SL-172154 Receives FDA Orphan Drug Designation in AML

Taylor Schreiber, MD, PhD

The FDA has granted orphan drug designation to SL-172154 as a potential therapeutic option for patients with acute myeloid leukemia (AML).¹

“[Patients with] AML have few options for treatment and a poor prognosis. [The] FDA’s decision to grant orphan drug designation to SL-172154 highlights the urgent need for new treatment options,” Taylor Schreiber, MD, PhD, chief executive officer of Shattuck Labs, stated in a news release. “This is an important first step in our progression to later-stage clinical studies, and we look forward to presenting additional data from the phase 1B dose expansion clinical trial [NCT05275439] of SL-172154 with azacitidine in [patients with] frontline higher-risk myelodysplastic syndromes and TP53-mutated AML during a poster presentation at the 2024 European Hematology Association Congress.”

SL-172154 is an investigational ARC fusion protein that inhibits the checkpoint interaction of CD47/SIRPα and activates the CD40costimulatory receptor. The agent is designed to boost the antitumor immune response in patients with advanced cancer.

SL-172154 is being evaluated as monotherapy and in combination with azacitidine (Vidaza) with or without ventoclax (Venclexta) in patients with AML and higher-risk myelodysplastic syndrome (MDS) in a phase 1a/b study. During the dose-escalation phase 1a portion of the study, patients needed to have relapsed/refractory AML or higher-risk MDS who received 1 but no more than 4 prior therapies. Specifically, those with MDS needed to have intermediate-, high-, or very high–risk disease per the International Prognostic Scoring System in order to be included in dose escalation.²

In dose expansion during phase 1b, investigators enrolled patients with previously untreated AML harboring TP53 mutations and previously untreated higher-risk MDS.

During phase 1a/b, SL-172154 was given intravenously on days 1, 8, 15, and 22 of each 28-day cycle. Azacitidine was administered at 75 mg/m² intravenously or subcutaneously once daily on days 1 through 7 or via a 5-2-2 dosing schedule. Following the dose-escalation portion, 3 mg/kg was selected as the dose of SL-172154 for the dose-expansion portion.

The co-primary end points were safety and selecting the recommended phase 2 dose for SL-172154 with azacitidine plus venetoclax. Secondary end points included preliminary antitumor activity and pharmacokinetics of SL-172154, both as monotherapy and as a combination component.³

Preliminary findings from the dose-expansion portion of the study demonstrated that all response-evaluable patients with TP53-mutated AML treated with SL-172154 plus azacitidine in the frontline setting (n = 11) achieved rapid blast reduction compared with baseline upon bone marrow assessment. Additionally, 3 patients achieved a complete response or a complete response with incomplete count recovery, and 7 more patients experienced stable disease.²

In the safety population (n = 14), most patients experienced an any-grade adverse effect (AE; 93%) and 50% experienced an infusion-related reaction. Other any-grade AEs reported in more than 15% of patients with TP53-mutated AML included constipation (36%), febrile neutropenia (36%), diarrhea (21%), and insomnia (21%). Two patients experienced grade 3 or 4 AEs that were possibly related to SL-172154. One patient—who had a history of coronary artery disease, recent arrhythmia, and hypokalemia in the setting of amiodarone use—experienced grade 5 cardiac arrest that was deemed a serious AE. Notably, there was no evidence of hemolytic anemia observed in any patients

Additional data from the phase 1b portion of the study evaluating SL-172154 in combination with azacitidine in patients with previously untreated TP53-mutated AML and higher-risk MDS are expected to be reported in the middle of 2024.

SL-172154 is also being examined in multiple phase 1 clinical trials for the treatment of patients with platinum-resistant ovarian cancer. The agent is being evaluated both as monotherapy (NCT04406623) and in combination with pegylated liposomal doxorubicin or mirvetuximab (NCT05483933).¹

References

1. Shattuck Labs announces orphan drug designation granted by the U.S. Food and Drug Administration (FDA) for SL-172154 for the treatment of acute myeloid leukemia (AML). News release. Shattuck Labs, Inc. June 10, 2024. Accessed June 10, 2024. https://ir.shattucklabs.com/investors/news-events/press-releases/news-details/2024/Shattuck-Labs-Announces-Orphan-Drug-Designation-Granted-by-the-U.S.-Food-and-Drug-Administration-FDA-for-SL-172154-for-the-Treatment-of-Acute-Myeloid-Leukemia-AML/default.aspx
2. Corporate overview. Shattuck Labs. May 2, 2024. Accessed June 10, 2024. https://s201.q4cdn.com/893592767/files/doc_presentations/2024/May/02/shattuck-labs_corporate-presentation_may-2-2024_vf.pdf
3. Phase 1 study of Shattuck Labs (SL)-172154 in subjects with MDS or AML. ClinicalTrials.gov. Updated March 26, 2024. Accessed June 10, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05275439