BTM 3566, a Novel Activator of the Mitochondrial Stress Response Induces Robust Therapeutic Responses in Diffuse Large B‐cell Lymphoma in vitro and in vivo

Introduction: Relapsed/refractory diffuse large B-cell lymphomas (r/r-DLBCL) are a therapeutic challenge, especially in patients not suitable for high dose chemotherapy, stem cell transplantation or patients who fail CAR-T-cell therapy. r/rDLBCLs exhibit considerable heterogeneity. BTM-3566, a novel compound demonstrating efficacy against diverse B-cell malignancies, with the most pronounced impact observed in DLBCL. BTM-3566 initiates the mitochondrial integrated stress response (ISR) via a unique mechanism governed by the mitochondrial protein FAM210B. Methods: Human cell line xenograft models were established using SU-DHL-10 cells (ATCC Cat# CRL-2963,RRID:CVCL_1889).For the patient derived xenograft models, all tumors were sourced from Crown Bio. Models were established in female mice with an average body weight of 25 grams. Results: BTM-3566 induces rapid apoptosis and in DLBCL cell lines with an IC50 of 400 nM. Responsive DLBCL cell lines include ABC, GCB, and double-hit and triple-hit lymphoma lines. In xenograft models using the DLBCL line SU-DHL-10, BTM-3566 once-daily oral treatment resulted in complete regression in all tumor-bearing animals. Most importantly, no subsequent tumor growth occurred for 2 weeks after cessation of therapy, indicating that treatment with BTM-3566 resulted in a durable complete remission in this model of double-hit DLBCL. Expansion studies into human DLBCL PDX models harboring a range of high-risk genomic alterations, including MYD88 mutations and MYC and BCL2 rearrangements, demonstrated response in 100% of the lines with complete tumor regression in 6 of 8 PDX models tested (Table 1). Pharmacokinetic studies in mice showed suitability for once daily dosing, with >50% of oral bioavailability and close to 6 hours of serum half-life. 14-day dosing in mice and dogs demonstrated excellent tolerability at therapeutic doses. BTM-3566 showed stability in human hepatocytes (IC < 5 ml/min*kg) as well and a favorable in vitro safety profile. Conclusions: BTM-3566 is an oral small molecule based on a pyrazolothiazol-backbone, developed for treatment of diffuse large B-cell lymphoma (DLBCL). Here we describe a novel, highly potent activator of the mitochondrial ISR, which is well tolerated in mice and dogs, has favorable pharmacokinetics and induces robust DLBCL regression in-vivo. An IND application in mature B-cells malignancies has been cleared by the FDA and Phase 1 study is ready to enroll in the second half of 2023. The research was funded by: Bantam Pharma Keywords: Genomics, Epigenomics, and Other -Omics, Patient-Derived Xenograft (PDX) Models Conflicts of interests pertinent to the abstract. Z. Bashir Consultant or advisory role: Bantam Pharma