonization and also to a better reflection of symptoms. Also, the skin redness is fair because we know that some patients, even without having visible lesions on their skin, their skin may react by becoming red when the skin goes into exposure to specific triggers like cold or heat, or they go to sauna or to the bathtub. And this is reflected by skin redness. And this is something different than a flush.
Therefore, I think it's also good because many patients experience the symptoms to take it in. And as Andy said, the best thing is that the symptoms being taken out by the MS2D2 for the readout are not lost because still captured, excuse me, still captured outside the total score assessment.
Great. Thank you so much.
Thank you. One moment for our next question. Our next question comes from the line of David Lebowitz with Citi. Your line is now open.
Thank you very much for taking my question. On the one patient that had the two grade 3s, could you tell us anything specific regarding that patient, their profile, their baseline that might have played a role in the grade 3s? And just to remind, did the grade 3s resolve?
Yeah. Thanks for the question. So you're referring to the patient at the 150 mg dose in Part 1b. And yes, that patient had increases in both their transaminases, specifically ALT, as well as reductions in neutrophils that occurred in cycle 3. The patient was discontinued. Both their labs returned to normal rapidly upon discontinuation, so that's resolved. The patient was devastated that they couldn't continue on the trial because their symptomatic improvement was remarkable. For the abundance of caution, they were discontinued. We'll point out that bezuclastinib does have a dose-dependent increase of frequency of lab abnormalities as evidenced by what we've shown in APEX at higher doses in the advanced population, by what we've shown in our PEAK lead-in study in combination with sunitinib at much, much higher doses and exposures in gastrointestinal stromal tumors.
So part of the calculation of picking the recommended phase II dose for the non-advanced systemic mastocytosis population is to go to a dose that, number one, continues to deliver very strong pharmacodynamic effect, but importantly, number two, avoids some of the dose-dependent low-grade and lab abnormality adverse events that we see at increasing doses of bezuclastinib. So sorry for the discontinuation, but it's helpful for us picking the appropriate dose going forward at a dose where we spare those events.
Good for that. And one additional question. When you look across all the symptoms in the analysis, they're not all, I guess, considered equal from the patient perspective as far as impact on their lives. Which ones do you view as the most important for determining how and whether a patient's to be treated, especially given the high-priced nature of these therapies?
Maybe I'll ask you to clarify your question. Your question is, looking at patients prior to therapy, how do you determine which symptoms would.
Which specific symptoms within the TSS ultimately determine what types of treatments basically, which symptoms bother the patients the most and drive them towards treatments?
Oh, okay. So I'll take a stab at it. And Dr. Siebenhaar, we'd certainly be interested to hear from your own experience treating these patients. To us, the way that our MS2D2 total symptom score is constructed is that each symptom is relatively weighted equivalently. So there's no skin is the most important, and then GI, and then fatigue, and then cognitive. They all are important. And that's certainly been our experience talking and meeting patients is that there's not a specific symptom that is most impactful to everyone, and then you move down to more sporadic symptoms. This is a disease of a multitude of symptoms. Some patients are bothered most by their skin symptoms, others most by the GI symptoms, others most by fatigue. And so really, it is an individualized disease. But certainly, Dr. Siebenhaar would be curious to hear your thoughts on that topic.
Yeah. Yeah. They'd be happy. So I must say, as you already said, Andy, there's not one or two symptoms that really drive the treatment decision. It's a combination of symptoms. And we always look at what is most impairing the patient on taking part in a normal daily life. And this could be diarrhea. This could be itch. This could be I have social interaction problems because of my skin lesions. So there's a lot of different things. And I want to stress here that by now, all other available treatment options we had available so far, they were not sufficient in controlling these symptoms. Antihistamines doesn't work in many combination with H2 and all the best supportive care. You see, this polypharmacy patients are on is not effective in sorry, there's a hammer next door. It's not effective in controlling these symptoms.
So, to make a long story short, if a patient, by measuring symptoms, are not controlled and non-control very well correlates to impaired quality of life and the inability to have a normal work productivity, to have a normal social and private life, and this will always trigger the treatment because this is our ultimate treatment aim. We want to bring patients back into their lives.
Thank you so much for taking my question.
Great. Yeah. Thanks for that. And just out of respect to Dr. Siebenhaar's time, I think we're going to take one more question and then wrap up the call.
Our next call will come from the line of Ami Fadia with Needham. Our final question.
Good morning. Thanks for squeezing me in and congrats on the data. Andrew, if you could provide us some additional color on the conversations that you've had with FDA. Sounds like you mentioned that you've sort of taken FDA's feedback in composing kind of this MS2D2 endpoint and the inclusion and exclusion of certain symptoms in there. How much of sort of sign-off have you received from the FDA, and what additional things need to be done to gain alignment with them at this stage? And have they seen data from SUMMIT Part 1 holistically? And I have one more question after that.
Okay. Thanks, Ami, for that. Yeah. So what we can say is, broadly, prior to the initiation of this process, we believe we had good alignment with the FDA on the process itself, so how one would go about creating a novel PRO. We feel very confident that we've followed the process, and we've let the data guide us to the appropriate novel patient-reported outcome measure as well as the construct of the total symptom score within that measure. So at this point, we now need to go back to the FDA. We acknowledge that dynamic, which we plan to do probably in Q2 of this year based on the timing of how you request meetings and how much time before the FDA will meet with you to demonstrate to them that we've followed the process.
Our expectation is that demonstrating that you've followed the rigorous process and allowed the process to guide you to the result that we've gotten to will likely lead to alignment on the PRO.
Okay. Great. My second question is for Dr. Siebenhaar. How do you anticipate physicians determining whether when bezuclastinib, say, comes to market a couple of years from now, and if physicians have already gained some experience with using Ayvakit, how do you think physicians will sort of determine which patient needs to be on bezuclastinib as opposed to Ayvakit? Would they delve deep into some of the components of the PRO tools to really identify what is best suited for the patient? If you could sort of give us some color on that. Thank you.
Yeah. It's an interesting question. So I mean, let's imagine what will be the situation in months from now when bezuclastinib also will become available. I mean, there will be some patients who are on Ayvakit, and some of them will be sufficiently controlled. Others may not. And more patients come up where an initial treatment decision needs to be taken. I think this all depends on our further experience we gain now. But from the data we have today, I could imagine the following. I could see a couple of patients on Ayvakit that are still not, despite Ayvakit, not completely controlled. They may have an improvement of the symptoms, but their symptom burden didn't come down to zero.
I think this could be a potential population which physicians will consider changing from avapritinib to bezuclastinib because there is reason to expect that bezuclastinib may give additional benefit to patients that are not sufficiently controlled. And from the what do I start from scratch with? I think, for my current understanding and my own perspective, it may depend on the baseline mast cell burden, maybe more than the maybe more than the symptom burden. So I'm coming back that it's important to measure both. Of course, by now, my personal decision, the higher the mast cell burden markers are, my decision probably will be more into the direction of bezuclastinib. But this is speculation for now. But I mean, from the data we have today, this would be my gut feeling. This would be a decision in the future.
[inaudible] even better positioning for bezuclastinib because we will see a given hit on Ayvakit that are not sufficiently controlled, although they are under treatment with Ayvakit.
Very helpful. Thank you.
Thank you. This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.