Kura Oncology, Inc. Investor update

Good afternoon, and welcome to the Kura Oncology and Caspian Therapeutics Investor Call on KO-7246 and diabetes. We remind you that today's discussion will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company. I'll now turn the call over to Dr. Troy Wilson, President, Chief Executive Officer of Kura Oncology, and Executive Chairman of Caspian Therapeutics.

Troy, please go ahead. Thank you, Greg, and good afternoon, everyone.

Today, we'll discuss why we created Caspian Therapeutics and how the KO-7246 data presented at EASD support our plans to develop menin inhibitors in diabetes. Joining me on today's call are Dr. Francis Burrows, Kura's Chief Scientific Officer, who led our research into menin inhibitors in diabetes, and who leads the team who discovered KO-7246, as well as Dr. Rob Spencer, Caspian's President and Chief Operating Officer. Francis will review the science behind menin inhibition in diabetes, and Rob's going to discuss how Caspian intends to translate those findings into a clinical development program. Caspian grew out of more than a decade of work in menin inhibition at Kura. We've pioneered menin inhibition, and that experience gave us the scientific foundation to investigate whether this biology could help restore the body's own insulin-producing capacity.

As the data developed, we saw an opportunity that warranted a focused development effort as well as a dedicated investment. Diabetes requires specialized capabilities and a development strategy tailored to metabolic disease. Caspian gives this program the dedicated leadership and financing while Kura remains focused on its oncology business. Kura contributed KO-7246 and related intellectual property and know-how to Caspian. The $50 million financing was led by BVF Partners with participation from the T1D Fund, Invus, Montanova, Eli Lilly and Company, Kura Oncology, and other investors. The proceeds are expected to support KO-7246 through IND-enabling development and initial clinical proof of concept, as well as to support advancement of a second menin inhibitor candidate. Caspian can access Kura's research, development, and corporate capabilities through an intercompany services agreement. This gives Rob and his team access to established expertise and infrastructure while directing more of Caspian's resources toward development.

Caspian has responsibility for advancing the program with oversight from its board of directors. Kura retains approximately 50% ownership, giving Kura stockholders meaningful participation in potential future value. We believe this structure puts the program in a position to advance efficiently with capital aligned to a specific clinical objective. The scientific basis for the investment is the focus of today's call. Francis, if you could please take us through the EASD slides.

Thank you, Troy. Our starting point is the loss of functional beta cell capacity in diabetes. Beta cells are the cells of the islets of the pancreas that make insulin. We're investigating whether we can help the body rebuild that insulin-producing capacity by inhibiting a protein called menin. Menin controls expression of CDK inhibitor genes in beta cells, thus acting as a brake on beta cell division. Studies of how the pancreas adapts to increased insulin demand, such as during pregnancy, suggest that menin inhibition can release that brake and allow beta cells to multiply. We're investigating whether a drug can harness this natural capacity for adaptation to help restore insulin-producing capacity in diabetes. KO-7246 is a potent, selective oral menin inhibitor developed with metabolic disease in mind.

At EASD, we reported data related to beta cell expansion, insulin production, blood sugar control, and durability after treatment stops using mouse, rat, and human models. We also compared KO-7246 with other compounds to understand where its activity and selectivity differ. Next one. Let's begin with the mouse model of type 2 diabetes. In this experiment, these animals had very, very high blood sugar when the treatment began, and as you can see in the light blue line, semaglutide lowered it rapidly, but that effect weakened over time. With KO-7246, on the other hand, blood sugar fell more gradually over seven weeks, while insulin levels concomitantly increased, shown on the right. That slower response is consistent with the process that takes time to build beta cell capacity.

Importantly, combining KO-7246 with semaglutide brought together both the rapid initial reduction in blood sugar and a sustained effect due to the menin inhibition. Despite increased insulin production, we observed no hypoglycemia, that is abnormally low blood sugar, in any KO-7246 treated mice, including in the combination group where insulin levels reach quite high. That matters. The aim is to restore glucose control without driving blood sugar too low, and it's encouraging evidence of integrated physiologic regulation of menin in this model. As they say, a picture is worth a thousand words, and I feel like this really captures the power of the approach of menin inhibition here. After only 28 days of exposure, we can see that the islets, the tissues containing the beta cells, have grown substantially and are staining positive for insulin. Improved blood sugar control accompanied expansion of the insulin-producing cell population. Next one. We next studied rats given STZ, a chemical that destroys beta cells and causes severe insulin insufficiency.

This model tests whether generating new beta cells can restore blood sugar control, although it does not reproduce Type 1 diabetes autoimmune attack. The positive control exogenous insulin lowered blood sugar quickly. KO-7246 took longer, but a substantial effect developed over 8 weeks. Some animals responded strongly, and others did not. Responders regained normal blood sugar control. In the same experiment, Icovamenib, also known as BMF-219, did not reduce fasting blood glucose or increase beta cell mass under the conditions tested. Let's take a closer look at this response in the next slide. This binary response, complete recovery in some animals and little or none in others, is consistent with how KO-7246 is intended to work.

It helps existing beta cells multiply, so there must be a sufficient surviving population to build upon. Our interpretation of these data is that animals with enough remaining beta cells could rebuild the insulin-producing capacity needed to restore glucose control, while those with too few lack the starting population needed for a meaningful response in this model. Among the KO-7246 responders, islets recovered to between 40% and 90% of healthy control levels by day 56. In other words, partial recovery was enough to restore normal blood sugar control. This combination of tissue recovery and functional benefit clearly distinguished KO-7246 from Icovamenib in this experiment. We then stopped treatment and followed the animals for another month. As you can see, in responders, blood sugar control was fully maintained. Next slide. Stimulated C-peptide, a marker of the body's own insulin production, also remained significantly elevated after that month, as shown in the chart here.

No further treatment, but at the same time, very little cell division remained at this point. In other words, functional benefit persisted after active proliferation had ended, supporting the possibility that treatment can rebuild insulin-producing capacity that continues working after drug withdrawal. We then tested human islet microtissues, which contain the appropriate proportions of the different cell types found in a pancreatic islet. KO-7246 increased beta cell proliferation in multiple donor samples. Under high glucose conditions that stress these cells and exist in diabetic patients, increasing the dose increased both beta cell proliferation and ultimately the proportion of beta cells in the islets. KO-7246 selectively stimulated beta cell proliferation without increasing proliferation of other cell types in these experiments.

The research compound harmine, a DYRK1A inhibitor, stimulated non-beta cells as well as beta cells, ultimately actually reducing the overall proportion of beta cells. KO-7246, therefore, expanded the cell population that we want to restore without stimulating broader cell growth in the microtissues. This selectivity matters because our goal is to rebuild the insulin-producing cell population without encouraging growth of surrounding cells. The results are consistent across complementary systems. Beta cell expansion with improved glucose control in rodent models of both Type 1 and Type 2 diabetes and selective beta cell proliferation in human islet microtissues. The human findings strengthen the case that the underlying biology extends beyond mice and rats. Finally, the direct comparisons help explain KO-7246's pharmacologic profile.

While both KO-7246 and bleximenib, another menin inhibitor being advanced in diabetes, were indeed active against menin, KO-7246 was about 3 times more potent than bleximenib in vitro and displayed superior antitumor activity at one-quarter of the dose in a menin-dependent mouse leukemia model. Icovamenib, on the other hand, showed a different profile. Although described as a menin inhibitor, it did not measurably block the menin-MLL interaction in our assay and showed no efficacy in the menin-dependent animal model, even at 8 times the dose of KO-7246. Instead, we observed robust inhibition of several kinases, including CDK9, a protein broadly involved in regulating protein synthesis, along with other kinases with reported roles in diabetes, such as c-Kit and ABL. These results do not support menin-MLL inhibition as icovamenib's mechanism, but do identify CDK9 as a distinct pharmacologic activity of this compound.