136 (PB126) - ALRN 6924 induces cell cycle arrest in bone marrow stem cells and hair follicles with dose-dependent degree and duration of effects after a single infusion in healthy volunteers

Abstract

Background: ALRN-6924 is a cell-permeating, stabilized alpha-helical peptide that binds to endogenous p53 inhibitors MDMX and MDM2, thereby activating p53 and its transcriptional target p21 to cause cell cycle arrest (CCA). This effect is limited to cells with wild-type, functional p53. For cancer patients with tumors bearing mutated p53, ALRN-6924 treatment selectively induces CCA in normal cells, allowing chemotherapy to preferentially target p53-mutant cancer cells that are actively cycling. Materials and methods: A Phase 1 study in heathy volunteers is being conducted to evaluate ALRN-6924 pharmacokinetics (PK) and pharmacodynamics (PD). In Part 1 (37 subjects; Voors-Pette et al, ESMO 2021) it was shown that a 1-hour intravenous (IV) ALRN-6924 infusion was safe, well tolerated, and transiently upregulates p21 in human bone marrow (BM) cells with minimal signal for apoptosis. In Part 2, we aim to directly measure dose-dependent CCA in the BM as well as in hair follicles (HFs) in female subjects across a range of doses by 1-hour IV infusion and 3-minute bolus IV injection. ALRN-6924 was administered as a single IV infusion or bolus injection at 0 (placebo), 0.3, 0.6, or 0.9 mg/kg to cohorts of 3 to 5 subjects. Subjects were evaluated for safety and tolerability. Plasma and serum samples were obtained to determine PK and levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation. BM was sampled 12 hours post-dose to directly measure CCA by flow cytometry in CD34+, lineage-negative BM stem cells. Occipital scalp skin was sampled by 2 mm punch biopsy for p21 immunohistochemistry in HFs. Results: As of June 20, 2022, 42 subjects (ages 18–59; 100% female) were enrolled and evaluated in Part 2. Subjects experienced only mild, transient adverse events (AEs), with nausea/vomiting as the most frequent related AEs. The degree and duration of serum MIC-1 elevation was dose-dependent. At 12 hours post-dose, the proportion of cycling BM stem cells was significantly reduced at all dose levels, while blinded pathology review suggested ALRN-6924-dependent p21 induction in anagen-phase HFs. Safety profiles, PK and PD were similar for both bolus and infusion. Conclusions: ALRN-6924 shows a favorable safety profile for use as a chemoprotection agent. CCA measured in BM supports prevention of chemotherapy-induced neutropenia, thrombocytopenia, and anemia, while HF results support chemoprotection for alopecia. Administration by IV bolus may simplify dosing vs. the current 1-hr infusion clinical regimen. The dose-dependent degree and duration of effects support development of a universal treatment schedule for broad use across cancer indications and types of chemotherapy. Conflict of interest: Ownership: Manuel Aivado, Vojislav Vukovic, and Allen Annis are employees and shareholders of Aileron Therapeutics Advisory Board: Ulrich Steidl is a member of the Scientific Advisory Board of Aileron Therapeutics Other Substantive Relationships: Britta Will and Kevin Randall are consultants to Aileron Therapeutics