Dr. Rafael Bejar reports

APTOSE PRESENTS HIGHLIGHTS FROM CLINICAL UPDATE WEBCAST FEATURING LATEST AVAILABLE DATA ON AML DRUG TUSPETINIB

Aptose Biosciences Inc. has released highlights from a clinical update event held today, Oct. 30, 2023, in conjunction with the European School of Haematology's (ESH) sixth international conference: Acute Myeloid Leukemia "Molecular and Translational": Advances in Biology and Treatment, being held in Estoril, Portugal.

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, Tex. 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 resensitizing VEN-resistant cells to VEN when given in combination. TUS/VEN may safely and successfully treat these VEN failures, as the company has already 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 per cent 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 continuing Aptivate study of tuspetinib:

Patient enrolment:

• 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 Oct. 23, 2023), and patients continue being enrolled.

Safety profile

In the most recent data cut (Oct. 23, 2023), the favourable 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 (milligram) 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 per cent and 60 per cent CR/CRh response rates across all patients and across FLT3-mutated patients, respectively, among evaluable VEN-naive patients at the 80 mg daily recommended phase 2 dose (RP2D);
• Tuspetinib demonstrated a 29-per-cent CR/CRh rate in VEN-naive FLT3 unmutated (wildtype) AML at 80 mg daily RP2D, unlocking the potential for TUS to treat the additional 70 per cent to 75 per cent 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 favourably with gilteritinib FLT3 inhibitor.

TUS/VEN doublet (TUS 80 mg/VEN 400 mg):

• Patients who have failed venetoclax treatment represent an increasing AML population in need of improved salvage therapies:
  • Over 90 per cent of recent United States 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 resensitize prior VEN failures to venetoclax (see poster presented at the ESH 2023 conference on-line).

Overall response rates (ORR) with TUS/VEN doublet (see the associated table, includes recent preliminary responses):

• 31 evaluable patients showed an ORR of 48 per cent (15 of 31);
• 81 per cent (25 of 31) of patients were VEN failures;
• 44-per-cent ORR (11 of 25) in VEN failures;
• 60-per-cent ORR (six of 10) in FLT3-mutant;
• 43-per-cent ORR (nine of 21) in FLT3-wildtype;
• Most patients are very early in treatment, having initiated dosing in the past two weeks to six weeks, and responses are expected to mature over time.

Multiple planned value-creating milestones ahead:

• TUS/VEN incremental data readout in R/R AML planned: ASH 2023;
• TUS/VEN further data on duration of response in R/R AML planned: Q1 and Q2 2024;
• TUS/VEN/HMA planned initiation of pilot triplet study in 1L AML: H1 2024;
• Extension into HR-MDS and CMML planned: Q4 2023.

The associated slides from the presentation are available on Aptose's website. The webcast of the presentation will be archived on-line.

About Aptose Biosciences Inc.

is a clinical-stage biotechnology company committed to developing precision medicines addressing unmet medical needs in oncology, with an initial focus on hematology. The company's small-molecule cancer therapeutics pipeline includes products designed to provide single-agent efficacy and to enhance the efficacy of other anti-cancer therapies and regimens without overlapping toxicities. The company has two clinical-stage oral kinase inhibitors under development for hematologic malignancies: tuspetinib (HM43239), an oral, myeloid kinase inhibitor being studied as monotherapy and in combination therapy in the Aptivate international phase 1/2 expansion trial in patients with relapsed or refractory acute myeloid leukemia (AML); and luxeptinib (CG-806), an oral, dual lymphoid and myeloid kinase inhibitor in phase 1 a/b development for the treatment of patients with relapsed or refractory hematologic malignancies.

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