Ladies and gentlemen, thank you for standing by. Welcome to top line results from SUMMIT trial in non-advanced SM patients. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. Instructions will be given at that time. Please be advised that today's conference is being recorded. I would now like to turn the conference over to Christi Waarich, Senior Director of Investor Relations. Please go ahead.
Thank you, operator. Today's call will review the positive top line results from our SUMMIT trial. These data were shared in a press release earlier this morning. You can find the press release in the Investors and Media section of our website at cogentbio.com. Before we get started, please be reminded that remarks made during this webcast may be forward-looking statements within the Private Securities Litigation Reform Act of 1995. These may include statements about our planned regulatory submissions and timelines, future presentations of clinical data, and financial projections. Please refer to our most recent filings with the Securities and Exchange Commission for a full discussion of our 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.
Great. Thanks, Christi. Good morning everyone. It's a great day for the non-advanced systemic mastocytosis patient community and obviously a great day for us here at Cogent. We're extremely excited to spend the next hour describing the results of our SUMMIT trial which compared bezuclastinib versus placebo in non-advanced SM patients. As you'll hear on the call, SUMMIT met all of its primary and key secondary endpoints with a powerful magnitude of benefit based on highly statistically significant comparisons to the control arm. Based on these results, we will work quickly to submit our NDA later this year and believe, following regulatory approval, bezuclastinib has the potential to establish itself as the preferred frontline standard of care for this patient population. To help us present and interpret these results today, Dr. Jessica Sachs and I are excited to introduce Dr. Nathan Boggs and Dr. Lindsey Ryan to the call this morning.
Dr. Boggs is the Allergy Division Director at Walter Reed and an investigator on the SUMMIT trial. He will provide a disease overview and set the stage for the unmet needs a new treatment would need to address in this patient population. Dr. Ryan is an Associate Professor in the Division of Hematologic Malignancies at Duke University and also an investigator on the SUMMIT trial. She will start by describing the SUMMIT trial design and baseline patient characteristics of the patients enrolled in the study. Dr. Ryan and Dr. Boggs together will share the top line results from SUMMIT across symptomatic benefit, objective measures of mast cell burden, as well as the safety and tolerability profile of bezuclastinib. Each of our distinguished guests will then present a case study from a SUMMIT patient in their own care.
Finally, I will provide some summary closing remarks and we'll turn the call over to questions from call participants. Before I hand the call over to Dr. Boggs, I'd like to remind folks here on slide 4 about the exciting 2025 we have planned at Cogent. First off, we're thrilled to be here today presenting the top line results from the SUMMIT trial which we feel confident will lead us to our first commercial approval in a rare disease patient population that currently has extremely limited available treatment options. In addition, during the balance of 2025 we will have the opportunity to present top line results from two additional pivotal trials of bezuclastinib, namely APEX and PEAK for patients with the advanced form of systemic mastocytosis and GIST patients, respectively.
All told, we could very well be just months away from a brand new blockbuster product with clear paths to approval in three distinct commercially attractive indications. Before we get ahead of ourselves, let's turn to our first pivotal trial results from the SUMMIT trial. Dr. Boggs, thanks for joining us and please take it away.
Thanks Andy. It's a pleasure to be here with you and Dr. Sachs and Dr. Ryan. The first slide is a background slide on systemic mastocytosis for the listeners. Systemic mastocytosis is a rare and debilitating disease characterized by neoplastic mast cell infiltration of extracutaneous tissues and symptoms of mast cell activation. Systemic mastocytosis has six subtypes. Non-advanced SM corresponds to the following subtypes: indolent SM, bone marrow mastocytosis, and smoldering systemic mastocytosis. Patients with non-advanced SM experience a variety of disabling and potentially serious and severe symptoms which significantly reduce health-related quality of life. Symptoms are caused by mast cell reactions and can include life-threatening anaphylaxis. Shown on the right are the five different domains that patients might have symptoms including neurocognitive with difficulty concentrating, difficulty remembering, brain fog, cognitive dysfunction, anxiety, and depression.
The constitutional symptom of fatigue, skin, including itching, flushing, skin redness and spots. GI symptoms including nausea, abdominal pain, diarrhea, vomiting, bloating, and acid reflux. An d then finally pain, headache, bone pain, and joint pain. Finally, agents targeting KIT D816V are used to treat advanced SM and non-advanced SM, but unmet needs remain. Adverse events like cognitive impairment, bleeding, and edema limit the dosing of other available agents. Available medications do not adequately control symptoms for patients or induce a complete remission. Smoldering systemic mastocytosis has no approved treatments. Next, I think Dr. Ryan is going to present the SUMMIT part two schematic shown on the next slide.
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Yes, we can hear you.
Perfect. Okay, I'm going to just go through the design of the study. This is the SUMMIT Part 2 study. As you can see, patients were randomized as part of this trial in a 2:1 fashion to receive bezuclastinib at the dose of 100 mg daily plus best supportive care medications in comparison to placebo plus BSC medications. Patients completed 24 weeks of active treatment with either bezuclastinib versus placebo and then moved on to an open-label extension as outlined here. In order to be eligible for participation in the trial, patients had to have been older than 18 with non-advanced SM as confirmed by central pathology review. It should be noted that patients receiving BSC were defined as having at least two antimediator therapies. I think of utmost importance is the fact that all patients included had moderate to severe symptoms associated with their systemic mastocytosis.
Interestingly, prior therapies were allowed and that included prior KIT inhibitor therapy. When we look to the endpoints of the study, I think of utmost interest, of importance is the primary endpoint, which is the mean change in total symptom score at week 24. We'll look at this data in a minute here. You see listed there several key secondary endpoints, which included a look at specific reductions in total symptom score and also several endpoints really assessing the burden of mast cell disease and s ome of those findings listed there included changes in serum tryptase, the KIT D816V VAF , and then changes in bone marrow mast cells. Next slide please. This is a slide here really looking at the demographics and the patients included within the context of this study.
And I think again, what I find to be of most interest here is the fact that this really does represent what we see clinically in terms of patient population. All folks had moderate to severe non-advanced SM symptoms. You can look at the number of patients included, which was 179 in total. A larger percentage of patients were female. If you look at the ECOG performance status, it was split 50/50 between a performance status of zero, one versus performance status of two. When we look at the clinical characteristics and subtypes included in this study, there were patients with indolent SM and also a group of patients with smoldering systemic mastocytosis, which is an important subgroup of patients.
If you look to the right on this slide, you'll see that there was a group of patients who had received prior KIT inhibitor therapy, and this includes those broad KIT inhibitors as well as more targeted agents such as avapritinib as listed there. The median number of best standard of care medications that these patients were on was at the time of screening and enrollment into study. We're going to look now at the baseline mast cell burden, which you can see listed there. I think of most interest is the median serum tryptase, which we'll delve a little bit more into in the next slide. If you look, the median serum tryptase for this group of patients was 40, and that was evenly split between the bezuclastinib and placebo treated patients. There was a subgroup of patients who had a serum tryptase of less than 20, and that was about 18% of patients in, as we see in that graph.
I think of real interest f rom the clinician and patient perspective is the baseline quality of life measures for these patients. You can see there's three different measures of patient reported symptoms there, including the MS.2D2 Total Symptom Score, which was again utilized as part of the primary endpoint for this study, and then two other scoring systems there, the mast cell quality of life score and the mastocytosis activity score. I think the important take home point here is that these patients really did have moderate to severe symptoms and that was representative across multiple patient reported scoring systems. I think this was again a heterogeneous patient population with multiple subgroups, which I'm really looking forward to seeing data from, and again with moderate to severe symptoms. Next slide. I think this is really perhaps the most exciting slide to look at in this slide deck.
What we see is the SUMMIT results demonstrate both clinically meaningful and statistically significant effects across all of the primary and secondary endpoints a s you can see in this table here. W e'll start with the primary endpoint. If you look at the mean change in total symptoms for week 24, you can see that was statistically significant in patients who received bezuclastinib versus placebo. Then if you look across the key secondary endpoints, all of these changes were statistically significantly different i n patients who received bezuclastinib in comparison to placebo, patients had significant reduction in symptoms and then also had significant reductions in various markers of mast cell burden and disease, including the serum tryptase, the KIT D816V Variant Allele Frequency or VAF, and then reduction in bone marrow mast cell burden as outlined there. Next slide, please.
I think to delve a little bit deeper into these endpoints and to take a little bit of a closer look, we're going to look specifically at the MS.2D2 Total Symptom Score. You can see very nicely depicted in the left the mean change from baseline and again, the total symptom scores, the primary endpoint as measured by the MS.2D2. Y ou can see a significant decrease in patients who received bezuclastinib in comparison to those who received placebo. If you look to the right, you can see the mean change in total symptom score at week 24 was 24.32 in bezuclastinib treated patients. That was in comparison to 15.41 in the patients who received placebo. The placebo-adjusted effect size was 8.91, which was highly statistically significant and a really significant and meaningful change for patients in terms of symptoms.
As an oncologist, I always have a specific interest in some of the bone marrow and other markers of mast cell disease. You can see a look at the tryptase and how that changed over the 24 weeks of treatment. You can see that 87.4% of patients who received therapy with bezuclastinib had at least a 50% reduction in their serum tryptase, again at week 24. That was in comparison to placebo-treated patients, for whom none of those patients had a reduction in serum tryptase. I think this is really exciting data and I'm going to turn it over now to Dr. Boggs to discuss the favorable safety profile that we're seeing.
Thank you, Dr. Ryan. On this next slide, we're showing that bezuclastinib demonstrated a favorable and manageable safety profile. In the table on the left, you can see the bezuclastinib cohort in the middle column and the placebo cohort on the right part of the table. For the treatment emergent AEs, 98% of the bezuclastinib cohort had TEA and placebo had 88%. Serious adverse events were 5% in placebo versus 4.2% in the bezuclastinib cohort. For treatment, dose reductions due to treatment related AEs, there were none in placebo and 11% in bezuclastinib. Discontinuations due to treatment related adverse events were 5.9% of the patients in the bezuclastinib cohort compared to zero in placebo.
The treatment emergent AEs that occurred in greater than 10% of patients in each cohort: in the bezuclastinib arm, hair color changes were found in 69% of the bezuclastinib cohort versus 5% in placebo, altered taste 23.7% in the bezuclastinib cohort compared to 0% in placebo, nausea 22% in the bezuclastinib cohort compared to 13.3% in the placebo cohort, ALT/AST increases 22% in the bezuclastinib cohort compared to 6.6% in placebo. H eadache 17.8% versus 11.7%, alopecia 11.9% versus 3.3%, and alkaline phosphatase increase 10.2% versus 3.3%. The big picture is that the majority of treatment emergent AEs were of low grade; 70% specifically were grade 1 and reversible. A variety of AEs occurred more often in the placebo group including dizziness, fatigue, arthralgia, and diarrhea. The only hepatic AEs reported were transient and manageable lab abnormalities, and only 5.9% of patients experienced a grade three or higher ALT/AST elevation.
No patient with transaminase AEs required hospitalization or even treatment intervention. All discontinuations due to treatment related AEs were due to transaminase elevations and all subjects fully resolved. The next slide, I'm going to present one of two patients that Dr. Ryan and I will present. This was a patient that enrolled in the trial at Walter Reed and she's a 44-year-old woman with indolent systemic mastocytosis and she was randomized to 100 mg of bezuclastinib. Her medical history is shown on the left as well as her best supportive care medications. Her medical history included dense skin lesions and you can see at the bottom of the figure BL corresponds to baseline. She had dense skin lesions as you can see in the middle photo and she had a mildly enlarged spleen at baseline. She also had asthma and obesity.
Her best supportive care medications included famotidine, loratadine, and cromolyn, and then once she was started in the trial, you can see that her MS.2D2 total symptom score percent change over time is shown in the middle. The percent change is shown going from time point zero up to 48 weeks. You can see she had a dramatic reduction in her total symptom score. This corresponded to her being able to discontinue all three best supportive care medications. The treatment-related AEs that she experienced is shown at the bottom left, and the only persistent AE was hair color change. The others resolved, including dysgeusia and hoarseness. After 48 weeks, you can see that her skin spots are basically totally gone. If you look at the top right, you can see some of the different endpoints. At the top, you can see tryptase, and at baseline it was 39.
By week 12, it had normalized. A normal tryptase is less than 11.5. Hers is actually even low for the average person, so 39 to 3.5, and that's sustained over time. The KIT D816V variant allele frequency, she started out at 0.19% and after 12 weeks it dropped to 0.03%, so over a tenfold change, eventually becoming undetectable. Then bone marrow mast cell burden, she started out 10% of her bone marrow was replaced by the systemic mastocytosis neoplasm. By week 24, at the bone marrow, at week 24, she had 1% bone marrow mast cells, and that we would consider a normal number for the average, f or the average person, 1% is considered normal. Importantly, CD25 expression in those mast cells at baseline was 100%, and that is one of the key features of systemic mastocytosis, that the mast cells have this abnormal expression of CD25 on their surface.
By week 24, none of the mast cells had CD25 expression, and the 1% of the bone marrow that is mast cell at week 24, none of them appear to be neoplastic. The MS.2D2 total symptom score, this is sort of recapitulating what you saw on the graph in the middle. She started out at 67.9 and quickly dropped at week 12 to 29, eventually reaching 22 at week 48. Her most severe domain of symptoms was in the neurocognitive domain, and her score was 7.8 at baseline, eventually dropping to 2.8, so a very dramatic reduction. This patient, in my mind, actually seems to have complete remission. We cannot detect the disease in her anymore and her symptoms are for the most part completely resolved. I'll hand the mic over to Dr. Ryan, who will present the second case.
All right, we'll talk a little b it about a second case here. I think what is striking to me as a treating physician is in reality any number of cases could have been described. What we'll talk about here is a 63-year-old gentleman with a really long-standing history of systemic mastocytosis and some high-risk features. This particular patient was randomized to 100 mg of bezuclastinib and you can see in the medical history really had significant findings and complications associated with having mast cell disease, which would include bone disease or osteoporosis, which we know happens at increased frequency in patients with SM. This particular individual also had some reflux disease and then significant skin-associated symptoms, which, when you look to the right, was the most severe domain reported i n terms of the total symptom scores. B est supportive care medications are listed to the left, i nitially that included four.
You can see as this particular individual was treated with bezuclastinib over the course of 24 weeks, they really had an impressive and meaningful decrease in the total symptom score, again as measured by the MS.2D2 over time. You can see that the baseline score was almost 76, and this at w eek 24, decreased to 19.5, which was a 74% reduction. If you look again at the most severe domain, this was skin at baseline, the score there was 8.1 and this was reduced to 3.3 at week 24 for a 60% reduction. When we dive a little deeper into the markers of mast cell disease and some more perhaps at the biology, we can look at the changes again in tryptase, KIT VAF, and then mast cell burden. This particular individual's baseline serum tryptase was 95.5. At week 24, this had declined to 7.9, so a 92% reduction.
There was a lovely decrease in the KIT D816V VAF from 5%, which is of note, a pretty high number for patients with indolent disease, down to 2% at week 24. As a hematologist, I find this particular excitement is the change in bone marrow mast cell burden. At baseline, 10% abnormal mast cells, which declined to 3% at week 24. I think of utmost interest is the CD25 staining, which went from being 100% positive at baseline to undetectable at week 24. In my mind, really suggestive and supportive of disease modification for this potential patient. Very exciting from the perspective of really modifying the disease. I think more importantly for this particular individual, treatment really has had a positive impact on quality of life, which from a patient perspective is truly phenomenal and as a treating physician also is phenomenal to see. I'm going to pass it over to Andy to really continue on with the discussion.
Great. Thank you Dr. Boggs and Dr. Ryan for sharing not only the SUMMIT results at a high level, but especially for those incredible case studies on the patients in your care. It's really amazing to see the top line charts and tables and listings that we review come to life with these essentially life changing patient stories. Listening to your commentary about the potential for bezuclastinib to help patients reach for a goal of complete remission is such an exciting thought for this patient community. Now here on slide 14, I'd like to take a few minutes to speak directly about how to interpret results from two clinical trials that use different patient reported outcome scales that are each designed to measure patient symptoms in this disease.
While originally Cogent was prevented from using the ISM SAF scale due to Blueprint's copywriting strategy, we found during the collection of patient data in our interactions with the FDA that there was a need to update the total symptom score composite items to more closely match the most frequent and severe symptoms reported by these non-advanced SM patients. Based on a rigorous approach, we see the MS.2D2 as an evolution in the field, resulting in a scale that better measures performance of a product designed to treat this patient population. As you can see in the two column table on the slide, the MS.2D2 and ISM SAF are generally quite similar with 8 of 11 identical items included in the composite score.
It's also critical to understand that as part of our MS.2D2 questionnaire, it measures a broader set of items than those included in the composite total symptom score and importantly includes all of the items you see in the ISM SAF column. What this allows us to do is analyze the SUMMIT data using the equivalent 11 items from the ISM SAF composite and when we do so, you can see in the line chart that the magnitude of effect for both bezuclastinib treated patients and placebo treated patients is highly consistent with the results shown from MS.2D2. Further, when one compares the placebo-adjusted effect size at week 24, the resulting differences are nearly identical using either MS.2D2 or ISM SAF items.
Now on slide 15, in preparation for this day, Cogent has been working closely with the SUMMIT investigators, physicians in the community who treat non-advanced SM patients, key patient advocacy groups, as well as the FDA, to establish the bezuclastinib Expanded Access Program, which is currently active and open to requests from systemic mastocytosis patients for no-cost access to bezuclastinib. We are excited that this program offers the opportunity for SM patients without satisfactory therapies to gain access to bezuclastinib to treat their disease as we work rapidly with regulators to seek full approval of bezuclastinib. Turning now to slide 16, let's come back to the APEX and PEAK trials, which are both on track to read out top-line results later this year.
With the favorable safety and tolerability profile described earlier from SUMMIT, coupled with the striking effect bezuclastinib had targeting cells with Exon 17 D816V mutations, we are even more excited to see the top-line results of the PEAK trial in GIST patients. GIST patients in the second-line setting following progression on imatinib represent a patient population that has not seen a new treatment approved in nearly 20 years. Therefore, we would expect rapid adoption with a successful trial result and approval. The results from the PEAK trial will be available once the pre-specified number of PFS events is reached, which has not yet occurred.
Separately, the impressive results of the SUMMIT trial also have us looking ahead to the top-line results from APEX, which is a trial studying the effect of bezuclastinib in patients with the advanced form of systemic mastocytosis driven by the same underlying cellular mutation, KIT Exon 17 D816V. Juxtaposing the current expectations of nearly ubiquitous edema, high-grade hematologic toxicity, frequent cognitive adverse events, and rare but serious bleeding events associated with the current standard of care, a safety and tolerability profile similar to what we presented from SUMMIT has the potential to quickly shift the treatment paradigm for this rare disease population. Finally, on slide 17, I'd like to highlight a few of the points that we've heard today. First, the magnitude of symptomatic reduction demonstrated by bezuclastinib, b oth the absolute and placebo-adjusted changes have set new benchmarks for total symptom score benefit in non-advanced systemic mastocytosis patients.
We believe this outsized effect was driven by the impressive anti-KIT disease-modifying activity provided by bezuclastinib, exemplified with nearly 90% of patients achieving greater than 50% rapid improvement in serum tryptase levels. Turning to safety, we would highlight that the rate of all grade and serious adverse events reported in the trial look very balanced between the bezuclastinib and even placebo arms. We are encouraged to see that only rarely did patients experience higher grade transient ALT/AST elevations, which in this small group of patients were effectively addressed with dose modifications. Importantly, besides these transient manageable lab abnormalities, there were no other hepatic adverse events of any kind reported on the SUMMIT trial, with the vast majority of other adverse events reported as grade one, many of which are on-target effects for KIT inhibitors and not associated with dose modifications,
the overall safety profile demonstrated by bezuclastinib is favorable for non-advanced SM patients. Taken together, the magnitude of the symptomatic improvement in objective measures of reduced mast cell activity coupled with the favorable safety profile position bezuclastinib as a very exciting new product with clear potential to become the standard of care for these non-advanced SM patients. This conclusion remains regardless of which PRO scale or composite item endpoint is used to analyze the SUMMIT results. Finally, looking further ahead, Cogent remains on track to submit our first NDA by the end of the year and also by then report top-line results from two additional pivotal trials in commercially attractive patient populations. With our current cash balance and recently announced debt facility with SLR, we are in a very strong financial position as we prepare for potential bezuclastinib approval and commercial launch in 2026.
What I'd like to do now is open up the call to questions from participants, and as a reminder, our guests Dr. Boggs and Dr. Ryan have graciously agreed to stay and help us with the Q&A. Operator, we are now ready to take our first question.
Thank you. To ask a question, please press star one, one on your telephone and wait for your name to be announced. To withdraw your question, please press star one, one again. The first question will come from Anupam Rama with JP Morgan. Your line is open.
Hey guys, thanks so much for taking the question and congrats on the update here. One for the company and one for the KOLs on the line. For the c ompany, can you help us understand the placebo performance you're seeing here in SUMMIT p art two and any contributing factors to consider? I think it's above historical norms if I remember correctly. For the KOLs on the line, based on what you know about bezuclastinib. Today in non-advanced SM patients, how. Would you position the product relative to avapritinib? Is this kind of a head-to-head decision making for a patient or a sequencing type of decision. Thanks so much.
Great. Anupam, appreciate the questions. Good to hear from you. I'll take the first question. As you mentioned, when you're reviewing the data, one of the things you notice is that the magnitude of effect on the placebo arm is, interestingly, maybe interesting is the best word, numerically higher than the magnitude of benefit of avapritinib itself from the PIONEER trial. While it's not exact to do cross trial comparisons, what we believe has happened over the past several years is that the expectation among non-advanced SM patients, especially those with the moderate to severe form of the disease, where many of these items, especially some of the items like fatigue and pain, which are known to be more sensitive to placebo effect across any disease, the expectation of these patients has grown for when they are expecting to be receiving a KIT inhibitor,
how much benefit are they expecting that to confer. As you mentioned, certainly the placebo effect on the SUMMIT trial is greater from a magnitude of benefit than we saw on the PIONEER trial. What's really exciting to us is that even in the face of that higher rate of placebo, bezuclastinib's activity and its very strong potent inhibition of the mutation created a situation where we continue to show highly statistically significant benefit across all of the endpoints, any way you measure it versus this outsized placebo effect. We're really, really pleased by the results of the trial, even in the face of a placebo effect that outperforms the active arm of the most recent pivotal study. I think you asked a great question. Kind of thinking fast forward into the future,
assuming that we garner an approval and both drugs are commercially available, how do physicians make a decision? I'll turn it over to Dr. Ryan and Dr. Boggs. Maybe the way I will ask them is when it comes to new patient presents or a patient presents in your office in this future state, maybe what would you tell them is better about avapritinib than bezuclastinib? How do you think you're going to go through this conversation that Anupam is asking about?
If it's okay with Dr. Ryan, I guess I'll start. Anupam, thanks for the question. Usually it's the patients that are making the decisions, so w e present them with the d ata and t hey make their decision. I think the data here speaks for itself. The total symptom score change in the SUMMIT trial from the treatment to placebo was 8.91 points compared to 6.4 in PIONEER. In terms of the mast cell burden reduction, I think it's pretty clear from the examples that were shown that patients may experience a complete pathological remission. I think that patients tend to, in my experience, and I'm speaking just for myself, but patients tend to want, tend to gravitate towards that idea of a complete remission. In terms of the safety, we have not had concerns with the safety of bezuclastinib. In fact, the edema that is seen with avapritinib 25 mg seems to be more, perhaps more problematic, I would say. T he hair lightening has not been a barrier to any of our participants.
Some people start out with light hair to begin with, so they may not notice it, and others, it doesn't seem to bother them. The patients will make a decision based off of that. I think it's pretty clear where most people at this point would gravitate towards.
I'll follow up and just add my perspective. I think first and foremost, it's phenomenal to have options. I think that is incredible and a s somebody who treats these patients, that is really just a phenomenal thing to see. I think my approach to patients with SM is really similar to how we approach patient care in general. I think the goal when you're treating a majority of diseases and, you know, specifically in the oncology space, is to really utilize the most effective option you can with the tolerable safety profile. I think, again, the data speaks for itself, as we just discussed and with what was just presented, you see a therapeutic intervention here which has the ability to not only positively impact patients from a symptom perspective, but also seems to have a pretty significant impact on the disease itself.
That is all, again, in line with the safety and adverse events profile that really is quite favorable. I think that is really an important part of the discussion that would be had with patients just in terms of discussing the options.
Thanks so much for taking our questions.
The next question will come from Andrew Behrens with Leerink. Your line is open.
Thanks. Congrats on the first of your three catalysts this year. I definitely think these results set things up nicely for the remainder of the year. Maybe one for the doc and one for the company. Wondering if the KOLs can put the results from SUMMIT into context with what they see with avapritinib at 50 mg, both in terms of efficacy as well as safety and tolerability. Andy, for you, can you comment on the responses you saw in the 7% of patients, I believe, that received another KIT agent prior to enrollment in the trial?
Great. Good to hear from you, Andy. Thanks for the question. I'll take the second question first, then I'll ask Dr. Ryan and Dr. Boggs to comment on your first question about the higher dose ava. With regards to a question about the small but important population of patients in the SUMMIT trial that had received prior avapritinib, I'm going to lump that question into a broader question, which is there's a lot of really interesting data that I would like to know the answer to right away and where do I find it in the slides. A couple things. We've had the data in our hands for literally a small number of days. What we did here is we got to a place where we could present the most important high-level, clear message we could as rapidly as we could to the outside world.
Now that we have statistical significance and highly statistically significant effect size across all of the alpha controlled endpoints, we can move on to analyzing this trial in a variety of different ways. We purposely held back some of the magnitude of benefit across those key secondary endpoints to help our friends like Dr. Boggs and Dr. Ryan and the other investigators ensure that we can publish these results in a very important journal. We can get a slot at a really important medical meeting to present this to the community, which is especially important as we prepare to get approval and launch the drug commercially.
I can't tell you the precise answer to your question, but what I can tell you is that as we work through these analyses and look at subgroups, look at different ways to consider the benefit of bezuclastinib, every day we do this, we find something that adds to the excitement of the story and really reinforces our confidence that bezuclastinib will become the standard of care for these patients. We're very much looking forward to being able to answer your question later this year at a major medical meeting. What I can tell you is that you should stay tuned for that. It's going to be a fun presentation of the full SUMMIT results. Your question about the dynamics in the market of physicians using off-label higher doses of avapritinib to overcome the lack of symptomatic benefit at 25 is a good one. Maybe I can ask Dr. Boggs and Dr. Ryan, do you do this? Do you think it's a good idea or would you prefer to have a prospectively collected data set like SUMMIT where you know the outcomes on benefit and risk as you discuss with your patients?
I can start with the answer to this one. I will say I am notably a rule follower and I really do try to really discuss with patients when I'm sitting in clinic the data that I know to be true. In reality, I think that the data that we have with avapritinib and what is available is data looking at the 25 mg daily dosing. I think that is the data that we know and the data that we have. I think, for me personally, I think the comparison is really between the two doses of approved therapy. I think that really is a discussion to have with patients. I tend to prescribe more on label. I think the data that we just saw would be the labeled, the 100 mg dosing would be the dosing for which we have the data.
I'm in the same boat as Dr. Ryan, Andrew. I have actually never, never prescribed avapritinib 50 mg for someone with non-advanced SM or indolent SM. I think we need more information about it before moving forward with it, including published articles that can be peer-reviewed articles.
Great, appreciate it. I'll just add a couple words, Andy, when you go back in time, we point out that there was a dose escalation portion of PIONEER which led the decision makers of that company to decide to run the pivotal trial at 25 mg. I don't think that they did that by guessing at what the right dose was. I think that they did that probably for a reason. Secondly, now that the owners of avapritinib are an incredibly well funded, giant multinational corporation, they have the resources and capability to run a 50 mg prospectively controlled trial should they believe that that is the right thing to do with that drug. We'l l wait to see if Sanofi launches such a trial in the near future.
Thank you.
Our next question is going to come from Michael Schmidt with Guggenheim. Your line is open.
Hey, good morning. Thanks for taking my questions and congrats o n positive top line data here. I know the symptom reduction, that total symptom score outcomes are obviously very strong across the b oard relative to avapritinib. I'm just curious if perhaps there a re any particular symptom domains where bezuclastinib h ad a particularly strong impact. If you could maybe quantitatively talk about that. Yeah, for the physicians, just in terms of clinical practice moving forward. J ust curious, I think you just talked about how to present new patients with the data. As you think about patients that a re currently receiving avapritinib in your experience w hat percentage of patients are not well controlled on avapritinib, t hat could be potential switching candidates as well. Thank you.
Great. Michael, good to hear from you. Thanks for the questions again. I'll start with the first one and then we'll ask Dr. Boggs and Dr. Ryan to weigh in on your second question. The answer to your first question is absolutely w e collect the data on individual items within the domains f or participants on the SUMMIT trial. I t falls under the same category where we're very excited to present that data later in the year. What I can kind of point you to, though, is with an average baseline severity on symptom scores in the upper 50s, you sort of need to sign up for most of these patients, have a multitude of symptomatic involvement to make the math work to get your scores up into the 50s, 60s, 70s, as exemplified by the case studies that Dr. Boggs and Dr. Ryan presented.
To get to a 24-point improvement on the scale, almost by definition, you would need to have noticeable effects across the board, across these domains and across the items. Without being able to tell you the specific numbers, I can tell you that bezuclastinib's effect is not limited to one domain or a small handful of items. Bezuclastinib, with its very powerful PD effect, targeting and removing in many cases all traces of mutant mast cell activity, leads to broad improvements across the symptomatic domains. Now, maybe I can ask Dr. Boggs and Dr. Ryan to weigh in on things like the patients that they're currently treating on ava. Maybe I'll ask you, how frequently do you see complete remission with patients on avapritini? 25 mg, like you've described on bezuclastinib.
Do you think that patients who are not in complete remission would be interested in a new therapy in the future?
This is Nathan Boggs. I haven't seen anybody in complete remission on avapritinib 25 mg. I think, you know, that's my experience, I think patients who are currently on avapritinib 25 mg would be very interested seeing the SUMMIT trial results and I think they would find the results very compelling and m any people would probably decide to switch.
This is Lindsey Ryan. I will say that I think this is the conversation, right? This is exactly what we do every time these patients come to clinic. I think what we're constantly doing in the setting of these chronic diseases is reassessing how patients are doing, how they're feeling, what's bothering them, what symptoms are most notable, what's the impact on their quality of life. I think that is something that we, again, make these assessments every time we talk to these patients. I think that this conversation of whether or not there's enough benefit on one agent versus another is something that's going to happen and should happen at every patient appointment.
I think there's going to be opportunity, again, every time that folks come to clinic to really discuss the current state of affairs for that patient and whether or not we can do better and should do better based not only on the symptoms the patients are reporting and impacts on their day, but also based on some of the parameters that we've seen, the serum tryptase and the KIT variant allele frequencies. I think this is really an ongoing, really important discussion that will continue to be had every time these folks are in clinic.
Doctor, just a quick follow up. Do you frequently see complete remissions on your patients on avapritinib 25 mg?
I don't know that we have looked for complete remissions per se. I don't know that we've really looked for that in terms of looking at repeat bone marrow biopsies and whatnot. We've definitely had patients with persistent symptoms, and I think there's definitely room for improvement from that perspective.
Great. I'll just add on to this question and share with the broader audience a qualitative piece of research that we did earlier this year to try to better understand the patient landscape. We've had a really interesting finding, which of course we're going to follow up now that we have the results of SUMMIT by interacting with patients. In a subgroup of 50 patients that we interviewed currently taking avapritinib, all non-advanced SM patients, we asked them about their satisfaction with the avapritinib treatment. You know, going in, we sort of thought maybe it would be pretty low. In honesty, they responded that they were happy with avapritinib and satisfied, which sort of got us scratching our heads because we had the same reaction when we talked to physicians that Dr. Boggs and Dr. Ryan just shared. We asked those same patients, what if there was a new drug?
How likely would you be to try it? Those same patients overwhelmingly suggested that they would immediately want to try a new drug. I think two things can be true. One, in a patient population that for decades had no biologic treatment options, when a new drug came along and many of them tried it, they had some benefit, but t hose same patients that are happy that they have some benefit are really looking for more benefit. With a data set like from the SUMMIT trial, we're very excited to provide potentially hope to these patients that are looking for not just a little benefit, but for really that sort of level that Dr. Boggs and Dr. Ryan described in the patients and the case studies is resolving all of their symptoms, not a few of their symptoms.
That's what's most excited us about this data set, and certainly the opportunity to go out and talk to patients about the potential to have that conversation.
Can I just add one additional comment? I will say, too, I think what is really of interest and excitement is really, again, also considering some of the markers of the disease biology. You have seen some of those key secondary endpoints. I'm personally really looking forward to seeing that data mature and grow further, because I think that is also of critical importance for these patients. Not only can we improve quality of life, but can we effectively modify the disease. That really, to me, is one of the holy grails of how we should be approaching these patients.
I also wanted to add that the symptom burden and the pathological disease burden seem to go hand in hand, and I think that was demonstrated with the two cases that were presented in the allergy community. I think we have a lot of experience with initial drugs coming to the market being really kind of really cool that there's something new that we can help a patient with. I'm thinking of asthma. Hopefully there are a few people who have heard of some of these drugs. For instance, omalizumab was the first drug to enter the asthma space, and that was great. Down the line, dupilumab came to the market for asthma, and it was pretty clear to most people that it was a more potent drug and also safe. I think we're seeing a similar thing here.
Our next question will come from Sam Slutsky with Lifesack Capital. Your line is open.
Hey, good morning, everyone. Thanks for taking the questions and great work on today's update. Just kind of a couple questions for the physicians. I've heard from other colleagues of yours that even at the 25 mg avapritinib dose that they do periodic blood work and liver function tests, kind of out of habit, I guess, a re you also doing this? Do the CNS adverse events with avapritinib ever come up in conversation with patients? Do they have reservations on this? Just the last question is how often do patients usually come into the clinic to get checked in with indolent SM?
Great, Sam, I appreciate the questions. I think I'll probably just ask the physicians to cover these things. They're all obviously topics that we think quite a bit about. Maybe we can start with Dr. Ryan. Do you already monitor patients on blood chemistry? Have you heard patients mention concerns about cognitive adverse events related to avapritinib treatment? How often in general do you see non-advanced patients?
In terms of how often, d o I see non-advanced patient population? I think in my practice in particular, that represents a majority of the patients that I see is the indolent and non-advanced SM patient population. We're seeing that frequently. I am coming from an oncology perspective, so I do routinely monitor when I have a Japanese community therapy [audio distortion] that is not amongst us and amongst the field, there's a reasonable expectation that with starting any new med, there will be some associated monitoring, especially up front. I tend to have a protocol or template as to how frequently I'm monitoring that we go through for the various therapies that we use. I do monitor folks as they're coming to clinic. There was one more question as part of that.
The last one, the concerns about cognitive.
I will say that that is something that I have seen personally in patients that have been treated. What I think is perhaps most interesting, you know, the systemic mastocytosis patient's community is really just that, it's a community. I think there's a lot of patients who are really well versed, well read, and who really think about their chronic disease and their illness. There's a lot of connection with other community members. I will say that there have been a lot of patients who have come to clinic who have actually brought that up first in discussion and for conversation.
I think there is definitely concern about cognitive adverse events, which again, I think is very reasonable and appropriate given that these are chronic medications in the context of chronic diseases and patients really want to be able to function, go about their daily life, be able to do their ADL. That's really of utmost importance to patients, as it should be.
One follow up before we ask Dr. Boggs the same question. Dr. Ryan, I know I've heard you in the past talk about maybe the positive side of monitoring from a patient perspective of educated patients in 2025 and going forward are really interested to know how their disease is responding to therapy. Maybe you could talk about that as well.
I think that goes along with, you know, we monitor serum tryptase and we monitor labs. I think for a lot of patients with chronic disease, and not necessarily, but disease in general, there is some comfort in seeing those labs and in getting that monitoring. I don't see it as a barrier to starting on a new therapy, personally, within the context of our patient population. Again, for folks who are living with chronic disease, I think a lot of people take comfort in having that information and being able to see not only stability, but also some change over time in some of the things that are clinically relevant, like, for example, the serum tryptase.
Great. Dr. Boggs, maybe as a follow up to some of the same questions, do you see or have you heard concerns from patients about cognitive adverse events on avapritinib? Representing the allergy community, I think there may be concerns from the investment community that allergists are not excited about monitoring drugs and m aybe you can comment on behalf of your colleagues your perspectives on that.
Yeah, thanks, Andy. Yes, patients sometimes report having cognitive side effects from avapritinib as well as edema. Those are just two well known side effects in addition to bleeding. I will say that avapritinib was actually probably not the first TKI that allergists had familiarity with. Allergists have played a role in not only systemic mastocytosis diagnosis and treatments, but also chronic eosinophilic leukemia, which allergists tend to call myeloid hypereosinophilic syndrome. The treatment for that is actually imatinib. I think allergists are starting with the background of information on imatinib and then avapritinib now as well. I think most allergists would probably, if I were to guess, routinely get labs for patients on a monthly basis until, as Dr. Ryan put it, there's disease stability. I don't see bezuclastinib being any different than the prior TKIs that have been utilized in the allergy clinic before. The periodic visits, I would say, would be monthly.
Our next question will come from David Lebowitz with Citi. Your line is open.
Thank you for taking my question. In terms of the challenges of comparing two different trials, could you discuss the potential impact of the inclusion of smoldering SM patients and bone marrow mastocytosis patients in the SUMMIT trial versus a trial that only looked at indolent SM patients?
Sure. David, thanks for your question. Our understanding is that as part of PIONEER and their definitions of the indolent systemic mastocytosis, they probably did enroll some bone marrow mastocytosis patients, but specifically excluded smoldering patients from their enrollment. As you see in our baseline characteristics, we did have about a dozen patients with smoldering disease enroll in the trial for that patient population. This offers, once we get to a scientific meeting, the opportunity to see for the first time prospectively collected data on an active therapeutic intervention on that disease s pecifically. I n general, I'm broadly generalizing that the symptomatic severity of smoldering patients would be expected to be higher. When you really get through the results of SUMMIT at a granular level, you'll see that they probably did contribute in a small way to that higher baseline severity of the patient population in the study.
What I can tell you though is that the numbers you see calculated for the magnitude of benefit and the placebo-adjusted benefit already take the difference in severity into account. If you remember, Blueprint came with top line data in a New England Journal with a modified intent to treat analysis, excluding certain patients and, you know, doing things that made their numbers look a little bit better than they looked in the label, in the label for Blueprint avapritinib. Based on the summary basis of approval, they were instructed by the agency to do an adjusted means ANCOVA analysis of the data, which is what our data are to start from. I think there are probably reasons why our patient population, including some subgroups, is more severe at baseline, but we've taken them into account already in doing the adjustment of the statistics.
Thanks for taking my question.
Absolutely.
Can I add a comment to that, Andrew?
Yeah. Of course.
I was just going to add that I do think the smoldering SM patient population represents an unmet need. Until this point, it has been a reasonably data-free zone. I think it's really important that these patients were included because we don't have data in that space. I think this really is an opportunity to see a need for those patients.
Great. Thanks, Dr. Ryan.
Our next question will come from Kelly Shi with Jefferies. Your line is out.
Ben, congrats on great results. I have two. First, on tolerability profile, we saw ALT/AST elevation improved from part one. Curious if you have noticed any, like a patient baseline difference from part one or other factors may contribute to this improvement or it was just a small sample size bias from part two. The second question to the doctors. Based on the SUMMIT trial outcome from today, what would be the read through to bezuclastinib's clinical benefit in systemic mastocytosis patients? Thank you.
Hi, Kelly. Good to hear from you. Thanks for the question. Just a clarification. Are you asking on that read through to the advanced the APEX study? Is that your question?
Yeah, that was my second question.
Okay, great. I'll take the first question. With sort of some small exceptions, we believe that the patient population we enrolled in part two of SUMMIT is highly analogous to the patient population we enrolled in part one of SUMMIT. We did not make any corrections for the inclusion criteria of excluding patients that would somehow have a higher likelihood of having ALT/AST elevations. What appears to be the case is that in a smaller phase one study where we understand folks may have been concerned about a signal of elevated ALT/AST, we now have that much larger data set and w hat this larger data set showed, and I'm thankful for Dr. Boggs' communication of this on the safety slide, is that we do see transient, reversible, manageable, infrequent, higher grade ALT/AST in a subset of patients.
Besides those lab abnormalities, there are no reported hepatic adverse events across the trial of any grade in any patient. The concerns from that earlier small trial that could grow into true liver consequences did not materialize. This drug has a characteristic again, of infrequent, manageable, transient ALT/AST elevations. I think what you've heard today from representatives of both the hematology and allergy communities is that this will not be a barrier to prescribing a drug with this magnitude of effect size for the patient population. Maybe now I can ask Dr. Boggs and Dr. Ryan, as you think about either your own ASM advanced patients or your colleagues' advanced patients, do you want to make some speculations about how a drug like bezuclastinib, which showed the results we reviewed today, might help that patient population.
I guess I'll start. Yeah, I mean, this drug is pretty great. We've had great experience with it. The patients with advanced SM, I would expect, would behave in a similar manner, especially if their disease is driven by the similar driving mutation KIT D816V. We would expect similar results. Other than that, because I'm not a part of the APEX trial personally, I would defer to Dr. Ryan to answer more of those questions. Yeah. I did want to mention that the minor ALT/AST elevations that occurred in a very small percentage of the participants did not lead to what we would call synthetic dysfunction or symptoms of the patients. As Andy mentioned, they resolved and patients were able to restart on the drug without it recurring. From my perspective, it seems to be something to watch out for, but not something to stop the drug, to not allow them to keep on the drug.
I will just add, in my perspective, as from a hematology side of things, with the advanced SM patient population, I think I'm excited. I'm excited to see the data. As the data from APEX matures, I was not an investigator on that study, but I think a large component of the advanced SM patient population is patients who have dual malignancies or perhaps two hematologic problems. The majority of that patient population is SM with an associated hematologic neoplasm or an associated myeloid neoplasm. I think it's exciting from my perspective as a hematologist, obviously, this is my perspective and my geeky side, to think about having effective therapies in that space to address the systemic mastocytosis component of SM-AHN or AMN, because that hopefully will result in our ability to better address both components of that particular type of systemic mastocytosis.
I think, in general, I am really looking forward to seeing that data as it comes out, hopefully soon here.
Great. Being cognizant of time and having some guests on the phone, maybe we can take one last question and then we'll try to wrap the call up for this morning.
Okay. The last question will come from Allison Bratzel with Piper Sandler. Your line is open.
Hey, good morning. Thanks for fitting me in. Just, you know, looking at the chart showing MS.2D2 score over time on slide 10, it's a little tricky to tell if you're seeing much in the way of a deepening of symptom response beyond 20 weeks or so. Maybe just on an individual patient level basis or qualitatively, is that something you saw in the trial and would expect to continue to see? You know, keeping a response over time as treatment duration increases, especially given some of the biomarker data like the data on mast cell burden reduction. Just hoping you could talk to that. Lastly, following up on the recent discussion on bezuclastinib liver safety for the KOLs, just based on SUMMIT part two data, would you anticipate that prescribers will monitor liver function in patients starting the drug?
Do you view that as an impediment to prescribing bezuclastinib over other KIT inhibitors? Any thoughts there would be helpful, thank you.
All right, great. Thanks for your questions. I'll ask Dr. Boggs and Dr. Ryan to weigh in on the second question. I sort of heard that they said absolutely not, but we'll maybe give them another bite at the apple on will any monitoring impede the interest in prescribing bezuclastinib? To your first question about deepening over time. Part of the design of this study, as you probably know, is that once patients complete, part two, which is a defined 24-week course, they're all given the opportunity, both active patients and then placebo patients, to cross over into SUMMIT part three, also known as the open-label extension. As we kind of roll forward into the future, one of the maybe most interesting parts of building upon the data you see today is exactly your question. How do patients on bezuclastinib do?
Do they continue to have deepening symptomatic benefit as they get to week 25, 30, 48, et cetera? You saw a couple patients in the case studies that answered that question definitively. Yes, they continue to have deepening effect sizes. Similar to an answer I gave earlier, we're very, very, very much looking forward to our opportunity to present a more fulsome data set and detailed results like the question you asked at an upcoming scientific meeting. We also need to remember that SUMMIT part two, based on the demand from the investigators, was enrolled incredibly rapidly. As of today, only a small fraction of the patients have made it to week 48, just based on the enrollment dynamics.
By the time we get later in the year and into 2026 and certainly before commercial approval, we will absolutely have the opportunity to present data that speaks directly to your question about will patient symptoms improve over time on bezuclastinib. Maybe I can end the Q& A session by asking Dr. Boggs and Dr. Ryan once again, do you see the low incidence of asymptomatic reversible LFTs as an impediment to using bezuclastinib in your patient practices.
I do not. I think that, again, lab monitoring is a reasonably expected and normal part of prescribing these types of medications. I don't think that this will vary significantly from what we do as part of standard practice for these patients.
I feel the same way as Dr. Ryan. This is Dr. Nathan Boggs. We already do monthly lab work for patients treated with avapritinib, including tryptase and hepatic enzymes, things like that. This really wouldn't change our protocol in any way in how we monitor patients on a TKI because again, the h epatic c hanges that may happen are a class effect. It's not specific to any 1 TKI.
Great. First of all, I really, really want to deeply thank Dr. Boggs and Dr. Ryan for taking the time to help us review and analyze the data over the past several days and then come this morning to answer questions from the investment community. It's very helpful to hear the perspectives of folks who represent the hematology and allergy communities who are the most frequent treaters of non-advanced systemic mastocytosis patients. Thanks to both of you for joining the call. Just before we finish up, I really want to extend a sincere thank you more broadly to all the physicians and patients who volunteered to conduct and participate in the SUMMIT trial. The trust and the sacrifice that you have put in Cogent and bezuclastinib has led directly to these amazing results. We are very much in your debt and gratitude.
We're excited to partner closely with those constituents, the physicians and the patients, to ensure that bezuclastinib is a treatment option for all of these non-advanced patients as soon as possible. In addition, I'd just like to recognize the amazing Cogent team whose tireless work has brought us to this transformative day for the company. I cannot imagine a better team to work with. It's an amazing day for patients. It's an amazing day for Cogent. With that, thanks to the participants for listening and I think we'll close the call this morning.
This concludes today's conference call. Thank you for participating. You may now disconnect.