ALRN-6924
We are implementing a clinical development strategy designed to maximize our opportunity to bring biomarker-driven, selective chemoprotection to all patients with p53-mutated cancer regardless of cancer type or chemotherapy.
*TAC=docetaxel, doxorubicin and cyclophosphamide chemotherapy regimen
We are currently conducting a clinical trial of ALRN-6924 in patients with p53-mutated breast cancer. The Phase 1b, open-label, single-arm, multicenter trial is designed to evaluate the safety, tolerability and chemoprotective effect of ALRN-6924 in up to 24 patients with p53-mutated breast cancer undergoing either neoadjuvant or adjuvant treatment with docetaxel, doxorubicin and cyclophosphamide, a chemotherapy regimen also known as ‘TAC’.
The primary endpoints are duration and incidence of severe neutropenia (Grade 4) in cycle 1. Secondary endpoints include the chemoprotective effect of ALRN-6924 on chemotherapy-induced alopecia, as well as other hematologic and non-hematologic toxicities. TAC will be administered every 3 weeks for 4 to 6 cycles based on investigators’ discretion. ALRN-6924 will be administered at 1.2 mg/kg on 3 consecutive days in each treatment cycle, Days 0, 1 and 2, while chemotherapy will be administered on Day 1.
The planned readouts for the breast cancer trial include data from initial patients in 4Q 2022, an interim analysis on 12 patients in 2Q 2023, and topline results from 20 patients in 3Q 2023.
We presented final results from our completed Phase 1b trial in patients with p53-mutated SCLC receiving second-line topotecan at the European Society for Medical Oncology (ESMO) Congress 2021. Following the interim proof-of-concept data presented in October 2020 from this study, these final results reinforced ALRN-6924’s ‘triple-play’ reduction in neutropenia, thrombocytopenia and anemia caused by chemotherapy, as well as a reduction in febrile neutropenia, platelet transfusions and red blood cell transfusions.
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.
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