ADV368-HD for Huntington’s Disease:
- First-in-class bispecific Sigma1 agonist and Sigma2 Antagonist
- Revolutionary design
- High Equipotency
- Selective Sigma1 and Sigma2
- Oral monotherapy
- Pharmaceutical profile
- Low potential for clinical drug-drug interactions
Mechanism of Action on Huntington’s Disease
ADV368 has been precisely designed to penetrate striatum cells to activate the Sigma-1 receptor improving response to unfolded proteins, reducing ER-stress, increasing cellular antioxidants, restraining inflammation, and promoting activity in macrophages, without changing mitochondrial Ca2+ concentration, maintaining neuronal homeostasis, with an equally potent bind the Sigma-2 receptor to restore damaged cellular processes such as cholesterol synthesis, and protein trafficking, and blocks amyloid precursor protein (APP) trafficking to prevent the aggregation of the mutant HTT protein.
Seeding activity of misfolded proteins was recently found at early stages of HD, before appearance of visible symptoms. ADV368 is believed to restore chaperone activity to prevent the aggregation of the Huntingtin, protect against hypoxia‐induced damage, alleviating neuroinflammation, increasing the density of dendritic spines, promoting neurogenesis and neuritogenesis, combined with the regulation of APP and synapse homeostasis, and mitigation of its synaptotoxic effects.
ADV368 is believed to prevent brain iron accumulation through its Sigma-2 antagonist activity, reducing brain damage and allowing control mechanisms to be re-activated, while its Sigma-1 agonist activity will prevent toxic effects by increasing the expression of neuroprotective factors, restoring the impaired brain-derived neurotrophic factor (BDNF) from the cortex to the striatum, increasing the striatal neurons, improving motor function and memory levels, and also alleviates iron trafficking disruption at the blood-brain barrier (BBB).
Therefore, ADV368 represents a disease-modifying therapeutic strategy and offers the opportunity to reverse Huntington’s disease by reducing the accumulation of HTT and correcting its effects.
The transition from the single-target to the dual-target (bispecific) drugs to treat complex diseases
Traditionally drugs have been designed with the aim of targeting a single biological entity, usually a protein (the so-called “on-target”), with high selectivity to avoid any unwanted effects arising from mistargeting other biological targets (“off-targets”). However, the severity of the current incurable pathologies, such as Huntington’s disease, has clearly demonstrated that such single-target drugs could be inadequate to achieve a therapeutic effect in the late stage of complex diseases.
In parallel, we have learned that molecules hitting more than one target may possess in principle a safer profile compared to single-targeted ones.
Building on such accumulating evidence, the concept of dual-target (bispecific) drugs has made rapid and spectacular progress from being an emerging paradigm when first enunciated at the beginning of 2000, to one of the hottest topics in drug discovery currently.
Prediction of the correct targets to combine relies on clinical experience from single-target drugs, an area that should be boosted considerably by quantitative systems pharmacology, a computer-based methodology that combines preclinical neuropharmacology, neurophysiology, and existing clinical information, allowing testing of combinations in a virtual human patient.
In complex diseases, such as Huntington’s disease, where single-target drugs have failed or show severe limitations, bispecific drugs emerge as a new and more effective therapeutic option.
In-vivo preclinical validation in progress.