Theresa Lavallee
Analyst · Oppenheimer
Thank you, Rosh, and good afternoon. Today, I will cover 3 topics. Two aspects for tagmokitug, as the CCR8 competitive field is evolving, I will briefly review the importance of pharmacology and drug development. And then I will review our own tagmokitug pharmacology data to date. These data have supported the opportunity to expand tagmokitug development with J&J T-cell engager, pasritamig, a novel combination with CCR8 depleting antibodies and a potentially complementary anticancer therapy. We are excited this is our first nonproprietary combination to advance to clinical development. So, let me start with reviewing some of our analysis plans for the casdozokitug randomized CATALYST-202 study. Having the casdozokitug study fully enrolled now allows for the biomarker analysis to be done. We have prioritized 2 aspects for data readouts, biomarkers associated with response and pharmacodynamic biomarkers to support contribution of effect for casdozokitug. The previous casdozokitug study provided a small data set suggesting that higher levels of IL-27 expression in tumors were associated with response. However, we had just 7 tumor samples, which is only 25% of the evaluable patients. Despite that, the analysis showed the tumors from the 4 patients with response had a higher level of IL-27 protein compared to the 3 progressive disease patients. In the current CATALYST-202 study, we have trained pretreatment tumor samples for almost all of the patients and expect to have IL-27 expression data when we read out the study. We also plan to perform circulating tumor DNA analysis. Circulating tumor DNA is emerging as an important biomarker to evaluate tumor burden and treatment response. As tumor cells grow, they shed DNA into the patient's blood. And many studies show a decrease in circulating tumor DNA levels following treatment correlates with better survival outcomes. Circulating tumor DNA already serves as a marker for minimal residual disease in hematological malignancies, and there is a large effort in the field to have the same for solid tumors. Given the delayed responses in HCC, we are interested in exploring this as an earlier surrogate marker for efficacy. Let me shift now to our cytolytic CCR8 antibody, tagmokitug, which we are investigating across a number of indications. As the competitive field is evolving with some teams pausing or stopping their programs, while others are advancing their programs into late-stage development, these disparate outcomes may be explained by the basics of drug development. Early phase clinical studies must answer 2 questions: right drug, right target. To have the right drug requires four critical pharmacological elements: good PK and potency, showing you can deliver the drug at the needed exposure, and thirdly, dose-dependent effects on the intended target, showing the drug has hit the target and affected the target as related to dose and fourthly, an acceptable safety profile alone in combination. The majority of the CCR8 antibodies aim for a bind and kill MOA to deplete intratumoral Tregs. However, as we have consistently stated, the CCR8 receptor is a GPCR. It is well known GPCRs are challenging to make selective and potent antibodies against. This is now being reinforced with the CCR8 class. In April, at the AACR meeting, Amgen and Gilead presented on their CCR8 programs. The data show mixed results, and these antibodies show a toxicity profile that is not seen by some other CCR8 programs. Amgen halted enrollment in their program after presenting data showing only 2 responses in 77 patients treated. About 1/3 of the patients were treated with a combination of AMZ355 and pembrolizumab. From the 12 with gastric cancer, one partial response was observed. These results contrast with the gastric cancer data from LaNova, now Sino Biopharma, where LM-108 in combination with PD-1 inhibitors demonstrated a 36% overall response rate. Gilead, in contrast, showed antitumor activity, including single-agent activity in tumor types known to have a high degree of CCR8+ Tregs. Gilead is now advancing their denikitug into Phase II development in multiple studies, and we await additional data sets. In summary, it would seem that many CCR8 programs that are stopping are doing so due to drug-like properties falling short and failing the right drug criteria. In contrast, tagmokitug has shown good pharmacology and has met all the criteria for right drug, excellent linear dose and dose-dependent PK, potency for both binding and killing the target, dose-dependent immune effects and acceptable safety profile, both with and without toripalimab. With the right drug under investigation, we have now turned our attention to answering the question of hitting the right target. As you have seen, we are aggressively pursuing data to support right combinations for the best efficacy across cancers, lines of therapy and immune context. We are evaluating tagmokitug in combination with either toripalimab, a PD-1 inhibitor or pasritamig, a T-cell engager. We plan to evaluate tagmokitug in other combination where Tregs are associated with therapy resistance such as ADCs or radiotherapy. We believe this will inform our development broadly across anticancer therapies on the best way to overcome Treg-driven resistance in cancer patients. With that, I will turn the call over to our Chief Commercial Officer. Sameer?