First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

Abstract

PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). METHODS This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. RESULTS Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm. CONCLUSION Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

Differentiation syndrome with lower‐intensity treatments for acute myeloid leukemia

“…A new class of TCP derivatives targeting LSD1 are also under clinical investigation, including iadademstat (ORY‐1001) 95 . A first‐in‐human phase I study of iadademstat monotherapy in R/R AML reported DS in 2/27 patients that was classified as drug‐induced, and one of those patients died from DS‐related complications despite prompt initiation of dexamethasone 96 . Early reports from the phase IIa ALICE study in elderly patients with R/R AML combining iadademstat with azacitidine recorded 1/18 patients with DS (grade 3) 97 …”

First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat

“…MAD AUC inf (D1) not reported as extrapolated AUC was > 20% b Pharmacokinetic parameters in the CSF cohort after administration of a single dose. CSF and plasma u concentrations, and CSF-to-plasma u ratios after a single dose of vafidemstat 2 or 4 mg. n = 3 subjects per timepoint AUC 0-inf area under the concentration-time curve within time 0 to infinity, AUC 0-t area under the concentration-time curve within time 0-24 h, CL/F apparent clearance, C max maximum (peak) concentration, CSF cerebrospinal fluid, D1 day 1, D5 day 5, MAD multiple ascending dose, plasma u plasma unbound, RAC ratio of accumulation (calculated from t ½ /K e ; K e elimination rate constant), SAD single ascending dose, ss steady state, t ½ terminal half-life, t max time to reach C max, Vd/F apparent volume of distribution [18], bomedemstat (IMG-7289) [19], CC-90011 [20], and INCB059872 [21]. Vafidemstat (ORY-2001) is the first KDM1A inhibitor envisaged for CNS disease and evaluated in healthy volunteers.…”

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy

“…Several irreversible LSD1 inhibitors are currently evaluated in clinical trials, including tranylcypromine, GSK2879552, IMG-7289, INCB059872, SP-2577 and CC-90011 [ 175 ]. Especially iadademstat has shown promising results in clinical trials in patients with MLL translocation [ 176 , 177 ]. In addition, trials examining the combination with ATRA as well as azacitidine are currently undergoing.…”