Aptose Biosciences provides clinical update on tuspetinib, luxeptinib

Aptose Biosciences has provided a clinical update of its lead oral myeloid kinome inhibitor, tuspetinib, as responses continue to emerge from a Phase 1/2 trial, and from its oral, dual lymphoid and myeloid kinase inhibitor, luxeptinib 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 as a monotherapy across four dose levels in acute myeloid leukemia 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 annual meeting, 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, 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 and wildtype 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. 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. Aptose also provided an update of the luxeptinib clinical program. Luxeptinib is an oral, first-in-class FLT3 and BTK kinase inhibitor in Phase 1 a/b clinical studies for the treatment of myeloid hematologic malignancies. This small molecule demonstrates potent inhibition of wild type and all mutant forms of FLT3 and cures animals of AML in the absence of toxicity in murine leukemia models. Just recently, a CR was achieved with a diffuse large B-cell lymphoma patient at the end of Cycle 22 with 900mg BID of the original G1 formulation. Previously, an MRD-negative CR was reported with a R/R AML patient receiving 450mg BID of the original G1 formulation. Collectively, these findings demonstrate luxeptinib is active against AML as well as lymphoid malignancies. The original G1 formulation of luxeptinib was hampered by poor absorption. The new "G3" formulation was designed and developed for more rapid absorption, more efficient absorption, longer retention, and greater accumulation. The new G3 formulation this year was tested as a single dose in 20 patients from a Phase 1 clinical program of luxeptinib. Modeling of the pharmacokinetic properties of G3 predicts steady-state plasma exposure from continuous dosing with 50 mg of G3 should be comparable to that of 900 mg of the original G1 formulation Q12h, representing up to an 18-fold improvement in bioavailability with G3. Aptose recently announced dosing of the first patient with continuous dosing of the G3 formulation in an ongoing Phase 1a/b clinical trial in patients with relapsed or refractory AML. A second patient now has initiated continuous dosing with the G3 formulation. The G3 formulation may result in greater exposures of luxeptinib and additional responses in these difficult-to-treat patient populations. Aptose expects that 9-15 patients will determine if G3 is safe and achieves desired exposures to deliver clinical responses.