All right. Hey, everyone. Thanks for joining this session with Erasca. Welcome to day two of the 2025 Bank of America Healthcare Conference. My name is Alex Stranahan. I'm a Senior Biotech Analyst covering Erasca here at Bank of America. In a moment, I'll welcome Jonathan Lim up to the stage. Jonathan is Chairman, Co-Founder, and CEO of Erasca. I believe he's going to run through some slides and introduce the company. With that, Jonathan, over to you.
Hey, everyone here at the B of A Conference. We have some exciting updates at Erasca. Before I start, I'll just encourage you to visit our website, erasca.com, where you'll find our latest SEC filings. We had an exciting news update yesterday. We have updates on three fronts. The first is that our RAS-Targeting Franchise has made meaningful progress towards clinical advancement with the IND clearance of ERAS-0015, which is our pan-RAS molecular glue, and then the IND submission of ERAS-4001, our pan-KRAS small molecule inhibitor, both of them ahead of schedule. The second point is that we are seeking a strategic partner for naporafenib. We still have high conviction that this can be a meaningful therapy for naporafenib and trametinib for patients with NRAS- mutant melanoma, but with a strategic partner to be able to bring this across the development, regulatory, and commercial finish line.
It then frees up focus as well as resources for us to really push forward aggressively on the RAS franchise. In that regard, the third update is that we were able to extend our cash runway from the previous guidance of H2 2027 to H2 2028. In this interesting macro environment, having more than three years of cash is really great for us. Our focus pipeline in terms of what we are spending our internal bandwidth as well as cash resources is on this slide. ERAS-0015 becomes our lead program of focus. This is about to enter into what we call AURORAS-1, which is a phase I dose escalation followed by expansion cohorts. ERAS-4001, as I mentioned, the IND was submitted. Once that's cleared, we will move into BOREALIS-1, similar dose escalation as well as expansion type of schema.
ERAS-12 is our discovery stage bispecific antibody against EGFR. The ideal RAS targeting molecule integrates three key attributes. It is really about preclinical activity, oral bioavailability, and then having a proprietary position. Both molecules satisfy all of these key attributes. At the center of the Venn diagram is really the ideal targeting of RAS. Especially with ERAS-0015, we think that if you can enable lower clinically active dose relative to the predecessor molecule that is in the clinic, that translates into a number of key attributes. I will show you side-by-side comparisons of ERAS-0015 in that regard. When you take these three attributes and you overlay the two RAS targeting assets that we have, ERAS-0015 could be a potential best-in-class pan-RAS molecular glue.
It works by the same mechanism of action in terms of CypA binding and then hunting for RAS to form a tripartite moiety as Revolution Medicines 6236, which really has done an excellent job of blazing a trail in RAS biology and has had some tremendous data. ERAS-0015, you can see the preclinical activity is very strong with sub-nanomolar to low-nanomolar IC50 across different mutations. In vivo, it requires just a phenomenally low dose to see meaningful tumor regressions across multiple models. The oral bioavailability is very high across all species. IP exclusivity is expected through 2043 with no patentability roadblocks identified to date. ERAS-4001 also is a very interesting molecule. I think the secret sauce here is the fact that it's KRAS selective.
It spares H/ NRAS, which thereby makes it a more interesting molecule in terms of having a potentially wider therapeutic window vis-à-vis the pan-RAS molecular glues for combinability. I'll talk more about that. Similarly, very good preclinical activity. It does require higher doses to see in vivo tumor regressions, but oral bioavailability is very high across all species tested. Coincidentally, the IP extends to 2043 with, again, no patentability roadblocks identified. I'm now going to do a deep dive on ERAS-0015, which is this potential best-in-class pan-RAS molecular glue. It all really stems from the cyclophilin A or CypA binding.
The 8-21-fold higher binding affinity to CypA versus RMC-6236 is really what enables more potent RAS inhibition because you're binding CypA much more tightly and you're creating more of these bipartite moieties that then go hunting for RAS and take RAS out of circulation as well as switch it off into the GDP state. As a result of that, you could see side-by-side cell-based potency of 6236 in gray, ERAS-0015 in blue. You can just see multiple-fold potency across all of the different cell lines tested. Even in areas where there was equipotency observed, for instance, in PK-59, you can see in vivo, RMC-6236 required 3 mpk to see tumor regression of 105%. You can see it with a green line on the figure on the left.
In terms of taking ERAS-0015, it only requires 0.3 mg or one-tenth of the dose to see the same degree of tumor regression. That CypA binding translates into stronger inhibition in terms of anti-tumor activity in vivo. The story is true also when you look at insensitive. What I showed you was a G12D model. This is now H727, which is a bellwether model of sorts. It is a G12V non-small cell lung cancer model where it takes 10 mpk of RMC-6236 to achieve tumor regression versus just 1 mpk for ERAS-0015. The story holds true for another G12V model in CRC. This is an SW620 where it takes 1/8 of the dose of ERAS-0015 versus RMC-6236 to see the same degree of tumor regression. G12R is an interesting mutation.
This is a mutation that's much more often found in the GTP or on-state versus GDP state. As a result, a lot of the pan-KRAS inhibitors have a tough time targeting this. You could see ERAS-0015, you only need mpk to see pretty profound tumor regression. When you do a side-by-side comparison, apples to apples comparison versus 6236, again, it's 1/10 of the dose to see comparable anti-tumor activity against G12R, which is the third most common mutation in PDAC. I'm now showing you some combination data of ERAS-0015 with anti-PD-1, which will be important in indications like non-small cell lung cancer. You can see that even on cessation of the monotherapy treatment as well as combination treatment stoppage, just a complete eradication of tumor in 7 out of 7 mice tested.
On KPC or tumor cell rechallenge, you can see that even absent any new dosing of the combo, the tumor or the anti-tumor immune system has already been primed where you could see that there's no further growth of tumor. Another advantage of the higher CypA binding affinity is seen in this partitioning effect of tumor levels versus blood levels of the drug. On the left-hand side, you could see ERAS-0015. On the right-hand side of this bar chart, you could see RMC-6236. For both molecules in light blue, you could see the blood levels go down from 4 hours to 24 hours. With the darker blue bars, you could see RMC-6236 levels decreasing from 4 hours to 24 hours. On a dose-normalized concentration basis, ERAS-0015 is staying persistently high.
The reason is that in most solid tumors, there is CypA overexpression where you get a lot more CypA in the tumor and associated microenvironment than you do in the blood. This could be another advantage of the higher binding affinity by having more tumor levels and sort of a preferential tumor distribution and longer residence time. This is not model-specific because we were able to observe this in both the PK-59 and the PSN1 models. From a PK perspective, we think that 15 looks really great in terms of lower clearance, longer half-life, higher bioavailability as measured by F % across multiple species vis-à-vis 6236. That looks promising. It also demonstrated very good overall ADME and toxicology properties. I will now do a deep dive on ERAS-4001.
This is a really potent D, V, and C inhibitor in terms of KRAS G12X, as you could see from this biophysical binding properties. It also hits KRAS wild type pretty hard, but you could see it's actually right side up in terms of the profile that you want because it hits DVC harder than wild type. It really doesn't touch H or NRAS very meaningfully. This also is not just a GDP state inhibitor. It also has GTP state or on inhibition where you could see single-digit nanomolar IC50 for 4001 in this RAS-RAF binding assay. Another eye chart you could see across different mutations, especially G12X, G13D, and KRAS wild type, very good single-digit to sub-nanomolar IC50 potency across these different cell lines. In vivo, that translates into very good anti-tumor activity in this G12D pink model at 100 mpk BID.
You could see doses as low as 30 mpk BID in both the PK-59 and the RKN ovarian models. This is that bellwether H727 model for G12V lung. You could see you got to sort of crank up the dose to 300 mpk, but it's really good to see that you actually do get regression even in this fairly insensitive model, which is very tough for most pan-KRAS molecules to be able to see this degree of inhibition or anti-tumor activity. This is a G12D PDAC CDX model where you could see very good tumor regression even at doses as low as 50 mpk. Similarly with PD-1, I think non-small cell lung cancer will be very interesting for both molecules to be explored.
You could see combination benefit, complete eradication of tumor in all seven mice tested here as well with no meaningful body weight loss. From a PK and oral bioavailability perspective, the oral bioavailability here, you could see ranges from 16%-27%. That really is in line with what you would want to see. Our target was something in the teens or higher, and this has really met, if not exceeded, our target product profile. The ADME and tox properties, we did discharge sort of the hERG signal with a GLP cardiovascular study in dogs. There was no observed QTc prolongation, so that was really comforting to see as well. KRAS alterations are most commonly found in the big three tumor types, namely colorectal, non-small cell lung cancer, and pancreatic cancer.
There is a long tail of different tumor types in which KRAS mutations are found. Our clinical development plan is really designed to maximize efficiency and probability of success, both as a monotherapy as well as various combinations with standard of care across multiple big three as well as long-tail tumor types. I will just end with our key milestones and clinical trial readouts for ERAS-0015, AURORAS-1. We have met and actually exceeded the guidance of IND filing. We actually got IND clearance by middle of Q2. We are guiding to phase one monotherapy data in calendar year 2026. ERAS-4001, I mentioned BOREALIS-1 will be winding up after AURORAS-1. We have met the mid-Q2 2025 IND filing for that with data also next year. Next year is a very exciting year for us.
Right now, we're really grateful to have more than $400 million on our balance sheet to be able to plow the bulk of that into advancing these RAS programs for the benefit of patients as quickly as we can. We look forward to keeping you updated of our progress as we go. Thank you very much.