On October 26, 2022 Aileron Therapeutics (Nasdaq: ALRN), a chemoprotection oncology company focused on fundamentally transforming the experience of chemotherapy for cancer patients, reported that detailed results from its completed Phase 1 study of ALRN-6924 in healthy volunteers at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) 2022 taking place in Barcelona October 26 – 28, 2022 (Press release, Aileron Therapeutics, OCT 26, 2022, View Source [SID1234622399]). The poster titled, "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" (Poster #136) is also available in the Scientific Resources section of Aileron’s website linked here.
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ALRN-6924 is a first-in-class MDM2/MDMX dual inhibitor that is currently in development as a novel, selective chemoprotective agent for patients with p53-mutated cancer. The findings presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) conference, which showed that ALRN-6924 induced p53-mediated cell cycle arrest in bone marrow stem cells and hair follicles, demonstrate the potential of ALRN-6924 to prevent chemotherapy-induced neutropenia, thrombocytopenia, and anemia, as well as chemotherapy-induced alopecia.
"While we previewed some of these new findings from our now completed Phase 1 study of ALRN-6924 in healthy volunteers earlier this year, we’re pleased to present the comprehensive results at an international scientific conference," said Manuel Aivado, M.D., Ph.D., President and Chief Executive Officer at Aileron. "These results contribute to the substantial body of scientific evidence that we believe has reliably and reproducibly demonstrated ALRN-6924’s potential as a biomarker-driven chemoprotective agent, driving us to work diligently to address the significant impact chemotherapy-induced toxicities have on cancer patients’ treatment experience and outcomes."
ALRN-6924 is designed to activate p53, which in turn upregulates p21, a known inhibitor of the cell replication cycle, thereby inducing cell cycle arrest to protect normal, healthy cells from chemotherapy-induced damage. The Phase 1 study in healthy volunteers was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALRN-6924. Aileron previously presented data from the study showing that a 0.3 mg/kg and 0.6 mg/kg 1-hour intravenous (IV) ALRN-6924 infusion was well tolerated, and transiently upregulated p21 in human bone marrow cells with minimal signal for apoptosis (n=37; Voors-Pette et al., ESMO (Free ESMO Whitepaper) 2021).
In the new findings presented today, 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. Bone marrow was sampled 12 hours post-dose to directly measure cell cycle arrest by flow cytometry in CD34+, lineage-negative bone marrow stem cells. Occipital scalp skin was sampled by a 2 mm punch biopsy for p21 immunohistochemistry in hair follicles.
In addition to the cell cycle arrest findings, ALRN-6924 continued to demonstrate a favorable tolerability profile, with subjects experiencing only mild, transient adverse events (AEs), with nausea/vomiting as the most frequent related AE. 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 the 3-minute bolus and 1-hour infusion, providing rationale for future development of ALRN-6924 bolus administration.
"These findings are particularly compelling as they support our selection of the 1.2 mg/kg dose for our ongoing Phase 1b trial in patients with p53-mutated breast cancer, as well as our evaluation of protection against both chemotherapy-induced neutropenia and alopecia in that trial," said Allen Annis, Ph.D., Senior Vice President, Research at Aileron. "Beyond informing the dose and schedule for our current trial evaluating ALRN-6924 in breast cancer patients being treated with docetaxel, doxorubicin and cyclophosphamide, or TAC, these results suggest this dosing regimen can be uniformly applied when developing ALRN-6924 as a chemoprotective agent with other chemotherapies and for patients with other p53-mutated cancer indications."