Aptose Biosciences Inc. ("Aptose") (NASDAQ:APTO, TSX:APS) today reported that the oral myeloid kinome inhibitor HM43239 has demonstrated durable single agent activity in patients with relapsed or refractory
Aptose Biosciences Inc. ("Aptose") (NASDAQ:APTO, TSX:APS) today reported that the oral myeloid kinome inhibitor HM43239 has demonstrated durable single agent activity in patients with relapsed or refractory acute myeloid leukemia (AML). Data were presented in an oral presentation today at the 2021 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.
HM43239 is an oral, once-daily, highly potent myeloid kinome inhibitor (MKI) designed to target key kinases operative in myeloid malignancies. In earlier preclinical studies, HM43239 demonstrated potent in vitro and in vivo activity against FLT3 ITD mutated as well as resistance-conferring D835 and gatekeeper (F691) TKD mutated AML. Additionally, HM43239 inhibited phosphorylation of SYK, known to be highly activated in AML and associated with resistance to FLT3 targeted therapy.
In the ongoing international Phase 1/2 study, thirty-four relapsed/refractory patients who had received at least one prior line of therapy were enrolled at multiple centers between March 2019 and August 2021, and treated at doses escalating from 20 mg to 160 mg. HM43239 delivered multiple complete responses (CR) and demonstrated clinically meaningful benefit in all responders, by either bridging successfully to hematopoietic stem cell transplant (HSCT) or leading to a durable response, as well as a favorable safety profile across all treated patients.
Highlights of Dr. Daver's ASH oral presentation:
- Among FLT3 mutant patients treated with 80 mg, 3 of 8 (37.5%) achieved a durable composite complete response (CRc, CR + CRi).
- At the 80 mg dose, a composite CRc rate of 25% was observed in both FLT3 mutant (including a prior gilteritinib failure patient) and FLT3 wild-type AML (including >1 year duration of response in a relapsed TP53m AML patient unfit for HSCT).
- At the 80 mg dose, 4 of 5 (80%) responders advanced to HSCT.
- Recently, another prior gilteritinib failure patient achieved PR after one cycle at the 120 mg dose.
- HM43239 showed 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.
- HM43239 plasma inhibitory assay (PIA) activity was dose-dependent with up to 90% phospho-FLT3 inhibition at dose levels ≥ 80 mg.
- The study is ongoing across several cohorts – the dose escalation cohort of 200 mg and the dose expansion cohorts of 120 mg and 160 mg are currently enrolling.
"HM43239 demonstrated clear genotype-agnostic clinical activity as a single-agent in one of the most challenging and most heterogeneus disease settings in oncology today – relapsed and refractory AML," said Rafael Bejar, M.D., Ph.D., Chief Medical Officer. "Importantly, HM43239 has demonstrated activity in patients with FLT3 wild-type AML, FLT3 mutated AML, NPM1 mutated AML, as well as in patients with mutations historically associated with resistance to targeted therapy, such as TP53, NRAS, KRAS, and others. We believe that the clinical activity observed to date could support a broad expansion program covering multiple genotypes and disease stages in AML, both as monotherapy and in combination with other active agents."
In addition, clinical data for luxeptinib and APTO-253 were presented at ASH. The posters are now available on the presentations page of the Aptose website here.
Clinical data from luxeptinib in patients with relapsed or refractory B-cell malignancies and relapsed or refractory AML were presented in poster presentations on Saturday by lead investigators Felipe Samaniego, M.D., Professor in the Department of Lymphoma and Myeloma at MD Anderson Cancer Center, and Aaron Goldberg, M.D., Ph.D, from the Department of Medicine, Leukemia Service, Memorial Sloan-Kettering Cancer Center. In both of these Phase 1/2 studies, luxeptinib has been generally well tolerated at dose levels of 450, 600 and 750 mg BID over multiple cycles, and is currently being dosed in 900 mg BID cohorts in parallel. Target engagement of BTK and FLT3, and anti-tumor activity, including dose- and exposure-dependent tumor reductions, have been observed in multiple patients collectively between the studies, including in patients with FL, DLBCL, CLL/SLL, and AML. In parallel with the ongoing dose escalation of the current formulation of luxeptinib in patients with B-cell malignancies and AML, Aptose has made significant progress in the development of a "next generation" formulation that could reduce total API administered, reduce pill burden, improve absorption, and increase exposure. Aptose expects to begin testing this new formulation of luxeptinib in the ongoing studies in patients with hematologic malignancies in the first half of 2022.
Clinical data from APTO-253 were presented in a poster presentation on Monday at the 2021 American Society of Hematology (ASH) Annual meeting by lead investigator Maro Ohanian, D.O., Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. In an ongoing Phase 1a/b trial, APTO-253 has been well-tolerated in the patients treated at 20, 40, 66, 100, 150 and 210 mg/m2 over multiple cycles, supporting continued dose escalation. In parallel with the ongoing dose escalation of APTO-253, Aptose has started to explore strategic alternatives to support the further development of APTO-253 in hematologic malignancies and solid tumors.
"Drug resistance remains a tremendous challenge in hematologic malignancies, and we plan to leverage our growing bench of kinase inhibitors to tackle unmet needs across multiple indications and multiple disease genotypes. Our newest and most mature investigational drug, HM43239, is demonstrating activity against some of the most challenging AML genotypes and we look forward to continuing to advance it towards registration-enabling studies," said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer. "Luxeptinib also continues to show positive trends of activity in both B-cell cancers and AML. We look forward to bringing on a new formulation of Lux that may help increase exposure levels further, and potentially deliver faster and deeper anti-tumor activity in hematologic malignancies."