Okay, I think we can go ahead and get started. My name is Allie Bratzel, a biotech analyst here at Piper Sandler. And it's my pleasure to introduce our next company, Immuneering. Joining us this afternoon, we have CEO and President Ben Zeskind, Chief Business Officer H.B. Brakewood, and Chief Accounting Officer Mallory Morales. Thank you all for joining us for the fireside chat. This will be a Q&A format, but I think, you know, Ben, maybe it would help out for investors newer to the story. If you could just give us kind of a brief intro to the company and how you approach cancer therapies.
Sure, that'd be great. First of all, I want to thank you, Allie, and the entire Piper team for having us here today. I want to thank everyone for listening and just remind everyone I'll be making forward-looking statements, so please see our disclosures for more information. So yeah, you know, our company believes that no one should be dying of cancer in 2024. Right? I mean, cancer is not, it's not magic, right? It's not some paranormal force. So it just has a couple of tricks that are really making it hard to make good therapies. One is that it's hard to distinguish it from healthy cells, right? It's a very subtle change in otherwise healthy cells, and that makes it tough to distinguish. And then the other is that it's just very adaptable, right? It changes very quickly.
So what, you know, and the way that manifests in therapies is around tolerability and durability, right? So, you know, a lot of cancer therapies are just very tough to take, right? Very poorly tolerated, and/or they just don't last that long, right? Eventually, the tumors get around it. So we set out to make new medicines that could address those two challenges. And, you know, for us, the MAP kinase pathway was a natural starting point because it, you know, it's overactivated in about half of all cancers. And within the MAP kinase pathway, MEK was an attractive target because it's downstream, right? It's downstream of KRAS, it's downstream of RAF. And so, you know, in theory, a good MEK inhibitor should have that broad activity. You know, it should block a variety of mutations in KRAS, in RAF as well.
So, and that breadth is really the key to increasing durability. And so the challenge was that, you know, all the MEK inhibitors to date had been, you know, really struggled with tolerability. And so we said, can we do this better? Can we set out to make, you know, a MEK inhibitor that would be really well tolerated? So try to address both the tolerability piece and the durability piece. And so that was the goal. And we had an informatics platform that we developed over the course of about a decade. And so we applied that. And that was, you know, it really gave us these interesting insights where, you know, it wasn't, you know, we saw that the MEK inhibitors were working best at early time points, at three hours and at six hours, whereas by 24 hours, they sort of weren't working as well.
Those were the insights that ultimately led us to the deep cyclic inhibition mechanism that we have today.
Great. And maybe, you know, in the context of lead asset 104, can you, you know, walk us through that approach of deep cyclic inhibition and why that, what benefits that gives you?
Sure. Yeah. So, you know, historically, most cancer drugs have been chronic, right? They shut down the pathway 24/7, right? And it's sort of the theory is the pathway is locked on, so you lock it off. You shut it down 24/7. You make drugs with long half-lives. And the challenge with that is, you know, we have these pathways for a reason other than for cancer to hijack them. And if you just shut them down 24/7, you're going to have a lot of effects on healthy cells. And that's, you know, that's where you see a lot of the tolerability challenges come in. So what the informatics data was telling us was, you know, essentially that, you know, you may not need to shut down the pathway 24/7.
As we sought to better understand those findings, you know, it really brought us back to some of the, you know, kind of the core principles in the field of oncology that go all the way back to, you know, Bob Weinberg and the discovery of oncogenes. You know, if you read the Hallmarks of Cancer papers by Hanahan and Weinberg, you know, sustaining proliferative signaling is one of the hallmarks of cancer. The MAP kinase pathway, among others, has to be always on in cancer. It's always on. Whereas the, you know, before these oncogenes are mutated, their signaling is more transitory. It's basically going from something that's transitory or intermittent to something that's always on. We said, if that's the case, you know, we don't have to go from always on to always off.
We just have to go from always on to transitory, right? And so this was how we came to the idea of deep cyclic inhibition, which is basically to provide a pulse of very intense inhibition. So whereas most MEK inhibitors historically have only gotten up to around their IC50 values where they, you know, shut down the pathway about halfway, you know, ours, we've shown now in patients 104 gets all the way above the IC90 for several hours a day. And so that really gives a much more complete shutdown of the pathway for those couple hours to really kind of restore the transitory signaling. But then with a short half-life, we drop off quickly to a near-zero drug trough, which basically restores the signaling.
So the way we like to think about it is while the malignant cells and the healthy cells both need MAP kinase signaling, they need it a little bit differently. So the tumor cells, they're always on, right? They have the sustained signaling. They need MAP kinase signaling kind of the way a person needs air, right? You can't hold your breath underwater for more than a few minutes. Same thing with the kind of the tumor cells with MAP kinase signaling. Whereas the healthy cells, it's transitory, right? They need it more the way a person needs hydration, right? A couple hours without a drink of water, you're fine. Five, six hours, you're getting pretty thirsty. But it's really not till 24 hours that it becomes this serious kind of dehydration situation. So that's kind of the concept, right?
We shut down the pathway very completely for several hours and then release by the end of the day, and the goal is to restore this kind of healthy transitory signaling to the MAP kinase pathway.
Excellent. And that I want to get to now, you know, your recent data update with, you know, lead asset 104. You know, it was very early, but very, very promising phase IIA expansion data, pancreatic cancer in combo with chemo. And I think your first patient experienced a CR, which.
Correct.
You do not see that in this indication. So yeah, just walk us through that data, you know, the highlights and also kind of what it means for 104 going forward in the IIA expansion cohorts.
Yeah, absolutely. So that's right. Yeah. So the data we announced in September, the very first patient in our phase IIA had a complete response. And you're absolutely right. That's extremely rare in pancreatic cancer. I mean, we've had investigators tell us they've never seen a CR in their careers in pancreatic cancer. In the phase III study of the chemotherapy, we're combining with gemcitabine and nab-paclitaxel. They had one CR out of 431 patients. So certainly very encouraging to see that in our very first patient in that arm in phase IIA. And to see it repeated across four scans as we disclosed in September. But what was also encouraging was the second patient, right?
So the second patient that we talked about in September had, you know, some of the longest diameters of minus eight on the first scan, minus 10 on the second scan, and then minus 40 on the third scan for a PR. And so that's to see that again, it's sort of, you know, encouraging as well with that combination. And, you know, people sometimes ask us, you know, were you surprised to have a CR in this combination? And, you know, we say yes and no. Yes in that it's so rare, but no in that it's exactly what the animal data told us would happen. So in April at AACR in San Diego, we shared data on this combination of gemcitabine, nab-paclitaxel, and IMM-1-104.
We saw that, you know, the triple combination, the same one we're testing in this arm of the phase IIA, basically flatlined the tumors in a durable way. That, you know, certainly what we announced in September that we saw in the first patient is very consistent with those animal data we had previously shared. You know, and then the other three patients we talked about in September were much earlier in the trial, you know, had only one scan that we announced. You know, the trends are encouraging as well. Overall, it was, you know, to have an initial ORR in that September update of 40%, when with the chemo you'd expect 23%, and then to have a disease control rate of 80% when you expect 50% with the chemo. All very encouraging. Early but encouraging.
Yes, and then maybe just expand on, you know, the safety data, biomarker data you saw there, and just kind of what that means for the 104, you know, clinical profile.
Yeah. So, you know, as we mentioned in September, you know, 104 was well tolerated in combination with the gemcitabine and nab-paclitaxel. So that was certainly good to see. In October at ESMO, we announced kind of more detailed safety data from our phase I and update on that from 54 patients. And, you know, that was very encouraging as well. In the table of treatment-related adverse events occurring in at least 10% of the patients, there was one single grade three, which, by the way, was a rash that resolved with topical cream. So really encouraging safety profile that we think is differentiated, certainly relative to any other MEK inhibitor, but even we think compares favorably to pretty much anything else that's out there for the MAP kinase pathway. And look, it matters a lot, right?
Safety, tolerability matters not just, you know, it's not just because patients feel better on the treatment, and they do. It's not just because they can stay on it, you know, in general when therapies are better tolerated, patients can stay on them longer. But also it enables more combinations. And, you know, most cancer patients in practice are treated with combinations. And the, you know, the limitation to most combinations is the tolerability. So to be able to have, you know, a treatment like 104 that, you know, has shown such encouraging tolerability in that phase I data that we talked about at ESMO, you know, it really, I think, enables combinations like the, you know, some of the ones we're assessing in the phase IIA and that we talked about in that update where we had the CR.
Yeah. Maybe another question on, you know, if you were surprised to see something and that, you know, were you expecting to see or would you expect to see more patients responding like patient two with the deepening of, you know, tumor shrinkage or deepening of response over time? You know, just thinking about your patients at the earlier time points who had only had a single scan, you know, trying to think ahead to, you know, what we might see from them when we get longer-term follow-up data. Just what are your thoughts there?
Yeah. I mean, certainly it was interesting to see that in the second patient that it was sort of a, you know, it took three scans to get to the kind of the RECIST response, although they were, you know, they were kind of shrinking all along. You know, it's funny because that's also a phenomenon that we saw in some of our animal data. In fact, in some of our animal studies, we would actually see the, you know, the tumors grow a little bit before they would shrink. So, you know, that is certainly a phenomenon that we've seen. And, you know, I think it's consistent with the mechanism of the drug, right? Where it's, you know, it's a little bit of a gentler but a, you know, potentially more durable type of effect.
So in terms of, you know, next updates for this cohort of patients, I guess what should we be looking forward to? And also, you know, what in terms of timing and then also in terms of what that might entail, you know, higher dose data, longer-term follow-up?
That's the question you're getting a lot, lately. Yeah. Yeah, absolutely. And look, I mean, you know, I understand, you know, given what we showed in September, you know, I think everyone's eager to hear updates on that arm, which is, you know, the gemcitabine nab-paclitaxel arm. We haven't guided to timing of those updates, but certainly, you know, we're pleased with enrollment. So, you know, I think you can expect, you know, additional patients. You can expect further data on the, you know, the patients that we talked about in September. You know, I think all that. And, you know, the other interesting thing about the update in September was those were all patients at 240 milligrams. So they were all part of the safety lead-in. And as we noted at that time, you know, we'd started dosing patients at 320.
You know, I think it's fair to assume the next update will include, you know, patients who are dosed at both 240 and 320.
Excellent. And so that discussion was on one of your phase IIA arms. You have a number of expansion arms, IIA expansion arms. So, you know, maybe walk us through those and kind of your rationale for going into the tumor types and combinations that you did. And then, you know, with you committing to providing an update from at least one additional arm before year-end, just help us understand what that might look like and what we should be expecting.
Absolutely. Yeah, so just for context, you know, the other forms of the trial, so there's the 104 in combination with gemcitabine nab-paclitaxel that we talked about. We have another combination arm also in first-line pancreatic cancer that's in combination with FOLFIRINOX. So there's those two combination arms. There's a pancreatic cancer monotherapy arm, which is mostly in second-line patients, although first-line patients are eligible too. And then we have two monotherapy arms in melanoma and lung cancer. So those are the five arms of the trial. And, you know, in terms of the rationale, I mean, you know, for us, a lot of it's driven by both the preclinical data, which, you know, we've done extensive evaluations in both humanized 3D tumor growth assays, which is a proprietary assay we have at our labs in San Diego, and then also in animal studies.
So, you know, we draw on a combination of that data and then also what we saw in the phase I. So that's how we kind of picked the three types of cancer. But, you know, it's really just the start, right? I mean, we had to prioritize, but, you know, I think there's, you know, any tumor that's driven by the MAP kinase pathway, we believe could potentially benefit from 104. So there's, you know, there's a broad scope there. And again, that also helps, you know, or we believe will ultimately help with durability because, you know, the broader you can go, the harder it is for the cancer to mutate around it. And I think we showed that in a prior update with our circulating tumor DNA data, right, where we had shown that there were no acquired alterations in RAS genes.
So in other words, you know, there was no mutation in RAS that a tumor could use to get around 104. There were acquired alterations in other pathways unrelated to the MAP kinase pathway, but not in RAS genes. And so that, you know, at that time, what we had said was, you know, by going to earlier line patients where they're likely to be more homogeneously dependent on the MAP kinase pathway in first line and then combining with chemotherapies like gemcitabine and nab-paclitaxel, you know, we think that'll help address the other pathways. And that played out certainly in the September update, I think the way we had suggested.
And then, I guess not to get too ahead of ourselves based on, you know, like five patients' worth of data from September, but, you know, it's hard not to think about a potential, you know, accelerated path, registrational path forward, just, you know, given the unmet need in first-line pancreatic and fast-track designation and all those things. I guess, is it reasonable to think, you know, that the door could be open for an accelerated approval path? And just like what, you know, what do you think you need to see for that to be, you know, an option?
Yeah. The unmet need in this field is just, I mean, it's just heartbreaking, right, for pancreatic cancer. It's really a terrible disease. And so we're, you know, we're happy to be able to try to do something about that. Really just incredible unmet need. And so you're right, we have the fast-track designation in both first and second-line pancreatic cancer, which, you know, I think is helpful. And, you know, what we said in January is certainly we believe that if, you know, in September, after the September update, you know, we believe there'd be a clear path to registration.
Now, you know, I can't comment really on what the specific path of the timeline would be, but, you know, certainly we, you know, we would do everything we could to, you know, bring this medicine to patients as quickly as possible, you know, as the data warrants.
Yeah, excellent. So maybe just, you know, to the extent that you can, help us think about 2025, just the cadence of clinical updates, you know, for 104, particularly for those, you know, phase IIA expansion cohorts. What can we be looking forward to?
Yeah. So we, you know, I think it's going to be an exciting and data-rich year. We haven't provided specific timing guidance beyond, you know, we've said, of course, by the end of this year, we'll have initial data from at least one other arm of the phase IIA and initial data from our initial PKPD and safety from our second program, which is 415. So, you know, I can't comment on specific timelines in 2025, but look, I mean, we're running a five-arm study with a good number of patients in each arm. And, you know, there's data coming in all the time. And certainly as it's material and mature, we like to share it and sort of keep folks updated. So, you know, I think you can expect a kind of a data-rich year ahead.
Yeah, I know. Data-rich year, those are, that's like music to every investor's ears, I think, and I think you've kind of touched on it on, you know, enrollment trends just with 104, and I know, you know, engagement, interaction with investigators has always been a hallmark of your clinical development, so maybe can you just talk to that more, you know, kind of what the reaction from the field has been as you've, you know, accumulated this data and just, you know, what's your experience been so far with investigators and the field?
Yeah. Well, certainly, firstly, we're very fortunate to have an incredible group of investigators who really, you know, I think understand the science, they understand the unmet need, you know, and really at great institutions, large and small throughout the country. So we're grateful to all our investigators and certainly to the patients and their families. You know, there's, you know, we were pleased with the progress of enrollment, I'd say even before the September update. You know, I think there's a lot of enthusiasm for the unique aspects of this study. I mean, you know, the arm, the gemcitabine nab-paclitaxel arm, right?
I mean, and the FOLFIRINOX arm, you know, for a first-line pancreatic cancer patient, these are attractive options, right, possibilities because they're getting, you know, a chemo similar to what they would get anyway, plus, you know, an experimental drug that's very well tolerated based on what we've seen in phase I and has the potential to add benefit. You know, these are attractive arms. And certainly with the data that we, you know, we announced in September, we saw, certainly we saw, you know, I guess additional, you know, enrollment was already going well, but it definitely had a positive impact.
Excellent. Okay. Yeah, I can imagine that. I think we're almost running up on time here. So maybe just kind of, you know, last question here. You mentioned your second asset, 415. Can you just kind of walk us through that, the approach, compare and contrast that to 104 and just help us understand, you know, where you are, clinical data you're generating and, yeah, your thoughts on that?
Sure. Yeah. So similar type of approach in that we're also targeting MAP with a deep cyclic inhibition approach. This has a faster cadence, so a shorter half-life. So it's designed to be given twice a day or BID as opposed to 104, which is once a day or QD. And just like on an old car radio, you'd sort of change the frequency and get a different station. You know, we think changing the frequency of that deep cyclic inhibition and sort of how we restore that transitory signaling could, you know, different frequencies could be optimal for different tumor types and different biology. And so one of the things we're looking at in this phase I is it's actually an even broader set of patients.
So, you know, whereas the phase I for 104 was all comers with evidence of a RAS mutation, here we broaden that with 415, we broaden it to evidence of a RAS or RAF mutation. So, you know, a broader set of patients depending on the MAP kinase pathway. So, you know, I think that's one of the, you know, one of the distinguishing factors. And, you know, we've guided to initial PK/PD and safety data by the end of this year. So that's coming. And yeah, it's an exciting time.
Yeah. Two assets in the clinic and lots of data cards to be turned over. Lots to look forward to. Any other topics you think are worth kind of flagging to folks or did we cover it?
No, I mean, I think just to emphasize really the unique combinability of 104, right? I mean, I think the data we shared in September, the complete response and partial response in those early pancreatic cancer patients, that's just the start, right? I mean, when you have a tolerability profile like we've shown with 104 against a pathway that's as ubiquitous as the MAP kinase pathway, you know, we think there's just a really broad range of potential combinations, you know, and we're exploring some of them in the clinic already and we've explored many more preclinically and shared a lot of that data. So, you know, we think there's a really unique opportunity for a drug like 104.
So this is just the start. Yeah.
Absolutely. Just getting started.
Just getting started. That's a good place, I think, to end our discussion, but I appreciate you stopping by and giving us this update.
Yeah. Thank you, Allie. Thanks for having us. And thanks everyone for listening.
Okay, great. Well, thanks everybody for joining us here on the third and final day of Piper Sandler's annual healthcare conference. I'm Joe Catanzaro, one of Piper's biotech analysts. It's my pleasure to welcome to this session Tango Therapeutics. Joining us is their President of R&D, Adam Crystal. Adam, thanks so much for joining us. Maybe before we jump into Q&A, I could sort of give you the opportunity over a minute or two to sort of introduce Tango to maybe those who aren't familiar and let them know what you've been up to and what we have to look forward to.
Absolutely. Thank you. So Tango Therapeutics is a biotechnology focused on finding therapies by leveraging synthetic lethality to discover novel targets in oncology. It was founded about eight years ago, really timing-wise empowered by the advent of high-throughput CRISPR screening, through which Tango and others have walked the course of identifying novel synthetic lethal genes, which can be targeted pharmacologically. Over that time, the company has gotten to the point we are now, which is with two molecules in the clinic, soon to be three, and a lead program, which we have released some public data on and demonstrated what we believe to be a proof of concept and are moving towards pivotal studies. In addition to that, we have a second program we could also talk about, named TNG260, which is a molecule in the immuno-oncologic space. From there, I'll ask you to guide me.
Yeah, that was perfect. Maybe I'll start with just sort of a high-level sentiment question. So you mentioned synthetic.