GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - VERASTEM INC

All right, so I'm Michael Schmidt, senior biotech analyst with Guggenheim. It is my great pleasure to welcome the next presenting company here with me. I have Veristem, Jonathan Pachter, CSO, and Tim Wu, head of development at Veristem. Is that right? Yes, and so obviously the last couple of months were very active, very exciting months for Veristem. You had new data presented for VS-7375, big capital raise as well. You announced the CEO transition. So how would you describe Veristems today and what should investors expect in the next year or so? I think we're where we want to be exactly. I mean, the, first of all, AbMak, the Faxinja, Copac, it's a RaphMak inhibitor with a Fax inhibitor. It was the first novel novel approval we got approved in May of 2025. So now we're at the point where our sales cover the commercial force. So that's really great to be break-even for that asset. And then, as you mentioned, the G12D inhibitor, VS7375, is really exciting, looking best in class really for any patient with a cancer driven by KRS-G12D, and that's really important in pancreatic cancer, colorectal, and lung cancer, which are obviously really large market cancers. So, great point. And as you say, the fundraise really lets us drive the clinical development program. We have a couple of trials that Ting will say more about that are gearing toward accelerated approval in the near term. And then it is a transition. I think you mentioned Dan Patterson, who's been the CEO since 2011, felt like he's delivered it to this point. And as we look toward commercializing the G12D inhibitor now in addition to the RAF-MEC and FAC inhibitor, I think Michael Bailey, the new CEO, coming in January 1st, is really well positioned to do that. Okay, great. So maybe a couple questions for Ting or Andy, Jonathan. On 7375, obviously you had a big data update, pre-ESMO. How does that drive your development path for the program, and how do you think it's positioned in this very active space of KRAS inhibitors? Yeah, and thanks for the question, Michael. I think the data that we have presented on October 14th that really highlight that we have the potential to be best in class for G12D space, and which means that that allows us to open a lot of opportunities across tumor types. Of course, obviously, PDAC, CRC, and also non-small cell lung cancer, and also the recent fundraise allows us to go like full steam for all these indications, and we are about to fully enroll for our, I would say PDAC and also CRC study towards the end of this year. non-small cell lung cancer to follow early next year. And then we are starting three phase three confirmatory study in the front line setting for these indication. So exciting times, I think it validates that we always have a great scientific story about the on and off inhibition, the really good exposure proportional across those levels. And now it's manifesting in the clinical data that's trending towards best in class. And of course this enables a lot across indications. Maybe just a couple of follow-ups. So your partner, GenFleet, went with 600 mgs per day dose in their China-based studies. You obviously decided to go higher in the U.S., kind of searing in on a 900 mgs per day dosage. Maybe just remind us of what you've learned about the safety profile at 900 mbs and, you know, how that perhaps compares to the 600 dose. Yes. So basically, GenFleet did not fully explore 900 milligram. I would say in general, they only dosed three patients in total at a 900 milligram dose, and they decided to go for speed for 600 milligram, given they have seen already favorable benefit risk. For us, we have fully characterized 900 milligrams. So a few things, as John probably has already alluded to in several kind of occasions, that we really have a good dose proportional increase in terms of exposure across the 600 and 900 milligram. And based on preclinical models, that 900 milligram is the more optimal dose that we have hit the optimal exposure. And the other thing is about the safety profile or tolerability profile is that 900 milligram is identical to 600 milligram and just a quick reminder that the main AE is GI disorders and predominantly low grade mostly grade one with around 10 to 15 percent grade two other than that it's a pretty clean safety profile so that justifies us to go for 900 milligram given no difference in terms of durability compared to 600. Okay. So in pancreatic cancer, which is one of the big focus areas for the field, you've reported a 41% response rate in second line plus patients. How robust are the results at this point and how mature was efficacy at the recommended phase two dose? Right. So for the PDAC data, obviously, I think this is a data set that clearly shows differentiation. So first, it's all the patients that we have dose at 900 milligram in a phase one study in a previous treated PDEK setting. We are not hiding any single patients. We're reporting the intended to treat population. So any patient with dose with 900 milligram, we're including in that data set. And also we are reporting all confirmed response. So in terms of data robustness, I think it tells us how rigorous we are about reporting the data. we report I intended to treat and also confirm response rate and also like as you probably noticed that although the sample size is not that large but I would say it's very consistent in every setting either in a second line or third line beyond I think it's a very competitive compared to what is available out there including Drexel RASF currently at standard of care and also the other GTOE D inhibitors okay one thing that supports that is the The consistency of the data across the board, I mean, I think that we had predicted in the preclinical models, predicted that the dual on-off profile long residence time would pay dividends as far as better efficacy, and also this dose proportional efficacy where we can maximally hit the target. And then if you look at molecular response, like KRAS G12D variant, the low frequency knockdown, we say it's extremely strong at 900 milligrams, and we can compare directly to data with Ericsson-RASIB or Zoldan-Rasib or Insights G12D, which they're leaving a lot of patients behind there, too. So it's not only, even though the 22 patients data set is really strong and consistent in those depths of responses with two complete responses in G12DP-DAC, which is, I think, a first, it's really, G12B is poor prognosis relative to other variants. So I think all of that together, the consistency really makes sense and validates that even further. Right. And last point to add is probably the durability of disease control. We are probably the first GTO data number that reports clinically meaningful, favorable PFS. I would say not the median PFS, but we are able to report a landmark PFS at six months, which is 67%. I think this also stacks very favorable against the competition. And one thing to know, like a lot of these major KRAS-GOD players did not report a single agent PFS data. also tells you like the robustness of the data great and so no one else is obviously pursuing an accelerated approval strategy in second line pdoc so that's unique to vera stem with your target d201 study enrolling how quickly could 73 potentially reach the market in second line pdac and what do you think the the efficacy bar is for accelerated approval in that setting I'll start, and John, if you want to add. So first is that the Target 201 study is almost like completely enrolled in the main cohort. We will announce once we complete enroll, we believe it will be before end of this year. So thinking about the out-of-state approval presidents out there, usually you need to hit out- of-state approvals that you have substantial kind of efficacy over state of care. also a component of benefit-risk and I believe that BS 7375 could hit that mark so thinking about what is available Center of Care currently is direction RAS-SIB and I think in their multidisciplinary review document they demonstrate a lower response rate in g12d population which is only 24% so when you think about the set approval bar with clearing the 95% confidence or lower bound i think once the data is consistent we could potentially hit that target with of course need to pair with substantial dor as well so we needed some time for the data to mature and we also have a pretty durable profile that doesn't have somatitis and also rash that also adds the benefit risk story now in terms of timing you need that dor to be mature so thinking about this we are aiming towards like a probably q2 potentially submission of course we need more communication with the VA to confirm the past to to that approval okay so it could even be the end of next year that we could be you know approval could come as early as that okay sounds which would be first the probably the first you told you just confirming is that second and plus or pure second line for PDET. Great. And then you're also looking at Cetuximab combination again, which is unique for Veristem. I don't think anyone else is doing that. So maybe talk to us about the rational. Yeah, I think Quanto is doing that, but I'll start preclinical and we'll talk clinical as well. So first of all, there was a really elegant paper from Channing Durr's lab this year where they took pancreatic cancer cell lines and they knocked out the CRISPR-Cas9, each individual gene, to say what best potentiates the efficacy of a RAS inhibitor in pancreatic cancer, and the strongest hit was EGFR. And they also looked, each time they treated with various RAS inhibitors, they saw an increase in phospho-EGFR in the pancreatal cancer cell lines. We've looked preclinically at RVS7-375, the G12D inhibitor with cetuximab, and we can get regressions with that combination in pancreatic models. So I think people accept for colorectal, it's obvious, based on breakwater with BRAF and based on the G12C inhibitors that anti-EGFR is the right combiner. But I think for pancreatal cancer, it also makes very similar sense. And then the clinical observations have really drawn that out. Yeah. Thanks, John. And a few clinical observation. One is that even at subtherapeutic doses, we have seen responses. And also for, I would say, higher dose level, we have seen deeper and more rapid responses in early observations. We are able to disclose some of these early observation towards like Q1 early next year, potentially in the medical conference. Of course, the target 201 study, we are doing a randomization between motor therapy and anti-EGFR in a second line setting. That will read out, I will say, mid-year, and we'll share that data as it matures. Okay, and just to confirm, so the 1q readout will also be second line PDAD, is that correct? It will be previs treated, and we probably will still disclose the phase one data, which is a 600 plus the tox data, and people will be able to compare with a 600 millotherapy to understand how much that anti-EGFR is adding. Okay, okay. And what is the purpose of the randomized second line evaluation? Oh, yes. And because, I mean, we need to establish a contribution component, especially when this is intended to have a sort of approval intent. It also informs about our frontline design because we also incorporate this anti-EGFR combo in the frontline. And this phase two randomization will also help us for the contribution component. So we don't need to run another like motor therapy in the phase three frontline. front line. So that's another benefit for this design. But in that phase two, we're moving quickly toward 80 patients, single agent and 80 patients with the cetuximab combination. And that would be potentially sufficient for accelerated approval for both. For the combination. For both the combination and the mono. Makes sense. Okay, great. And then, yeah, questions on target 301, which is your frontline PDAC phase three study, where it's a three-armed design. So you're combining with either Staximab or with Gemnapacutaxel, correct? So you're not adding Forfirinox on some of your competitors? Why not? Yes, and I think it's a choice. So we didn't dose patients combined with Forfiranox, and that is a choice because we believe that we are a tolerable agent, and we want to extend the patient experience and not combine with the most, like the toughest chemotherapy out there. I mean, there are RAS inhibitors out there that claims that they are very tolerable, but when you combine with the most, like, toughest chemotherapy, you're kind of losing that advantage of being tolerable. And because we are a more active drug, and combined with GMP, we believe that we can convert similar efficacy, or ORR, to those agents who combine with profirinox. The other point I want to make is that because for these frontline convos, patient cannot be on chemotherapy forever. Usually they need to stop or decrease the dose intensity around this three to four months mark because of either of hematologic AE or neuropathy. And what is left is the single agent. So once you have a more potent single agent, you get a better chance to win on PFS because from that around like four months to whatever PFS you benefit, you are alone for the single-agent. So I think that's the other point that people So sometimes I get lost on these response rate, how high you can get. But at the end of the day, when you are in a randomized study to read out a PFS, it's a single agent activities that matters. So I think that's a really important point that you really need to look at the single agent activity. Some companies, if you don't have single agent activity, you can obfuscate that by going to combinations very soon. But ultimately, the single-agent activity is gonna be the thing that carries the day. And then that's the fact that we're combinable as well gives us an advantage across the board. And your control arm will obviously include both chemotherapy choices. Yeah, we're allowing either. That's correct. What additional phase one data will you generate in frontline PDAC in the near term, if any? Yes, I can do that. So we're currently enrolling for the frontline GMP combo. And, of course, we'll do the same regimen in our phase three. is kind of keeping the momentum for our phase one study. I think that will also serve as important evidence that this is, like, we want to generate, of course, exciting data to help our phase three enrollment. So we plan to disclose that frontline GMP combo data and likely, together with the cytotoxic frontline data from our phase two in a future medical meeting, sometime Q2 next year. And I'd say across all three indications, colorectal, lung, and pancreatic, we're really setting up for success in the frontline combination so again with gem nab for for pancreatic we're testing that we've already cleared 900 there yeah with chemo IO we're we're testing that in the phase two and I mean we're testing that and similarly with modified full flux six plus EGFR we're testing that the phase 2 trial and for colorectal front line maybe then And switching to colorectal, so a few moving parts here, so Insight is enrolling a third line study with Cetuximab, RevMed recently announced a front line study with chemo and Cetoximab. What is your, remind us of your development path in colorector and how that, you know, might fit in with the field. Absolutely. I think our development strategy is very consistent across the three large indications. We are running these phase two single arm previous treated studies for the intent for a CER approval. I think the benchmarks are pretty clear for CRC and also non-small cell lung cancer. And we're doing a frontline confirmatory study for CRCE will come by first half of next year. And we believe that there's a very fair chance for a CERO approval in the third line beyond setting where the benchmark is long-term BEV, around 6% of OR, 5.6 months of PFS. So if we can demonstrate a meaningful ORR plus a DOR, I think there's a fair chance that we can follow the precedence of being approved in that third line beyond setting. What is a good response rate, you think, for any KRAS-situximab combination in a third line setting? And what do you think is needed to translate into PFS or OS benefit? Right. I think in the third line beyond setting, like a 30% response rate will be probably the benchmark for a CERA approval. Of course, our partner, Genfleet, had reported 44% response rates in that population with a 600 plus detox. We have more than 50 patients dose in the phase two study currently. Obviously, that will come later, but we have full confidence given the consistency of data that we've seen so far that we have a very good chance for a CERA approval or hitting that benchmark in the third line beyond setting. Now, the question about the OR translating to PFS, I think in the later line setting, something around 6.5 months, 7 months will be quite meaningful compared to the on-serve VEV, and a lot of these KOLs give a feedback that response rates still matter because although these patients are having PFS most of these agents are not ideal with a lot of side effects, and response rate still matters in some patients in this setting. I think the last question around, like, okay, the current, the recent failure of CRYSTAL-10, like, how does it affect? I think this is a different setting because they are not able to combine with chemotherapy. They did it in the second line versus chemotherapy. I don't think that's a great analog, I would say. For us, we're aiming for front line combined with chemo add-on. I think that will give us a really good chance, considering the breakwater precedent, that we'll convert a meaningful survival benefit in the frontline setting. And in the third-line colorectal setting, really the best response rate of what's left there is about 6% response rate. Monotherapy. With fruquitinib, right, so 30% is a vast improvement relative to that. Yeah. Then, so lung cancer trailing a little bit behind the other two opportunities, just reminders of your registration path in lung cancer. Yeah, it's quite similar. Like, we are running this Target D202 study, enrolling for pre-vis treated and non-small lung cancer patients who receive at least one line of care, including a plant-based chemotherapy and a mere checkpoint inhibitor can be eligible for this study. Now, I think one of the distinguish from the other study is that for our study, we don't restrict prior texane status. And we will allow prior texa exposure in this study. That is quite different from the others, I would say, G12D inhibitors or penras inhibitors as done in the past. Now the benchmark here is also very clear that the standard of care is docetaxel or docetexel plus ramucirumab, with a response rate ranging from 13% to 23%. And what we have demonstrated in our October disclosure, that 600 mg already, I think, will be able to clear the aceropropyl path of the bar. And then we are testing 900 as a go-forward dose. If the dose response we have seen other indication holds, we'll be able to demonstrate something really substantial and even better than what has been shown in the KRS-Geo space, best around 50%. I think we'll be able to exceed that. And then coupled with a frontline combination with stand-up care in the frontline setting starting first half of next year will be our development path. The other thing that we've heard that's important in lung cancer is that brain meds are a real problem and the tricomplex inhibitors, which are very large molecules, we've heard don't really cross the blood-brain barrier. So we have a cohort in our phase 2 in lung of 25 patients with asymptomatic brain mets, and we're looking at reduction of those brain mets, I think that'll be really important. We've been told that everybody would use this as the preferred agent if we can't affect brain mets. And then there's been a lot of interest in industry looking at sort of novel, novel combinations that are chemotherapy-free, you know, be it with PRMT5 inhibitors. We saw a PARP1 inhibitor combination concept recently, and then PanRAS perhaps as well. So how do you, what is Verisem planning in that regard? Yeah, I mean, preclinically, really, let me actually back up for a second. I think that it's really sad to me in this day and age of RAS inhibitor success that we can just deliver a median of 12 months overall survival for patients with pancreatic cancer. I think that's just a call to action. So I think any combination that can get you three years, five years would be wonderful. In preclinical models, when we look at PureMT5, a combination that's really striking, I mean, we can either get very long complete responses or very long, very deep responses when we combine in various. So there, I think if you have pancreatic cancer, that's probably bad news. But then I think ultimately, if you hear that you have G12D and M-TAP deletion, that would be good news. That really suggests that you could ultimately get a really safe oral regimen or frontline that should give you a long-term response. So we're close to announcing who that partner will be. We've looked, you know, there are a few variables in the PMT5 space that we've looked at carefully, and we think that we'll move forward quickly with that. That'll be mainly in PDAC that we do that combination. As far as PanRAS, I think, you know, combining Zoldan and Darix are similar agents. They're both tricomplex inhibitors. I think they share a lot of the same resistance mechanisms. I think taking a more orthogonal combination, like our on-off dual that's a switch-two binder together with a PanRas is really intriguing, and the preclinical data have been amazing. And kind of tracing the x-axis, you just can knock out tumor growth and get deep regression. And so we've partnered with Eraska for that with their pan-RAS. We're both currently doing preclinical characterizations, although we communicate a lot about that. And I think one of the things I'm really interested in is can we lower the dose enough of the pan-RAs that we don't bring in the rash and stomatitis, but we still benefit from that synergy that the preclinical models predict okay I think part we've thought about that as well it's interesting all right so unfortunately we're up on time so we will talk about that Copac next time okay look forward to it appreciate the time and thanks very much the keras g12c program thank you so much great yeah thank you