SL-172154 Earns FDA Orphan Drug Status in Acute Myeloid Leukemia

Investigators are currently assessing treatment with SL-172154 in combination with azacitidine for patients with higher-risk myelodysplastic syndrome (MDS) and AML harboring TP53 mutations as part of a phase 1a/1b clinical trial (NCT05275439).

The FDA has granted orphan drug designation to the investigational ARC fusion protein SL-172154 as a treatment for patients with acute myeloid leukemia (AML), according to a press release from the developer, Shattuck Labs, Inc.¹

SL-172154 is designed as a bi-functional fusion protein targeting CD47 expressed in malignant cells and CD40, which is seen in antigen-presenting cells.² The agent may block the CD47 axis through Sirpa binding, thereby coating the tumor cell surfaces with the ARC and allowing the CD40L side to bind to CD40 on the immune cells. This binding process then facilitates enhanced antigen presentation to CD8-positive and CD4-positive T lymphocytes and tumor cell phagocytosis via the antigen-presenting cell.

“[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 at Shattuck, said in the press release.¹

Investigators are currently assessing treatment with SL-172154 in combination with azacitidine for patients with higher-risk myelodysplastic syndrome (MDS) and AML harboring TP53 mutations as part of a phase 1a/1b clinical trial (NCT05275439). According to Schreiber, additional findings from the phase 1b dose-expansion portion of the trial will be presented in a poster session at the 2024 European Hematology Association (EHA) Congress.

In the open-label, multicenter trial, investigators are evaluating the preliminary activity, pharmacokinetics, and safety of SL-172154 administered as monotherapy or as part of various combination regimens.³ Patients will first receive SL-172154 intravenously by itself, SL-172154 plus intravenous azacitidine, or SL-172154 plus azacitidine and venetoclax (Venclexta) orally.

In part D of the trial, investigators will further assess the safety and efficacy of SL-172154 among approximately 60 patients with previously untreated higher-risk MDS. Patients included in part D will be assigned to one of 3 groups: SL-172154 at 3 mg/kg plus azacitidine, SL-172154 at 1 mg/kg plus azacitidine, or azacitidine only.

The trial’s primary end points include the safety and tolerability of SL-172154 as well as a recommended phase 2 dose. Secondary end points include the antitumor activity, immunogenicity, maximum serum concentration, and volume of distribution.

Patients 18 years and older with confirmed AML or morphologically confirmed MDS per 2016 World Health Organization criteria are eligible for enrollment on the trial. Additional eligibility criteria include having an ECOG performance status of 0 or 2, availability of bone marrow aspirate samples at baseline and during treatment for exploratory research, and recovery from prior anti-cancer therapy in the case of relapsed/refractory disease.

Those with active central nervous system (CNS) involvement with leukemia or who require treatment with agents apart from hydroxyurea to manage blast counts within 14 days of beginning study treatment are ineligible for enrollment. Patients are also unsuitable for study entry if they have receipt of a live attenuated vaccine within 30 days of beginning treatment with SL-172154, evidence of active bleeding or bleeding diathesis, clinically significant or uncontrolled cardiac disease, or major surgery within 14 days of beginning treatment.

Investigators are also evaluating treatment with SL-172154 for patients with platinum-resistant ovarian cancer as part of a phase 1b study (NCT05483933). In this trial, patients will be assigned to receive SL-172154 in combination with pegylated liposomal doxorubicin or mirvetuximab soravtansine-gynx (Elahere).⁴

The trial’s primary end points include the safety and tolerability of SL-172154 and a recommended phase 2 dose when administered in combination with pegylated liposomal doxorubicin or mirvetuximab soravtansine. Secondary end points include overall response rate per RECIST v1.1 criteria and immunogenicity.

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 11, 2024. https://tinyurl.com/ys944stn
2. Pipeline: SL-172154. Shattuck Labs, Inc. Accessed June 11, 2024. https://tinyurl.com/mkkt7urm
3. Phase 1 study of Shattuck Labs (SL)-172154 in subjects with MDS or AML. ClinicalTrials.gov. Accessed June 11, 2024. https://tinyurl.com/bdcm8ytj
4. Phase 1b study of SL-172154 administered with combination agent(s) in subjects with ovarian cancers. ClinicalTrials.gov. Accessed June 11, 2024. https://tinyurl.com/mwfuahk2