Immuneering Corp Q4 FY2022 Earnings Call

Welcome to the Immuneering 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. As a reminder, this call is being recorded today, Monday, March 6, 2023. I would now like to turn the conference over to Laurence Watts of Gilmartin Group. 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 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 described in the section titled risk factors on an annual report on Form 1-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.

Thank you, Laurence. Good afternoon, everyone, and thank you for joining our fourth quarter and full year 2022 financial results conference call. This is the first earnings 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 about our plan for the upcoming year and about the timing of our ongoing clinical trials. 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-1-104 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 and 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. This will enable us to develop treatments with the potential to benefit large numbers of patients globally with RAS-driven cancer. 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 designed to help patients with any mutation in KRAS, NRAS or HRAS, providing 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 cancer cells are always on. They need the MAP kinase pathway all the time, whereas healthy cells use the pathway more intermittently. 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 suffix that works. 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’re trying to accomplish. Importantly, both pan and multi tend to be associated with therapies that do not distinguish between wild-type RAS in healthy cells and 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. I’m being slightly light-hearted 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 their oncologists. The potential of our approach is supported by our preclinical data, and we are sharing some of our modeling data this week as 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. We’re not saying that every single RAS-mutant model responded, but 64 of the 75 models tested, or approximately 85%, did respond. At least one model displayed a response to IMM-1-104 for each observed RAS mutation, regardless of the mutation position or amino acid substitution. This preclinical data suggests there’s no RAS mutation we know of that’s off limits to IMM-1-104. 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 is the fact that we dosed the first patient less than 2 months after receiving IND clearance. 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 2 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 IMM-1-104 because PK is such an important part of how IMM-1-104 achieved universal-RAS activity in preclinical studies. I mentioned earlier that malignant cells depend on continuous signaling of the pathway, while healthy cells can tolerate more interruptions. 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. The problem with this approach is that healthy cells use the MAP kinase pathway too, which raises issues of tolerability. The conventional wisdom has been to make drugs with long half-lives, dosed in such a way as to always maintain target occupancy to maintain drug trial. However, if we keep doing the intuitive thing, we’ll keep getting the same result, the old no pain, no gain philosophy. We decided to rewrite the rules in the design of IMM-1-104, which began with a counterintuitive observation from our disease-cancelling technology platform, that earlier time points did a better job of reversing disease at the transcriptomic level than later one. This helps 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 IMM-1-104 to pulse the tumor with a significantly higher free fraction CMAX, or in plain English, a very high peak drug exposure. Yet we also have a short half-life 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. This aims for every day to be a drug holiday for the healthy cells, while being judgment day for the tumor. IMM-1-104 has demonstrated preclinical activity with strong tumor growth inhibition in each animal model we have tested, including KRAS-G12C, KRAS-G12F, KRAS-G12D, KRAS-G12V, as well as NRAS mutant animal models. We can now also say approximately 85% of the 75 RAS-mutant models we tested in our humanized 3D tumor growth assays responded to IMM-1-104. This positions IMM-1-104 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 CMAX. The PK and safety data we expect to share in mid-2023 is crucial. If IMM-1-104 achieves in humans 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 involves serious responsibility, requiring our full focus and undivided attention. We have made a decision to suspend our early-stage neuroscience program and focus ongoing development activities solely in oncology. The 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. The oncology pipeline, which is now our sole focus, started less than 5 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 latest data.

Thank you, Ben. I’d like to start off by highlighting a key factor that distinguishes Immuneering from other biotech companies in the oncology space. Our aim is to develop drugs for larger patient populations using translational bioinformatics and humanized 3D tumor growth assays. We believe this enables us to design drug candidates with favorable activity and toxicity profiles. A prime example of this application is the pharmacokinetics and target engagement of our lead asset, IMM-1-104. IMM-1-104 was designed to have a short half-life that can lead to higher free drug fractions while still achieving near-zero drug troughs, enabling deep cyclic pathway inhibition. We designed IMM-1-104 to overcome resistance from CRAF-bypass. We project approximately a 2-hour half-life in humans, much shorter compared to other MEK inhibitors which have multi-day half-lives. Our preclinical data suggests potential for robust activity in pancreatic cancer, melanoma, non-small cell lung cancer, colorectal cancer, and other solid tumors with RAS-mutant disease. We’ve identified NRAS-driven melanoma and KRAS-driven pancreatic cancer as two potential high-priority indications that we believe are largely unaddressed and may be broadly sensitive to IMM-1-104. We have reported on 132 tumor models that span over a dozen tumor types with various mutational profiles, and we observed broad activity in 64 out of the 75 models or approximately 85% that display mutant RAS. There was no specific RAS mutation where we didn’t see potential activity. Additionally, our translational research team is further evaluating KRAS mutant lung cancer and KRAS mutant colorectal cancer to identify biomarkers that enrich for highest potential monotherapy response. In 2022, Immuneering presented three abstracts on two programs: two at the American Society of Clinical Oncology, or ASCO, in May 2022; and one at the SITC Annual Meeting in November 2022. The first abstract, a head-to-head comparison of IMM-1-104 versus sotorasib or adagrasib in KRAS mutant pancreatic cancer demonstrated lack of tumor growth inhibition by both sotorasib and adagrasib in the KRAS-G12V mutant Capan-2 pancreatic ductal adenocarcinoma tumor model. In contrast, IMM-1-104 observed tumor growth inhibitions of 49% to 84% across all doses and schedules tested. The second abstract we presented at ASCO found KRAS mutant pancreatic cancer and NRAS mutant melanoma were the most broadly sensitive to IMM-1-104 in patient-aligned 3D human tumor growth assays, thus included among the expected target indications for Immuneering's Phase 1/2a clinical trial. Finally, the third abstract presented at SITC highlighted the preclinical activity of our second pipeline asset IMM-6-415 as a single agent, as well as in combination therapy with checkpoint inhibitors in RAS-mutant colorectal cancer and non-small cell lung cancer models driven by diverse MAP kinase pathway mutations. IMM-6-415, combined with immuno-oncology agents may have the potential to overcome resistance in the MAP kinase pathway and provide deeper and more durable responses. We expect to file the IND with the FDA for IMM-6-415 in the fourth quarter of 2023. As Ben mentioned, for IMM-1-104, we expect to share initial Phase 1 pharmacokinetic and safety data in mid-2023.

Thank you, Brett. Just before you do that, if I could just say that Scott joined our team in 2019, at the time when everyone said, why do you need a Chief Medical Officer when you’re years from the clinic? We said two reasons: we want a clinician’s perspective in our preclinical development, and to lay groundwork to really hit the ground running in Phase 1. I’m proud of the great team Scott has built and the great job they’ve done in getting our trial up and running. So with that, over to you, Scott.

Thank you, Brett and Ben. I’m delighted about the progress we’re making in our first-in-human clinical trial evaluating IMM-1-104 in a Phase 1/2a open-label study, designed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy. IMM-1-104 is administered as a once-daily oral monotherapy for adult cancer patients with RAS-mutated solid tumors in an advanced setting, and requires that they've already failed at least one line of systemic standard-of-care treatment. This Phase 1 open-label study utilizes a Bayesian mTPI-2 escalation design for IMM-1-104, including a dose escalation phase and dose evaluation phase to establish an optimized Recommended Phase 2 Dose or RP2D candidate in mid-2024. This is expected to segue into a Phase 2a dose expansion with approximately 160 total patients in four parallel cohorts that independently evaluate monotherapy treatment effects in RAS-mutated melanoma, pancreatic cancer, non-small cell lung cancer, and colorectal cancer. The primary endpoint of the Phase 2 trial will be response rate, defined by objective radiographic response assessment, measured by radiographic imaging changes from pre-treatment baseline. This is first observed for each patient at two months and continues every eight weeks thereafter for patients receiving benefit from the study drug for up to 48 weeks of treatment. Overall, we’ve received great enthusiasm from our investigators across five clinical sites in the United States, who are all eager to enroll patients as soon as possible. In fact, we have a robust waitlist for patients. Our Phase 1 program is now open to all comers with evidence of any RAS mutation, including KRAS, NRAS and HRAS, as IMM-1-104 is designed to be broadly active in tumors addicted to MAP kinase pathway signaling. In November 2022, we successfully dosed our first patients in the trial. For the time being, that’s all we’ve disclosed, but I expect that much more to say in the coming months as we begin to share data from the trial laid out in today’s guidance. I’ll turn the call over to Mallory to cover our fourth quarter and full year financials.

Thank you, Scott. In addition to the financial results summarized in our press release issued earlier today, I will share some key financial highlights on this call. You can also find additional information in our Form 10-K that was also issued earlier today. As of December 31, 2022, our cash, cash equivalents, and marketable securities were $105.5 million, compared with $150.2 million as of December 31, 2021. Operating expenses for the fourth quarter of 2022 were $14 million compared to $11.1 million for the fourth quarter of 2021. Full year 2022 operating expenses were $51.9 million, compared to $34.8 million for full year 2021. The increase in total operating expenses in 2022 was primarily due to the advancement of IMM-1-104 through IND and into our Phase 1/2a clinical trial, as well as employee-related costs due to increased headcount. Net loss attributable to common stockholders was $13.2 million for the quarter ended December 31, 2022, compared to $10.8 million for the quarter ended December 31, 2021. Net loss attributable to common stockholders for the full year 2022 was $50.5 million, compared to $33.5 million for the full year 2021. As of February 27, 2023, we have 26,436,109 shares outstanding. In terms of our cash runway, management expects our cash, cash equivalents, and marketable securities to be sufficient to fund operations into the fourth quarter of 2024. That concludes the financial update. I’ll now turn the call back over to Ben.

Thank you, Mallory. Mallory and her team are doing a phenomenal job, and we’re lucky to have them. Let me wrap things up by saying that nobody should be dying of cancer in 2023. I’ll say that again, nobody should be dying of cancer in 2023. Cancer doesn’t work by magic or some paranormal force. It operates by a set of biological mechanisms that are actually well understood. It’s good at hiding among healthy cells and essentially hijacks the person’s body, taking them hostage. The challenge is how do you kill the hijackers with less risk to the hostages? How do you achieve a therapeutic index? Today, companies have either gone narrow by targeting a single mutation such as KRAS-G12C, or they’ve gone broad but in a way that hits wild-type RAS in healthy cells. At Immuneering, we believe it’s time to go broad. We believe that deep cyclic inhibition represents a fundamentally new way of focusing the activity against malignant cells, taking out the hijackers with less risk to the hostages. It’s time to make medicine with the potential for universal-RAS activity. In the past 24 hours, we’ve released new preclinical data we’ll be showcasing at AACR targeting RAS this week, which demonstrates the universal-RAS activity of IMM-1-104 in preclinical models. Our clinical trials are moving forward rapidly, as our enrollment criteria are truly universal-RAS, and soon it will be time to share data showing how deep cyclic inhibition is playing out in humans. We believe 2023 is shaping up to be Immuneering's breakout year, and we aspire to make 2023 a year that marks an important turning point in the battle against cancer. I’d like to thank all of our patients, clinical investigators, and stakeholders for their continued support of Immuneering, and I look forward to updating you all in the coming months about our progress towards our goal of a universal-RAS therapy for cancer patients. I will now open the call up for questions. Operator?

Our first question comes from the line of Swapnil Malekar from Piper Sandler.

Thank you for taking my questions. I have a couple of them. The first one is can you comment on how many patients have been dosed in the IMM-1-104 trials so far? And what is the extent of the data that will be presented in the mid-2023 update?

Hey, Swapnil, thanks for the question. We’re really pleased with the progress of the trial, and I think we provided very detailed guidance today, probably more granular than many companies often do. We’re really excited to share the initial PK and safety data in mid-2023 and the rest of the data as we’ve outlined.

Got it. Okay. And then I have one follow-up. Regarding the AACR poster tomorrow, what additional data does the poster include that has not been previously presented? From this new preclinical study, are you seeing any specific trends related to tumor types or mutation status that could inform your ongoing clinical trial in terms of patient selection? Thank you for taking my questions.

Sure. Thanks, Swapnil. I’ll hand it over to Brett in a second to see if there’s anything he wants to add. The poster is available on our website. One of the key takeaways from the poster is really the universal-RAS activity we’re seeing – about 85% of the cell lines that we tested with RAS mutations in the humanized 3D tumor growth assay are really responsive to IMM-1-104. There’s really no mutation that’s not responsive; every mutation has at least one model that’s responsive. Let me see if there’s anything Brett would like to add.

Thanks, Ben. And hey, Swapnil. I would add that the poster is really a deep-dive into a broad panel of tumor models that we’ve evaluated that have RAS and other MAP kinase pathway and non-MAP kinase pathway-driven mutations. It really is a deep look into our core platform, our humanized 3D tumor growth assay platform that we’ve used and vetted additionally with in vivo studies on the back end, including those we’ve discussed like MIA PaCa, A549, SK-MEL-2, and others.

So it just really broadens the scope of models that we’ve released publicly. I think all of this contributes to the universal-RAS activity we’ve seen preclinically, and frankly, supports the enrollment criteria for our clinical trial, which is truly open to patients with any mutation in KRAS, NRAS, or HRAS. So, with that, thanks for your question, Swapnil.

Thank you. One moment for our next question. Our next question comes from the line of Michael Yee from Jefferies.

Hi, guys, this is Tina from Mike. I just had a couple of quick questions, and congrats again on the progress. What doses are you using right now to dose escalate? Are the low doses you're starting at therapeutic at all, where we could potentially see responses in that mid-2023 or second half update? I know you just said that you would be seeing or sharing PK/PD and safety data, but just wondering if there is a potential for efficacy data or response to be seen there.

Sure. Yeah. Thanks for the question. I can take the first part, and I’ll hand it over to Brett to speak a bit to the second part. Again, we’re really pleased with the progress of the trial. We’ve provided some very granular guidance today that should hopefully be helpful in knowing when we’re going to share data. So that’s really what I’d say about the trial. Brett, maybe you want to speak to some color on the PD model?

Yeah, absolutely, happy to. So we’re looking at two orthogonal pharmacodynamic assays: one is an induction-based assay, PBMCs, and the other is an oncogene-driven PD assay, where we’re looking at the reduction from baseline of a KRAS-driven model. The key thing we’re looking for is attenuation of the MAP kinase pathway at the level of MEK inhibitor. I believe that answers my question. I’ll turn it back to you, Ben.

Thank you. I guess just a quick follow-up on safety. I know you guys are going to be sharing a lot of that data this year. Given that it’s a cyclical MEK inhibition, what kind of tox profile are you looking to see that gives you confidence around the hypothesis of cyclical inhibition?

Yeah. Thank you. The tolerability we’ve seen in preclinical models has been really quite good. We’ve described that across multiple animal studies, each of which have shown very strong tumor growth inhibition in different models with different mutations in the RAS pathway and in each of those we’ve seen very little body weight loss – no more than 3% to 6%. So really good tolerability. That’s a key point. Seeing a single short half-life is really important too. I think that’s fundamental to the deep cyclic inhibition mechanism, seeing the short half-life and the high CMAX, manyfold higher CMAX. But let me see if Brett wants to add anything.

No, I think you covered a lot, Ben.

Okay. Thanks again for that question. Let’s take the next one.

Thank you. One moment for our next question. Our next question comes from the line of Yaron Werber from Cowen.

Hi, this is Joyce on for Yaron. Thanks for taking our question. Maybe just a couple on IMM-6-415. What additional preclinical data are you collecting right now? How are you thinking about your clinical development program and the potential design of a Phase 1 trial? How do you think about selection of focused tumor types versus what you're doing for IMM-1-104?

Yeah. Thanks, Joyce. We look forward to seeing you at your conference tomorrow. We’re excited about IMM-6-415 and it is on track to file the IND by the end of this year. Just as we’re calling IMM-1-104 the universal-RAS program, we’re calling 415 a universal MAPK program. The key difference is that 415 has a shorter half-life; we project it’ll be an idea for twice a day in humans versus 104, which is once a day. We think this tuning will optimize unique biology, and we showed in our SITC poster late last year responses as a monotherapy in RAS and RAS-mutant disease. I think you can expect the clinical trials to focus initially on monotherapy that’s our initial focus, given the very nice data we’re seeing as a monotherapy.

Well, it’s a work in progress. We’re evolving it. The objective is to integrate multiple aspects of the MAP kinase pathway, including RAS and RAS-driven disease.

Thank you, Scott.

Okay. Thanks.

Okay. Thanks, Joyce. Next question, please.

Thank you. One moment for our next question. Our next question comes from the line of Jeff Hung from Morgan Stanley.

Thanks for taking my questions. I have two on this week’s AACR data. You indicated that no particular mutation position or amino acid substitution was exclusively found to cause resistance to drug exposure. So based on what you’ve seen, which mutations do you expect to be particularly challenging or relatively easier to treat?

Sure. Hey, Jeff, thanks for the question. They’re all universal-RAS; we haven’t seen any difference among the different mutations at different positions in KRAS, NRAS or HRAS regarding sensitivity or resistance to 104. That makes sense as we target MEK and therefore target downstream of RAS. It’s logical that we are agnostic to the specific mutations. Where we do start to see differences in responses is related to mutations in other parallel pathways unrelated to MAP kinase. For instance, we've disclosed that in our Phase 2a in the colorectal cancer arm, we plan to look specifically at APC wild-type patients who are KRAS mutated, which may indicate that the APC mutation may be a little more challenging. But let me see if Brett wants to add anything.

I would add that the drivers for resistance to 104 are not the mutation profile upstream; it has more to do with the profile of mutations in a given model. We’ve outlined this extensively for NRAS models, where NRAS mutation actually sets up for utilization or addiction. Addiction is defined by how many compensatory mutations in parallel pathways exist. Therefore, more compensatory events mean lower likelihood of single-agent response.

Great. Thanks. The data generated in 3D tumor growth assays, would you expect broader activity in rodent models in humans?

Absolutely. So, for example, we've disclosed that the depth of sensitivity or response in the 3D-TGA; deeper responding models like MIA PaCa-2 and SK-MEL-2 show regressions or mid-cycle regressions in vivo. Intermediate response profiles such as A549 show stable disease or flat-lining tumors in vivo. When you start mapping different response profiles along with molecular characteristics, you see the broadest single monotherapy response potential in KRAS pancreatic cancer and NRAS melanoma.

Thanks, Brett. This unique and proprietary capability allows us to conduct proprietary 3D tumor growth assays, which enable us to assess the response profiles of different mutational profiles. We highly encourage everyone to visit those labs. Just referencing the 132 models, how many companies have run 132 models on their lead program? This proprietary view allows us to project onto patient populations using real patient data to identify and prioritize indications.

Great. Thanks so much.

Thank you, Jeff. Next question, please.

Thank you. One moment for our next question. Our next question comes from the line of Mark Breidenbach from Oppenheimer.

Hey, good afternoon. Thanks for taking my questions. This first one goes back to something Ben mentioned; this is a drug that acts on MEK, which is downstream from RAS. I guess, I’m finding myself wondering why we should be at all surprised that activity you’re observing is independent of specific RAS mutations; shouldn’t that be the case for any MEK inhibitor? Is there something different with this one?

You’re right. In theory, MEK has always been a great target, but it hasn’t lived up to its potential yet. That’s really because the first generation MEK inhibitors had two main challenges. Number one, they were limited mainly to RAS-mutant disease and secondly, very poorly tolerated. This was largely due to the chronic inhibition paradigm, where you shut down the pathway 24/7. This creates challenges for the MAP kinase pathway in healthy cells.

Our core thesis is that deep cyclic inhibition, in combination with mechanisms that resist CRAF-bypass, is critical. The example shows that existing MEK inhibitors trap you into sustain adaptive resistance mechanisms, much like a snowplow that builds up snow in front of it and slows its effectiveness. Our ability to avoid that is due to deep cyclic inhibition.

Okay. I guess, I’m also just wondering if you included more conventional MEK inhibitors in your screen against humanized 3D tumor models and saw any differences there?

We haven’t guided on that at this point. But we have run a head-to-head comparison of IMM-1-104 versus binimetinib in the NRAS Q61R SK-MEL-2 model, where we saw mid-cycle regressions with 104, but very minimal effect with full dose binimetinib.

Okay. Great. Lastly, with respect to the timing of the expansion cohorts?

Given that RP2D stands for Recommended Phase 2 Dose, it would be hard to start the Phase 2 until we have the recommended Phase 2 dose.

In the spirit of dose optimization, we’re proactively volunteering to have a dose evaluation phase, where we’re calling it internally Phase 1b. We’ll come up with a candidate dose or RP2D candidates and evaluate them further before starting Phase 2.

Got it. Thank you.

Thanks again, Mark. Next question, please.

Thank you. One moment for our next question. Our last question comes from the line of Michael Schmidt from Guggenheim Partners.

Hey, guys, thanks for taking my question. Just maybe a quick follow-up on the Phase 1 study. Based on the enrollment criteria, what tumor histologies would you expect to enroll predominantly? Based on that, where would you expect to see early clinical activity as you reach higher doses?

Our Phase 1 enrollment criteria is quite broad, indeed. It’s truly universal-RAS; any solid tumor patient with any mutation in KRAS, NRAS or HRAS is eligible to be screened. We have not specified a particular tumor type for the Phase 1, but we’ve identified what we believe are the most likely Phase 2a areas for dose expansion based on our humanized 3D tumor growth assays and the informatics we described earlier.

The Phase 1 investigators are clinician scientists we've involved in protocol development and are excited about the clinical proof of concept. They are actively looking to enrich the tumor types we focus on.

Okay. Thank you.

Great. Thanks, Michael.

This concludes today’s conference call. Thank you for participating. You may now disconnect.