Lisa Rojkjaer
Analyst · Joe Pantginis with H.C. Wainwright
Thanks, Dave. I will now provide an update on our progress over the first quarter and plans for the remainder of the year. I'm on Slide 14. Our hematology and oncology pipeline focus is the clinical development of R289, our potent and selective dual IRAK1 and IRAK4 inhibitor in lower-risk myelodysplastic syndrome, or MDS, and the expansion of olutasidenib beyond relapsed or refractory IDH1 mutated AML in collaboration with academic partners. Our Phase Ib study of R289 in patients with relapsed or refractory lower-risk MDS is progressing well. Shortly, I'll provide an update on the study as well as our planned next steps for R289. As far as olutasidenib development is concerned, our strategic collaborations continue to advance into additional therapeutic areas. MD Anderson is evaluating olutasidenib in several IDH1 mutation-positive indications, including AML, MDS and CMML. In addition, olutasidenib is also being evaluated as a maintenance therapy and as a co-targeted therapy in AML. The 5 MD Anderson studies are active and enrolling. CONNECT Phase II TarGeT-D study evaluating olutasidenib in combination with temozolomide, followed by olutasidenib monotherapy as maintenance treatment in newly diagnosed pediatric and young adult patients with IDH1 mutation-positive high-grade glioma is also active and enrolling patients. Lastly, we're partnering with the National Institutes of Health and National Cancer Institute's MyeloMATCH Precision Medicine Trial Initiative. The planned study will evaluate olutasidenib in first-line IDH1 mutated AML and MDS. We're excited about olutasidenib's potential to provide a new treatment option in these underserved patient populations and look forward to seeing the data that these studies generate in the future. Now I will discuss R289, our novel dual IRAK1 and IRAK4 inhibitor. I'm on Slide 16. I'd like to remind you about the treatment landscape for lower-risk MDS. MDS is a clonal disorder of hematopoietic stem cells leading to dysplasia and ineffective hematopoiesis. The main consequences for patients are anemia and transfusion dependence, which adversely impact their quality of life. In addition, infections, iron overload from transfusions and subsequent organ dysfunction all negatively impact the patient. Therapies used in the upfront setting include erythropoiesis stimulating agents, or ESAs, if patients are eligible or luspatercept. Luspatercept and imetelstat are also approved for ESA failure transfusion-dependent lower-risk MDS patients. Finally, hypomethylating agents or HMAs are also approved. However, the percentage of patients achieving transfusion independence is low. With 8-week transfusion independence rates approaching 40% with luspatercept and imetelstat, there is still a need for safe, effective therapies for previously treated transfusion-dependent lower-risk MDS patients that are relapsed, refractory to or ineligible for ESAs. On Slide 17 is the value proposition of R289 in lower-risk MDS, which we believe can address the unmet need, particularly for transfusion-dependent patients. There are about 12,000 previously treated lower-risk MDS patients in the U.S. that could benefit from a novel therapy like R289. Dysregulation of inflammatory signaling is key to the pathogenesis of lower-risk MDS, and IRAK1 and 4 mediate this process. Blocking both IRAK1 and 4 may suppress marrow inflammation and leukemic stem and progenitor cell function and restore normal hematopoiesis. R835, the active moiety of R289, blocks toll-like receptor and IL-1 receptor signaling in vitro and was active in various preclinical models of inflammation. Clinical proof of concept of this anti-inflammatory effect came from a healthy volunteer study in which R835 markedly suppressed LPS-induced cytokine release compared to placebo. As a reminder, R289, which is currently being evaluated in the clinic, is the oral prodrug that is rapidly converted to R835 in the gut. From the FDA, R289 has both Fast Track designation for the treatment of patients with previously treated transfusion-dependent lower-risk MDS and Orphan Drug Designation for MDS. Both designations underscore the agency's interest in this rare disease, the unmet need of the patient population and the agency's willingness to collaborate with Rigel in the development of R289. R289 has thus far demonstrated a promising clinical profile with both encouraging preliminary safety and efficacy in our Phase Ib study, which was presented at ASH this past December. Now on Slide 18, you can see the design of our multicenter open-label Phase Ib study in patients with relapsed/refractory lower-risk MDS. The Phase Ib study evaluates the safety, tolerability, PK or pharmacokinetics and preliminary efficacy of R289 in patients with lower-risk MDS and is also designed to select the dose for future studies. The dose escalation phase evaluated 6 different R289 dosing regimens that are administered once or twice daily using a modified 3+3 design. In the dose expansion part of the study, which is currently enrolling, up to 40 transfusion-dependent relapsed/refractory lower-risk MDS patients are being randomized to receive R289 doses of either 500 milligrams once or twice daily in order to select the recommended Phase II dose for future clinical studies. On Slide 19, you'll see highlights from the dose escalation phase data that were presented at the ASH meeting in December. I encourage you to review the corporate presentation in the Investors section of our website, which includes the full data set. 33 patients were enrolled. The median age was 75 and the median number of prior therapies was 3, with around 70% of the patients having received prior luspatercept and HMAs. In addition, the majority of the patients had a high baseline transfusion burden. This elderly, heavily pretreated patient population is truly representative of the low-risk MDS patient population with the highest unmet medical need. Overall, R289 was generally well tolerated with a low incidence of grade 3/4 cytopenias and infections. There was one dose-limiting toxicity reported, a grade 3/4 AST/ALT increase at 750-milligram daily dose level and no evidence of dose-dependent toxicity across the other dose groups. The swimmer plot you see shows an overview of transfusion events by dose group, starting with the lowest dose group, 250 milligrams daily at the top. Red cell transfusions occurring over 16 weeks prior to start of R289 are shown to the left of the colored bars, establishing the baseline transfusion frequency for each patient. Of 18 evaluable patients receiving doses of 500 milligrams daily or higher, 6 patients or 33% achieved red cell transfusion independence or RBCTI lasting for 8 weeks or longer. In 4 patients, RBCTI lasted for more than 16 weeks and for 3 patients for more than 6 months. The median duration of RBCTI was around 23 weeks, ranging from 9 weeks to more than 24 months. Also, the median time to onset of RBCTI was about 2 months. While this is a small data set, we're encouraged by these results given the highly refractory nature of these patients. In summary, R289 was generally well tolerated with an encouraging safety profile and promising preliminary efficacy in an elderly heavily pretreated transfusion-dependent lower-risk MDS patient population. The next steps for our R289 clinical development program are on Slide 20. We plan to complete enrollment of the dose expansion phase of the study and select the recommended Phase II dose for future studies in the second half of this year. We anticipate sharing an update on the study, including top line data from the dose expansion phase by the end of 2026. Once the recommended Phase II dose has been selected, we will evaluate R289 in a cohort of less heavily pretreated patients who are relapsed/refractory to or ineligible for ESAs in the same study. Upon completion of the Phase Ib study, we plan to follow up with the FDA to discuss a potential registration study, which will potentially initiate in 2027. With its mechanism of action, we believe that R289 has potential in other indications where the pro-inflammatory cascade plays a role, and we'll provide more details as our plans progress. Now I'll pass the call to Dean to discuss our results for the quarter. Dean?