Arvinas, Inc. (NASDAQ: ARVN) recently presented data from the first-in-human clinical trial of arv-102, the company’s investigational proteolysis targeting chimera (protac) leucine-rich repeat kinase 2 (lrrk2) degrader. The trial demonstrated substantial reduction of lrrk2 in cerebral spinal fluid (CSF) with a positive safety/tolerability profile and favorable pharmacodynamic outcomes.
The key findings from the trial are as follows: Arv-102 was generally safe and well tolerated with no serious adverse events reported after single or multiple doses. Arv-102 exposure in the CSF increased in a dose-dependent manner after single and multiple doses, indicating brain penetration. At a single oral dose of at least 60 mg, and once daily repeated oral doses of at least 20 mg, arv-102 achieved greater than 50% lrrk2 reduction in the CSF and greater than 90% lrrk2 reduction in the peripheral blood mononuclear cells (PBMCS), indicating substantial central and peripheral lrrk2 protein degradation. Inhibition of rab10 phosphorylation in PBMCS and reduction of bis(monoacylglycerol)phosphate (BMP) in urine following single doses of arv-102, signifying downstream lrrk2 pathway engagement.
Arv-102 is a novel investigational oral protac designed to cross the blood-brain barrier and target lrrk2. According to Noah Berkowitz, M.D., Ph.D., chief medical officer at Arvinas, "the ability of arv-102 to cross the blood-brain barrier and degrade the lrrk2 protein offers a potentially transformative therapeutic approach in the treatment of devastating neurodegenerative diseases."
The safety profile of arv-102 is notable: * Of the 47 volunteers across all single ascending dose (SAD) levels, the primary treatment related adverse events were headache and fatigue. No serious adverse events were reported in either the SAD or multiple ascending dose (MAD) cohorts.
Pharmacokinetic and pharmacodynamic evaluations revealed: Arv-102 exhibited median maximum concentration (tmax) 6 hours after oral administration. The area under the concentration-time curve in the first 24 hours post dosing (AUC0-24) and the maximum plasma concentration (Cmax) increased in a dose-dependent manner. Arv-102 levels in CSF increased in a dose-dependent manner in both the SAD and MAD cohorts. At single doses of greater than or equal to 60 mg and repeated doses of greater than or equal to 20 mg, lrrk2 reduction of greater than 90% in PBMCS was observed. * Arv-102 at single doses of greater than or equal to 30 mg induced greater than 50% decreases in peripheral phospho-rab10t73, a lrrk2 substrate and biomarker for downstream lrrk2 activity.
Arvinas is continuing its investigation of arv-102 in neurodegenerative diseases associated with lrrk2 and lysosome dysfunction and has initiated dosing in the SAD cohort of the phase 1 clinical trial with arv-102 in patients with Parkinson's disease in the fourth quarter of 2024.
Arv-102, which is an oral, brain-penetrant investigational protac designed to degrade leucine-rich repeat kinase 2 (lrrk2), offers potential in the treatment of neurological diseases, including Parkinson's disease and progressive supranuclear palsy.
Arvinas is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through its protac (proteolysis targeting chimera) protein degrader platform, the company is pioneering the development of protein degradation therapies designed to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs. The market has reacted to these announcements by moving the company's shares -5.7% to a price of $6.5. For the full picture, make sure to review Arvinas's 8-K report.
