Shattuck Labs Reports Positive Interim Data from Phase 1B Trial of SL-172154 with Azacitidine in HR-MDS & TP53 Mutant AML

Shattuck Labs, Inc., a clinical-stage biotechnology firm specializing in bifunctional fusion proteins, recently shared exciting interim data from their Phase 1B dose expansion trial of SL-172154 combined with azacitidine (AZA). This trial targets patients with higher-risk myelodysplastic syndromes (HR-MDS) and TP53-mutated acute myeloid leukemia (AML). The announcement was made during the European Hematology Association 2024 Congress.

The data indicated promising efficacy in HR-MDS patients, particularly those with TP53 mutations. In this group, an Objective Response Rate (ORR) of 67% was observed, with a 58% rate of initial complete remission (CR) or marrow complete remission (mCR). As of the latest data, the median overall survival had not been reached. Furthermore, 43% of frontline TP53m AML patients responded to the treatment, with a 33% rate of CR or complete remission with incomplete hematologic recovery (CRi). Here, too, the median overall survival remains undetermined.

The safety profile of SL-172154 in combination with AZA was deemed manageable. Infusion-related reactions (IRRs) were noted as the most common adverse events, but no grade 3 or higher IRRs occurred when patients were premedicated with dexamethasone. No evidence of destructive anemia was reported. In the HR-MDS cohort, 42% of patients experienced grade 3 or 4 adverse events likely related to the treatment, with three treatment discontinuations and one death due to sepsis, which was considered unrelated to SL-172154. For the TP53m AML cohort, 33% of patients reported grade 3 or 4 adverse events related to the treatment, with three deaths due to conditions not linked to SL-172154.

The interim results also revealed encouraging biomarker data. Four out of five HR-MDS patients and two out of four TP53m AML patients who achieved complete remission showed clearance of TP53 mutations. These findings suggest a significant pharmacodynamic effect of CD40 activation in peripheral blood, potentially correlating with clinical remission.

Shattuck's focus now lies in further developing SL-172154 for HR-MDS and TP53m AML, given the lack of current treatment options and the potential for quick regulatory approval. Enrollment for a randomized, controlled trial in HR-MDS is already underway, with plans for regulatory discussions later this year to finalize the registrational strategy for SL-172154.

Despite promising results in ovarian cancer (PROC) treatment with SL-172154, Shattuck has decided not to further pursue this avenue due to the competitive landscape, although they will continue to monitor progression-free and overall survival in treated patients. Their primary focus will remain on advancing the treatment of AML and HR-MDS.

These updates highlight SL-172154's potential as a leading CD47 inhibitor in hematologic malignancies, emphasizing its differentiated mechanism of action and potential for rapid clinical progress. This breakthrough could represent a significant step forward in the treatment of high-risk blood cancers, offering new hope for patients with limited options.