Lomond Therapeutics has announced positive results from its Phase 1 clinical trials of lonitoclax, a next-generation BCL-2 inhibitor. The single ascending dose studies in healthy volunteers demonstrated a promising safety profile and robust target inhibition, suggesting potential advantages over existing BCL-2 inhibitors like venetoclax. The data supports further development of lonitoclax for the treatment of hematologic malignancies, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML).
Phase 1 Trial Results
The Phase 1 trials assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of oral, once-daily lonitoclax in healthy volunteers. Key findings include:
- No significant safety signals were observed at exposures where robust inhibition of BCL-2 was achieved, as measured via ex vivo activation of caspase in CLL primary cells.
- Concomitant administration of itraconazole, a strong CYP3A4 inhibitor, did not significantly alter lonitoclax exposures, suggesting a reduced risk of drug-drug interactions.
These results indicate that lonitoclax may offer improved tolerability and a lower risk of drug accumulation compared to venetoclax, potentially enabling safer outpatient treatment regimens.
Lonitoclax: A Next-Generation BCL-2 Inhibitor
Lonitoclax is designed to selectively target BCL-2, a key pro-survival protein overexpressed in various cancers. The drug's unique binding mode aims to improve selectivity for BCL-2 over BCL-xL, potentially reducing hematologic and immune toxicities associated with venetoclax. Additionally, lonitoclax has a shorter half-life and reduced P4503A4 inhibition properties, which could mitigate the risk of tumor lysis syndrome and drug accumulation.
Preclinical studies have shown that lonitoclax exhibits monotherapy activity and synergistic effects when combined with azacitidine, FLT3 inhibitors, and menin inhibitors in AML xenograft models. Notably, lonitoclax demonstrated minimal immunosuppressive activity on B cells, CD8 T cells, and NK cells in preclinical models, suggesting a potential advantage in maintaining immune function during treatment.
Clinical Development and Future Directions
"The positive PK, PD, and safety findings from our Phase 1 trial mark the first clinical data that underscores the differentiated profile and promising potential of lonitoclax compared to venetoclax and venetoclax-like molecules for AML, CLL, and potentially other oncology indications patients," said Dr. Iain Dukes, Chief Executive Officer of Lomond Therapeutics. The company is currently advancing lonitoclax in an ongoing CLL study, with plans to explore its potential in other hematologic and solid cancers.
