Abstract 1791P
Background
ALRN-6924 is a cell-permeating, stabilized alpha-helical peptide that binds with high affinity to endogenous p53 inhibitors MDM2 and MDMX. ALRN-6924 activates p53 in cells with wild-type, functional p53. Therefore, for patients with tumors harboring mutated p53, pre-treatment with ALRN-6924 may transiently induce cell cycle arrest in normal cells, allowing chemotherapy to selectively target cancer cells that are actively cycling.
Methods
A phase 1 study in heathy volunteers is being conducted to evaluate ALRN-6924 PK and PD including its ability to initiate p53 transcriptional regulation and induce transient cell cycle arrest in human bone marrow. The trial has three parts: the objective of Part 1 was to determine a dose of ALRN-6924 that could induce preferential cell cycle arrest in bone marrow cells. In Part 2, the time to onset, magnitude and duration of bone marrow PD effects were determined. Part 3 is designed to induce a transient, uninterrupted cell cycle arrest in the bone marrow for a prolonged amount of time. Subjects are being evaluated for safety and tolerability; blood, skin, and bone marrow samples are obtained for PD evaluation.
Results
At the time of abstract submission, a total of 37 subjects (females and males aged 18-65) were enrolled and evaluated in Parts 1 and 2 of the trial. In Part 1, a total of 14 subjects (6 placebo, 4 each at 0.3 and 0.6 mg/kg of ALRN-6924) received one infusion of study drug and samples were obtained 8 hours post dosing. Both dose levels showed robust induction of p21, a p53-regulated mediator of cell cycle arrest, in bone marrow cells on IHC evaluation. In Part 2, 23 subjects allocated to 8 groups received a single 0.3 mg/kg dose of ALRN-6924. Samples were obtained at 4, 8, 12, 16, 20, 24, 36 and 48 post infusion. The 0.3 mg/kg dose showed excellent tolerability: subjects experienced only mild, transient AEs. Robust p21 induction was observed in bone marrow cells, with peak expression between 4 hr and 16 hr following ALRN-6924 administration.
Conclusions
ALRN-6924 is safe and effective in inducing cell cycle arrest in bone marrow cells. The results support the evaluation of ALRN-6924 as a chemoprotective drug in cancer patients receiving chemotherapy.
Clinical trial identification
2020-003178-34.
Editorial acknowledgement
Legal entity responsible for the study
Aileron Therapeutics Inc.
Funding
Aileron Therapeutics Inc.
Disclosure
D. Ferrari, A. Annis, M. Aivado, V. Vukovic: Financial Interests, Personal, Full or part-time Employment: Aileron Therapeutics. U. Steidl: Financial Interests, Institutional, Funding: Aileron Therapeutics. All other authors have declared no conflicts of interest.