A phase 1 dose escalation and dose optimization study to evaluate the preliminary safety, tolerability, pharmacokinetic, pharmacodynamic, and clinical activity profile of AUTX703 in participants with relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes
Abstract
Phenotypic cell state plasticity is a key hallmark of cancer and is an intrinsic vulnerability of tumor cells. Targeting drivers of cell state plasticity defines an emerging area of biology that is relatively underexplored in cancer therapies. Cell states and their associated transitions are regulated by chromatin modifications and cell state specific transcriptional programs. Lysine acetyltransferase 2A (KAT2A) and its paralog KAT2B are epigenetic enzymes involved in normal human development and have been shown to play a critical role in regulating somatic cell fate decisions. KAT2A expression has been shown to homogenize transcriptional programs to sustain stem cell phenotypes, while loss of KAT2A has been shown to promote differentiation. Alterations in KAT2A and/or KAT2B expression and activity have been noted in multiple cancers including acute myeloid leukemia (AML).
AUTX-703 is a potent, selective, and orally bioavailable degrader of KAT2A/B. In preclinical studies, AUTX-703 potently inhibited cell growth and increased myeloid and monocytic differentiation in primary AML patient cells dosed ex vivo. Sensitivity to AUTX-703 was mutation agnostic and cell state dependent; response was positively correlated with granulocyte monocyte progenitor (GMP) cell state. In an AML patient-derived xenograft (PDX) model, dosing with AUTX-703 was demonstrated to prolong survival and increase monocytic differentiation in bone marrow. (Duparc et al. Blood, 2024)
AUTX-703-001 is an…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 703 participants or records.
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