Transcript of Key Opinion Leader Event Event Details Date: 2025-05-31 Company: Actuate Therapeutics, Inc. Ticker: ACTU-US Link to access replay: https://lifescievents.com/event/actuate/ Company Participants Daniel Schmit

Transcript of Key Opinion

Company: Actuate Therapeutics, Inc.

to access replay: https://lifescievents.com/event/actuate/

Company Participants

Christopher Liu - Managing Director,

Lucid Capital Markets

Albert Lowe - Analyst,

Kaveri Pohlman - Managing Director, Clear Street

Ramakanth Swayampakula - Managing

Director, Senior Healthcare Analyst, H.C. Wainwright

Silvan T rkcan - Analyst, Citizens

MANAGEMENT DISCUSSION SECTION

name is Dan Schmitt. I'm the President and CEO of Actuate Therapeutics. I really appreciate you taking the time out of a very busy, hectic,

completely lled schedule to make time to meet with us tonight. This is a KOL discussion focused on the Phase 2 topline data that

was presented this afternoon by Dr. Deva Mahalingam on the 1801 3b study in rst-line treatment of metastatic pancreatic cancer.

The trial represents a major milestone in our development of elraglusib, and we're really honored to have four world-renowned clinical

leaders in GI oncology here with us to provide their perspectives and insights.

now my pleasure to introduce our panel. Dr. Colin Weekes to immediately to my left is Director of pancreatic research at Massachusetts

General Hospital and Associate Professor at Harvard Medical School. His research focuses on early drug development and targeting the tumor

microbial environment in pancreatic cancer. He is also leading a trial with elraglusib in combination with FOLFIRINOX in metastatic pancreatic

Dr. Deva Mahalingam is a professor of medicine and GI

oncologist at Northwestern's Robert H. Lurie Cancer Center. He directs the Clinical Trials O ce and the Developmental Therapeutics

Unit where he leads early phase research across GI malignancies. He is also the principal investigator in our Phase 2 Part 3B trial and

was the presenter in the main session today.

Dr. Rachna Shro is a nationally recognized expert

in pancreatic and biliary cancer. She co-chairs the SWOG Hepatobiliary Subcommittee. She led GI ASCO 2024 as the Chair and is the national

And last but not least, Dr. Tanios Saab is a David F.

and Margaret T. Grohne Professor at the Mayo Clinic and Chair of Hematology and Medical Oncology in Phoenix. He leads GI cancer research

across the Mayo Clinic cancer centers and co-chairs several national committees, focused on hepatobiliary cancers.

So, please join me in welcoming all four of our panelists.

I'm really proud to have them here. So thank you.

What I'd like to do is, this is a reside chat.

I try to make it as conversational as possible. But I'd like to begin with Dr. Weekes and ask him to provide an overview of the pancreatic

cancer treatment landscape, existing treatment regimens and his experience with elraglusib. And then after that, we'll have Dr. Mahalingam

discuss the Phase 2 1801 3B study, and the results that were presented this afternoon. And then following that data review, we're going

to open it up to the panel with Dr. Shro and Dr. Saab, who will share their perspectives on the data and how elraglusib may ultimately

t into the treatment paradigm. So after those discussions, we'll open it up to the oor for any questions that you may have.

So, Dr. Weekes, the oor is yours.

All right. Hello, everyone. So I think I would like

to do is just sort of outline in general sort of how we think about pancreas cancer. And that stems from patients who have localized disease

all the way to metastatic disease, which is what we're going to talk about ultimately. And so in patients with metastatic - or excuse

me, localized disease, we sort of break those down into resectable versus borderline resectable and locally advanced.

And right now, it is somewhat controversial in terms

of what chemotherapy we use in that setting. But the two real chemotherapies that we use are either nab-paclitaxel plus gemcitabine or

FOLFIRINOX. And then there's most recently now NALIRIFOX which is, I think, just a fancy version of FOLFIRINOX. So I think for most of

us, we think about FOLFIRINOX and now they're perhaps more similarly.

I would also say that I think that when we think about

treating these patients, it's really sort of two treatment, two therapeutic paradigms, either sort of gemcitabine nab-paclitaxel or a

FOLFIRINOX paradigm. And I think what's beginning to come out is that we have these di erent molecular subtypes of pancreas cancer.

And those patients may respond di erently to di erent types of these chemotherapy regimens. And so I think this, like, if

I'm talking to my patients about it, I'll say, okay, there's male and female pancreas cancer cells and the cancer tumors are an amalgamation

of these male and female cells. And it may be that, let's say, the female cells respond to chemotherapy with FOLFIRINOX better than, say,

the male cells. And what we also know is that sometimes these cells can transition from male to female and that process is called epithelial-mesenchymal

transition, EMT. And that's one of the ways that elraglusib works by inhibiting the EMT.

In addition to that elraglusib potentially also alters

the immune function. So, we saw today in the presentation that we see an augmentation of CD8 positive T cells and then the release of

Granzyme B from those T cells. So that demonstrates that, in fact, not only the T cells present, but they're actually active in killing

cells. So, that's the importance of that piece of information that was presented today.

And then in addition to that, elraglusib potentially

targets the proliferative pathway, which is shown by its ability to inhibit NF-kappa B. And so, it functions in many ways in pancreas

cancer. And I think that's important in terms of pancreatic cancer because pancreas cancer, if I was to cut that tumor open, it would

look very di erent than, say, if I cut a lung cancer tumor open.

So, if I cut a lung cancer tumor open and look at it, what I'm going to see is lung cancer cells only versus in the pancreas cancer, what

we see is an amalgamation of cells.

The plurality of those cells are actually the tumor

cells. We also see what are called cancer associated broblasts, and there's also called the desmoplastic

reaction, which is the stroma, the

concrete of the tumor.

And all of those things are active

in pancreas cancer. And it turns out that elraglusib potentially targets all of those di erent components of the tumor. So, I think

that's one of the unique things about elraglusib as a drug for pancreas cancer.

So, as you said, I have experience with FOLFIRINOX.

So, I've been doing a clinical trial for FOLFIRINOX over the last couple of years. And I think what I've sort of come to the conclusion

from that experience, that study is a small study. So, it's a total of 60 patients, and it's randomized to receive FOLFIRINOX. And then

we were also using a drug called Losartan, which is a blood pressure medicine. But we think that Losartan alters the function of the stroma.

And so, that's why we're doing that and also alters potentially that whole EMT process. So, we are asking the question if we give elraglusib

with FOLFIRINOX we alter the EMT process and we maintain cells in a female state with a response to FOLFIRINOX. And then, I think the

interesting thing for us in that study is we do have some incredibly long responders, who have done really well on that. We've done well

in that study. These patients had a very high burden of disease to begin with, and they did very well.

All the patients that we took care of on that study,

it's a much smaller study of 60 patients total. But all the patients that we treated on the study had eye or vision changes. Those vision

changes lasted for just about 24 hours, and then they were fine after

that. So, it wasn't anything that was permanent. And that's - these are patients who were on study for some of them for two years

and really didn't have any problems. So, I don't see that as a sort of an inhibitory toxicity of this particular drug.

So, I think the question really then becomes, which one

of these pathways do we go down in terms of drug development? I think both pathways are valid. I think that the control arm for one study

versus another. I think there's a question out there about that. I think from my perspective, you want to do a control - the control

arm should be whatever the arm is that you're combining the drug with. And so, you're asking that question, right? Does that drug improve

this chemotherapy, FOLFIRINOX because that drug improve this chemotherapy, nab-paclitaxel, and gemcitabine?

I think the real importance of

this study at the end of the day and I'll be quiet is, if you think about pancreas cancer, drug development. So now, FOLFIRINOX and -

excuse me, FOLFIRINOX was studied in 2011. I think nab-paclitaxel with gemcitabine is around 2013. So, it's been quite some time since

we've had anything that says it improves outcomes for patients with these chemotherapy backbones despite a lot of negative trials. Right?

So, we could ll this room with negative trials. So, I think that's really the importance of this study, is that for the rst

time, seeing an overall survival bene t.

The magnitude of that bene t, I think, is actually