Arvinas Presents First-in-Human Data for Investigational Oral PROTAC ARV-102 Demonstrating Blood-Brain Barrier Penetration, and Central and Peripheral LRRK2 Degradation
Arvinas (ARVN) presented promising first-in-human clinical trial data for ARV-102, their investigational oral PROTAC LRRK2 degrader, at AD/PD™ 2025. The trial demonstrated that ARV-102 successfully penetrates the blood-brain barrier and achieves substantial LRRK2 protein degradation in both central and peripheral systems.
Key findings showed ARV-102 was well-tolerated with no serious adverse events. At single doses ≥60mg and daily doses ≥20mg, the drug achieved >50% LRRK2 reduction in cerebrospinal fluid and >90% reduction in peripheral blood mononuclear cells. The Phase 1 trial included single ascending dose (SAD) cohorts (10-200mg) and multiple ascending dose (MAD) cohorts (10-80mg).
The company has initiated a Phase 1 trial in Parkinson's disease patients and expects to complete enrollment and present initial data from the SAD cohort, as well as initiate the MAD cohort, in 2025.
Arvinas (ARVN) ha presentato dati promettenti del primo trial clinico sull'uomo per ARV-102, il loro investigativo degrader PROTAC LRRK2 orale, all'AD/PD™ 2025. Il trial ha dimostrato che ARV-102 riesce a penetrare la barriera emato-encefalica e a raggiungere una significativa degradazione della proteina LRRK2 sia nei sistemi centrale che periferico.
I risultati chiave hanno mostrato che ARV-102 è ben tollerato senza eventi avversi gravi. A dosi singole ≥60mg e dosi giornaliere ≥20mg, il farmaco ha ottenuto una riduzione >50% di LRRK2 nel liquido cerebrospinale e una riduzione >90% nelle cellule mononucleate del sangue periferico. Il trial di Fase 1 ha incluso coorti a dose ascendente singola (SAD) (10-200mg) e coorti a dose ascendente multipla (MAD) (10-80mg).
La società ha avviato un trial di Fase 1 in pazienti affetti da malattia di Parkinson e prevede di completare l'arruolamento e presentare i dati iniziali della coorte SAD, oltre a iniziare la coorte MAD, nel 2025.
Arvinas (ARVN) presentó datos prometedores del primer ensayo clínico en humanos para ARV-102, su degradador PROTAC LRRK2 oral en investigación, en el AD/PD™ 2025. El ensayo demostró que ARV-102 penetra con éxito la barrera hematoencefálica y logra una degradación sustancial de la proteína LRRK2 tanto en los sistemas central como periférico.
Los hallazgos clave mostraron que ARV-102 fue bien tolerado sin eventos adversos graves. A dosis únicas ≥60mg y dosis diarias ≥20mg, el fármaco logró una reducción >50% de LRRK2 en el líquido cefalorraquídeo y una reducción >90% en las células mononucleares de sangre periférica. El ensayo de Fase 1 incluyó cohortes de dosis ascendente única (SAD) (10-200mg) y cohortes de dosis ascendente múltiple (MAD) (10-80mg).
La compañía ha iniciado un ensayo de Fase 1 en pacientes con enfermedad de Parkinson y espera completar la inscripción y presentar datos iniciales de la cohorte SAD, así como iniciar la cohorte MAD, en 2025.
Arvinas (ARVN)는 AD/PD™ 2025에서 그들의 연구 중인 경구 PROTAC LRRK2 분해제인 ARV-102에 대한 첫 번째 인간 임상 시험 데이터를 발표했습니다. 이 시험은 ARV-102가 혈액-뇌 장벽을 성공적으로 통과하고 중앙 및 말초 시스템 모두에서 LRRK2 단백질의 상당한 분해를 달성함을 보여주었습니다.
주요 발견은 ARV-102가 심각한 부작용 없이 잘 견딜 수 있음을 나타냈습니다. 단일 용량 ≥60mg 및 일일 용량 ≥20mg에서 이 약물은 뇌척수액에서 LRRK2를 >50% 감소시키고 말초 혈액 단핵 세포에서 >90% 감소를 달성했습니다. 1상 시험에는 단일 상승 용량(SAD) 집단(10-200mg)과 다중 상승 용량(MAD) 집단(10-80mg)이 포함되었습니다.
회사는 파킨슨병 환자를 대상으로 1상 시험을 시작했으며, 2025년까지 SAD 집단의 초기 데이터를 발표하고 MAD 집단을 시작할 것으로 기대하고 있습니다.
Arvinas (ARVN) a présenté des données prometteuses d'un essai clinique de première intention chez l'homme pour ARV-102, leur dégradateur PROTAC LRRK2 oral en cours d'investigation, lors de l'AD/PD™ 2025. L'essai a démontré qu'ARV-102 pénètre avec succès la barrière hémato-encéphalique et atteint une dégradation substantielle de la protéine LRRK2 à la fois dans les systèmes central et périphérique.
Les résultats clés ont montré qu'ARV-102 était bien toléré sans événements indésirables graves. À des doses uniques ≥60mg et des doses quotidiennes ≥20mg, le médicament a obtenu une réduction de >50% de LRRK2 dans le liquide céphalorachidien et une réduction de >90% dans les cellules mononucléées du sang périphérique. L'essai de phase 1 a inclus des cohortes à dose unique croissante (SAD) (10-200mg) et des cohortes à dose multiple croissante (MAD) (10-80mg).
La société a lancé un essai de phase 1 chez des patients atteints de la maladie de Parkinson et prévoit de finaliser l'inscription et de présenter les données initiales de la cohorte SAD, ainsi que de commencer la cohorte MAD, en 2025.
Arvinas (ARVN) hat vielversprechende Daten aus der ersten klinischen Studie am Menschen für ARV-102, ihren experimentellen oralen PROTAC LRRK2-Degrader, auf dem AD/PD™ 2025 präsentiert. Die Studie zeigte, dass ARV-102 erfolgreich die Blut-Hirn-Schranke durchdringt und eine erhebliche LRRK2-Proteinabbau sowohl im zentralen als auch im peripheren System erreicht.
Wichtige Ergebnisse zeigten, dass ARV-102 gut verträglich war und keine schweren unerwünschten Ereignisse auftraten. Bei Einzelgaben ≥60mg und täglichen Dosen ≥20mg erreichte das Medikament eine >50%ige Reduktion von LRRK2 in der Gehirn-Rückenmarks-Flüssigkeit und eine >90%ige Reduktion in peripheren Blutmononuklearzellen. Die Phase-1-Studie umfasste Einzel-Dosierungsgruppen (SAD) (10-200mg) und Mehrfach-Dosierungsgruppen (MAD) (10-80mg).
Das Unternehmen hat eine Phase-1-Studie bei Parkinson-Patienten gestartet und erwartet, die Rekrutierung abzuschließen und erste Daten aus der SAD-Gruppe sowie die Einleitung der MAD-Gruppe im Jahr 2025 zu präsentieren.
- Successful demonstration of blood-brain barrier penetration and LRRK2 protein degradation
- Strong safety profile with no serious adverse events reported
- Significant efficacy with >90% LRRK2 reduction in peripheral blood cells
- Advancement to Phase 1 trial in Parkinson's disease patients
- Treatment-related adverse events including headaches in 17.1% of treated subjects
- Post lumbar puncture syndrome observed in 17.1% of treated cohort
Insights
Arvinas presents compelling Phase 1 data for their PROTAC degrader ARV-102 that represents a significant milestone for their neuroscience pipeline. The results demonstrate three critical achievements for a CNS therapeutic candidate: blood-brain barrier penetration, substantial LRRK2 protein degradation (>50% in CSF and >90% in peripheral blood), and a favorable safety profile with no serious adverse events.
The data validate Arvinas' PROTAC technology in neurodegenerative conditions by showing that oral ARV-102 can effectively reach and degrade a target protein in the brain. This is particularly noteworthy because LRRK2 dysfunction is implicated in both Parkinson's disease and progressive supranuclear palsy, representing substantial market opportunities. The dose-dependent responses observed in both single and multiple ascending dose cohorts suggest a predictable pharmacological profile.
Beyond target engagement, the downstream pathway modulation (inhibition of Rab10 phosphorylation and reduction of BMP in urine) confirms the drug is producing the desired biological effects. The advancement to testing in Parkinson's disease patients signals strong confidence in these results. While early-stage, these data substantially de-risk Arvinas' CNS platform by demonstrating their degrader technology can effectively operate in the challenging environment of the central nervous system.
This first-in-human data represents a significant technical validation for Arvinas' PROTAC platform in neurodegenerative diseases. Successfully demonstrating blood-brain barrier penetration with meaningful target degradation addresses a critical question about whether Arvinas' technology could effectively translate to CNS conditions.
The achievement of >50% LRRK2 reduction in CSF and >90% reduction in peripheral blood at reasonably low doses (60mg single dose, 20mg multiple dose) suggests excellent potency. The clean safety profile—particularly important for chronic neurodegenerative conditions—further strengthens the clinical potential. The favorable pharmacodynamic outcomes and downstream pathway engagement provide strong biological validation.
From a pipeline perspective, this success potentially unlocks significant value beyond this specific program. With LRRK2 established as a viable CNS target for their platform, Arvinas could pursue additional neurodegenerative targets, substantially expanding their addressable market beyond their core oncology focus. The initiation of patient trials suggests accelerated development, potentially shortening time-to-market. While revenue remains years away, these results meaningfully de-risk Arvinas' diversification strategy and validate their platform's versatility across therapeutic areas.
– Data demonstrate that ARV-102 was well tolerated, orally bioavailable, and brain-penetrant; ARV-102 achieved central and peripheral LRRK2 reduction indicating substantial LRRK2 protein degradation in healthy volunteers –
– Findings support continued evaluation of ARV-102 in neurodegenerative diseases associated with LRRK2 dysfunction; a Phase 1 trial in patients with Parkinson's disease has been initiated and is currently enrolling –
NEW HAVEN, Conn., April 04, 2025 (GLOBE NEWSWIRE) -- Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company working to develop a new class of drugs based on targeted protein degradation, today 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. In the trial, ARV-102 demonstrated substantial reduction of LRRK2, a multifunctional protein that has been implicated in Parkinson’s disease (PD) and progressive supranuclear palsy (PSP), in cerebral spinal fluid (CSF), with a promising safety/tolerability profile and favorable pharmacodynamic outcomes. Results from the randomized, double-blind, placebo-controlled single ascending dose (SAD) cohort of the Phase 1 healthy volunteer trial, and initial results from the multiple ascending dose (MAD) cohort, were shared in a presentation at the 2025 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD™ 2025) in Vienna, Austria.
The SAD cohort evaluated ARV-102 doses ranging from 10 mg to 200 mg. The MAD cohort evaluated doses ranging from 10 mg to 80 mg. Key findings from the trial showed:
- 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 than90% 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. While LRRK2 is primarily known for its role in PD, emerging evidence suggests that it also plays a role in tauopathies, including PSP, and that LRRK2 dysfunction may contribute to the development and progression of both diseases.
“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,” said Noah Berkowitz, M.D., Ph.D., Chief Medical Officer at Arvinas. “We believe these results support continuing our ARV-102 clinical program and building upon our body of evidence for this lead PROTAC degrader candidate in our neuroscience pipeline.”
Data presented at AD/PD™ 2025
The ARV-102 Phase 1 study is designed to assess the safety, pharmacokinetics, and pharmacodynamics of orally administered ARV-102 in healthy male volunteers. This is a single-center, randomized, double-blind, placebo-controlled trial evaluating outcomes in both SAD and MAD cohorts. In the SAD cohort, volunteers were randomized 3:1 to either placebo or a single dose of ARV-102 (10 mg, 30 mg, 60 mg, 90 mg, 150 mg, or 200 mg) on day 1 with follow-up until day 10. In the MAD cohort, volunteers were randomized to either placebo or a once daily dose of ARV-102 (10 mg, 20 mg, 40 mg, or 80 mg) for 14 days with follow-up until day 28.
Safety Profile
- At the time of data cutoff (March 13, 2025), the SAD cohort of the Phase 1 clinical trial is completed and the MAD cohort is ongoing. Based on evaluation of the available data from single and multiple oral doses, ARV-102 was well tolerated in healthy volunteers.
- Of the 47 volunteers across all SAD dose levels, the primary treatment related adverse events were headache and fatigue. Headaches occurred in
17.1% (6/35) of treated individuals compared to0% (0/12) in placebo controls. Fatigue occurred in8.6% (3/35) of the treated individuals compared to25% (3/12) in placebo controls. - Procedural pain associated with the lumbar puncture occurred in
28.6% (10/35) of treated individuals compared to41.7% (5/12) in placebo controls. Post lumbar puncture syndrome was only observed in the treated cohort, at a rate of17.1% (6/35). - No serious adverse events were reported in either the SAD or MAD cohorts.
ARV-102 Exposure in Plasma and CSF
- 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 and the median terminal plasma half-life (t1/2) was 73 hours.
- ARV-102 levels in CSF increased in a dose dependent manner in both the SAD and MAD cohorts.
Pharmacodynamic Evaluation
- 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; data for this endpoint in the MAD cohort is pending. - ARV-102 at single doses of greater than or equal to 30 mg resulted in greater than
90% decrease of BMP in urine, a biomarker of lysosomal function; data for this endpoint in the MAD cohort is pending. - In CSF, ARV-102 induced dose-dependent LRRK2 reduction, with greater than
50% LRRK2 reduction at single doses of greater than or equal to 60 mg and repeated doses of greater than or equal to 20 mg.
Arvinas believes these results support continued investigation of ARV-102 in neurodegenerative diseases associated with LRRK2 and lysosome dysfunction.
- In the fourth quarter of 2024, Arvinas initiated dosing in the SAD cohort of the Phase 1 clinical trial with ARV-102 in patients with PD (EUCT 2024-516888-84-00). The Company expects to complete enrollment and present initial data from the ongoing SAD cohort of the Phase 1 clinical trial in patients with PD and initiate the MAD cohort of the Phase 1 clinical trial in patients with PD, in 2025.
Additional detail on the ARV-102 data presentation at AD/PD 2025 follows below:
Session Title: First-In-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of ARV-102, a PROTAC LRRK2 Degrader, in Healthy Males (ID:1963)
Session Type: Symposium: LRRK2, Alpha-Synuclein, Parkin: Diagnosis and Therapeutic Targets (ID:83)
Date: Friday, April 4, 2025
Lecture Time: 3:20 p.m. - 3:35 p.m. CET
About ARV-102
ARV-102 is an oral, brain-penetrant investigational PROTAC designed to degrade leucine-rich repeat kinase 2 (LRRK2), which is a large, multidomain scaffolding kinase. Increased activity and expression of LRRK2 have been implicated in the pathogenesis of neurological diseases, including LRRK2 genetic and idiopathic Parkinson’s disease and progressive supranuclear palsy.
About Arvinas
Arvinas (Nasdaq: ARVN) 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 harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs, including vepdegestrant, targeting the estrogen receptor for patients with locally advanced or metastatic ER+/HER2- breast cancer; ARV-393, targeting BCL6 for relapsed/refractory non-Hodgkin Lymphoma; and ARV-102, targeting LRRK2 for neurodegenerative disorders. Arvinas is headquartered in New Haven, Connecticut. For more information about Arvinas, visit www.arvinas.com and connect on LinkedIn and X.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the potential for Arvinas’ investigational oral PROteolysis TArgeting Chimera (PROTAC) degrader ARV-102 to treat neurodegenerative diseases associated with leucine-rich repeat kinase 2 (LRRK2) dysfunction; the ability of ARV-102 to cross the blood-brain barrier and degrade the LRRK2 protein offering a potentially transformative therapeutic approach in the treatment of neurodegenerative diseases; the first-in-human data for ARV-102 supporting continuing the ARV-102 clinical program and building upon Arvinas’ body of evidence for ARV-102 in its neuroscience pipeline; LRRK2 dysfunction contributing to the development and progression of Parkinson’s disease (“PD”) and progressive supranuclear palsy (“PSP”); and Arvinas’ plans relating to the completion of enrollment and presentation of initial data from the ongoing single ascending dose cohort of the Phase 1 clinical trial of ARV-102 in patients with PD, and initiation of the multiple ascending dose cohort of the Phase 1 clinical trial of ARV-102 in patients with PD, including timings thereof. All statements, other than statements of historical facts, contained in this press release, including statements regarding Arvinas’ strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
Arvinas may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on such forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements Arvinas makes as a result of various risks and uncertainties, including but not limited to: whether Arvinas will be able to successfully conduct and complete development for its product candidates, including ARV-102, including whether Arvinas initiates and completes clinical trials for its product candidates and receives results from its clinical trials on its expected timelines or at all; Arvinas’ ability to protect its intellectual property portfolio; whether Arvinas’ cash and cash equivalent resources will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; and other important factors discussed in the “Risk Factors” section of Arvinas’ Annual Report on Form 10-K for the year ended December 31, 2024 and subsequent other reports on file with the U.S. Securities and Exchange Commission. The forward-looking statements contained in this press release reflect Arvinas’ current views with respect to future events, and Arvinas assumes no obligation to update any forward-looking statements, except as required by applicable law. These forward-looking statements should not be relied upon as representing Arvinas’ views as of any date subsequent to the date of this release.
Contacts:
Investors:
Jeff Boyle
+1 (347) 247-5089
Jeff.Boyle@arvinas.com
Media:
Kirsten Owens
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Kirsten.Owens@arvinas.com
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