On December 13, 2023 Shattuck Labs, Inc. (Shattuck) (NASDAQ: STTK), a clinical-stage biotechnology company pioneering the development of bi-functional fusion proteins as a new class of biologic medicine for the treatment of patients with cancer and autoimmune disease, reported initial topline dose-expansion data from its ongoing Phase 1A/B clinical trial of SL-172154 in combination with AZA in frontline HR-MDS and TP53m AML patients (Press release, Shattuck Labs, DEC 13, 2023, View Source [SID1234638533]). Initial data from the dose-expansion cohorts build on the complete dose-escalation data featured in a poster presentation on December 11, 2023 at the 65th ASH (Free ASH Whitepaper) Annual Meeting.
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"Both the frontline HR-MDS and TP53m AML expansion cohorts enrolled quickly after completion of the dose escalation study in the middle of this year, and we are pleased to share initial efficacy data, which begin to demonstrate the activity of SL-172154 beyond what is expected of AZA alone. In dose escalation, we saw a monotherapy response to SL-172154 in a heavily pre-treated relapsed/refractory (R/R) TP53m AML patient that allowed the patient to receive a stem cell transplant. That patient remains disease free." said Dr. Lini Pandite, MBChB, M.B.A., Chief Medical Officer of Shattuck. "In frontline, the rate of complete responses in both the HR-MDS and TP53m AML cohorts is already encouraging, and when coupled with the observation of peripheral blood count recovery in most patients that have not yet achieved a complete response, and the fact that many of these patients are very early in their course of treatment and have not yet reached the median time at which a complete response is expected for azacitidine, suggests that the complete response rate may continue to improve in the coming months. As a result, we have amended both studies to increase the sample size and look forward to providing another update by mid-year 2024."
Phase 1B Trial of SL-172154 in Frontline TP53m AML and HR-MDS
Key takeaways: Early efficacy observed for SL-172154 in combination with AZA in previously untreated HR-MDS and TP53m AML:
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HR-MDS: In 14 evaluable patients with previously untreated HR-MDS (13 of whom had TP53m or deletion), five patients achieved a CR. Four patients achieved a mCR (3 with hematologic improvement in at least one lineage), and two patients achieved stable disease (both with hematologic improvement in at least one lineage).
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TP53m AML: In 11 evaluable patients with previously untreated TP53m AML, two patients achieved a CR. Another patient achieved a CRi and was taken to allogeneic hematopoietic cell transplantation (allo-HCT). Seven additional subjects with stable disease had blast reductions, five of which had recovery of platelets or neutrophils and remain on study and their response may improve. One subject died during the first cycle.
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Safety: Preliminary data suggest that SL-172154 has an acceptable safety and tolerability profile in combination with azacitidine.
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Data Overview: As of the data cut-off date of December 1, 2023, 14 frontline patients enrolled in the TP53m AML cohort, and 22 frontline patients enrolled in the HR-MDS cohort. Initial enrollment was completed in the fourth quarter of 2023 and Shattuck has elected to expand the cohorts with additional data expected mid-year 2024.
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Preliminary signs of anti-tumor activity: Early signals of activity, in the form of rapid blast count reductions, were observed in 100% of frontline TP53m AML patients treated with SL-172154 in combination with AZA who received an on-treatment bone marrow biopsy. Most patients in the HR-MDS cohort showed blast count reductions with hematologic improvement early in the treatment course.
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SL-172154 had an acceptable safety and tolerability profile: Infusion-related reactions (IRRs) were the most common SL-172154 related treatment-emergent adverse events (TEAEs).
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In the TP53m AML and HR-MDS cohorts, IRRs were reported in seven patients (50%) and seven patients (32%) respectively.
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Grade 3 or 4 AEs related to SL-172154 were reported in two patients (14%) in TP53m AML and four patient (18%) in HR-MDS, including IRR (2), increased AST (1), increased ALT (1), fatigue (1), hypoxia (1), pneumonia (1), chondrocalcinosis (1), and febrile neutropenia (1). There were no reports of destructive anemia.
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In the TP35m AML expansion cohort, there was one Grade 5 AE of cardiac arrest reported in one patient with history of coronary artery disease, recent arrhythmia, and hypokalemia in the setting of amiodarone use. In the HR-MDS cohort, there were no Grade 5 AEs related to SL-172154 reported.
Phase 1A Trial of SL-172154 in R/R AML and HR-MDS and Frontline TP53m HR-MDS
A copy of the ASH (Free ASH Whitepaper) presentation, titled "Safety, Pharmacodynamic, and Anti-Tumor Activity of SL-172154 as Monotherapy and in Combination with Azacitidine (AZA) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes/neoplasms (HR-MDS) Patients (pts)," is accessible under posters in the "Our Science" section of Shattuck’s website.
Key takeaways: Anti-tumor responses were observed as monotherapy and in combination with AZA. SL-172154 alone and in combination with AZA had an acceptable safety profile, consistent with the safety profile of the individual agents (see SL-172154 safety above). No destructive anemia was observed.
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Data Overview: As of the data cut-off date of September 15, 2023, 32 adult patients with R/R AML and HR-MDS received SL-172154 as monotherapy or in combination with AZA in the parallel staggered dose-escalation portion of a Phase 1A/B clinical trial. Patients had a median of two prior lines of therapy. An additional five subjects with frontline TP53m HR-MDS received SL-172154 with AZA.
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Preliminary signs of anti-tumor activity: Monotherapy response in a R/R AML patient and early signals of anti-leukemic activity (in the form of blast count reductions) in patients with R/R AML who received SL-172154 in combination with AZA were observed in a dose-dependent manner.
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SL-172154 monotherapy activity (Morphologic Leukemia-Free State) was observed in a heavily pretreated R/R AML patient and subsequently proceeded to allo-HCT.
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Patient achieved MLFS (blast reduction from 19% to <5%) after one cycle of SL-172154.
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Anti-tumor activity was also observed in combination with AZA in previously untreated TP53m HR-MDS patients. Out of four evaluable previously untreated TP53m HR-MDS patients, there was one CR and one mCR. One patient with mCR and one patient with SD proceeded to allo-HCT. The patient in a CR remains in a CR long term.
Conference Call at 8:00 a.m. ET Today
Shattuck will host a conference call today at 8:00 a.m. ET featuring key opinion leader Dr. Naval Daver, MD, (Professor, Director Leukemia Research Alliance Program, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX) to present the initial data from the frontline expansion cohorts in HR-MDS and TP53m AML. Additionally, a review of data from the poster presentation featured at the 65th ASH (Free ASH Whitepaper) Annual Meeting will be discussed. To listen to the live webcast, please visit the Investor Relations page of the Shattuck Labs website here. Participants may register for the call here. While not required, interested participants are encouraged to join 10 minutes prior to the start of the event.
A replay of the webcast will be available following the conclusion of the live call and will be accessible on the Company’s website.
About SL-172154
SL-172154 (SIRPα-Fc-CD40L) is an investigational ARC fusion protein designed to simultaneously inhibit the CD47/SIRPα checkpoint interaction and activate the CD40 costimulatory receptor to bolster an anti-tumor immune response in patients with advanced cancer. Multiple Phase 1 clinical trials are ongoing for patients with PROC (NCT04406623, NCT05483933) and patients with AML and HR-MDS (NCT05275439).