8-K: Aptose's Tuspetinib Triplet Shows Strong AML Data

Aptose Biosciences reported positive early data from its Phase 1/2 TUSCANY trial, showing high response and MRD-negativity rates for its tuspetinib-based triplet therapy in newly diagnosed AML patients.

Summary

• Aptose Biosciences provided an early data update from its Phase 1/2 TUSCANY trial for tuspetinib (TUS) in combination with venetoclax (VEN) and azacitidine (AZA) as a frontline therapy for newly diagnosed Acute Myeloid Leukemia (AML).
• The TUS+VEN+AZA triplet therapy demonstrated a 90% (9/10) overall Complete Response/Complete Response with Partial Hematological Recovery (CR/CRh) rate across all dose cohorts (40 mg, 80 mg, 120 mg TUS).
• At the 80 mg and 120 mg TUS dose levels, 100% CR/CRh rates were observed.
• The therapy achieved 70% (7/10) Measurable Residual Disease (MRD)-negativity among all subjects and 78% (7/9) among CR/CRh responders.
• Notably, 100% CR/CRh and MRD-negativity rates were achieved in patients with difficult-to-treat mutations including TP53, FLT3-ITD, and RAS mutations (5/5 patients).
• The treatment also showed 100% CR/CRh in FLT3 wildtype AML, which represents 70% of the AML population.
• No significant safety concerns, dose-limiting toxicities (DLTs), prolonged myelosuppression, QTc prolongation, differentiation syndrome (DS), or treatment-related deaths have been observed across all dose cohorts.
• Nine out of ten dosed patients remain on study, and enrollment is advancing to the 160 mg TUS dose level.
• The trial was initiated in December 2024 and is being conducted at 10 leading U.S. clinical sites.

Sentiment

Score: 9

Explanation: The filing presents highly positive early clinical data for a novel triplet therapy in AML, showing superior efficacy (CR/CRh and MRD-negativity rates) and a favorable safety profile compared to existing standard of care, particularly in difficult-to-treat patient populations. This strong clinical performance indicates significant potential for the drug.

Positives

• Achieved 90% overall CR/CRh rate (9/10 patients) with the TUS+VEN+AZA triplet therapy.
• Demonstrated 100% CR/CRh rates at the 80 mg and 120 mg TUS dose levels.
• Showed high MRD-negativity rates: 70% among all subjects and 78% among CR/CRh responders.
• Achieved 100% CR/CRh and MRD-negativity in patients with adverse TP53, FLT3-ITD, and RAS mutations (5/5 patients), which are typically difficult to treat.
• Observed 100% CR/CRh in FLT3 wildtype AML, a large segment of the AML population.
• Maintained an excellent safety profile with no significant safety concerns, DLTs, prolonged myelosuppression, QTc prolongation, differentiation syndrome, or treatment-related deaths.
• No relapses reported to date and no loss of MRD-negativity observed, including in one patient with over 7 months of follow-up.
• The therapy appears to achieve complete responses more quickly at higher dose levels of TUS.

Negatives

• The only non-responder was a patient at the initial 40 mg TUS dose level who did not achieve TUS exposures previously associated with response, indicating potential sub-optimal dosing at the lowest level.

Risks

• Ability to obtain the capital required for research and operations and to continue as a going concern.
• Inherent risks in early stage drug development, including demonstrating efficacy.
• Development time/cost and the regulatory approval process.
• The progress of clinical trials.
• Ability to find and enter into agreements with potential partners.
• Ability to attract and retain key personnel.
• Changing market conditions.
• Inability of new manufacturers to produce acceptable batches of GMP in sufficient quantities.
• Unexpected manufacturing defects.

Future Outlook

Enrollment in the TUSCANY trial is advancing to the 160 mg TUS dose level. The company anticipates enrolling 18-24 patients by late 2025 and will release additional data as it becomes available. The goal is to establish TUS+VEN+AZA as an improved, durable, and well-tolerated frontline therapy for diverse AML populations.

Management Comments

• "We already have data from three different TUS dose levels in the TUSCANY trial, and the data continue to strengthen at higher doses of TUS and over time. We are building a strong case for TUS+VEN+AZA as a triplet frontline therapy of choice to address a broad AML population, including subgroups with the most adverse of mutations." William G. Rice, Ph.D., Chairman, President and Chief Executive Officer of Aptose.
• "As illustrated in the data highlights, the addition of TUS to VEN+AZA appears to boost response rates and MRD-negativity while maintaining favorable safety and tolerability, and the 100% CR/CRh and 100% MRD-negativity rates among the five biallelic TP53-mutant, FLT3-ITD, and RAS-mutant AML cases are exciting to see, as this can correlate with longer overall survival. We have observed a trend towards achieving CRs more quickly at the higher dose levels, so we are keen to see the activity as we advance into the 160 mg TUS dose cohort." Rafael Bejar, M.D., Ph.D., Chief Medical Officer of Aptose.

Industry Context

The announcement relates to the development of a frontline therapy for newly diagnosed AML patients who are ineligible for induction chemotherapy. The TUS+VEN+AZA triplet aims to be a mutation-agnostic treatment, addressing a broad and mutationally diverse AML population. This positions it as a potential improvement over existing standard-of-care treatments like VEN+AZA alone, particularly for patients with difficult-to-treat mutations.

Comparison to Industry Standards

• The TUS+VEN+AZA triplet achieved a 90% CR/CRh rate across all subjects, compared to 65% for VEN+AZA alone (DiNardo et al., 2020).
• For NPM1-mutant AML, TUS+VEN+AZA showed 100% CR/CRh (2/2), compared to 67% for VEN+AZA.
• In FLT3-ITD mutated AML, TUS+VEN+AZA achieved 100% CR/CRh (2/2), significantly higher than 61% for VEN+AZA.
• For TP53-mutant AML, TUS+VEN+AZA demonstrated 100% CR/CRh (2/2), a substantial improvement over 52% for VEN+AZA.
• MRD-negativity rates among all subjects were 70% for TUS+VEN+AZA, compared to 23.4% for VEN+AZA (Pratz et al., 2021).
• Among CR/CRh responders, MRD-negativity was 78% for TUS+VEN+AZA, versus 40.9% for VEN+AZA.
• For 'Intermediate Benefit' patients (FLT3-ITD or RAS-mutated), TUS+VEN+AZA achieved 100% MRD-negativity (3/3), compared to 27.9% for VEN+AZA (Döhner et al., 2024).
• For 'Lower Benefit' patients (TP53-mutated), TUS+VEN+AZA achieved 100% MRD-negativity (2/2), compared to 14.5% for VEN+AZA.

Stakeholder Impact

• **Patients:** Potential for a more effective and safer frontline treatment option for newly diagnosed AML, especially for those ineligible for induction chemotherapy and those with adverse mutations, potentially leading to better outcomes and extended survival.
• **Shareholders:** Positive clinical data could significantly increase the company's valuation and investor confidence, given the large unmet medical need in AML.
• **Medical Community:** The data suggests a promising new therapeutic approach for AML, potentially influencing future treatment guidelines and research directions.
• **Competitors:** The strong efficacy data, particularly in difficult-to-treat populations, could pose a competitive challenge to existing AML therapies and those in development.

Next Steps

• Advance enrollment to the 160 mg TUS dose level in the TUSCANY trial.
• Continue enrolling patients in the TUSCANY trial, with an anticipated 18-24 patients by late 2025.
• Release additional data from the TUSCANY trial as it becomes available.

Key Dates

Recommendation

The early Phase 1/2 data for tuspetinib in combination with venetoclax and azacitidine in newly diagnosed AML is exceptionally strong, demonstrating significantly higher CR/CRh and MRD-negativity rates compared to the current standard of care, particularly in high-risk patient populations. The excellent safety profile observed to date further de-risks the program. Given the large unmet need in AML and the potential for this triplet therapy to become a new frontline standard, these results indicate substantial future value creation for Aptose Biosciences. The progression to higher dose cohorts and continued enrollment suggest a robust development path.

Keywords

AML, Acute Myeloid Leukemia, Tuspetinib, TUSCANY trial, Oncology, Precision medicine, Clinical trial, Hematology, Biotechnology, Venetoclax, Azacitidine