Actuate Therapeutics, Inc. Common stock H.C. Wainwright 28th Annual Global Investment Conference

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 elraglusib, 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 elraglusib 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 elraglusib plus zoldonrasib was much more effective than either agent alone. The same was demonstrated in combination studies with Darzalex plus elraglusib.

These are both murine and human models of cancers that are refractory to treatment that show synergistic effects by combining elraglusib 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 elraglusib 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 elraglusib in the bloodstream of 210 nanograms per mil, which is about 0.5 micromolar. 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 elraglusib. We have tested number of doses from 3 to 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/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 elraglusib 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%.