Immuneering Corporation

Welcome to the Immunering Fourth Quarter and Full Year 2022 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ensure that we have ample time to address everyone's questions during the Q&A session, we would ask for a limit of one question and one follow-up question per person. To ask a question at that time, please press star followed by 11 on your touchtone phone. As a reminder, this call is being recorded today, Monday, March 6, 2023. I would now like to turn the conference over to Lawrence Watts of Gilmartin Group. Please go ahead.

Thank you, operator. Joining us on the call today from Immuneering are Chief Executive Officer Ben Ziskins, Chief Scientific Officer Brett Hall, Chief Medical Officer Scott Barrett, and Vice President of Finance and Treasurer, Mallory Morales. During this conference call, management will make forward-looking statements, including statements relating to guidance and timing of data readouts for IMM 1.104 and IND submission of IMM 6.415. These forward-looking statements are based on the company's current expectations and inherently involve significant risks and uncertainties. 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 results to be different from these statements include factors the company describes in the section titled Risk Factors on our annual report on Form 10-K filed with the SEC today, March 6, 2023. 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 now turn the call over to Chief Executive Officer Ben Zeskind. Ben? Thank you, Lawrence.

Good afternoon, everyone, and thank you for joining our fourth quarter and full year 2022 financial results conference call, the first such call we are hosting in our company's 15-year history. Let me start by assuring you that we do not plan to host an earnings call every single quarter. We will probably do them more than once every 15 years, though, maybe somewhere in between. Today, we have a lot to say, though, about our plan for the upcoming year and about the timing of our ongoing clinical trial. Our goal is to create medicines for large populations of cancer patients, and we took one giant leap in that direction in 2022 as the first patient was dosed in our Phase 1-2A trial of IMM-1104 for the treatment of RAS-mutated solid tumors. We are proud to be a clinical-stage oncology company thanks to years of hard work by so many immuneers, and we are looking forward to sharing updates as the trial proceeds. Before I cover our achievements in 2022 and recent events, let me first take a step back and give everyone context on our counterintuitive approach to drug development. It is our belief that the name of the game in cancer therapy is not how do you kill cancer cells, it's how do you kill cancer cells with less risk to the healthy cells. It's all about therapeutic index. And historically, that has been really hard, and that's why cancer drugs are so commonly associated with such bad side effects. such poor tolerability. At Immuneering, we are developing what we believe is a fundamentally new way to achieve therapeutic index, a novel way to hit the tumor hard while going easy on the healthy cells. And we think it'll enable us to develop treatments with the potential to benefit large numbers of patients globally with RAS-driven cancers. Most companies either go narrow by developing medicines that target specific individual RAS mutations, such as KRAS G12C, or they go broad and hit wild type RAS in healthy cells and they hope to find a dose that harms the tumor more than the patient. In other words, unfortunately, this approach frequently leads to high toxicity. They say no pain, no gain. We believe cancer patients deserve better. They deserve less pain and more gain. We are working to rewrite the rules to develop therapies that are designed to help patients with any mutation being KRAS, NRAS, or HRAS, and that aim to provide more durable effects with better tolerability. Our approach utilizes a novel mechanism called deep cyclic inhibition, which is designed to maximize therapeutic activity while providing improved tolerability and durability. We aim to do this by taking advantage of the fact that the cancer cells are always on. They need the MAP kinase pathway all the time, whereas healthy cells use the pathway more intermittently. And I'll have more to say on that shortly. But first, we needed to figure out how to describe our approach. And there really wasn't an existing prefix or a suffix that worked. The closest ones were multi and pan. And it's not wrong to say we see pan-RAS activity preclinically. But pan is a prefix from the ancient Greek. And it sounds like cookware. And it just doesn't capture the excitement and the newness of what we are trying to accomplish. Both pan and multi tend to be associated with therapies that do not distinguish between the wild-type RAS in healthy cells and the mutant RAS in cancer cells, which raises concerns about therapeutic index and long-term tolerability for those therapies. So we adopted a phrase that aptly describes this uniquely broad approach and our fundamentally new way of achieving therapeutic index, and it's universal RAS. And I'm being a bit lighthearted about the name, But let me assure you that we believe the potential for universal RAS activity is incredibly serious and incredibly important to cancer patients and to their oncologists. The potential of our approach is supported by our preclinical data, and we are sharing some of our modeling data this week at the AACR Targeting RAS Conference. As described in our poster presentation, we tested 132 different cancer cell line models in our proprietary humanized 3D tumor growth assays in our labs in San Diego, including 75 models with RAS mutations, 75. We're not saying that every single RAS mutant model responds, but 64 of the 75 models tested, or approximately 85%, did respond, and at least one model displayed response to IMM1104 for each observed RAS mutation regardless of the mutation position or amino acid substitution. So this preclinical data suggests there's no RAS mutation we know of that's off-limits to IMM1104. And for our clinical trial enrollment criteria, any solid tumor patient with any mutation in KRAS, NRAS, or HRAS is eligible to be screened for our Phase I trial. As a result of these broad inclusion criteria and the robust preclinical data we have generated to date, we're seeing great enthusiasm from our clinical investigators. And one indicator of that is the fact that we dosed the first patient less than two months after receiving IND clearance. With enrollment ongoing, we are today providing guidance on when we could expect to report initial data readouts from the trial. Currently, we expect to share initial PK and safety data in mid-2023, initial pharmacodynamics and updated PK and safety data in the second half of 2023, the announcement of a recommended Phase II dose, and additional safety data in mid-2024 with additional trial updates on a periodic basis. We believe human PK data is a particularly important milestone for IMM1104 because PK is such an important part of how IMM1104 achieves universal RAS activity in preclinical studies. I mentioned earlier that malignant cells depend on continuous signaling of the pathway, while the healthy cells can tolerate more interruptions. But one of the rules of targeted cancer therapy has been chronic pathway inhibition, which means if a pathway is locked on by a driver mutation, you must lock it off or chronically ablate it 24-7. And the problem with this approach is that healthy cells use the MAP kinase pathway too. We have this pathway for reasons other than for cancer to hijack it. But the conventional wisdom is you make drugs with long half-lives, and they're dosed in such a way as to always maintain target occupancy, to maintain a drug trial. And it's intuitive, right, to shut down the pathway 24-7. But if we keep doing the intuitive thing, we'll keep getting the same results. the old no pain, no gain philosophy. So we decided to rewrite the rules in the design of IMM1104. IMM1104 began with a counterintuitive observation from our disease-canceling technology platform that earlier time points did a better job of reversing disease at the transcriptomic level than later ones. And that helped us to realize that you may not actually have to shut down the pathway 24-7. You just have to prevent it from being on 24-7. So we designed IMM1104 to pulse the tumor with a many-fold higher refraction Cmax, or in plain English, a very high peak drug exposure. Yet, we also have a short half-life in order to enable sufficient inhibition of the pathway while still achieving a near-zero drug trough to allow the drug to clear the system and reset the pathway each day, a process we call deep cyclic inhibition. So our approach aims for every day to be a drug holiday for the healthy cells and every day to be judgment day for the tumor. IMM1104 has demonstrated preclinical activity with strong tumor growth inhibition in each animal model we have tested, including KRAS G12C, KRAS G12F, KRAS G12V, KRAS G12V, as well as NRAS mutant animal models. And as I said earlier, we can now also say approximately 85% of the 75 RAS mutant models we tested in our humanized 3D tumor growth assays responded to IMM1104. This positions IMM1104 to be the first and only MAP kinase pathway inhibitor with the potential for universal RAS activity. Achieving that in humans depends on good tolerability with a short half-life and a high CMAP, and that's why the PK and safety data we expect to share in mid-2023 is so important. If IMM-1104 achieves in humans anything like what we have observed preclinically, I believe it has the potential to be truly game-changing for large numbers of cancer patients in the near term. This is also a serious responsibility, and it requires our full focus and our undivided attention. So, we have made the decision to suspend our early-stage neuroscience programs and focus ongoing development activities solely in oncology. Suspension of our neuroscience program, as well as other non-core adjustments, extends our projected cash runway by one quarter into the fourth quarter of 2024, which is reflected in the updated runway guidance we have provided today. The oncology pipeline, which is now our sole focus, started less than five years ago as a research project by an extraordinary consultant named Brett Hall who subsequently became our chief scientific officer. Let me now turn the call over to Brett to say a few words about our unique approach and our latest data.