Odyssey: A First-in-Human Study of the Aldehyde Dehydrogenase (ALDH) Inhibitor Abd-3001 in Patients with Refractory/Relapsed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)
Authors: Benajiba Lina , Colle Julien , Heiblig Mael , Loron Sandrine , Soret-Dulphy Juliette , Berchard Paul , Yazir Mühübe , Basset Laurent , Venton Geoffroy , Larcher Marie-Virginie , Daltro De Oliveira Rafael , Fossard Gaëlle , Martin Guillaume , Perez Mileidys , Ceylan Ismael , Pelletier Annick , Kiladjian Jean-Jacques , Costello Régis 
Published: December 2024

Introduction
The ALDH1 subfamily contributes to AML pathogenesis and resistance to therapy by enhancing cellular detoxification mechanisms and contributing to an immunosuppressive microenvironment. Overexpression of ALDH1 occurs frequently in AML and is associated with resistance to chemotherapeutic regimens and poor prognosis.
ABD-3001 is a specific inhibitor of ALDH1 with demonstrated activity in preclinical models of inducing cell death in AML blasts while sparing healthy cells. ABD-3001 is a potential therapeutic candidate for patients with refractory/relapsed AML, who have a high unmet need for new treatment approaches to overcome chemotherapy resistance and improve their prognosis.
Methods
ODYSSEY (NCT05601726) is a Phase I first-in-human open-label dose escalation study evaluating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ABD-3001 in patients with relapsed/refractory AML or high-/very high-risk MDS, who are ineligible for intensive or new generation targeted therapy. The study comprises a single ascending dose part (Part A), followed by a multiple ascending dose part (Part B).
In Part A, patients received single and fixed 4-hour IV infusions of ABD-3001 in a 3+3 dose escalation design starting at 18 mg/m2. Subsequent doses were 54, 135, 270, 405, and 540 mg/m2. The primary endpoint was to assess the recommended dose range of ABD-3001 for Part B based on the incidence of dose-limiting toxicities (DLTs). Secondary endpoints included safety (using NCI CTCAE v5.0) and PK parameters. PD assessment and biomarkers were exploratory. Here we report results from Part A.
In Part B, 36 patients will be randomized to one of three ABD-3001 doses: 270 mg/m2 twice weekly, 405 mg/m2 twice weekly, or 540 mg/m2 once weekly, for up to three 28-day cycles.
Results
As of July 18, 2024, 21 patients were enrolled and received treatment (18 with AML, 3 with MDS). Mean age was 69 years (standard deviation: ±13; range: 27-83), 38% were female, and the majority (76%) had Eastern Cooperative Oncology Group Performance Status of 1.
Overall, 18 patients (85.7%) experienced a Grade ≥1 treatment-emergent adverse event (TEAE); seven (33.3%) had Grade 3/4 TEAEs. Nine patients (42.9%) had treatment-related AEs (TRAEs), including four (19.0%) with Grade 3/4 TRAEs. Among six patients who received 540 mg/m2 ABD-3001, four (66.7%) experienced TRAEs; two had Grade 3/4 TRAEs, considered DLTs.
PK data indicated that the exposure to ABD-3001 correlates with the dose administered. The half-life of the major metabolite of ABD-3001 (CEY1410) was 10h at 18 mg/m2 and 15h at 405 mg/m2.
PD evaluation indicated biological activity from the lowest dose of 18 mg/m2. Inhibition of the ALDH1A1 target enzyme activity ranged from 0.25h to 6h and increased with the dosage; full recovery was observed within 48h. JNK protein phosphorylation (pJNK) - a marker of cellular stress related to the mechanism of action for ABD-3001 - mean Tmax was 3.10h at doses 18 and 54 mg/m2, and was 6.16h at doses 135-405 mg/m2. There was a correlation between pJNK:JNK ratio (T8h/Tinf) and CEY1410 Cmax (r=0.974).
Improvements in hematologic parameters at Day 7 were observed across dose groups in 11 patients (52.4%). Three patients (14.3%) had sustained hematologic improvement, not requiring red blood cell and/or platelet transfusion after ≥2 months, including one who had received the lowest dose of 18 mg/m2.
Authorization for compassionate use has been obtained for one patient who experienced sustained hematologic recovery after treatment with ABD-3001 in ODYSSEY Part A. This patient had secondary AML refractory to multiple therapies and had relapsed following a bone marrow transplant. Two months after receiving a single dose of ABD-3001 (405 mg/m2), their blast count decreased from 70% to 13%, and no major toxicities were observed.
Conclusions
Part A of the first-in-human ODYSSEY study demonstrated that ABD-3001 was well tolerated with single-dose administration. PK data indicated dose correlation and dose-dependent biological activity was correlated with PK. Although efficacy was not a predefined objective, early signs of hematologic improvements were observed with three patients benefiting from a long-term treatment effect. Ongoing Part B, evaluating up to three cycles of ABD-3001 at doses informed by Part A, will provide a larger data set to further evaluate tolerability and preliminary efficacy signals to guide future studies.