Mechanism of Action Data from Our Healthy Volunteer Study
We presented preliminary results from our Phase 1 pharmacology study of ALRN-6924 in healthy volunteers at the International Society for Experimental Hematology (ISEH) 2021 Scientific Meeting and ESMO 2021. These preliminary results demonstrated that a 0.3 mg/kg and 0.6 mg/kg 1-hour intravenous (IV) infusion of ALRN-6924 was well-tolerated, and transiently upregulated p21 in human bone marrow cells with minimal signal for apoptosis (n=37).
In October 2022, we presented additional and final results from the healthy volunteer study at the EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics, in which cell cycle arrest was directly measured in the bone marrow and hair follicles of an additional 41 females. ALRN-6924 was administered as a single 1-hour IV infusion or 3-minute bolus injection at 0.3, 0.6, or 0.9 mg/kg to cohorts of 3 to 9 subjects and compared to placebo. Plasma and serum samples were obtained to determine PK and levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation.
The results showed that ALRN-6924 induced p53-mediated cell cycle arrest in bone marrow stem cells and hair follicles. The degree and duration of serum MIC-1 elevation was dose-dependent, indicating more durable p53 activation at higher ALRN-6924 doses. At 12 hours post-dose, the proportion of cycling bone marrow stem cells was significantly reduced at all dose levels. Blinded pathology review suggested ALRN-6924-dependent p21 induction in anagen-phase hair follicles.
Safety profiles, PK and PD were similar for both a 3-minute bolus and 1-hour infusion, providing rationale for future development of ALRN-6924 bolus administration.