공시 • Dec 13
Aptose Biosciences Inc. Updates Clinical Responses, Breadth of Activity, and Safety Across Four Dose Levels of Tuspetinib in Difficult-to-Treat Acute Myeloid Leukemia Populations
Aptose Biosciences Inc. (Aptose) provided a clinical update of its lead oral myeloid kinome inhibitor, tuspetinib (formerly HM43239), as responses continue to emerge from a Phase 1/2 trial, and from its oral, dual lymphoid and myeloid kinase inhibitor, luxeptinib (formerly CG-806) in an ongoing Phase 1a/b trial. Tuspetinib, a once daily oral agent designed to target FLT3, SYK, and JAK kinases but avoid targets that drive toxicities, safely delivered complete remissions (CR/CRh/CRi/CRp) as a monotherapy across four dose levels (40mg, 80mg, 120mg, and 160mg) in acute myeloid leukemia (AML) patients that previously had been failed by chemotherapy, Bcl-2 inhibitors, hypomethylating agents, competitor FLT3 inhibitors, and hematopoietic stem cell transplants. Data are being presented at the 2022 American Society of Hematology (ASH) annual meeting by lead investigator Naval G. Daver, M.D., Associate Professor in the Department of Leukemia at MD Anderson Cancer Center, showing tuspetinib delivers single agent responses in very ill and heavily pretreated relapsed or refractory AML patients of mutationally-defined populations, including those with AML harboring wild-type FLT3, ITD or TKD mutated FLT3, or mutated forms of NPM1, MLL,TP53, NRAS, KRAS, DNMT3A, RUNX1, various slicing factors, and other genes. As of October 6, 2022, 60 heavily pretreated relapsed/refractory AML patients were enrolled at multiple centers and treated at doses escalating from 20 mg to 200 mg, with further dose exploration at the 40 mg, 80 mg, 120 mg and 160 mg dose levels. Prior to Aptose licensing tuspetinib, Hanmi Pharmaceutical Company demonstrated complete remissions at the 80 mg dose level. As of January 1, 2022, Aptose assumed control of clinical trial activities and has demonstrated additional complete remissions at the 120 mg, 160 mg, and now the 40 mg dose levels. Many responders were bridged successfully to hematopoietic stem cell transplant (HSCT), while others not eligible for HSCT remained on tuspetinib with a durable response and no drug related myelosuppression even after months of continuous dosing. The noteworthy safety and potency profile position tuspetinib, in both FLT3 mutated (FLT3+) and wildtype (FLT3-WT) AML patients, potentially to become the kinase inhibitor of choice to combine with venetoclax and hypomethylating agents to deliver high response rates without exacerbated myelosuppression or life-threatening toxicities and potentially to become the preferred agent for maintenance therapy to prevent relapse after HSCT or drug-induced complete remissions. Such roles can define the ultimate therapeutic success for patients and commercial success for tuspetinib. In addition to 5 CRc and 1 PR reported at ASH 2021, 4 new CRc and 3 new PR have been generated thus far during 2022. New responses during 2022 were achieved with 160 mg,120 mg, 80 mg, and 40 mg. Among efficacy evaluable patients treated with 80 mg, 120 mg, or 160mg, the following response rates were achieved: FLT3+ 8 of 21 (38.1%). FLT3-WT 4 of 21 (19%), plus additional CRi since data cutoff date. FLT3+ with prior FLT3i 3 of 11 (27.3%). FLT3+/NPM1+ 4 of 6 (66.7%). FLT3+/NPM1+/DNMT3A+ 3 of 4 (75%). N/K-RAS+ 3 of 8 (37.5%). Significant bone marrow leukemic blast reductions were observed broadly in FLT3+ and FLT3 wildtype patients across multiple dose levels, comparable to reported gilteritinib data, but in more heavily pre-treated relapsed and refractory AML patients (waterfall chart available on Aptose website). Vignettes of patient experiences highlight the potency and breadth of tuspetinib to deliver complete remissions among several mutationally-defined populations with a diversity of adverse mutations. Tuspetinib continued to show a favorable safety profile with only mild AEs and no DLTs up to 160 mg per day, and no drug discontinuations from drug related toxicity. No drug related SAE, drug related deaths, differentiation syndrome. No drug related AE of QT prolongation No DLT through 160 mg level – one DLT of muscle weakness at 200 mg (not rhabdomyolysis). No observed muscle destruction – no AE of elevated creatinine phosphokinase (CPK). Avoids many of the typical toxicities observed with other tyrosine kinase inhibitors. Aptose has identified a safe therapeutic range with a broad therapeutic window, spanning the dose levels of 40, 80, 120 and 160 milligrams. For the APTIVATE expansion trial that has initiated patient enrollment, Aptose has selected 120 mg as the initiating single agent expansion dose and 80 mg as the initiating dose selected for combination with venetoclax. The trial is designed to confirm activity through patient enrichment of specific mutationally defined AML populations, including FLT3-mutant patients who have been failed by a prior FLT3 inhibitor, as supported by fast-track designation and a significant response rate to date.