Objective: To evaluate translational target engagement of HER-096, a CDNF-derived peptidomimetic, in preclinical models of Parkinson’s disease (PD) and in a Phase 1b clinical study in patients with PD.

Background: Dysregulated cellular stress responses and mitochondrial dysfunction are central contributors to PD pathophysiology. HER-096 is a brain-penetrating modified peptide based on the active site of the endogenous unfolded protein response (UPR) modulator CDNF. It is being developed as a potential disease-modifying therapy for PD, with a mechanism aimed at targeting UPR-related pathways and restoring mitochondrial function. Preclinical studies have demonstrated a consistent UPR modulation and mitochondrial signature, supporting a translational biomarker strategy for clinical evaluation.

Method: HER-096 has been evaluated in established in vitro and in vivo PD models by studying UPR-related changes and using functional mitochondrial assays. A multi-layered design with proteomic and transcriptomic profiling from various matrices including extracellular vesicles was used to characterize pathway-level effects. A Phase 1b clinical study employing twice-weekly dosing for four weeks was completed in patients with PD to assess safety, tolerability, and target biology related exploratory biomarkers. Various omics approaches as well as more targeted proteostasis and mitochondrial biomarkers were analysed.

Results: In preclinical models, HER-096 robustly mitigated proteostasis and mitochondrial dysfunction. Integrated omics analyses demonstrated modulation of pathways related to endoplasmic reticulum and mitochondrial stress. In the Phase 1b study, HER-096 was generally well tolerated. Treatment was associated with robust changes in proteostasis-associated proteins and improvement in exploratory mitochondrial biomarkers, consistent with the mechanistic signature observed in experimental systems and supporting clinical verification of the target mechanism.

Conclusion: Concordant effects on the target mechanisms on a pathway-level across multiple datasets in both preclinical models and in patients provide translational evidence that HER-096 engages disease-relevant pathways. These findings support continued clinical development of HER-096 as a mechanistically targeted therapeutic candidate for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/translational-target-engagement-of-her-096-demonstrates-concordant-proteostasis-and-mitochondrial-modulation-in-preclinical-models-and-patients-with-parkinsons-disease/