SL-172154 Receives FDA Orphan Drug Designation in AML


Key Takeaways

  • SL-172154 received orphan drug designation for AML, highlighting the need for new treatment options.
  • SL-172154 inhibits CD47/SIRPα and activates CD40, boosting antitumor immune response.
Taylor Schreiber, MD, PhD

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


  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.
  2. Corporate overview. Shattuck Labs. May 2, 2024. Accessed June 10, 2024.
  3. Phase 1 study of Shattuck Labs (SL)-172154 in subjects with MDS or AML. Updated March 26, 2024. Accessed June 10, 2024.
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