FDA Clears IND for Phase 1 Study of Lonitoclax in Relapsed/Refractory AML
FDA clears lonitoclax for a phase 1 trial in relapsed/refractory AML, promising improved safety and efficacy over existing therapies.
US FDA
- The FDA cleared the investigational new drug (IND) application for a phase 1 multicenter study of lonitoclax in relapsed/refractory (R/R) acute myeloid leukemia (AML).
- The study will evaluate the safety, feasibility, and efficacy of lonitoclax in this patient population.
- Lonitoclax is a BCL-2 inhibitor with comparable antitumor activity to venetioclax (Venclexta) in both B-cell and myeloid malignancy models.
The FDA has cleared the IND application for lonitoclax, a novel BCL-2 inhibitor, enabling the initiation of a phase 1 multicenter trial in patients with R/R AML.1
This upcoming study will assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of lonitoclax in combination with azacitidine. The trial will feature both dose-escalation and -expansion cohorts and aims to enroll up to 60 patients across multiple investigative sites, with initiation expected in the third quarter of 2025.
Microscopic, photorealistic image of leukemia cells - Generated with Adobe Firefly
"The acceptance of our third US IND is an important milestone for Lomond Therapeutics", said Iain Dukes, chief executive officer of Lomond Therapeutics, in a press release. "This IND clearance allows us to begin the next stages of our clinical development for lonitoclax focusing on acute myeloid leukemia. Through this phase 1 study, we aim to advance our understanding of safety, tolerability, manufacturing feasibility, and mechanism of action of lonitoclax."
Lonitoclax represents a new generation of BCL-2 inhibitors, engineered to address some of the limitations observed with current therapies like venetoclax. BCL-2 is a key antiapoptotic protein commonly overexpressed in AML and other hematologic malignancies.2
While venetoclax has shown clinical benefit, its use can be restricted by dose-limiting toxicities, immunosuppressive effects, and risks such as tumor lysis syndrome and CYP3A4-mediated drug-drug interactions.1
Designed with improved selectivity for BCL-2 over BCL-xL, lonitoclax exhibits a shorter half-life and reduced CYP3A4 inhibition—features intended to lower the risk of tumor lysis syndrome and avoid drug accumulation. Preclinical data suggest lonitoclax has comparable, if not superior, antitumor efficacy to venetoclax in both lymphoid and myeloid malignancies, with a favorable safety profile. Notably, lonitoclax shows limited immunosuppressive activity on B cells, CD8+ T cells, and natural killer cells, potentially preserving immune function in treated patients.
Preclinical studies have also demonstrated lonitoclax’s synergistic potential when combined with azacitidine, FLT3 inhibitors, and menin inhibitors in AML xenograft models. Additionally, ex vivo caspase activation in chronic lymphocytic leukemia (CLL) primary cells has been observed at exposure levels that were well tolerated in healthy volunteer studies, supporting the drug’s pharmacodynamic activity and clinical potential.
If successful, lonitoclax may offer a safer, more targeted outpatient treatment option for patients with R/R AML and possibly other BCL-2–dependent malignancies such as CLL and low-grade lymphomas.
