Research and Development
Advancing the next generation of treatments for diseases of the central nervous system
Arvinas is pioneering the discovery of novel PROTAC® (proteolysis-targeted chimera) protein degraders in neurologic diseases, which have historically been difficult to treat. Many central nervous system (CNS) targets are considered “undruggable,” and are further complicated by the difficulty of delivering therapeutic agents into the brain. We are moving into new and exciting territory, developing PROTAC® protein degraders against neurodegenerative diseases, beginning with tauopathies and synucleinopathies. There is a high unmet need in many neurologic diseases, including neurodegenerative diseases, where no disease-modifying therapies have been approved.
Differentiated pharmacology could improve outcomes
We believe the differentiated pharmacology of our PROTAC® protein degraders has the potential to translate into improved clinical outcomes for patients in therapeutic areas with limited or ineffective treatment options, as is the case in many neurological indications. Differentiation of the PROTAC® platform versus other therapies include:
Ability to cross the blood-brain barrier (BBB), which is a substantial challenge for monoclonal antibodies and genomic therapies.
Ability to enter cells of the CNS, which may allow for the degradation of pathogenic proteins (such as mutant or oligomeric tau) from inside the cell, thus preventing both intracellular dysfunction and “prion-like” spread of pathologic tau into the extracellular space and healthy neurons.
Iterative (often described as “catalytic”) activity, by which a single PROTAC® protein degrader molecule can induce the degradation of hundreds of copies of the disease-causing protein.
Potential for Oral dosing, unlike other therapies that may require intrathecal or intravenous (IV) dosing.
In preclinical studies, Arvinas has demonstrated the ability to create PROTAC® degraders that can be dosed peripherally and cross the blood-brain barrier. While this research is in its early stages, we believe PROTAC® protein degraders represent a promising new approach to treating diseases linked to pathogenic tau and alpha-synuclein.
Arvinas is progressing two named programs (tau and alpha-synuclein) and a number of undisclosed programs earlier in preclinical development.
The agents listed below are currently under investigation. Their safety and effectiveness have not yet been established.
The Tau protein is normally found in axons of healthy neurons of the central nervous system, and when it is mutated or under pathologic conditions, it has been implicated in a group of diseases known as tauopathies. Of these disorders, Alzheimer’s is the best known. In this group of diseases, the pathologic tau protein dissociates from axons and forms insoluble clusters of aggregated proteins in the brain known as tangles.
In preclinical studies, Arvinas has demonstrated that tau PROTAC® protein degraders could be dosed peripherally and degrade pathogenic tau in a mouse tauopathy model. The data shown here are for two different PROTAC® degraders, PROTAC-A and PROTAC-B.
1 Tg2508 is a murine pathologic tau model (P301L). 2 AUC, area under the curve; 3 mpk, milligrams per kilogram
**** Tukey’s multiple comparisons test P < 0.0001
Alpha-synuclein (α-syn) is an abundant neuronal protein that localizes predominantly to presynaptic terminals within the brain. While the precise normal function of this protein is not fully understood, the pathologic aggregation of α-syn is implicated in synucleinopathies. The most common of these diseases is Parkinson’s.
In preclinical studies, Arvinas has demonstrated that α-syn PROTAC® protein degraders can specifically degrade oligomeric forms of α-syn, which form aggregates in patients with diseases such as Parkinson’s. The data shown here are of rat neuronal preparations expressing human forms of α-syn, in which two different PROTAC® protein degraders, PROTAC-1 and PROTAC-2, degrade aggregated forms of α-syn, as measured by the ratio of staining intensity for a pathologic aggregated form of α-syn versus background.
1 Assay is of primary rat neurons expressing A53T human α-synuclein, with pre-formed fibrils (PFF) added or not. In the absence of α-synuclein-specific PROTAC® protein degraders, α-synuclein forms aggregates induced by PFFs (green fluorescence in cellular images). When PROTAC® protein degraders specific for oligomeric α-synuclein are added, the ratio of oligomeric α-synuclein:cell mask (background fluorescence) is decreased.
- Cacace, A. Discovery of Brain Penetrant PROTAC Degrader Molecules That Target Pathologic Tau and alpha-Synuclein Protein Species. Presented at: Targeted Protein Degradation Summit. October 24, 2019. Boston, MA.
- Cacace, A. PROTAC Discover Engine: Harnessing power of oral blood brain barrier penetrant degraders and new E3 ligases. Presented at: Platform Biology Protein Society Meeting. July 14, 2021. Virtual.
- Change, Shao, Muckle. Tau: enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies. Science. 2021 February 26; 371(6532).
- Oliveira et al. Alpha-synuclein research: defining strategic moves in the battle against Parkinson’s disease. Npj Parkinson’s Disease. 2021;7:65.
- Tabrizi, Ghosh, Leavitt. Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease. Neuron Review. 2019 March 6;101(5):801-819.