Immuneering Corporation (IMRX) Earnings Call Transcript & Summary

Welcome to the Immuneering conference call to discuss a positive data update from the 3 pancreatic cancer arms of the company's ongoing Phase IIa trial of IMM-1-104. [Operator Instructions]. As a reminder, this call is being recorded today, Tuesday, January 7, 2025. I would now like to turn the conference call over to Laurence Watts of New Street Investor Relations. Please go ahead.

Thank you, operator. Joining us on the call today from Immuneering are Chief Executive Officer, Ben Zeskind; Chief Scientific Officer, Brett Hall; Chief Accounting Officer, Mallory Morales; and E.B Brakewood, Chief Business Officer; as well as Dr. Alan Sandler, a consultant to the company. During this call, management will make forward-looking statements, including statements related to its Phase IIa trial of IMM-1-104 as well as the timing of additional data from the study and the company's development plans. Our actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. Factors that could cause these results to be different from the statements include factors the company describes in our annual report on Form 10-K and our quarterly reports on Form 10-Q. Immuneering undertakes no duty or obligation to update any forward-looking statements as a result of new information, future events or changes in its expectations. With that, I will turn the call over to Ben Zeskind, Chief Executive Officer of Immuneering. Ben?

Thank you, Laurence. Good morning, everyone and thank you for joining our conference call. We're excited to share with you a positive data update from the 3 pancreatic cancer arms of our ongoing Phase IIa trial of IMM-1-104. Our goal as a company is to help cancer patients live longer and feel better. Too many patients have to choose one or the other and it shouldn't be that way. I believe today's update demonstrates that we have made substantial progress towards this goal. During today's presentation, I'll be making forward-looking statements. Please read our disclosures on Slide 2 for more information regarding these. All data I will be discussing today is as of the December 5 cutoff date unless otherwise noted. Since we want to help patients live longer we decided to start with a target that has already been proven to do exactly that, MEK. MEK is part of the RAS, RAF, MEK pathway that drives many different cancers and when a registered MEK inhibitor is added in combination with the RAF inhibitor for patients with BRAF mutant melanoma, the MEK inhibitor adds about 6 months of survival when compared to the RAF inhibitor alone. So that's a great combination for patients and it's also a good business. If you look at sales of that combination and add in the contributions of the 3 other currently approved MEK inhibitors, it's about $2.4 billion in net sales in 2023. But the currently approved MEK inhibitors aren't perfect. They're limited mainly to patients with BRAF mutant tumors and there's plenty of room for improvement on tolerability. We set out to build a better MEK inhibitor, one that could help more patients live longer and feel better. And to do that, we're pursuing 2 specific goals. Our first goal is to expand the indications beyond BRAF to also include the large number of patients with tumors driven by RAS and other mutations in this pathway. Our second goal is to improve the tolerability and that's something that could benefit both the patients with BRAF mutant cancers who already receive MEK inhibitors as well as patients with cancers driven by RAS and other mutations in the pathway who do not have that option. Based on these goals, we developed a new MEK inhibitor called IMM-1-104 with a very different set of characteristics. And today, we're sharing a substantial update of clinical data that supports the benefits of this approach. Let's start with our goal of expanding indications beyond BRAF to RAS-driven cancers and beyond. Over 90% of pancreatic cancer is RAS mutated and the number is even higher when you include other mutations that activate this pathway. We are profoundly excited to report that in first-line pancreatic cancer patients who receive IMM-1-104 in combination with modified gemcitabine/nab-paclitaxel, we continue to see excellent activity with a 43% overall response rate and an 86% disease control rate, both of which compare very favorably to historical benchmarks. These response rates include a confirmed complete response which is extremely rare in pancreatic cancer. For anyone in oncology, when a site calls and tells you they can't find the cancer anymore. That's an emotional moment and we can only imagine what it feels like for a patient to receive that news after 1 scan, let alone multiple scan. Today, we're also sharing initial data from the other 2 pancreatic cancer arms of our trial. In the IMM-1-104 plus modified FOLFIRINOX arm in first-line patients, we have a confirmed partial response with a 100% reduction. That's a second example of target lesions completely disappearing in a patient treated with 104, this time in a patient with a very common KRAS-G12D mutation. In monotherapy in second-line pancreatic cancer patients, we have a confirmed partial response with a 67% reduction. Based on the strength of these data, we've started planning a pivotal trial of IMM-1-104 plus modified gemcitabine/nab-paclitaxel. And we also plan to initiate additional Phase IIa combination arms this year. In terms of our second goal of improving tolerability, today, we're sharing new safety data where we continue to see a highly differentiated tolerability profile of 104, both alone and in combination with modified gemcitabine/nab-paclitaxel. In total, we've now shared safety data from 96 patients. We believe there is a broad potential of IMM-1-104 to enable new combinations and replace existing MEK inhibitors in established combination for patients with a wide variety of tumors driven by BRAF, RAS or other mutations in this pathway. 104 is by far the best tolerated MEK inhibitor we're aware of. Just as one example of that, we have a patient from the Phase I portion of our trial who has now been on treatment for 11 months and who has gained nearly 20 pounds. This patient is also showing improved quality of life. This is a third-line pancreatic cancer patient who had progressive disease on 2 lines of prior chemotherapies but now has stable disease with a 25% reduction in target lesions with 104. Not only is this really encouraging progress for that patient but strong evidence of the durability, activity and tolerability of 104. So how is 104 able to yield such different results from prior MEK inhibitors? It's oral and patients take it once daily every day. The chemistry of 104 causes the concentration of the drug to quickly hit a higher maximum or Cmax than other MEK inhibitors and then through a shorter half-life, the concentration quickly drops to a lower minimum or trough than other MEK inhibitors. 104 also prevents MEK activation by RAF, something no approved MEK inhibitor does. So basically, 104 is designed to hit the pathway harder or more deeply than other MEK inhibitors but in a cyclic way that's designed to improve tolerability. We call it deep cyclic inhibition and it's the key to how we are able to achieve the kind of clinical results we are sharing today. So far, the first 5 arms of our ongoing Phase IIa trial are focused on the goal of expanding beyond the indications where MEK inhibitors are already approved into pancreatic cancer as well as RAS mutant melanoma and lung cancer. Starting with our first arm, using IMM-1-104 plus modified gemcitabine/nab-paclitaxel in first-line pancreatic cancer, here, you can see the historical benchmark ORR from gemcitabine/nab-paclitaxel is only 23%, which really highlights the unmet need in this area. And we've received some very encouraging FDA designations for IMM-1-104, including orphan drug designation, fast track in first-line and second-line pancreatic cancer as well as fast track in NRAS mutant melanoma. Overall, our trial has seen a huge uptick in enrollment over the past few months. With over 75 pancreatic cancer patients enrolled across all 3 arms as of the data cutoff date. Pancreatic cancer has extremely low 5-year survival rate and there are few treatment options and those options aren't very good and hence, first-line pancreatic cancer patients face a difficult choice. They essentially live longer or feel better. It's an or, not an and for the 2 categories of therapy that are currently most commonly used in the first line. FOLFIRINOX and related treatments do a bit better than gemcitabine/nab-paclitaxel on efficacy but they're worse on tolerability. Whereas for gemcitabine/nab-paclitaxel and related treatments, you see a bit of a decrease in efficacy but an improvement in tolerability. With 104 plus modified gemcitabine/nab-paclitaxel we aim to give patients a better option. They shouldn't have to choose between activity and tolerability. They should be able to live longer and feel better and that's our goal. And I believe the data I'm going to share with you today shows we're making substantial progress toward that goal. To put some numbers behind the symbols on the previous page, these are the overall response rates, disease control rate, complete response rates and survival data for the 2 current standards of care. Either way, it's tough. For gemcitabine/nab-paclitaxel, you're looking at a 23% ORR but some improvement in the neutropenia, the fatigue and the diarrhea compared to FOLFIRINOX. Again, our goal is to give patients a better option. Today, I'm delighted to share that we have a 43% overall response rate for patients responding to IMM-1-104 plus modified gemcitabine/nab-paclitaxel including a complete response with 100% regression. I'll note that both of the partial responses are confirmed across multiple scans as is the complete response. The other thing we find very encouraging is that all the patients shown in the waterfall plot have reductions in their sum of longest diameters. Given the historical benchmark of about 50% disease control rate you would expect a left half of this waterfall plot, if you will and we're just not seeing that here, which is very, very, very encouraging. We believe this shows IMM-1-104's potential in combination to really offer better efficacy in that first-line setting. It also has the potential to offer better tolerability. This table shows the treatment-emergent adverse events for the combination that are observed in at least 10% of patients. You can see no Grade 4 events. You can count on one hand the number of Grade 3s in any category and also see a modest number of Grade 2s and Grade 1s. Importantly, there were no serious adverse events related to IMM-1-104 and to state the obvious, some of these specific adverse events are associated with the gemcitabine/nab-paclitaxel part of the combination. With regard to Grade 3 or Grade 4 neutropenia, we're only seeing 10%, no Grade 3 to 4 fatigue and 5% diarrhea. So when you combine that excellent safety profile with the 43% ORR, 86% disease control rate and 14% complete response rate that we're reporting together, all together, what we're reporting today compares very favorably to the historical precedent for the current first-line standard of care agents. Our goal is to give patients a better option where they can have better efficacy and better safety. And as a result, they can live longer and feel better. And we believe if these data trends continue, we have a clear path to registration with this combination. We have started planning for a pivotal trial, which I will talk about more in a few minutes. And we're not the only ones. Our KOLs feel the same way. The quote on this page is from Toni Saab, who's an investigator for the trial and of course, a legend in the pancreatic cancer space at the Mayo Clinic. This is what he had to say about the data. Very promising. If these trends continue, this combination may provide improved efficacy and tolerability versus gemcitabine/nab-paclitaxel in first-line pancreatic cancer. And he also speaks to the broader potential for IMM-1-104 by saying, having a MEK inhibitor that appears to be as well tolerated as IMM-1-104 may provide new opportunities for patients with different types of cancer. We also have 3 other excellent members of our pancreatic cancer SAB who are similarly enthusiastic about IMM-1-104 and particularly this combination for pancreatic cancer. Let's move on to the second arm now because we're also very encouraged by what we're seeing there in first-line patients in combination with modified FOLFIRINOX. In our combination of IMM-1-104 with modified FOLFIRINOX, we're seeing encouraging initial data, including a 100% reduction. And the only reason that response is designated a partial response and not a complete response is that there is 1 lymph node that remains. We're also very encouraged by the CA 19-9 data for that patient which is a blood-based biomarker of pancreatic cancer progression, which has dropped dramatically and that patient remains on treatment. We find it very encouraging that all of these evaluable patients have their lesion shrinking. Specifically, we think the 100% reduction we're seeing in this combination with modified FOLFIRINOX helps to corroborate the complete response that we saw in the combination arm with modified gemcitabine/nab-paclitaxel. Turning to the third arm in our update. Let's look at IMM-1-104 as monotherapy in second-line pancreatic cancer. Now here, the benchmark for gemcitabine is 3% in second-line pancreatic cancer patients previously treated with FOLFIRINOX like most of our second-line patients. And in light of that and for many other reasons, we're very encouraged by what we're seeing here. Currently, we're seeing a 5% overall response rate, including 1 deep regression, which is a confirmed partial response with a 67% SLD reduction and a disease control rate of 52%. We're very encouraged that so many of the patients have shrinking lesions on IMM-1-104 monotherapy and are continuing on treatment across a variety of different RAS mutations. In summary, we're extremely pleased by this initial data in terms of activity but also in terms of tolerability, which I will now turn to. We have 21 patients worth of tolerability data in this arm. Note that this table shows the treatment-related adverse events observed in at least 10% of patients, Put simply, IMM-1-104 is very well tolerated. There are no Grade 3 or 4 events in the table, 1 or 2 grade 2s in each category and then a few grade 1s. What I believe we're looking at then is highly differentiated tolerability relative to anything that's been seen before for a MEK inhibitor. And that, therefore, sets up IMM-1-104 as a highly suitable candidate for both monotherapy and combination therapy. Given what we're seeing so far and given that suitability for combination therapy, we're now planning 3 additional arms for our Phase IIa trial. This year, we plan to initiate an arm treating patients with IMM-1-104 plus a RAF inhibitor in BRAF mutant melanoma, similar to that approved combination that I referenced earlier as well as 2 other combination arms in melanoma and lung cancer, respectively, where we plan to utilize IMM-1-104 in combination with an anti-PD-1. Importantly, we are also receiving inbound requests for investigator-initiated trial. Investigators are hearing that there's finally a MEK inhibitor that's well tolerated and have come to us with ideas to further expand the impact. As I mentioned earlier, based on the success we've seen thus far in the combination of IMM-1-104 with modified gemcitabine/nab-paclitaxel in the first-line-setting, we are planning for a prospective global Phase III trial with patients randomized between IMM-1-104 plus modified gemcitabine/nab-paclitaxel and the standard of care gemcitabine/nab-paclitaxel in a first-line setting with typical endpoints for a pivotal oncology trial. Of course, this is all subject to change and based on the ongoing Phase III results and subsequent regulatory feedback. But it's important to note that if trends continue, we believe we have a clear path forward to registration for this combination. So to wrap things up, our goal of expanding the indications for MEK inhibitor use continues, strengthened by the promising results we've shown you today, which have included responses across all 3 pancreatic arms and a highly favorable 43% ORR and 86% DCR in our combination with modified gemcitabine/nab-paclitaxel. Looking to the year ahead, we expect to share additional Phase IIa data in the second quarter, which should prove further guidance for our prospective pivotal trial, the planning for which is underway. In addition, we plan to initiate 3 additional Phase III combination arms during the year. In terms of improving the tolerability profile for treatments where MEK inhibitors are already in use, we're delighted to have amassed a safety database for IMM-1-104, both alone and in combination of 96 patients. This excellent tolerability profile that is the best any of us have ever seen, speaks to the broad potential of IMM-1-104 to be combined with many BRAF and RAS-mutant cancers, representing significant upside for shareholders in terms of the prospective unmet needs that IMM-1-104 could address. As a reminder, MEK inhibitors are already a very impactful class of therapies, helping patients live longer and driving $2.4 billion in sales. We believe the clinical data we've shared today shows IMM-1-104's potential to do much better or as one of our clinical investigators asked, is this the MEK inhibitor we've been waiting for. And with that, we're happy to take questions. Operator?

[Operator Instructions] And with the first question, that question comes from the line of Jay Olson from Oppenheimer.

Congrats on these really encouraging results and thank you for providing this update. Can you talk about the number of patients you're planning to enroll in the 2 combination arms in first-line PDAC? I think you may have previously mentioned a number of 30 per cohort. But we were wondering if you were planning to expand the number before starting the pivotal study. And then we had a follow-up question, if we could.

Jay, great speaking with you and thanks for the question. You're right. So the targets for each of those combination arms are about 30 patients each. And so that's -- those are the targets that we're working with currently. And so we're really excited that we're already seeing a 43% ORR that's really dramatically higher than the benchmark that you would expect. The fact that the entire waterfall plot is pointing down is just really encouraging. It's highly consistent. The fact that across all 3 of the pancreatic cancer arms, we're seeing these clear activity, deep, profound regressions and all that with just incredible tolerability. So we're excited with the data we have today.

Yes, just as a follow-up, can you talk about your current thinking on the pivotal study, the time line to starting the study and are you planning to run the study independently?

Yes, great question, Jay. And the data we have here clearly supports the pivotal study and the planning that we're doing for that. So with -- and obviously, it's subject to regulatory authority feedback and the continuing data. But our goal is to start the study by the end of this year. So that's the goal early next year. But if things continue as they are, we think we can go very quickly towards the pivotal study. And we're excited to do that just given how differentiated these data are relative to the current options available for first-line pancreatic cancer patients. I mean it's really a tough choice for them between the currently available options. So for us to be able to come in with an option that has a much higher overall response rate, we're seeing a higher rate of complete response in target lesions to have another 100% regression. And then to do all that with such good tolerability, we believe it's kind of full speed ahead towards a pivotal trial.

Our next question comes from the line of Allison Bratzel from Piper Sandler.

A big congrats on this data update. Maybe just one on potential dose response. Would you say you're seeing much in the way of a dose response for 104 on tolerability and efficacy between the 240 and the 320 mg doses? I guess it's a little hard to see one just now but obviously, it's limited data and I'd be interested in your take. And then on a related note, could you also talk to whether you're seeing a deepening of response over time? Just wondering if some of those patients with stable disease and only a couple of scans might eventually get closer to response.

Allison, thanks. Great questions. And you're absolutely right. I mean if you look at the waterfall plot on Slide 7, this is colored by dose, right? You can see many of these patients are from the safety lead-in at 240, which makes the data, frankly, all the more exciting, right, to see such good responses at 240 and then we have some initial patients at 320 is very encouraging as well. So we're exploring both doses given just how profoundly strong the response is even at 240. So in terms of activity, looking great at 240 and continuing to look great as we add in those 320-milligram patients. And as for the tolerability, there's not substantial differences. When we look at the monotherapy from Phase I, there's maybe slight differences between the 2 but it's not dramatic. And either way, it's just incredible tolerability, whether it's 240 or 320, it's dramatically better tolerability than any MEK inhibitor any of us have seen before. So that combination is great. The combination of this just highly differentiated tolerability and then the strong response. In terms of the durability question, you're absolutely right. We've seen patients who have been 8% on a first scan, 10% reduction of lesions on a second scan and then they dropped down to 40% for a partial response. So absolutely. I guess as another example of that in the modified FOLFIRINOX arm, the patient with 100% regression, I believe that occurred on a second scan, right? So the first -- and then was confirmed on a subsequent scan. But so that's another example where we absolutely do see deepening responses over time. And that's why we're so encouraged really across all 3 of these arms that there are so many patients staying -- remaining on treatment and continuing. So it really -- we're excited to see how things progress for those patients as they continue on treatment and they're able to continue on treatment because the tolerability is so good and that's certainly a big part of it.

Our next question comes from the line of Graig Suvannavejh from Mizuho.

Congrats team on the great data, really stellar. I'm curious, given your plans to expand for -- with 3 additional arms and also with your plans to start a pivotal perhaps by year-end or early next year, can you just remind me your cash runway? I believe, on your third quarter update, you got a cash runway to the second half of '25. Could you just remind us kind of where you are and how you might think about funding on a go-forward basis? And then maybe a follow-up question, which is just on the data that you're seeing. I appreciate that you're moving forward or planning to move forward with the combination on one of the 2 first-line combinations that you're testing here. Any thoughts in terms of the data that you showed us, if there were differences in the patients that were enrolled that might have led to different responses? Or how do you envision the 2 combinations side by side if you do plan to move forward with 104 in the first-line setting?

Graig, thanks a lot for the question. And I actually really like the word you used, stellar, to describe the data. I think that's exactly right. These are stellar data. We're going to use that. Thank you. But in terms of funding, prior to today's announcement of the 3 new arms, we had guided to cash into the fourth quarter of 2025 based on our existing plans. And given the stellar data in today's announcement, we believe we're going to have multiple options moving forward to fund all these exciting new programs either alone or in partnership with others. And in terms of the data and the 2 different chemotherapy combinations, I think the data we have today from the 104 plus gemcitabine/nab-paclitaxel is so compelling, so profoundly different from what's currently available for first-line patient, right? To have a 43% ORR, have a complete response, to have the whole waterfall plot going down, the left half of the waterfall plot missing. And to do all that with tolerability that's, that we believe, compares so favorably to historical benchmarks, it's just a very clear decision to move forward with the planning for that pivotal. And I think with the other arms, we'll see, right? The data is very, very encouraging with what we know to date. And as it continues to play out, I think we'll really make kind of independent decisions about each of the arms in terms of how we take them forward. But we're excited about all of that. I mean if you look at the second-line monotherapy data, there's all those patients on the right half are continuing on treatment, right? So to Allison's earlier question about the durability and the fact that these responses sometimes develop after multiple scans and continue to deepen, we're really excited to see how that plays out. So continue to be very excited about each of these arms but -- and the data, we agree with stellar.