SL-172154: Brief Review of its R&D Progress and the Clinical Result in 2023 ASH

In 2023 ASH, the 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) will be reported orally.

SL-172154's R&D Progress

The drug SL-172154 is a fusion protein that targets CD40 and CD47. Fusion proteins are a type of therapeutic agent that combines two or more proteins to create a new molecule with enhanced therapeutic properties. The therapeutic areas targeted by SL-172154 include neoplasms (abnormal growth of cells), digestive system disorders, endocrinology and metabolic diseases, hemic and lymphatic diseases, and urogenital diseases. 

Currently, the drug is in Phase 1 of clinical development, which means it is being tested in a small group of patients to evaluate its safety and dosage. And the clinical trial areas for SL-172154 are primarily in the United States, United Kingdom, and Canada. The key indication is Acute Myeloid Leukemia and Myelodysplastic Syndromes. .

Detailed Clinical Outcome of SL-172154

The objectives of this dose escalation cohorts include evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic effects and efficacy per IWG 2006 for MDS and ELN 2017 for AML.

In this study, SL-172154 was administered IV weekly of a 28-day cycle as monotherapy or with AZA 75 mg/m2 for 7 days per cycle. mTPI-2 was used for dose escalation with a DLT threshold of 20%. Pts ≥ 18 years old with R/R HR-MDS or R/R AML were eligible for dose escalation cohorts. In addition, UnTx pts with TP53 mutant (TP53m)-MDS were eligible for SL-AZA cohorts.

The result showed that Infusion-related reactions (IRRs) were the most common SL-172154-related treatment-emergent AEs (TEAEs) reported in 13 (68%) and 8 (44%) pts in SL-mono and SL-AZA cohorts, respectively. IRRs (51 events) were Grade (G) 1 or 2 except for 3 G3 events (1 each at 6 mg/kg SL-mono and SL-AZA; 1 at 3 mg/kg SL-mono). Other SL-172154-related TEAEs observed in ≥ 3 pts were AST increased (4; 21%), ALT increased (3; 16%) and nausea (3; 17%) in SL-mono cohorts, and nausea (3; 17%) in SL-AZA cohorts. All events of AST/ALT increased were transient. Only one DLT (G3 IRR in the 6 mg/kg SL-AZA cohort) was reported, which required a dose reduction to 3 mg/kg. As of July 10, 2023, in SL-mono cohorts, 1 pt with R/R AML post 7+3, FLAG and VEN/AZA achieved Morphologic Leukemia-Free State (blast reduction from 19% to <5%) after 1 cycle of 6 mg/kg SL-172154. In 12 evaluable pts with R/R AML receiving SL-AZA, although no objective responses (OR) were observed, relative reduction in bone marrow (BM) blasts from baseline was reported in 2/5 pts at 1 mg SL-AZA (-50%, -75%) and 5/7 pts at 3 mg SL-AZA (ranging from -35% to -90%). SL-172154 induced elevations in serum IL-12p40, IP-10, IL-8, IL-10, MIP3α and MCP1: greater response at 3 mg/kg compared to 1 mg/kg while similar between 3 and 6 mg/kg. 

It can be concluded that SL-172154 was well tolerated up to 3 mg/kg as monotherapy and in combination with AZA. Preliminary efficacy signals were detected in UnTx TP53m-MDS and R/R AML. A response to SL-172154 monotherapy, dose-dependent increases in serum cytokines and accumulation of mature myeloid cells in BM suggest a potential role for CD40 stimulation. Based on the safety, preliminary efficacy and pharmacodynamic activity, 3 mg/kg SL-172154+ AZA is being evaluated in treatment naïve pts with TP53m AML and HR-MDS.

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