On October 30, 2023 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated oral kinase inhibitors to treat hematologic malignancies, reported highlights from a clinical update event held today, October 30, 2023, in conjunction with the European School of Haematology (ESH) 6th International Conference: Acute Myeloid Leukemia "Molecular and Translational": Advances in Biology and Treatment, being held in Estoril, Portugal (the "ESH 2023 Conference") (Press release, Aptose Biosciences, OCT 30, 2023, View Source [SID1234636427]).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The webcast event featured a comprehensive review of up-to-date clinical data for Aptose’s lead compound tuspetinib (TUS) by Rafael Bejar, MD, PhD, Aptose’s Chief Medical Officer, and featured Naval G. Daver, MD, Professor, Director Leukemia Research Alliance Program, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX. Dr. Daver is the lead investigator on Aptose’s APTIVATE trial of tuspetinib and is recognized for significant achievements in the development of novel acute myeloid leukemia (AML) treatments, including several combination therapies.
Tuspetinib (TUS) is a once-daily, oral, precision targeted kinase inhibitor that suppresses select kinases that drive the proliferation of AML. These key kinase targets include the SYK, FLT3, JAK1/2, mutant forms of KIT, RSK2, and the TAK1-TAB1 kinases operative in AML, while other kinases are avoided to promote safety.
AML care has shifted toward venetoclax (VEN) containing combination regimens and a new population of difficult-to-treat VEN relapsed patients ("VEN failures") is emerging. Tuspetinib’s safety, activity, mechanism of action, and convenient dosing make it ideal for combination therapy. Importantly, TUS directly targets VEN resistance mechanisms (suppresses mutated FLT3, mutated KIT, SYK and mutated JAK1/2 of the JAK/STAT pathway, RSK2 of the RAS/MAPK pathway, key oncogenic growth and proliferation signals, and MCL-1 expression). This means that TUS targets pathways and may lead to re-sensitizing VEN-resistant cells to VEN when given in combination. TUS/VEN may safely and successfully treat these VEN failures, as we already have observed clinically, and an accelerated approval path may be available for VEN failure relapsed or refractory (R/R) AML patients treated with TUS/VEN.
"We are really pleased by our growing safety and efficacy data on tuspetinib in very difficult-to-treat AML patient populations," said Dr. Bejar. "This includes activity in FLT3-unmutated patients, a population that accounts for more than 70% of AML and has few effective treatment options. Additionally, tuspetinib’s significant activity in patients who have failed venetoclax treatment – a rapidly-emerging population of particularly high unmet medical need – provides a clear development pathway for tuspetinib with the potential for accelerated approval."
"The safety and efficacy data we’ve seen with the tuspetinib/venetoclax combination is very encouraging, suggesting that tuspetinib may effectively treat the large number of VEN failures we are seeing frequently in our clinics," said Dr. Daver. "Data from the TUS/VEN doublet gives us confidence to move tuspetinib forward into a TUS/VEN/HMA triplet for the treatment of frontline newly-diagnosed AML patients. Tuspetinib is an exciting agent, and I am happy to be part of the clinical development team."
Clinical Findings
Aptose provided updated clinical findings from the ongoing APTIVATE study of tuspetinib:
Patient Enrollment
More than 140 patients have been treated with tuspetinib to date
91 patients have received TUS as a single agent
Aptose anticipated dosing up to 30 patients with TUS/VEN by the ESH 2023 Conference; however, investigator enthusiasm resulted in dosing of 49 patients (as of October 23, 2023), and patients continue being enrolled
Safety Profile
In the most recent data cut (October 23, 2023), the favorable safety profile remained consistent for TUS and TUS/VEN treated R/R AML patients:
No TUS related adverse events (AEs) of QTc prolongation
No observed differentiation syndrome
No TUS related non-hematologic serious AEs
No TUS related deaths
No rhabdomyolysis or AEs of elevated creatine phosphokinase (CPK)
No TUS related dose-limiting toxicities (DLT) from 20 mg level through 160 mg level
One DLT of muscle weakness at 200 mg
Occurred in patient with high exposure
Not rhabdomyolysis │ No muscle destruction
Avoids many typical toxicities observed with other FLT3, IDH1/2, and menin inhibitors
In TUS/VEN doublet, no unexpected or new safety signals were observed
Tuspetinib Single Agent
Tuspetinib as a single agent was well-tolerated and highly active among relapsed or refractory (R/R) AML patients with a diversity of adverse genotypes. TUS single agent delivered 42% and 60% CR/CRh response rates across all patients and across FLT3-mutated patients, respectively, among evaluable VEN-naïve patients at the 80mg daily recommended phase 2 dose (RP2D)
Tuspetinib demonstrated a 29% CR/CRh rate in VEN-naïve FLT3 unmutated (wildtype) AML at 80 mg daily RP2D, unlocking the potential for TUS to treat the additional 70-75% of the AML population without FLT3-mutation not currently addressed by any approved tyrosine kinase inhibitors
Responses were achieved across four dose levels
Responses were shown to mature over time with sustained blood count recovery during continuous dosing
Several responders were bridged to potentially lifesaving transplant (HSCT)
Durability was observed when HSCT was unavailable
Tuspetinib single agent response rates compare favorably to gilteritinib FLT3 inhibitor
TUS/VEN Doublet (TUS 80mg/VEN 400mg)
Patients who have failed venetoclax treatment represent an increasing AML population in need of improved salvage therapies
Over 90% of recent U.S. patients enrolled in the APTIVATE trial were VEN failures
VEN resistance involves mutations in multiple pathways to evade BCL-2 blockade
Tuspetinib directly targets pathways involved in VEN resistance
By shutting down these pathways, tuspetinib appears to re-sensitize prior-VEN failures to venetoclax (see poster presented at the ESH 2023 Conference here)
Overall Response Rates (ORR) with TUS/VEN Doublet (see Table below, includes recent preliminary responses)
31 evaluable patients showed an ORR 48% (15 of 31)
81% (25 of 31) of patients were VEN failures
44% ORR (11 of 25) in VEN failures
60% ORR (6 of 10) in FLT3-mutant
43% ORR (9 of 21) in FLT3-wildtype
Most patients are very early in treatment, having initiated dosing in the past 2-6 weeks, and responses are expected to mature over time
Overall Response Rates
Patient Population Aug 1, 2023
10 patients evaluable
of 15 dosed Sep 1, 2023
15 patients evaluable
of 26 dosed Oct 23, 2023
31 patients evaluable
of 49 dosed
Prior-VEN Failures 44% (4 of 9) 38% (5 of 13) 44% (11 of 25)
FLT3-Mutant 67% (2 of 3) 67% (4 of 6) 60% (6 of 10)
FLT3-Wildtype 43% (3 of 7) 33% (3 of 9) 43% (9 of 21)
Overall 50% (5 of 10) 47% (7 of 15) 48% (15 of 31)
Response Types 1CR│3CRi│1CRp 1CR│6CRi 2CR│7CRi│6PR
Multiple Planned Value-creating Milestones Ahead
TUS/VEN incremental data readout in R/R AML planned: ASH (Free ASH Whitepaper) 2023
TUS/VEN further data on duration of response in R/R AML planned: 1Q & 2Q2024
TUS/VEN/HMA planned initiation of pilot triplet study in 1L AML: 1H2024
Extension into HR-MDS and CMML planned: 4Q2023
The associated slides from the presentation are available on Aptose’s website here. The webcast of the presentation will be archived here.