Okay, you can go ahead. Good afternoon, folks. Here we have Dan Schmitt from Actuate Therapeutics. Today, he's going to present us the drug development path for oral elraglusib, and then after his presentation, we would come back and have some questions for him.
Thank you. Okay. I appreciate everybody attending today. Forward-looking statements were used in this presentation. Just a little bit of background. Actuate Therapeutics was founded back in 2015 based on a portfolio of small molecule, highly specific kinase inhibitors targeting GSK-3β. That's a known quantity both in CNS disease and in oncology. The lead from that portfolio is known as ELRA. It's been in clinical trials in over 500 patients to date, where it's shown significant efficacy in a number of very difficult to treat cancers. These include complete responses in diseases such as metastatic pancreatic cancer, checkpoint refractory metastatic melanoma, Ewing sarcoma, and neuroblastoma.
Our most advanced program is in metastatic pancreatic cancer, and I'll be showing you some data from that, where not only do we have complete responses, but we have significant increases in overall survival, which is the gold standard for approval with the FDA now. The drug is active on its own but has demonstrated synergies both with standard of care chemotherapeutics and in data released last week, we have new data showing that we have synergies with the RAS inhibitors. We've done all the work to date with an IV formulation, but we have a brand-new oral formulation coming into the clinic that we believe will be superior on top of a drug that has already demonstrated significant results. From an IP perspective, we have a very long runway. The composition of matter extends out to 2037, 2038, with the PTE going out to 2043.
The oral will be longer than that because it's going through registration review now and should have 2043 as a basis to go forward. I'm showing you data now, the Kaplan-Meier curves from our most advanced program. This is first-line treatment of metastatic pancreatic cancer. These data were presented at ASCO 2025 and one of the plenary sessions, as a trial in progress. The data were updated in the beginning of 2026 at ASCO GI and at ASCO 26. First compound in 12 years to show a significant increase in overall survival in first-line metastatic pancreatic cancer by being used in combination with gemcitabine/abraxane and using gemcitabine/abraxane in the control patients. A 40% increase in median overall survival, a doubling of one-year overall survival, and a fivefold increase in two-year also overall survival.
Key points on the Kaplan-Meier are clear separation of the curves very early on, indicative of a direct tumor effect and a very long survival tail indicating an IO effect. It is very much like a KEYTRUDA curve, where we see continued survival as patients progress. It is not just us who are blowing our own trumpet or identifying this as an opportunity to advance the treatment of pancreatic cancer. We were featured in Time Magazine earlier this year under "Two new drugs offer hope for pancreatic cancer." One is Revolution Medicines; the other is Actuate Therapeutics. The development strategy going forward is to expand the pipeline potential. I have said that all the work to date has been done with an IV formulation. We have a new oral formulation coming that we believe will be superior.
The second is to advance the pathway to be a standard of care backbone, not only in pancreatic cancer, but in other cancers where this target is important as well, and in combination with the RAS inhibitors. The third leg of the three-part strategy is to advance this in rare pediatric cancers where there is significant unmet need, and the drug has some significant progress. I will just quickly go through the mechanisms of action. What is understood about GSK3 is that in cancer cells, it is a master regulator of some key oncogenic processes and pathways, most notable being NF-κB mediated processes for cancer cell survival. That is a key profile of cancer cells as they grow and refuse to die, either naturally through apoptosis or due to chemotherapy, such as NF-κB mediates chemoresistance.
What has been shown is if you down-regulate GSK3, you down-regulate those NF-κB mediated processes of cell survival. What has also been shown in the clinic as well as pre-clinically, is that inhibition or direct knockout of GSK3 results in upregulation of immune response. This has been shown in turning cold tumors hot, driving neoantigen presentation. In the clinic, it has also been shown that driving those immune processes, not only upregulating the activation and mobilization of NK cells and T cells in colorectal patients. We have data from our most advanced pancreatic trial that I have shown you that in pre- versus post-treatment biopsies in those patients treated with elra, there was significant recruitment of CD8 positive and granzyme B positive cells into the tumor itself. That was not demonstrated in biopsies taken from the control patients. Those are treated with gemcitabine/abraxane only.
The difference being elraglusib and the difference being recruitment of immune cells into the tumors. The questions come to us, how are you going to compete with the RAS inhibitors and the RAF inhibitors? The answer is, we will not compete with them. We believe they are very important drugs. They are coming to the clinic and showing prowess. But one has to realize that that is a very competitive field right now, and also nobody is being cured in those trials. Ultimately, the patients progress. What we understand from the clinic now is when patients become RAF refractory, they progress very quickly. It is almost a square wave of disease progression and death. What is known about the RAS pathway is that adaptive mechanism, when tumors become refractory, they use the tumor escape nodes associated with NF-κB mediated processes. We address that pathway.
The idea to be competitive is not correct. We will be compatible and combined because together we have a synergistic approach of they down-regulate driver mutations, we down-regulate the escape nodes, and together we should have synergy. That has been demonstrated in a news release this past week, where we have independent research going on, both at Mayo and at Northwestern University, on testing elra plus two different RAS inhibitors for additive or synergistic effect. Across 20 different cell lines, both human and mouse, in KPC RAS refractory tumor models, 20 of 20 of them showed either synergistic or additive activity. Basically, the combination of elra plus [zoldonrasib] was much more effective than either agent alone. The same was demonstrated in combination studies with [Dara] plus elra.
These are both murine and human models of cancers that are refractory to treatment that show synergistic effects by combining elra plus the newest promising agents, the RAS inhibitors, and we are very excited about this. The mechanism of action and preclinical data support elraglusib as a potential combination therapy, not only with multiple RAS inhibitors, but in multiple diseases that RAS inhibitors will be used. Earlier this year, we were featured in Nature Medicine for the results of our clinical trial in first-line metastatic pancreatic cancer, and some important notes were featured in that article. One is that the combination, as I showed you in the Kaplan-Meier curves, had a significant overall outcome, hazard ratio of 0.62, which means a 38% reduction in the risk of death just by adding elra on top of standard of care.
A subgroup analysis showed that for patients who could achieve at least one full cycle of treatment, four doses, the effect became even more pronounced. It was a 50% increase in overall survival; hazard ratio reduced to 0.58. This is in keeping with all of the preclinical and clinical data we have seen so far, which shows that more elraglusib exposure results in better outcomes. We recently completed an efficacy versus exposure relationship analysis. Looking for a common factor that differentiated patients who did very well from those who did not. It turns out that there is a factor involved here that shows patients who could achieve an average daily concentration of elra in the bloodstream of 210 ng per mil, which is about 0.5 µM. It is a very low level. But those who were at that or above had a significantly better outcome than those who did not achieve it.
A hazard ratio of 0.48. This is a threshold target for efficacy that dictates better outcomes. The interesting thing was only 60% of the patients in that clinical trial achieved that threshold and still carried the trial to significance, meeting its primary endpoint and the data that I have discussed. How do we get more patients to that level? Well, it turns out that it is not increasing the dose of elra. We have tested number of doses from 3- 15. In this trial, we tried 9.3. That was the therapeutic dose. It is not increasing the dose but increasing the frequency of dosing that dictates the exposure levels of this drug. We have 60% of the patients achieving that target exposure, and we can improve that with the oral formulation. We have a brand-new optimized tablet. It is 95% bioavailable. It can be dosed daily.
We believe based on the PK parameters and investigations so far that we can get patients to that threshold exposure with one to two tablets a day. We have IND clearance for a phase I/phase II accelerated trial, Project Optimus compliant from the FDA, and we are ready to go forward with this accelerated development plan that has a very thin dose escalation with a backfill design that will allow us to bring in patients of interest very early on. Those patients of interest include checkpoint refractory metastatic melanoma, where we have ample clinical evidence of monotherapeutic response. We will also be looking at metastatic pancreatic cancer as probably as a second line in combination with [ Darzalex]. Following the advance in these indications, we will be pursuing both metastatic colorectal cancer and metastatic refractory non-small cell lung cancer.
One, because we have clinical evidence from earlier clinical trials that these histologies are responsive of elra in combination, but also because the RAS inhibitors are going there, and where RAS inhibitors go, we will go as a combination agent. We have significant evidence of efficacy in pediatric cancers as well, both in Ewing sarcoma and in neuroblastoma. You may have seen a press release earlier this year showing that we have been selected to be included in CRUK's BEACON2 trial based on preclinical evidence that this drug could be curative in combination with standard of care. Also, from our clinical evidence in pediatrics, where we had responses in the most difficult to treat cancer. This is the number one killer of kids with cancer under the age of five, and it has a survival rate of less than 10%.
We have responses and a CR there as well. Cancer Research U.K. approached us, asked us to participate in the trial, and this is a way to move forward in a rare pediatric disease that has PRV eligibility on minimal investment on part of the company. We have three-leg stool in terms of our strategy going forward. Continue to validate the [elraglusib ]plus RAS combos in PDAC and in other cancers. In the meantime, develop the oral tablet, so its combinability in these keys diseases is set. On the third leg, continue to pursue the pediatric, particularly on a very low investment rate with a high potential of a PRV on the other end. Thank you for your time.
Perfect.
Quick overview.
No, that is very good. The pivot to the oral tablet is the biggest change in the story.
Right.
This year. The phase II PK work that you had done showed patients who had a C average of 210 ng per ml, above that number did actually meaningfully better.
Absolutely.
With a hazard ratio of 0.48, but only about 60% of those weekly IV patients did get there. Can you walk investors through why you think oral tablet is a better fix for that, rather than simply dosing them-
Yeah.
-twice weekly?
Well, the psychology of a pancreatic patient is not as straightforward as you or I would think if we had the disease. We did a once a week versus twice a week run-in to this trial, and there was a lot of drop-offs because patients with pancreatic cancer don't want to spend their time coming to the clinic twice a week.
Okay.
The clinician saw it as not clinically viable nor commercially attractive. The oral allows us to dose patients, dose them up, and dose them daily. We've already completed the 28-day tox studies. We know that we can dose this daily. We finally reached an MTD with this drug, with the oral for the first time. We couldn't do it with the IV because we're capped in the amount of volume you could infuse into a patient. But the oral allows us to dose up and the MTD, the maximum tolerated dose, turned out to be 5 x the therapeutic dose. There're a lot of room to move up, expose patients to more, and achieve better outcomes than just infusing it once a week.
As you said, you have a clearance from the FDA to start the IND, and you're planning to do this-
Second half of this year.
-the second half of this year.
Yes.
What needs to get done between now and then?
Well, there's a lot of operational issues on site recruitment, contracts, IRB reviews. We don't see those as gating issues. We just see that as work as going forward.
In terms of the study, the phase I/II is a monotherapy planned in refractory melanoma, non-small cell lung cancer, colorectal and pancreatic cancer, with PK and RP2D as the endpoints are expected.
Yes.
in the second half of 2027.
Yes.
For you to continue on this pathway, what do you think is a successful outcome? Do you think investors need to see the monotherapy efficacy signal at all?
Well, I think that is definitely a target for this drug and dosing patients up to a place where we can start to see probably objective response rates in metastatic melanoma and potentially AML,
Hmm.
-which is undergoing internal consideration right now because we know that AML is highly sensitive to this drug.
Okay.
But I think that it's setting the stage so that we can quickly move into these large market opportunities, such as second-line Pancreatic that will drive the value for the customers. We already have one institution who is setting up a study design for a combo study with [Dara] in second-line patients and is very enthusiastic about doing so based on what they understand of the disease process, the mechanism of action, and the profile of elra. I think that starting that study as well will drive not only investor positive return but BD interest as well.
And then in terms of the paper that you talked about, the phase II study, which was published in the Nature Medicine paper, that showed 10.1 months of median OS versus 7.2 months and almost doubled the one-year survival there. I think you've taken this data and started working with the EMA to try and see if you could get a single trial acceptance.
Right.
Where do those discussions stand at this point? Do you think you will switch at the EMA as well into the oral study then?
Yeah, so I think that the EMA and FDA both required full phase III trials, not only of Actuate but of Revolution Medicines, of Verastem, and others in this space. They want to see full phase III trials. Our decision to move to the oral was driven by the fact that the RAS inhibitors will be oral. The standard of care will include the RAS inhibitors going forward. The ability to combine with them and potentiate better outcomes made a lot more sense to us than driving forward with the IV program that we originally had proposed to the FDA and EMA. So, it was a pivot to a much better outcome in three years than we would've had otherwise.
In terms of the preclinical work that you've shown at the ASCO, there were kind of two pieces of information which came out of that. One was that looking at the KRAS wild type and P53 wild type patients, they did best on the monotherapy, but when you did the RAS combination, it looked like it was targeting the mutant population better. How do you reconcile this?
No, I think this is an excellent question. I think it's looking at the same issue from two different perspectives. If you take a RAS mutant disease and you inhibit it with a RAS inhibitor, you've taken care of that RAS mutation, then you throw elra on top as we showed the data today-
Hmm.
-and you get significant synergy. In our clinical trial, there were patients with RAS wild type disease. The RAS mutation had been taken care of. We put elra on top of it, and they did significantly better. It's almost like therapeutic intervention to get there with a RAS inhibitor or just no mutation, elra shows its prowess, and those patients in our clinical trial did significantly better based on that profile. It's just a matter of which intervention, natural or inhibitor, but it really strengthens the story of this agent. It's not a single mutation-driven asset. This has the ability to treat patients across a broad spectrum within the same disease. Those data coalesce very nicely to speak to that story.
Very good. Last question from me. On pediatrics, elra was selected to do the BEACON2 with Cancer Research UK starting with the 20-patient dose confirmation cohort before expanding this to a roughly 75 patient randomized study. You're expecting to start the study in the first half of 2027.
Yes.
Operationally, how does this study get run? What do you think about, or how should investors think about the potential voucher-
Yeah.
-which could actually be a pretty good non-dilutive-
Yeah.
-funds?
Yeah. We were very clear. This is another independent third-party validation of this program. Cancer Research U.K. is very well known, very well respected, and the fact that they came to us was very satisfying. The first part of this trial is being run as a clinical proof of concept that we can combine with these agents in these patients and show outcomes. The second half of the study will be designed as a registration trial.
Hmm.
There's very minimal, it's nominal funding from the company along with supply of drug. Ultimately, if it proves out that we can have significant outcomes, that second half of that registration trial we plan to use for registration in the E.U. and U.S. Ultimately, we already have rare pediatric designation, so this indication would be PRV eligible.
Yeah.
Again, I have told you this a number of times. I am a big believer if you have something for kids with cancer, you should do something for kids with cancer. This is an opportunity for us to do this in one of the most deadly diseases in childhood oncology. We have a great team in Cancer Research U.K. to help us along with it.
Fantastic. Thank you very much, Dan. Thanks and good luck.