First results from the Phase 1 study of APL-4098, an oral potent GCN2 inhibitor for the treatment of Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) and Myelodysplastic Syndromes (MDS)/AML Free

Background: Patients with R/R AML and MDS/AML have a very poor prognosis, with most patients dying from disease-related complications. Therefore, there remains an unmet medical need for new effective and well-tolerated therapies to manage R/R AML and MDS/AML.

General control nondepressible 2 (GCN2) is an evolutionarily conserved kinase and a pivotal regulator of the integrated stress response (ISR). GCN2 is activated in response to amino acid deficiency. Activation of GCN2 phosphorylates translation initiation factor eIF2α resulting in the attenuation of global protein synthesis and a transcriptional rescue program. GCN2 activation in response to amino acid deprivation is a mechanism by which tumor cells, including leukemic cells, can survive under nutrient stress. GCN2 inhibitors may thus represent a novel class of therapeutic agents with anti-leukemic activity.

APL-4098 is a novel potent and selective small molecule inhibitor of GCN2. APL-4098 inhibits AML leukemic cell viability ex vivo and AML tumor burden in non-clinical in vivo models where APL-4098 depletes AML patient-derived (PDX) leukemic stem cells (LSCs) and acts in synergy with the BCL-2 inhibitor venetoclax for enhanced depletion of AML PDX LSCs and blasts. The selective and highly efficacious profile of APL-4098 is ideal for clinical investigation in R/R AML and MDS/AML.

Methods:This Phase 1 study (NCT06372717) was designed to assess the safety and preliminary efficacy of APL-4098 in R/R AML and MDS/AML. The study includes dose escalation as monotherapy and in combination with azacitidine. Dose escalation was performed initially using an Accelerated Titration Design (ATD) and then the Bayesian Optimal Interval (BOIN) design to determine the Recommended Phase 2 Dose (RP2D) of APL-4098. The study is enrolling patients with R/R AML and MDS/AML with no available therapies known to provide clinical benefit.

The primary objective of the study is to evaluate the safety and tolerability of APL-4098. Secondary and exploratory objectives include assessment of preliminary efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of APL-4098. APL-4098 is administered orally once daily in 28-day cycles as monotherapy or in combination with azacitidine 75mg/m² for 7 days until disease progression, unacceptable toxicity, or patient withdrawal from the study. A Safety Review Committee (SRC) reviews all data prior to each dose escalation decision and on a regular basis.

Results: As of 27 June 2025, 21 patients (pts) have been treated with APL-4098 monotherapy across 4 dose levels of 20 mg, 40 mg, 60 mg and 100 mg. The median age was 71 years (range: 52-84). 18 had R/R AML (14 with adverse genetics) and 3 had R/R MDS. The median prior lines of therapy was 2 (range: 1-6). The median duration of treatment was 31 days (range: 4-126). Seven patients remain on treatment. No dose limiting toxicities (DLTs) were observed across all 4 dose levels.

APL-4098 has been well tolerated. Treatment emergent adverse events (TEAEs) have been predominantly grade 1 and 2 severity. Most frequently observed TEAEs suspected to be related to APL-4098 include nausea (48% any grade; 14% grade 3) and vomiting (24% any grade; 14% grade 3).

A reduction in AML blast counts has been observed in 5 out of 9 patients with a disease assessment at C2D1, including 2 heavily pre-treated patients with pathogenic TP53 mutations.

The PK profile of APL-4098 showed linear and dose-proportional characteristics with terminal phase elimination half-life supporting once daily dosing. Samples were analysed for key mechanistic and cellular markers indicative of APL-4098 PD activity. An exposure-dependent induction in mRNA expression of CHAC-1, a pro-apoptotic stress response gene, was observed indicative of APL-4098 therapeutic activity.

Updated data will be presented at the congress.

Conclusions: APL-4098 is a potent, selective GCN2 inhibitor that has demonstrated excellent non-clinical potency, selectivity and efficacy properties. Dose escalation of APL-4098 in R/R AML and MDS/AML patients is ongoing with a good tolerability and safety profile. APL-4098 shows dose-proportionate PK supporting once daily oral dosing and demonstrated exposure-driven PD activity at the transcriptional level. This study will inform the RP2D that will be examined in efficacy studies of APL-4098 as monotherapy and in combination with azacitidine. Future combinations studies with venetoclax / azacitidine are also planned.