Dosing of oral ARV-102 begins in healthy volunteers in Phase 1 trial

Arvinas developing therapy for Parkinson's, other neurodegenerative diseases

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A first participant has been dosed in Arvinas’ first-in-human Phase 1 trial testing ARV-102, its oral therapy candidate for neurodegenerative conditions, including Parkinson’s disease and progressive supranuclear palsy, or PSP, an atypical parkinsonian disorder.

The Phase 1 trial — now enrolling healthy volunteers at the Centre for Human Drug Research, in the Netherlands — aims to evaluate the safety and tolerability of ARV-102. It’s also assessing the experimental therapy’s pharmacokinetics, meaning its movement into, through, and out of the body, and its pharmacodynamics, or its effects on the body.

Arvinas developed ARV-102 using the its proprietary PROTAC protein degradation platform, which tags disease-causing proteins for breakdown.

The key to this investigational therapy it that it’s designed to cross the blood-brain barrier, a highly selective membrane that shields the central nervous system, comprised of the brain and spinal cord, from systemic blood circulation. It then can target for degradation the leucine-rich repeat kinase 2 (LRRK2), a protein known to be overactive in Parkinson’s and PSP.

“Parkinson’s disease and progressive supranuclear palsy are devastating diseases and this important step of dosing the first healthy volunteer with ARV-102 marks a significant milestone in our commitment to develop transformative therapies for patients living with neurodegenerative diseases,” Angela M. Cacace, PhD, senior vice president, neuroscience and platform biology at Arvinas, said in a company press release.

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Mutations in the LRRK2 gene, which provides instructions for making the protein of the same name, are one of the most common genetic causes of Parkinson’s.

The LRRK2 protein also is thought to be overactive in Parkinson’s even when patients don’t have a mutation. Its overactivation in microglia cells — the immune cells of the brain responsible for protecting neurons from different types of threats — has been linked with brain inflammation, also called neuroinflammation.

According to preclinical data, which was presented by Cacace in a company webcast, ARV-102 reduced the levels of LRRK2 in human microglia cells.

In nonhuman primates, oral administration of ARV-102 reached deep brain regions, including the cortex, as well as the striatum and the cerebellum, which are two brain regions involved in voluntary movement control.

In the cortex and striatum, ARV-102 led to a 87% degradation of LRRK2, and in the cerebellum of 89%.

There is a high unmet need in many neurologic diseases, and unlike other therapeutic modalities designed to inhibit LRRK2 activity, ARV-102 is … uniquely designed to cross the blood-brain barrier.

Moreover, in a mouse model of Parkinson’s disease, ARV-102 showed a better target engagement and a greater potency when compared with a traditional LRRK2 inhibitor, or blocker. The reduction in LRRK2 also was detected in primates’ cerebrospinal fluid, the liquid which surrounds the brain and spinal cord.

In addition to safety and tolerability measures, the Phase 1 trial also will evaluate the degradation of LRRK2 as well as exploratory assessments of LRRK2 pathway biomarkers.

“There is a high unmet need in many neurologic diseases, and unlike other therapeutic modalities designed to inhibit LRRK2 activity, ARV-102 is an investigational oral PROTAC degrader uniquely designed to cross the blood-brain barrier and degrade the LRRK2 protein,” Cacace said.

During the webcast, Cacace called the findings of the therapy in the primates “very exciting.”

Now, Arvinas is focused on testing the experimental treatment in humans.

“As a pioneer in targeted protein degradation, we believe that PROTAC degraders have great potential to change the treatment paradigm for patients with neurodegenerative diseases,” Cacace said.