Shots:

• Angela Cacace Sr. VP, of Neuroscience and Platform Biology at Arvinas, shares insights from the preclinical trials evaluating ARV-102 for treatment of neurodegenerative diseases and dosing people with the first oral formulation (ARV-102) to treat neurodegenerative diseases
• ARV-102, a novel oral PROTAC® protein degrader, is designed to cross the blood-brain barrier and target leucine-rich repeat kinase 2 (LRRK2)
• Angela sheds light on the company’s portfolio of neurodegenerative disorder

Saurabh: Congratulations on entering phase 1 and on the first subject's dosing! Can you enlighten us more about your phase 1 trial? 

Angela: We are really excited about our first-in-human dosing of ARV-102, our investigational, oral PROTAC® (PROteolysis-TArgeting Chimera) protein degrader designed to cross the blood-brain barrier and target leucine-rich repeat kinase 2 (LRRK2). The clinical program is designed to generate data including evaluation biomarkers of PROTAC-induced LRRK2 degradation and pathway engagement, thereby establishing proof of mechanism.

The phase 1 clinical trial of ARV-102 is enrolling healthy volunteers at the Centre for Human Drug Research (CHDR) in Leiden, the Netherlands with a goal of determining the dose as well as evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARV-102.

Saurabh: How does ARV-102 differ from other classes of drugs used in the treatment of neurodegenerative diseases? 

Angela: Our PROTAC® protein degraders belong to a new class of drugs designed to harness the cellular ubiquitin-proteasome (the body’s natural disposal system) for the destruction of disease-causing proteins. Our PROTAC protein degrader molecules work by directing the disease-related proteins to the proteasome for removal, in contrast to other molecules which inhibit the activity of disease-related proteins. Once the protein has been targeted for proteasomal degradation, the PROTAC is released, making it available for another round of activity. This iterative activity provides the potential for activity at low levels in the brain when compared to inhibitors. This is important as LRRK2 catalytic activity, scaffolding function, and increased expression have been shown to play a role in neurodegenerative diseases. ARV-102 has been designed to specifically destroy LRRK2, a key protein driving disease in progressive supranuclear palsy (PSP) and Parkinson’s disease, and also to penetrate the blood-brain barrier following oral dosing which is currently under clinical investigation. Additionally, there are no approved drugs in this class for neurodegenerative disease.

Saurabh: Can you shed some light on the preclinical trial results of ARV-102? 

Angela: We have carried out extensive preclinical studies on ARV-102 and are enthusiastic about our LRRK2 PROTAC® protein degrader for several reasons. First, in preclinical models, ARV-102 was shown to significantly increase lysosome number and activity in cells when compared to LRRK2 kinase inhibitors. Our preclinical studies suggest that following a single oral dose, the LRRK2 PROTAC degrader molecule is ~100 times more potent than kinase inhibitors at impacting both the target and lysosomal pathway marker, Phospho RAB, in the brain. ARV-102 crossed the blood-brain barrier in preclinical models and reached the brain at the anatomic sites of action required for Parkinson’s disease and PSP treatment. And finally, our LRRK2 PROTAC degrader is being studied following a single oral daily dose which, from a patient perspective, could be beneficial when compared to many other genomic technologies which require intrathecal administration into the spinal cord to reduce pathologic proteins.

Part of our efforts with our preclinical studies is the identification of pathway and disease relevant biomarkers in the blood and cerebrospinal fluid that we can examine over time. As our clinical trials progress, we will be able to track changes that will give us an indication of how we are impacting important pathways that are disease relevant.

Saurabh: As you said earlier, ARV-102 may also be helpful in the treatment of neurological diseases like Parkinson's and progressive supranuclear palsy (PSP). Could you elaborate on that? 

Angela: There is a lot of research supporting the role of LRRK2 in neurodegenerative diseases. There are familial mutations and genetic variants that implicate increases in LRRK2 activity and expression in Parkinson’s disease. Research from the broader community suggests that reducing the amount of the LRRK2 protein may have a greater impact on the disease process than simply inhibiting it.

Of note, recent studies by Mark Cookson and his colleagues have shown increased expression of LRRK2 occurs in microglia, a cell type that contributes to neuroinflammation in postmortem brains of Parkinson’s disease patients[i].

Researchers at the University of Alabama at Birmingham have shown a reduction in LRRK2 by about 50% using antisense oligonucleotides (ASOs) experimentally induced alpha-synuclein aggregation[ii] and dopaminergic neuron loss in a mouse model of Parkinson’s disease[iii]. Additionally, reducing LRRK2 levels versus inhibiting the kinase activity has been shown to rescue death of neurons in vitro and in an animal model in response to experimentally induced alpha-synuclein aggregation[iv], a known disease driver of Parkinson’s disease[v].

Finally, in PSP, a rapidly progressing neurodegenerative disease characterized by tau pathology, LRRK2 genetic variants are associated with accelerated progression and time to death[vi]​.

Based on this, and other research, we feel there is a very strong rationale for an oral, blood-brain penetrant, LRRK2 PROTAC® degrader molecule to be explored as a potential treatment option for Parkinson’s and other neurodegenerative diseases.

Arvinas is pioneering the discovery of novel PROTAC protein degraders in neuroscience. We are very excited to evaluate ARV-102 as a novel therapy that could address the significant unmet need in Parkinson's, PSP, and other neurological diseases.

Saurabh: How many subjects are expected to be enrolled in this phase 1 study? Based on non-clinical study results what are your expectations from the ongoing trial? 

Angela: We have not disclosed enrollment expectations. Our phase 1 study had been designed to evaluate safety and establish proof of mechanism by evaluating biomarkers of PROTAC®-induced LRRK2 degradation and pathway engagement.

Saurabh: As discussed, ARV-102 degrades vs. inhibits LRRK2. So, how do you believe that this may revolutionize the treatment of patients with neurodegenerative diseases? 

Angela: We believe that our PROTAC® protein degraders have the potential to change the treatment paradigm in neurodegenerative diseases. Preclinically, we have observed that LRRK2 PROTAC protein degraders differentiate from kinase inhibitors by enhancing both the number and degradative capacity of the lysosome in cells, reducing pathologic tau in cells and animal models, while having the ability to penetrate deep brain regions following oral dosing. We intend to evaluate disease relevant biomarkers in cerebrospinal fluid of patients as we advance our clinical program.

These preclinical results support our belief in the potential for our PROTAC protein degraders to make meaningful advances for treatment options in neurological diseases where very few disease-modifying therapies exist today. We’re excited about the opportunity and thank our entire Arvinas drug discovery and development team for their commitment.  

Saurabh: Do you have any plans for collaboration or partnership in the development of AVR-102? 

Angela: We are currently well-funded to move forward with our current plans; however, we are always assessing partnership or collaboration opportunities that would accelerate and broaden development plans.

Saurabh: Is there any other region or drug that you are currently working on? 

Angela: Together with the fantastic Arvinas neuroscience team, I am excited to be applying our cutting-edge blood-brain barrier penetrant PROTAC® platform on drug targets that are genetically implicated in neurodegenerative diseases and that we are now exploring in the clinical setting. In addition to LRRK2, we are looking to tackle other causes of neurodegenerative conditions such as mutant Huntingtin, alpha-synuclein, pathologic tau, and other disease-causing proteins. By reducing these proteins, we believe that a disease modifying therapeutic approach is possible. The potential of our PROTAC protein degrader small molecule platform technology is what brought me to the company, and it is that pioneering spirit that fuels our team every day. Thank you for this opportunity to share more about Arvinas and our PROTAC protein degraders!

Image Source: Canva

About the Author:

Angela M. Cacace, 

Ph.D., Senior Vice President, Neuroscience and Platform Biology, Arvinas

Dr. Angela Cacace serves as Senior Vice President of Neuroscience and Platform Biology at Arvinas. Dr. Cacace brings more than two decades of biopharmaceutical research and pharmacology experience, contributing to four marketed drugs and over 18 development candidates.

Previously, Dr. Cacace served as the Vice President of Biology at Fulcrum Therapeutics, where she built the biology platform and delivered the first development candidate for the treatment of facioscapulohumeral muscular dystrophy (FSHD).

Additionally, Dr. Cacace was the Director of Neuroscience and Genetically Defined Diseases at Bristol Myers Squibb, where she spearheaded alternative therapeutic modalities and was a co-inventor on several development candidates. Throughout her time at Bristol Myers Squibb, she was responsible for building research-wide teams and initiatives, including the Lead Profiling Function, GPCR High Throughput Screening Team and the Cellular Resource Team. While serving as a Sr. Principal Scientist in Cancer Biology at Pfizer, together with her team, she discovered a novel anti-angiogenic antibody development candidate.

Dr. Cacace received her B.S. in Biology from Fairfield University, Ph.D. in Pharmacology from Columbia University and completed her postdoctoral research in Oncology at Bristol Myers Squibb and the National Cancer Institute.

[i] Langston RG, Beilina A, Reed X, Kaganovich A, Singleton AB, Blauwendraat C, Gibbs JR, Cookson MR. Association of a common genetic variant with Parkinson's disease is mediated by microglia. Sci Transl Med. 2022 Jul 27;14(655):eabp8869. doi: 10.1126/scitranslmed.abp8869. Epub 2022 Jul 27. PMID: 35895835; PMCID: PMC9809150.

[ii] Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, Swayze EE, Kordasiewicz HB, West AB, Volpicelli-Daley LA. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids. 2017 Sep 15;8:508-519. doi: 10.1016/j.omtn.2017.08.002. Epub 2017 Aug 10. Erratum in: Mol Ther Nucleic Acids. 2021 May 29;24:1051-1053. Erratum in: Mol Ther Nucleic Acids. 2021 Aug 13;25:152-154. PMID: 28918051; PMCID: PMC5573879.

[iii] Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, Swayze EE, Kordasiewicz HB, West AB, Volpicelli-Daley LA. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids. 2017 Sep 15;8:508-519. doi: 10.1016/j.omtn.2017.08.002. Epub 2017 Aug 10. Erratum in: Mol Ther Nucleic Acids. 2021 May 29;24:1051-1053. Erratum in: Mol Ther Nucleic Acids. 2021 Aug 13;25:152-154. PMID: 28918051; PMCID: PMC5573879.

[iv] Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, Swayze EE, Kordasiewicz HB, West AB, Volpicelli-Daley LA. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids. 2017 Sep 15;8:508-519. doi: 10.1016/j.omtn.2017.08.002. Epub 2017 Aug 10. Erratum in: Mol Ther Nucleic Acids. 2021 May 29;24:1051-1053. Erratum in: Mol Ther Nucleic Acids. 2021 Aug 13;25:152-154. PMID: 28918051; PMCID: PMC5573879.

[v] Skibinski G, Nakamura K, Cookson MR, Finkbeiner S. Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J Neurosci. 2014 Jan 8;34(2):418-33. doi: 10.1523/JNEUROSCI.2712-13.2014. PMID: 24403142; PMCID: PMC3870929.

[vi]  Edwin Jabbari, PhD, Shunsuke Koga, MD, Rebecca R Valentino, PhD, Regina H Reynolds, MSc, Raffaele Ferrari, PhD, Manuela M X Tan, BPsych, et al. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. The Lancet Neurology. VOLUME 20, ISSUE 2, P107-116, FEBRUARY 2021. https://doi.org/10.1016/S1474-4422(20)30394-X

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