Camizestrant caused a reversible dose- and time-dependent heart rate reduction in vivo (maximum 53 bpm reduction in dogs) by decreasing sinoatrial node pacemaker current activity.
Does camizestrant reduce heart rate via a sinoatrial node pacemaker channel mechanism in preclinical models?
Camizestrant induces a reversible reduction in heart rate by decreasing sinoatrial node pacemaker current activity.
p-value: p=<0.001
Camizestrant-induced heart rate reduction is mediated via a sinoatrial node pacemaker channel mechanism Hall, Andrew Primo ; El-Haou, Saïd; Villar, Inmaculada C; D. Molla ; Kwan, Maggie; Purbrick, Stuart; Henry, David; Kirk, Jason; Hawthorne, Glen; S. Canzolino ; Harding, Joanna; Harmer, Alexander; A. Bucchi ; Roberts, Liz; Pointon, Amy; Protze, Stephanie; M. Baruscotti Penultimo ; Wright, Lindsay Ultimo 2026 Abstract Camizestrant, a next-generation selective estrogen receptor (ER) degrader and complete ER antagonist, has been associated with a reversible dose- and time-dependent heart rate (HR) reduction in clinical studies. This nonclinical investigation aimed to understand the mechanism of camizestrant-induced HR reduction. The effects of camizestrant on HR in vivo were assessed in rat and dog telemetry studies. Effects on pacemaker channel function in vitro were assessed using patch-clamp electrophysiology in Chinese hamster ovary cells expressing human hyperpolarization-activated cyclic nucleotide-gated channel 4 (hHCN4), human embryonic stem cell (hESC)-derived sinoatrial node (SAN) cardiomyocytes, and primary rat SAN cardiomyocytes. In dogs, 28-day repeat-dose camizestrant administration caused a reversible dose- and time-dependent HR reduction (maximum reduction of 53 beats per min bpm on Day 25 vs pre-study levels at 20 mg/kg). HR reduction was also noted in rats (maximum reduction 89 bpm vs vehicle 23% on Day 5 of a 7-day study at 75 mg/kg). Responses to chronotropic stimuli (e.g., atropine and isoprenaline) were reduced in dogs treated with camizestrant. Camizestrant-induced HR reduction was still present following combined sympathetic (atenolol) and parasympathetic (atropine) inhibition in dogs, as well as vagotomy in rats. Camizestrant reduced hHCN4 current density in Chinese hamster ovary cells, as well as beat rate and "funny" pacemaker (If) current activity in hESC-derived SAN cardiomyocytes. Camizestrant at 75 mg/kg for 7 days significantly reduced If current activity versus vehicle in isolated SAN cardiomyocytes. These results support the hypothesis that camizestrant exerts a pharmacologic, reversible reduction in HR by decreasing SAN pacemaker current activity.
Hall et al. (2026) studied Healthy animals and in vitro models (investigating camizestrant-induced heart rate reduction). Camizestrant vs. Vehicle was evaluated on Maximum heart rate reduction from pre-study levels in dogs on Day 25 (p=<0.001). Camizestrant caused a reversible dose- and time-dependent heart rate reduction in vivo (maximum 53 bpm reduction in dogs) by decreasing sinoatrial node pacemaker current activity.