PROTAC® Protein Degraders: How Arvinas is Pioneering Potential Next-Generation Treatments for Neurodegenerative Diseases
The toll of neurodegenerative diseases in the U.S. is devastating and, with an aging population, is growing worse by the day. For instance, an estimated 6.7 million Americans over 65 are living with Alzheimer’s disease, the most common form of dementia, a figure that could double by 2050, according to the Alzheimer’s Association.1 Rates of other neurodegenerative disorders, such as Parkinson’s disease, are also rising.2 Improved molecular testing and greater physician awareness have led to modest increases in the prevalence of a rarer neurodegenerative condition, Huntington’s disease.3
There is a profound unmet need, and new therapies are needed for these debilitating conditions. Arvinas is evaluating a novel approach called targeted protein degradation that the company pioneered, which may one day have the potential to provide new therapies for many of these devastating diseases.4 Arvinas’ PROTAC® (PROteolysis TArgeting Chimera) protein degraders, which work by activating the cell’s natural machinery that degrades abnormal proteins, are already being evaluated in clinical trials for several oncology indications. Now, we are exploring the potential for targeting proteins that are thought to cause a variety of neurodegenerative diseases.5
These and many other neurodegenerative diseases have largely defied efforts to discover effective treatments for their debilitating symptoms with many having central nervous system (CNS) targets that have long been considered “undruggable.” Furthermore, developers have struggled to design small-molecule therapeutic agents capable of passing through the blood-brain barrier to reach these targets.6 Gene based therapies and monoclonal antibodies do not cross the blood-brain barrier, so small molecule PROTAC® degraders may offer a significant therapeutic opportunity as potential treatments for neurodegenerative diseases.
PROTAC® protein degraders use a novel mechanism to target proteins implicated in neurological pathology and dysfunction. Unlike typical small molecule inhibitors, they do not simply block their targets’ enzymatic or signaling activity. Instead, they harness a natural pathway known as the ubiquitin-proteasome system within cells to target pathologic proteins.6
Importantly, some PROTAC® protein degraders can cross the blood-brain barrier and can be engineered to target only disease-causing proteins and spare healthy proteins.7 Once in the brain, these agents can degrade diseased proteins.8
Arvinas is currently conducting preclinical studies of several PROTAC® protein degraders to explore their pharmacological potential to remove disease-causing proteins that have historically been highly challenging to target with conventional small molecules, including those that have historically been considered “undruggable” and thought to contribute to Parkinson’s, Alzheimer’s, and Huntington’s diseases.
Variants of the LRRK2 (Leucine-rich repeat kinase 2) gene are one of the most common genetic risk factors for Parkinson’s disease, having been associated with both familial (inherited) and sporadic (no family history) cases. Certain LRRK2 variants have been linked to increased activity and expression of the enzyme LRRK2 kinase, which has been reported in some Parkinson’s disease patients and has been shown in preclinical studies to contribute to pathophysiology, further suggesting it may have a role in the origin and development of the condition.9
Human genetics and preclinical animal model data suggest that reducing the LRRK2 protein by 50% may impact pathology and dysfunction in Parkinson’s disease.5 Therefore, degrading LRRK2 in the brain may be beneficial for the treatment of this neurodegenerative condition. Arvinas has developed PROTAC® molecules that are highly selective for degradation of the LRRK2 protein.5 In preclinical studies using mice bred to express the most common familial mutation of the gene, LRRK2 G2019S, these molecules have been potent degraders of LRRK2 in the brain.5,9
Much research on the cause of Alzheimer’s disease has focused on tau, a protein found in axons, the neuronal component that sends signals to other cells as electrochemical waves that are required for healthy brain function. Mutated or pathogenic tau dissociates from microtubules that normally stabilize the axon and negatively impacts neurons as well as the supporting glia by forming pathologic tau that ultimately results in cell dysfunction and death, in addition to forming “neurofibrillary tangles,” the hallmark pathologic feature of Alzheimer’s disease.5
In preclinical studies, Arvinas has shown that the form of tau associated with neuronal tangles can be targeted with PROTAC® protein degraders. In a mouse model of tauopathy, PROTAC® degraders eliminated 95% of pathologic tau.11 In addition to Alzheimer’s disease, other neurodegenerative conditions characterized by the accumulation of tau, or tauopathies, could be candidates for PROTAC® protein degraders, such as frontotemporal dementia and progressive supranuclear palsy.9
Huntington’s disease is a rare but devastating disorder linked to a mutation in the HTT (Huntingtin) gene. This variant results in a mutated version of a protein known as mHTT that causes aggregation, aberrant cleavage of the protein and, ultimately, the loss of striatal neurons, which are located in a brain region associated with motor control.12 Arvinas has developed PROTAC® molecules that target and degrade mHTT in cells, including neurons, while sparing healthy HTT.5 In ongoing preclinical studies conducted in mouse models of Huntington’s disease, Arvinas is studying the effects of clearing pathologic mHTT protein.13
Arvinas recognizes the challenges faced by patients with these and related disorders, which is why we remain committed to developing this exciting new approach to treating neurodegenerative diseases. Arvinas is making strides in that mission and hopes to submit an investigational new drug or clinical trial authorization (IND/CTA) application for the first CNS-penetrant PROTAC® to emerge from our neuroscience therapeutic pipeline by the end of 2023.
1. 2023 Alzheimer’s Disease Facts and Figures, p. 26. alzheimers-facts-and-figures.pdf. Accessed July 19, 2023.
2. GBD 2017 US Neurological Disorders Collaborators. Burden of Neurological Disorders Across the US From 1990-2017
A Global Burden of Disease Study. JAMA Neurol. 2021;78(2):165-176.
3. Medina, A, et al. Prevalence and Incidence of Huntington’s Disease: An Updated Systematic Review and Meta-Analysis. Mov Disord. 2022;37(12):2327-2335.
4. Bond, MJ, and Crews, CM. RSC Chemical Biology. 2021;2(3):725-742.
5. Arvinas website: Neuroscience. Neuroscience | Arvinas Accessed July 20, 2023.
6. Bekes, M, et al. Nature Reviews: Drug Discovery. 2022;21(3):181-200.
7. Hendricson, A. Discovery & Optimization of PROTAC® Molecules That Selectively Reduce Mutant Huntingtin. Presented at: CHDI Annual Meeting; Dubrovnik, Croatia; April 24, 2023; Discovery & Optimization of PROTAC Molecules That Selectively Reduce Mutant Huntingtin.pdf
8. Cacace, A. PROTAC Discovery Engine: Harnessing the power of oral blood brain barrier penetrant degraders and new E3 ligases. Presented at the Protein Society Meeting; July 14, 2021; virtual.
9. Zhao, Y and Dzamko N. Drugs. 2019;79:1037–1051.
10. Silva, MC, et al. eLife. 2019;8:e45457.
11. Cacace, A. Discovery of Brain Penetrant PROTAC Degrader Molecules That Target Pathologic Tau and alpha-Synuclein Protein Species [1-22]. Presented at: Targeted Protein Degradation Summit; Boston, MA; October 24, 2019. https://s3.us-east-1.amazonaws.com/arvinas-assets.investeddigital.com/scientific-publications/Cacace_TPD-10-24-2019_final.pdf
12. Jarosińska, OD and Rüdiger, SGD. Frontiers of Molecular Bioscience. 2021 Nov 12;8:769184.
13. Cacace, A, et al. Orally Administered PROTAC® Molecules Selectively Clear Pathologic Proteins in CNS & Muscle. Presented at the Society of Neuroscience 2022 Meeting; November 12-16. San Diego, CA. November.