ASCO 2025 | Phase II trial of elraglusib, a GSK-3ß inhibitor, in untreated mPDAC

This study initially started as a three-arm randomization because we were looking at two schedules of elraglusib. One was a twice-weekly schedule with chemotherapy, gemcitabine, and the other one was a once-weekly schedule. And a predefined interim analysis was done showing that the weekly and the twice-weekly regimen were equivalent in terms of efficacy. Importantly, we felt it was more manageable and would lead to better patient compliance because patients would want to come in just once a week for their treatment as opposed to twice a week. So the study then became a two-to-one randomization with the primary endpoint being initially the one-year overall survival rate during the run-in to kind of have the readouts as well as the data readouts throughout the study. And then when the study completed, we were able to then use the median overall survival as the primary endpoint, which is what we read out. So the findings, what we saw is that in this study, we randomized up to 286 patients, about 250 of them were treated, 155 in the elraglusib once-weekly arm in combination with gemcitabine and the control arm had 78 patients. And the study basically showed that the elraglusib in combination with gemcitabine resulted in a statistically significant improvement in overall survival at 10.1 versus 7.2 months with a hazard ratio of 0.63 with a 37% reduction in the risk of death. Now in pancreatic cancer, these are rarely seen in the space of pancreatic cancer where we are seeing a hazard ratio kind of in the 0.63 range. So this 37% reduction in the risk of death is certainly meaningful. And there was other secondary endpoints that we looked at, including like PFS, and the PFS were comparable between the arms. And so the question really is why is there a survival benefit despite the PFS being comparable? The overall response favored the elraglusib arm, but the question is why the survival? And so we always postulated that elraglusib had an immunomodulatory function, and a lot of the correlatives that were built into the trial to study that as well. So from a baseline cytokine assay, we found that CXCL2 is a key differentiator. And when you have a higher level of CXCL2 at baseline, it predicts a better response to elraglusib treatments. So that’s one of the biomarkers we are going to tease out a little bit more as we get more data. But certainly, it’s a strong biomarker as a predictor for at least the treatment effects that we saw. And then in tumor biopsies that we had pad biopsies in the patients, the patients who were treated on the elraglusib arm, we saw CD8 positive and granzyme positive T cells suggesting activated T cells in the tumor microenvironment only in the elraglusib treated tumors, but not the controlled tumors. Now, the number of pad biopsies is not as much as we would like to do to kind of have a strong correlation, but it at least kind of gives us the postulates that the survival benefit that we are seeing in patients, and many of them are living beyond 12 months and 18 months, and some even beyond 24 months, might be driven by the immunomodulatory mechanism as well. But we believe there’s also a tumor reprogramming that happens, whether it’s the EMT, the reduction in fibrosis that allows the chemotherapy to get in. So we think that that drives the efficacy benefits. In terms of safety, the drug as a single agent was extremely safe. We rarely saw any kind of side effects related to the drug. The one common thing that we see is this thing called visual disturbances. Visual disturbances are because GSK3 beta regulates the activity of the photoreceptors in your eyes, basically your rods and cones, but there is no structural damage because our phase one trials, we did all of this kind of evaluation and there’s no retinal damage and stuff. So what actually happens is that when the drug is infused, you get this kind of C-max, which is a concentration of the drug reaches a level in the first day of the infusion. So usually a few hours later, patients describe it as a brightening or a darkening of their perception of brightening and darkening, and usually lasts just a few hours. So a lot of patients say, hey, you know, they go back from the infusion, they’re back home, and most of the things start kind of resolving. And so it’s a kind of a transient effect, but doesn’t leave a damaging effect to the eye. And we have looked at that in multiple ophthalmology follow-up, at least in the earlier trials. The other side effect of note is we saw more neutropenia. The grade 3 neutropenia levels were higher in the elraglusib arm versus the GNP-only arm. And we believe that the neutropenia is driven by what we think is elraglusib kind of what’s just modulating the stem cell recovery. So we know in single agent treatments, we see that it allows stem cells to start regenerating as part of its function. But the chemo comes in and causes, kind of reduces the stem cell in the production in the elraglusib, driven by the elraglusib, which is why we see more neutropenia. But in the tumors, we also see decreased MDSCs as well. So suggesting that elraglusib is doing one of two things, it’s kind of affecting the renewal of hemopoietic stem cells. And the other part of it is its effect on the MDSCs as well. But despite this neutropenia, the rates of febrile neutropenia and sepsis are very low and comparable between both

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