Good day, and welcome to the 2024 Cogent Biosciences webcast. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I'll now like to turn the call over to Christi Waarich, Senior Director of Investor Relations. Please go ahead.
Thank you, Operator. Today's call will review updated APEX and SUMMIT data. These data were shared at ASH and in a press release over the weekend and this morning. You can find the press releases in the Investors and Media section of our website at cogentbio.com. 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 timelines, including 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 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?
Great. Thanks so much, Christi. Yeah, my name is Andy Robbins. I'm the CEO of Cogent Biosciences. We're really, really excited today to host this call and share the updated results from both our APEX and SUMMIT trials. Here on slide three, I'm pleased to share that in addition to myself and our Chief Medical Officer, Jessica Sachs, today on the call, we welcome Dr. Dan DeAngelo, who is the Chief of the Division of Leukemia at the Dana-Farber Cancer Institute. Dan later will help walk us through the data from the presentation shared at ASH this weekend and will also be available later for Q&A near the end of the call. Now, on slide four, I continue to be amazed at the broad pipeline our Cogent team is creating. Today, we'll really be focused on the two systemic mastocytosis indications for bezuclastinib.
Just briefly, to remind folks, we have another completely separate bezuclastinib phase III trial in second-line GIST patients that is fully enrolled and scheduled to read out by the end of 2025. If that trial is successful, second-line GIST alone represents more than a $1 billion annual U.S. sales opportunity. In addition, our research team continues to make great progress with four programs now publicly disclosed, including the first Cogent-invented molecule known as CGT-4859, which is our potent, selective, and reversible FGFR2 inhibitor beginning its phase I program this quarter. Now, on slide five, you'll see some surprising news that we announced this morning: that the SUMMIT part two pivotal study is now fully enrolled, surpassing our enrollment target with 179 patients on study. Not only did we surpass the planned number of patients, but we did so six months faster than originally planned.
This is a direct result of the efforts of our incredible clinical development team, as well as a reflection of the overwhelming interest we received from investigators and patients to participate in the SUMMIT study, with 265 patients screened within a nine-month period this year. Amazingly, over 90% of these patients were naive to previous KIT inhibitor treatment, reinforcing just how exciting the potential of bezuclastinib is to this patient population. As you'll see on the slide, we have accelerated the expected timing of our top-line results and now plan to share these results in July of 2025, which is literally right around the corner. Here on slide six, I want to remind you about the profile of bezuclastinib. Bezuclastinib has a unique profile as a highly potent, highly selective KIT mutant inhibitor, sparing other commonly implicated receptor tyrosine kinases, including PDGFR, CSF1R, FLT3, and VEGFR.
In addition, as a non-CNS penetrant molecule, it is not associated with cognitive disorders and adverse events related to other CNS penetrant drugs in the class. We have now treated over 600 patients on bezuclastinib across trials and on a wide variety of doses. What we have seen is a very well-tolerated, predictable molecule with the potential to offer real hope to patients with systemic mastocytosis and gastrointestinal stromal tumors. Turning now to slide seven, I'd like to remind everyone of the commercial opportunity and where we stand in the development process. We are conducting three registration-directed trials known as Summit, PEAK, and APEX, and the collective market opportunity across these three indications is well in excess of $3 billion in the U.S. alone. As announced this morning, both Summit and PEAK are now fully enrolled, each of which surpassed enrollment targets noticeably ahead of schedule.
All three studies remain on track to deliver top-line results in 2025, beginning with SUMMIT in July. Now, on slide eight, I'd like to talk a little bit more about systemic mastocytosis patients, as I've heard some misperceptions recently from the investment community. At the highest level, systemic mastocytosis is a KIT D816V mutant-driven disease divided into several subgroupings. Approximately 10% of these patients are diagnosed with the advanced form of the disease, which is a disease of mortality. The current standard of care for these patients is effective but comes with a host of off-target safety and tolerability challenges, including risk of intracranial hemorrhage, cognitive disorders, peripheral and periorbital edema, and frequent high-grade hematologic toxicity that speaks to a clear unmet need for these patients.
The other 90% of systemic mastocytosis patients are diagnosed with non-advanced disease, and that's grouped itself into indolent systemic mastocytosis, bone marrow mastocytosis, and smoldering systemic mastocytosis. Patients with SSM, BBM, and moderate to severe ISM experience a notable burden from their symptoms, impacting their work, social activities, and overall well-being. These patients remain in desperate need of finding disease-modifying agents that can inhibit the driver mutation in order to improve their symptoms and, by association, their quality of life. Before I turn the call over to Dr. DeAngelo to review our data, I'd like to take a minute to review the results from the only FDA-approved treatment for non-advanced mastocytosis patients known as avapritinib.
You'll see here that in the PIONEER pivotal trial in ISM patients, avapritinib demonstrated a mean reduction in symptoms of just over 30% at 24 weeks, and 25% of the patients taking avapritinib achieved at least a 50% improvement in symptoms. This company reported a similar magnitude of improvement when looking at impact on most severe symptoms at baseline and overall quality of life. We acknowledge that this trial was an important first step forward for patients with non-advanced systemic mastocytosis who had no approved treatments prior to this study. What you'll see later in our presentation is that bezuclastinib has the potential to take this level of symptomatic improvement in patients to a whole different level, and that has us very excited to see the results of the now completed SUMMIT part two study. But before we get to that, I'd like to introduce Dr.
D'Angelo, who will first review results that were presented this weekend at the ASH annual meeting from our APEX part one study of bezuclastinib, followed by his review of our SUMMIT part one data, which will be presented later today at ASH. Dan?
Thank you, Andy. Good morning, everyone. Welcome from San Diego, where it's nice and dark out. I had the luxury of presenting on behalf of my co-authors the updated assessment of bezuclastinib in part one of the APEX study in advanced systemic mastocytosis. If Andy, if I can move to slide 11. This slide depicts the study trial as it is, and the report that was done at ASH really focuses on the part one or dose optimization of the study. In the part one dose optimization, patients were allocated to four different dose levels: 50 mg twice a day, 100 mg twice a day, 200 mg twice a day, or 400 mg once a day. Now, this was the original formulation. To improve the bioavailability and decrease the pill size, there was a dose optimization and a change in the formulation.
The 100 mg twice a day dose is equal to the 150 mg once daily dose in the optimized formulation. This was confirmed when we treated a few extra patients in the stage one, and then, as Andy's already alluded to, the part two of the APEX study is actively accruing and almost fully accrued, where we anticipate 55 patients with measurable mIWG C findings to be valuable. There's two additional cohorts that are more exploratory, up to 15 patients with advanced systemic mastocytosis based on the WHO, and I'll review that in a second, but without mIWG findings.
And then a really exciting cohort of patients, up to 20 patients with systemic mastocytosis and an associated hematologic neoplasm, but whose AHN is high risk either at presentation or who progresses during study, and they're going to be receiving concurrent therapy, which has not been done before, with either azacitidine or Hydrea, depending on the AHN. In the box on the bottom left, you can see the comparable PK from the 100 mg twice daily original formulation to the 150 mg optimized formulation. Cmax and AUC are essentially equal, and so we think we have a very good dose to move forward to. So if we can move to slide number 12. In this part one of the APEX study, 33 patients were enrolled, but 32 patients were treated. There was one patient who came off study prior to initiation of therapy. The median age was 68.
Of the 32 patients that were dosed, two-thirds were male. Most of the patients had a good performance status, but 15% of patients had a poor performance status of an ECOG two or three. It's not surprising, as similar to other studies, 70% of the patients enrolled had systemic mastocytosis with an associated hematologic neoplasm. This is the most common histologic subtype in patients with advanced SM. 22 out of 32 patients were TKI- naive, which is an important comment that we can discuss later, how physicians really wanted to use an agent without the notable side effects that Andy had mentioned. The other 10 patients had received prior TKI therapy. All 10 had received midostaurin, and half of those had received both midostaurin and avapritinib.
60% of the patients had high-risk mutations in SRSF2, ASXL1, and RUNX1, and as expected, 90% of patients had a KIT D816V, the canonical KIT mutation in systemic mastocytosis. The median peripheral blood VAF was 6%, the median bone marrow mast cell burden was 30%, and the median serum tryptase was 153. When I reviewed the publication for the avapritinib EXPLORER, these were almost identical to the demographics in that study. Of the 32 patients dosed, 27 of them had mIWG C findings that were valuable, and then the median time on treatment was 16 months. Andy, if I can move to the next slide, this is slide 13. Here we show the responses by mIWG.
I think it's important to notice or to note that the patients were enrolled based on central review of pathology number one, and number two, they all had central adjudication confirmation that they had advanced disease, and then furthermore, a central review committee reviewed all the responses on study, so these were not local responses, but centrally adjudicated, so of the 27 patients who were evaluable by mIWG, the overall response rate was 52%. This included CR, CRH, PR, and clinical improvement, which is a reduction in the C finding. If you exclude that clinical improvement, just looking at CR, CRH, PR, impressively, 48% had an overall response rate, and the CR, CRH rate was 26%. Now, most of these patients are ongoing, and so we expect that these responses were deepened.
The response to patients who were TKI therapy naive was higher than those patients with prior TKI exposure. If we can move to the next slide, this is slide 14. Here we show the Pure Pathologic Response. This is an exploratory endpoint. This is probably what most hematologists use. This objective measure of mast cell burden. So we look at reduction in mast cell burden in the bone marrow, reduction in the serum tryptase level, as well as the CBC. What we don't do is review the C findings because C findings can be cumbersome to review, number one. And number two, it's hard to know whether the C findings are related to the mast cell disease or the AHN disease. So in this exploratory endpoint, pure pathologic response, all dosed patients are eligible for evaluation.
So here we have a denominator of 32, and the overall response rate now looking at CR and PR was 88%. Very impressive response in terms of reduction in mast cell burden. Also important is the median time to achieve a response, which was only 2.1 months. Moving to the next slide, these are waterfall plots of bezuclastinib on a patient level demonstrating deep reductions in the markers of mast cell burden. So on the left-hand side of the slide, we see a reduction in serum tryptase. In the middle, we see a reduction in the bone marrow mast cell burden, and on the right, a reduction in the KIT D816V bearing allele frequency from the peripheral blood. 94% of patients achieved a greater than 50% reduction.
All the patients who were evaluable for an assessment achieved a greater than 50% reduction in their bone marrow mast cell burden, and 93% of patients achieved a greater than 50% reduction in the peripheral blood KIT-bearing allele frequency. Moving to the next slide, we can see that the median progression-free survival and the duration of response was not met on the study. You can see on the Kaplan-Meier curves really impressive progression-free survival. The bottom curve is all patients, all 27 patients, in fact, that were evaluable for mIWG. In the upper curve, you can see the 100% progression-free survival at the optimized or the selected dose of 100 mg twice daily. The progression-free survival rate at 24 months or two years was 82%, rather impressive.
In the bottom right-hand corner, you can see that there were patients who progressed, but no patient on study had progression of their systemic mastocytosis at all. Of the seven patients who progressed, they all progressed within the AHN component. Three transforming to leukemia, two had progression of their underlying myelodysplastic syndrome, and two had worsening of their chronic myelomonocytic leukemia or CMML. There was an amendment, as I alluded to in the prior slide, where we are now allowing patients to receive concurrent therapy. And so three patients of those seven who met after the amendment have rolled over to the expansion cohort, combining bezuclastinib with azacitidine. So it would be exciting to see how these patients do, but it's still early for that. Moving to the next slide, important safety. This is slide 17. Again, the median duration of treatment was 16.2 months.
It's important to note that the majority of hematologic adverse events were low grade. They were reversible and did not require dose reduction. It's also extremely important to point out that there were no intracranial bleeding events or cognitive impairment noted with bezuclastinib on the study. There were four serious adverse events reported. I think these have been reported previously: one grade four thrombocytopenia, one grade four GGT elevation, but this was confounded by cholelithiasis or gallstones and an underlying ampullary lesion. There was a grade three hypersensitivity, which was a mediator flare from the underlying mastocytosis, and a grade three infection with leishmaniasis. 12 patients required dose reduction due to adverse events, but eight of these patients were treated at the 400 mg daily dose. Two patients discontinued due to current treatment-related adverse events, and both of these patients had elevation of their transaminase level.
But it's important to note that of the patients treated at the 100 mg twice daily dose, there has been no discontinuation due to adverse events. Two patients required dose reduction for thrombocytopenia, but again, no discontinuation. If we can move to the next slide, this is slide 18. If we look at the overall response rate by mIWG, again, there are 27 out of the 32 patients who were evaluable for response. This slide shows the responses per dose. And if you can see that the 100 mg twice daily dose, now six patients, arguably this is a small set, but again, this dose finding, I think it's important. The overall response rate was five out of six or 83%. And this was regardless if you looked at CR, CRH, PR with clinical improvement, or even if you excluded clinical improvement, you still had an 83% overall response rate.
Also, impressively, if you look at just the complete response, CR, CRH, half of the patients, 50%, achieved a complete remission. So if you move to the next slide now, this is 19. This was the conclusion slide from my ASH presentation. Bezuclastinib has an encouraging safety profile with deep, durable responses, 50% overall response rate per mIWG, and 88% overall response rate per the PPR, pure pathologic response. These deep reductions demonstrated across all commonly used biomarkers of mast cell activity. Important to note that both the duration of remission or response and the median progression-free survival were not reached, and at two years, the PFS was 82%. The majority of hematologic adverse events were low grade, reversible, and did not require dose reduction.
Focusing at the 100 mg twice daily dose in part one, this resulted in optimal efficacy and safety with an 83% overall response rate per mIWG. All patients receiving the 100 mg twice daily dose achieved a PR better based on PPR, and there were no discontinuations at this dose level due to adverse events. Reminding you that the 100 mg twice daily dose in the original formulation is equal to the 150 mg once daily dose in the optimized formulation. Enrollment to part two is ongoing. It's almost completely accrued, and so we'd be very excited to see that. There was also a trials in progress poster that's being presented today to update the audience and the participants in that particular trial design. If we can move to the next slide, this is just a summary break. So we're going to move now to update of the SUMMIT.
Now, this is being presented at ASH today in poster format by Lindsay Rein, my colleague from Duke. So the trial design, if we move to slide 21 for the SUMMIT, again, phase 2, and very similar, this is a dose one. There was a dose one optimization where the original formulation was people were randomized between 100 mg once daily, 200 mg once daily. There was also a brief at a higher dose versus placebo. All patients received best supportive care to try and alleviate mediator symptoms. Once the formulation was changed, the optimized formulation, patients received 100 or 150 of the optimized formulation or placebo. The current expansion, as was already mentioned by Andy, has just completed accrual, which was impressive that this was so rapid.
This included patients at 100 mg of the optimized formulation daily, plus best supportive care versus placebo, and patients were randomized in a one-to-one fashion. Once patients completed their blinded portion, they had open label extension. In the next slide, we'll show you the patients that are being discussed and presented at this year's ASH. This included patients in part one who received the selected dose of 100 mg daily. If you look at 54 patients who started, there were 18 patients who were selected or assigned the 100 mg dose. You can see here there were 19 patients who were assigned placebo and 17 patients who were assigned higher dose levels. Of the 19 patients who were assigned placebo, once they finished their blinded period, they were crossed over to open label extension, and nine of those patients were assigned the 100 mg dose.
The report includes 18 selected and nine who had open label expansion, so 27 patients total. There was one discontinuation due to an adverse event in follow-up. Moving to the next slide, slide 23. This looks at the demographics of the 27 patients who either were assigned the original 100 mg dose or who crossed over to 100 mg in the open label extension. Two-thirds of these patients were female. The median age was 52. Most of these patients had a preserved ECOG performance status with only one patient of ECOG 2. Now, the impressive portion of this demographic slide is the bottom, where what is typical in patients with ISM is the polypharmacy. You can see here, all patients had at least two or more baseline supportive care meds, which is important to try and modify or mitigate the mediator flare that patients get.
But however, 25.9% of patients were receiving four or more supportive care meds. There was only one patient who had prior amitriptyline. I would argue that people vote with their feet. That was the reason why this study accrued so quickly is because there is this unmet need. The next slide is a busy slide, but it's one of my favorite slides, slide 24. And so this shows on the left in a box some of the baseline mast cell characteristics. So 21 out of the 27 patients had a D816V in the whole blood. The median bone marrow mast cell burden was 10%. Serum tryptase level median was 37. Most patients had a tryptase level greater than 20, but we did allow a small number of patients with tryptase less than 6. And you can see here using the MS2D2 total symptom burden at baseline, the mean was 48.3.
The mean quality of life at baseline is 52.7, and the MAS at baseline was 42.3. If you look at the right wheel diagram, you can see where the most severe symptoms were. They fall into a variety of different classifications, either in the green portion of the curve on the left-hand side, those that are cutaneous with itching, flushing, skin redness due to the lesions, or just a total number of urticaria pigmentosa lesions that can be very problematic. In the orange, the overall well-being, fatigue, and tiredness. At the bottom are the more difficult ones that patients get, the mediator flare that leads to cognitive impairment. These are for the mast cells. There are patients who I enrolled on the study that were unable to work because they just couldn't function and focus, bone pain, and so on and so forth.
So different areas of severity with respect to some of the baseline symptoms that patients had on entry to the SUMMIT trial. Moving to the next study, the next slide, I'm sorry, slide number 25. Here we look at the adverse events. All-cause treatment-emergent adverse events are listed here. Again, the median duration on bezuclastinib in this portion for the 18 patients was 56 weeks. Those are patients who were initially assigned. Of the nine patients who had open-label extension, again, these were assigned placebo and then crossed over to 100 mg. The median exposure was 40 weeks. So the majority of these treatment-emergent adverse events were low-grade and reversible. It's extremely important, similar to the APEX, that we did not see any intracranial bleeding or cognitive impairment that was reported.
Among the patients experiencing liver function abnormalities, there were five patients that resolved without dose modification and remained on study. Two patients resolved with dose reduction, including one patient with a posture-related grade three SAE who subsequently re-escalated to the original 100 mg dose, remains at the 100 mg dose without any recurrence, so likely it may have an alternative explanation, and two patients with grade three events that resolved after discontinuation, so there were no long-term issues with these adverse events. Moving to the next slide, slide 26, we see in the SUMMIT at the 100 mg dose that rapid, deep, and sustained reductions in serum tryptase, which is a marker of mast cell burden, occurred over the 24 weeks of treatment.
This is represented in the right graph showing how within four weeks or one cycle, there was a marked reduction, and then a continued reduction in the serum tryptase level. Almost 90% of patients had a greater than 50% decrease by four weeks, which is a really rapid decline. Of the patients with baseline tryptase of greater than 20, 95% of patients treated at the 100 mg dose of bezuclastinib achieved a less than 20 ng/mL level of their serum tryptase. Moving to the next slide. Now we start looking at data with respect to symptom improvement. So here we're looking at the MS2D2 total symptom reduction. You can see that we start seeing reductions right away, and they continue to deepen.
The MS2D2 total symptom score reduction had a mean of 27.6 points, and the total symptom score reduced from baseline by a mean of 55.8%. So by 24 weeks of active treatment, 31% of patients had reductions or discontinuations of their best supportive care meds. And as I alluded to in the demographic slide, most of these patients are being treated with extreme polypharmacy with multiple drugs. The next slide, slide 28, shows really a patient-by-patient reduction in the individual MS2D2 total symptom score. And you can see here on this waterfall plot that 88% of patients achieved at least a 30% reduction in their MS2D2 total symptom score. And 76% of patients reached at least a 50% reduction in their MS2D2 total symptom score. The next slide tries to provide granularity as to the type of symptoms.
As I've alluded to in that initial slide, showing the symptoms at baseline in that wheel format, this is more of a waterfall plot. Looking at the left, the most severe symptom reduction. And then you see symptoms from the cutaneous portion, the skin, fatigue, and neurocognitive, gastrointestinal, or just pain, either headache or bone pain. And you can see in the dark green, pooled active treatment, the 100 mg over 12 weeks in the reduction of the individual symptoms and symptoms across the board reduced. And in the lighter green, you can see the pooled active for the additional 12 weeks or 24 weeks total, arguing that even though there's a marked reduction after 12 weeks, symptom improvement across the board in all areas continues to improve and deepen. Next slide. So here we look at quality of life. This is slide number 30.
These are patients, again, treated at the 100 mg of bezuclastinib. All patients had significant improvement in their quality of life. Among the patients receiving this 100 mg dose for 24 weeks, the reduction in the quality of life score was by 25.4 points. And again, among patients receiving the 100 mg active dose for 24 months, the total score reduced from baseline by an average of 48.9%. So you can see in the diagram that the reduction for a patient with moderate impact on quality of life to mild impact, that's how the scores are really pooled and graded. So improvement across the board. And I think the important thing is that the improvement in quality of life continues to deepen or improve with continued therapy. So the next slide, slide 31, which is my last slide.
conclusion, data from part one of SUMMIT, including the patients assigned at the 100 mg dose as well as the open-label extension, showed that bezuclastinib was safe, led to robust improvements in symptoms and biomarkers of mast cell burden in these patients with non-advanced systemic mastocytosis. I think this provided evidence of a favorable safety and tolerability profile. The majority of treatment-emergent adverse events were low-grade and reversible, and no treatment-related bleeding or cognitive impairment was noted.
The rapid and sustained reductions in symptom severity based on the MS2D2 and quality of life measures, as well as objective biomarkers, were noted, with 76% and 88% of patients respectively treated at the 100 mg dose having 50% or 30% reduction in their total symptom score, substantial reductions in the most severe symptoms at 12 weeks with continued improvement by 24 weeks, and clinically significant deep reductions across all symptoms using the MS2D2 tool observed at 24 weeks. After 24 weeks, 31% of patients had reductions with discontinuation of their best supportive care meds to help with what was being used at baseline to help mitigate some of their symptoms. As noted, part two has completely enrolled well ahead of schedule, and we look forward to these results next year. With that, I'll end. Thank you.
Great. Dan, really, really appreciate you joining us. I can't even imagine what your calendar looks like this weekend at ASH. You're a very busy guy. And so again, we really appreciate you joining us early this morning to walk through the APEX and the SUMMIT data. Before we open up the line for questions, I do want to share a few more slides, which I think might help certainly the investment community with the interpretation of these results. So first, here on slide 33, we try to address, which we understand, some confusion about the difference between two distinct tools that are used to calculate total symptom score for non-advanced systemic mastocytosis patients. You'll see here on the graph presented a green line, which is identical to the symptomatic improvement Dr.
D'Angelo reviewed a little earlier, showing that patients on 100 mg of bezuclastinib in the SUMMIT trial demonstrated a 56% mean improvement in total symptom score at 24 weeks using a set of symptomatic items from our MS2D2 tool, which is shown in the column that has the green color on the bottom. You'll see a separate dotted line also plotted on this graph, which represents the same patients scored on total symptom scores using symptomatic items from the ISM-SAF scale, which is shown in the column with the pink at the bottom on the right. Not only did the total symptom score using the ISM-SAF items result in an identical mean 24-week score of 56%, but the scores for patients in our trial at each four-week increment were also nearly identical, whether you use the items from MS2D2 or the items from ISM-SAF.
Turning to slide 34, we've summarized the key results from patients receiving 100 mg of bezuclastinib on the summit trial across the most relevant clinical endpoints used to measure improvement in non-advanced systemic mastocytosis patients. While improvements in the composite mean scores for TSS and quality of life are themselves impressive, what has resonated most with investigators is the 76% rate of achieving at least a 50% reduction in symptoms, which is triple the expectation of the currently available therapy and the depth of response bezuclastinib achieves on an individual patient's most severe symptom at baseline, regardless of specific domain or item. With the doubling to tripling of effect size across these clinically important measures, we eagerly await the results of SUMMIT part two that are now on track for July of 2025.
On slide 35, we reviewed patient data from 16 of our SUMMIT patients who have been treated with the 100 mg dose of bezuclastinib for at least 48 weeks. While early, this deepening of response is very encouraging. As you can see, symptomatic improvement improves from 56% mean improvement at 24 weeks up to 65% mean improvement at 48. Similarly, for this subset of patients, you'll see 88% of them achieve at least a 50% reduction in symptoms at 48 weeks, up from an already impressive estimate of 76% at week 24. This speaks directly to the potential durability of bezuclastinib in the patient population, as nearly every patient receives clinically meaningful benefit from this treatment. Finally, I'd just like to review where we stand with the development of bezuclastinib. We remain on track to communicate top-line results from all three registration-directed trials in 2025, beginning with SUMMIT in July.
With both SUMMIT and PEAK pivotal studies enrolling months ahead of schedule and surpassing target enrollment goals, we are confident that we have the interest and support of the investigator and patient communities in both systemic mastocytosis and gastrointestinal stromal tumors. With combined potential U.S. annual sales of over $3 billion, Cogent has an extremely attractive setup for investors entering 2025. Now, what I'd like to do is turn the call over to our operator for questions about the data we've shared this morning. Operator?
Thank you. If you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, please press star one one again. Our first question comes from Christopher Raymond with Piper Sandler. Your line is open.
Thank you. Thanks for this presentation. Maybe a question for Dr. DeAngelo. Doctor, you've worked with bezuclastinib and avapritinib. Maybe just a question regarding your indolent SM patients in your practice. Knowing you have to see, I guess, the full data from SUMMIT part two before really judging, but just assuming this efficacy and safety data sort of holds up, I think I heard you say on the call regarding trial enrollment that people are voting with their feet. Maybe just talk about how you might decide which option, Bezu or avapritinib, would be best for your ISM patients once they're both sort of commercially available. And then maybe talk about how you and your colleagues view the risk-reward trade-off here, especially on the safety side with the choice of these drugs potentially happening as early as next year. Thanks.
Thanks, Chris, for the question. Dr. DeAngelo, I'll turn it over to you.
Sure. So yeah, I think it's interesting that you raise that question about what I decide because when you're in the clinic room with the patient and on their journey, it's not what I decide. It's what we decide. It's a group discussion. And maybe I have a slightly different patient population or mix, but I can tell you that my patients are well-informed when they come in. And if they're not eligible for the trial or they can't get on the trial and now that the trial is closed, having to prescribe avapritinib, they don't want that drug because of the neurocognitive or the association. And I have to say, well, at 25 mg, it's unlikely to get that. And I think the difficulty in the advanced setting is that it's really hard to dose 200.
And I was at a scientific meeting last night, and most of my colleagues are dosing lower dosing of avapritinib in the advanced setting just to try and mitigate or guide around that. Of course, in that setting, the problem there is you're getting a markedly slower response rate and lower response rate. So I actually don't think that I understand the question, but I don't. At least in my clinical practice, bezuclastinib, at least in the advanced, is without the association of neurocognitive intracranial bleeding and the potential to combine with alternative therapies is clearly exciting.
My anecdotal experience, because we don't have the readout of SUMMIT, as you'd pointed out, is the fact that there seemed to be this plateau on the PIONEER study, and there was a proportion of patients who just didn't benefit, or when they benefited, they lost their improvement in their symptom control. I just haven't seen that. Of course, that's anecdotal because it's a small number of patients. But I think it's reflective of what the data I just reported out is that patients continue to get deeper and deeper and deeper improvements with the ability to reduce their best supportive care meds. I think that makes sense, right? Because the APEX is dosing at 150 and the SUMMIT is dosing at 100. So you're two-thirds of the dose. In my opinion, of course, I'm an oncologist, so I'm used to dealing with toxicity.
None of these toxicities are of really any particular issue. In the avapritinib, you're dosing at 200, which I just told you is almost untenable. And the PIONEER is dosed at 1/8 of that at 25, which is probably way too low. And most of my patients on that have had to be dose escalated in order to get their symptoms controlled. So just moving forward, if both agents are available, after a discussion, I don't see that there's much of an issue. And then, as I alluded to at the beginning, my patients come to me saying, "I don't want to go on that drug. I want to go on this drug." And that's true with not just this disease, but other diseases. And that may be a selection in Boston, a well-read, well-informed group of patients who know exactly what they want.
It's a discussion and negotiation. So I just don't think that it's not going to be what I decide. It's going to be what we decide.
Great. Thank you very much.
Thank you. Our next question comes from Anupam Rama with JP Morgan. Your line is open.
Hey, guys. Thanks so much for taking the question. Maybe a quick one for the company as well as Dr. DeAngelo. And so, Andy, maybe for you, can you talk about the enrollment curve in SUMMIT and the factors that led to this sort of early enrollment completion? Was it more sites getting online? Did you see an uptick sort of post-Quad AI? I think the data were originally year-end and then second half and now in July. And then for you, Dr.
D'Angelo, I think one thing that the street is debating here is really kind of the discontinuation rate that you're seeing in non-advanced patients. I know that it's small numbers, but can you talk to that sort of benefit-risk ratio following on Christopher Raymond's question on just discontinuation? And maybe talk to what portion of patients are unsatisfied with their outcomes with avapritinib at 25 mg?
Great. Anupam, I appreciate the question. And Dr. DeAngelo, I'll take the first one, and then I'll hand it over to you. So getting to your question, Anupam, about the enrollment dynamics, it really watching the enrollment of SUMMIT Part 2 vastly exceeded our expectations. So if you remember, we really kicked off that trial right around Quad AI. So in 2024, we started and finished. We began screening patients in early February, and we stopped screening patients in the middle of October.
That's 265 patients in about nine months. On an annualized basis, that would have been about 350 patients if we had taken it for a year. And that occurred in the first year of a commercial launch of the first drug ever approved for this patient population. So again, as I mentioned in my prepared remarks, over 90% of the patients who screened into the trial were naive to avapritinib. The other thing I can share with the group is a dynamic that we found very, very interesting. So in the middle of September, with Dr. DeAngelo's help, we had an opportunity to share the results preliminarily from the summit results you're seeing today with the investigators in sort of a private meeting. And the result of that is the screening and the enrollment for patients in the summit trial accelerated.
We did that in an attempt to ensure we were going to complete enrollment in Q1. And what happened is we screened almost 50 patients in the five and a half weeks after showing them the data you just saw. And so that really speaks to a level of excitement about the symptomatic improvement and comfort about the tolerability profile that these 70 investigators around the world saw and interpreted when they reviewed the same data you're seeing today. Now, before I turn it over to Dr. DeAngelo, let me just quickly go through because I know Anupam, your question is probably on the minds of others. So if you look at the patients who discontinued, one of those patients we described a year ago at ASH of 2023. And so you can remember that that patient had really, really high outer range exposure to bezuclastinib.
And then after discontinuing from the trial, also had to discontinue subsequent 25 mg avapritinib therapy for high-grade hematologic toxicity right after taking the drug. What's very important to point out is that all patients with regards to transaminases are reversible. These are asymptomatic events in all cases and reversible in all cases. So these patients who discontinued, their AST/ALT returned to baseline within a couple of weeks of discontinuation with no evidence of liver injury. So maybe, Dr. DeAngelo, if you want to add anything about your level of concern about this patient population in this dynamic?
Yeah. No, no. I completely agree. I mean, I think the asymptomatic AST/ALT rises, as you mentioned, it's often reversible and patients can continue with the same dose. It may be due to polypharmacy. They're on a lot of different medications. So trying to sort that out, it's rare that patients have to discontinue. And the asymptomatic nature really differentiates it from the other side effects that we're seeing with avapritinib with myelosuppression and intracranial or cognitive issues, which is really a barrier. And then do you want me to answer the other question, or?
Yes, sir. Go ahead.
Yeah. So the other question is kind of an interesting one, although it's hard to put numbers on it. How many patients are dissatisfied? The studies are not measured that way, right? They're looking at improvement. So 30% reduction in baseline symptoms. So patients feel better on avapritinib. I'll rephrase your question. The majority of patients at the 25-mg dose, although there was a reduction in the symptoms in the vast majority, there wasn't resolution of symptoms, one.
There seemed to be a plateau where patient improvement got better but didn't continue to get better with time. There were patients who came off study to receive off-label dose escalations. There were patients who have been dose escalated now on the amendment. That hasn't been published or reported yet, the experience with going from 25 to 50. I can tell you my personal experience is you're able to capture some improvement in symptoms by going to 50. When I go higher than that, then I start to get neurocognitive issues, and then I have to go back down. There's a sweet spot between improving symptoms and trying to manage the neurocognitive issues that are seen with avapritinib. I'm hopeful that we'll get some of that data from more granular data from the PIONEER study.
But it'll be important to know in a CONSORT diagram that a lot of patients came off to receive off-label dose escalations. So I'm not sure if that completely addresses your question, but it's probably the best I could do.
Thanks so much for taking our questions, guys.
Thank you. Our next question comes from Kelly Shi with Jefferies. Your line is open.
Thank you for taking my questions. So in non-advanced systemic mastocytosis, does the AST/ALT increase correlate with the depth of response? And also, is it dose-dependent, or it's actually not relevant either? Thank you.
Yeah. Thanks for the questions, Kelly. No, the early question is no, we don't see any clear response between transaminases and symptomatic improvement. And then the answer to your other question is across the doses we're seeing, not just in the SUMMIT trial, but also in the APEX study.
Then, interestingly, also in the PEAK study. We've now tested over 600 patients on bezuclastinib across a variety of patient populations, a variety of doses. What I can say is that even though much of this data is blinded from the pivotal studies, we still have a fantastic PK and safety team that reviews these blinded data on a regular basis. What I can tell you is that across doses, across these trials, the profile remains highly consistent and that the transaminase elevations are asymptomatic and reversible in all cases. There have been no events that have led to any medical issues, no events that have led to hepatic outcomes, no Hy's Law cases reported. We have no evidence of DILI. For a significant majority of these cases, the time to onset has been within the first four cycles.
And then, as we mentioned before, in the very rare cases where a patient is discontinued, the reversibility is measured in a matter of a handful of weeks. And so across doses, across indications, across patient populations, we believe that this profile will be the profile of bezuclastinib moving forward. And certainly, we appreciate Dan's perspective that in the non-advanced population, that this is not a barrier to prescription. And it certainly does not appear to be a barrier to any use in diseases of mortality like ASM or GIST.
Thanks for the insights.
Thank you. Our next question comes from Andrew Berens with Leerink. Your line is open.
Hi. Good morning, and thanks for taking my questions. Congrats on the progress and the impressive efficacy. It's certainly a potent agent relative to many of the other ones.
Just wondering, this is for the company, and then I have a question for Dr. DeAngelo. Wondering how confident you are that you have the right dose in ISM. I don't think we've seen lower doses in ISM. I know you had some at ASM, but correct me if I've missed it. If there aren't any lower doses, how much efficacy do you think you would lose by going to 75 mg or 50 mg? And I know you're probably not going to specifically disclose FDA interactions, but just wondering if you could give us an idea when Project Optimus discussions would likely have occurred. And then for Dr. DeAngelo, Cogent has taken a different approach than Blueprint. They're emphasizing efficacy versus Blueprint's dosing lower and then giving docs the option to dose higher. Just wondering which strategy you think you would prefer at ISM.
Would you prefer to start lower and escalate as patients needed, or would you prefer to start higher and then go lower as needed?
Thanks. Okay. Great. Again, Dan, I'll throw the second question over to you after I make some comments on the first one. Andy, there's a practical issue, which is the good news, is that the pivotal study is already enrolled and enrolled way faster than we thought it was going to enroll based on patient and investigator demand for getting onto the SUMMIT protocol. Certainly, once your pivotal trial is enrolled, typically the next step isn't to go searching for doses. What we can say, though, is that there doesn't seem to be a very noticeable linear relationship between dose of bezuclastinib and the asymptomatic reversible lab abnormalities that we're talking about.
If you look at the profile, other than this, again, asymptomatic adverse event we're talking about, at the 100-mg dose, we really don't deliver any noticeable adverse events that patients feel, which is really the profile we're trying to go for. It's maximizing symptomatic improvement by getting up to that target engagement where we think we're approaching IC90 type D816V target engagement without giving symptoms. If you look at that safety table, those are treatment emergent adverse events below the AST/ALT. All of those adverse events below that, many of those are characteristics of the disease itself. And because this is a TEAE table, what I can share with you is only about a third of those events below the transaminase row are assessed as related to drug. And I think all of those are grade one. So we have this theoretical talk about choosing a dose.
There's nothing to spare by going down. I can show you a scatterplot of AST/ALT and bilirubin elevations for 25 mg of avapritinib, which is published in their summary basis of approval, and I'd encourage people to take a look at it. At 25 mg of avapritinib, which is well, well below any clinically relevant target engagement, they have several patients who are above five times upper limit of normal on AST and several patients who are above three times upper limit of normal on bili, so these transaminase elevations are characteristic of kinase inhibitors. They're characteristic of KIT inhibitors. They're characteristic of avapritinib at 25 mg, so we really feel strongly that there's nothing to be gained by running a trial below this dose because you're not sparing anything that won't occur sporadically with KIT inhibitors regardless.
With regards to Optimus, what I can tell you is that we've interacted with the FDA multiple times over several years on bezuclastinib across all three programs, and it has not been part of the discussions.
Did you want me to?
Oh, yeah. Sorry, Dan, you want to?
So you raised a very fascinating question about starting low, going high, or just starting at the dose that we've selected. And I think Andy has illustrated some of the reasons there. You also have to remember the history, right? So when we were doing the EXPLORER study, at that point, we were designing the PIONEER study. And we were seeing these intracranial. It was amazing. Kudos to Blueprint for able to guide a drug. I mean, that would have killed most drugs, right? But we were able to mitigate the symptoms by establishing clear platelet parameters and dosing issues.
And so the concern from the FDA was that patients with ISM have a relatively normal life expectancy. There's some data from SEER data. Maybe it's a little shortened, but nevertheless, there's this prolonged survival as compared to advanced. So it has a different risk-benefit. And the FDA was very, very concerned about any intracranial bleeding. And so there was the part one portion of the PIONEER that's never been published but was presented by Cem Akin at ASH back in 2019 or 2020, I believe, where they looked at 50 versus I'm sorry, 25 versus 50 versus 100 versus placebo. And arguably a small number of patients, so it's really hard to get good, accurate data. But it seemed like the 100-mg dose, you gave deeper and faster responses, but you got responses across the board, and you just didn't see any toxicity at the 25.
We were very, very concerned with any neurocognitive issue cutting that study down. We went very low, as low as you could go. Fortunately, we were still able to get a positive study out of it. I just don't think, as Andy had mentioned, that we need to do that. I mean, the issue is that a substantial proportion of patients on the PIONEER had to come off to get higher dosing. With higher dosing, you saw more toxicity. I have patients. I mean, this is not a benign disease, right? There are some patients who are moderately affected, but I have a patient who spent two days in the ICU after getting a flu vaccine on an Epinephrine drip due to an anaphylactic reaction.
Or a patient when I was coming to ASH who was in the emergency room with idiopathic anaphylaxis who were not on bezuclastinib, but on standard of care therapy. These are complicated patients. And so more rapid reductions and controls of their symptomatology is, I think, the goal of the caregiver, myself, in terms of trying a reduction. But there's a little bit of a history there in terms of why the 25-mg dose was done. I don't think it was done out of scientific valor. It was done out of real concern for anything would have just derailed that study. So I hope that answers your question.
Thank you. Our next question comes from Sam Slutsky with LifeSci Capital. Your line is open.
Hey. Good morning, everyone. Thanks for taking the questions. I guess any view on what % of avapritinib-treated patients are suboptimal responders in ISM, or I guess a different way to kind of think about it is, what's the best way to think about the proportion of patients already on avapritinib who might be able to derive additional symptom benefit from the higher dose intensity of bezuclastinib?
Yeah. Sam, thanks for the question. I think Dr. DeAngelo has asked a slightly different flavor of this question earlier. I'll answer it a little bit from the company's perspective, and then I'll let Dan add anything else he wants to. We work very carefully in this disease, as most biotech companies developing drugs in rare diseases, with patient advocacy groups.
And what I can tell you in our communication with them and with several patients directly is that we don't often find, if ever, a patient who says, "I am completely happy and all of my symptoms are gone taking 25 mg of avapritinib." We certainly acknowledge, based on the data presented in PIONEER and the real-world anecdotes we hear back, that oftentimes patients' skin symptoms do noticeably improve on avapritinib. It's harder to find patients whose symptoms outside of the skin domain get noticeably better on 25 mg of Ava. And I think that is why both the investigators, like Dr. DeAngelo, but also the company, Blueprint, have a strategy of trying to get folks to take higher doses.
The real big question mark with higher doses, as Dan has outlined nicely, is at what level do you start to see symptomatic issues like edema, symptomatic issues like cognitive disorder, and then potentially safety issues like high-grade heme tox or intracranial hemorrhage. But Dan, maybe if you want to say a few words about, do you see completely controlled 25 mg avapritinib symptomatic patients? Do you think that patients on 25 mg of avapritinib might still be looking for something that can help them get to deeper symptomatic control?
Yeah. Nobody has resolution of their symptoms. I think it's a very good point. And it's hard to do cross-trial comparison here. This is not a randomized study. So we have one study, and we have a second study, and they're slightly different groups of patients, of course. But anecdotally, in my experience, nobody has resolution of their symptoms.
They just have reduction in their symptoms, and I think that is really the hallmark where there are patients on the Summit trial where it seems to all intents, their symptoms are gone. Now, it's not everybody. I only see a small subset of the patients. We need to see what the data is from Summit, from the placebo, the large trial that just closed, so we'll have to see more data, but that's my take, is that you see reduction but not resolution, and I think with a higher dose, you might have seen it, but then you're going to get the toxicity, so we're hoping on the bezuclastinib that more and more patients are having resolution of all their symptoms, but we'll see.
Okay. Great. So just for the investment community, I promised our friend Dan that we'd be done at 6:00 A.M. his time so we could go to Starbucks. So let's maybe take one more question, and then we can send him on his way.
Thank you. And our last question comes from David Lebowitz with Citi. Your line is open.
Thank you very much for taking my question. If you compare the populations of both APEX and SUMMIT in terms of what types of patients are included with that of Ayvakit, how might you, I guess, put that in the context of what we saw for efficacy and potential impacts on safety?
Okay. Thanks, David. I'll take a stab at that, Dan, if you want to add anything. We did our best to try to enroll highly analogous patient populations when compared to the comparable trials.
So EXPLORER, PATHFINDER versus APEX in the ASM population, and then PIONEER versus SUMMIT in the non-advanced population. I'll point out a couple of important differences. We allowed for smoldering and bone-involved non-advanced systemic mastocytosis patients to enroll in the SUMMIT study while they were excluded from the enrollment in the PIONEER study. And then maybe the most important distinction, I think the baseline characteristics of the patients look highly analogous across all the studies. But we, for reasons of time, allowed for prior avapritinib use in our studies where it's not their fault. They didn't allow prior bezuclastinib because bezuclastinib hadn't been developed yet. So those are, in my opinion, probably the two most important distinctions. But Dan, if you want to add anything.
Yeah. I mean, the original PIONEER study was written to include both ISM and SSM. And so when we started seeing the intracranial bleeding in the EXPLORER and the decision was made to go with the 25-mg dose and the PIONEER, the investigators felt that that was too low of a dose to include SSM. So the study was amended to exclude those patients. And that's why SSM was not included. And there's not that many SSM patients, but they were included in the SUMMIT trial. So just to add clarity to that.
It's always helpful to have the people who actually did the trials on the call. So thanks for that color, Dan. So at this point, I just really want to extend a sincere thanks to Dr. DeAngelo for being on the call with us and helping us think through these results and present the results. I also want to thank the Cogent team, who's amazing.
And on our two biggest pivotal studies delivered enrollment six months plus in advance of what we thought was possible comparing to other companies that have come before us. And I'm just really proud of the Cogent team for doing that. We are very excited for 2025 to see the results of our pivotal studies. We feel very strongly that bezuclastinib's profile is going to emerge as the best-in-class option for both systemic mastocytosis and GIST patients. And then just as I close the call, my biggest thank you is to the patients and their families for putting their trust in Cogent and bezuclastinib in our clinical trials. We certainly appreciate the investigators' help in introducing us to these patients, but it's really the bravery of the patients who are willing to accrue to these studies that'll help us figure out exactly what this drug looks like.
So sincere thanks to them as well. At this point, I think we're going to wrap it up today. And thanks, everybody, for joining and your questions.
Thank you for your participation. This does conclude the program. You may now disconnect. Everyone, have a great day.
Thank you.
You're welcome.