Lomond Therapeutics Holdings, Inc. announced that the U.S. Food and Drug Administration has cleared its Investigational New Drug application for a Phase 1 multicenter study evaluating lonitoclax in patients with relapsed/refractory acute myeloid leukemia. The clinical-stage biotechnology company, co-founded by Orbimed, Torrey Pines Investment and Dr. John C. Byrd, focuses on developing best-in-class and first-in-class medicines for hematological malignancies.
"The acceptance of our third U.S. IND is an important milestone for Lomond Therapeutics," said Iain Dukes, Chief Executive Officer of Lomond Therapeutics. "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."
Novel BCL-2 Inhibitor Design
Lonitoclax represents a selective BCL-2 inhibitor engineered to address the limitations of venetoclax, the current standard BCL-2 inhibitor. The drug demonstrates novel binding with best-in-class potency and selectivity against BCL-2, a key pro-survival protein overexpressed in many cancers.
To mitigate the hematologic and immune toxicities observed with venetoclax, lonitoclax was designed with unique binding properties to improve selectivity for BCL-2 over BCL-xL. The molecule incorporates a shorter half-life and reduced P4503A4 inhibition properties to mitigate tumor lysis syndrome and drug accumulation risk, respectively.
Preclinical Efficacy and Safety Profile
Preclinical studies demonstrate that lonitoclax has monotherapy activity in pre-clinical models and shows synergistic activity when combined with azacytidine, FLT3 inhibitors, and menin inhibitors in AML xenograft models. Unlike venetoclax, lonitoclax exhibited minimal immunosuppressive activity on B cells, CD8 T cells, and NK cells in preclinical models.
The drug has completed a series of healthy volunteer studies where no significant safety signals were observed at exposures where ex vivo activation of caspase in chronic lymphocytic leukemia primary cells was observed, serving as a surrogate marker of BCL-2 inhibition in tumors. These findings emphasize important advantages over venetoclax and venetoclax-like molecules in safety, tolerability and feasibility of outpatient treatment.
Phase 1 Trial Design
The Phase 1 study will evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of lonitoclax in combination with azacitidine in relapsed/refractory AML patients. The study design includes both dose escalation and expansion phases, with enrollment planned for up to 60 total participants.
Lomond Therapeutics plans to initiate the study in the third quarter of 2025 across multiple investigative sites. The trial aims to establish the safety profile and mechanism of action of lonitoclax while exploring its therapeutic potential in combination therapy for AML patients.
Company Platform and Strategy
Lomond Therapeutics utilizes a proprietary hybrid AI platform from Expert Systems Inc., leveraging proprietary data, chemistry/biology tools, knowledge and expertise to identify valuable molecular mechanisms of pathology. This approach enables the rational design and accelerated discovery of best-in-class and first-in-class therapies targeting escape mutations in hematologic and solid cancers.
The company's goal is to become a leader in developing novel breakthrough medicines that maximize clinical benefit when treating hematologic and solid malignancies. The lonitoclax program represents the company's strategy to safely target AML and chronic lymphocytic leukemia patients both as monotherapy and in combination with other targeted therapies.
