RESEARCH AND DEVELOPMENT | PIPELINE

Mechanism of Action:
ARV-102 is an investigational, orally bioavailable and brain-penetrant PROTAC designed to specifically target and degrade leucine-rich repeat kinase 2 (LRRK2) in neurodegenerative diseases. LRRK2 is a large, multi-domain scaffolding protein that impacts protein homeostasis and contributes to neuroinflammation in pathological disease states. Preclinical data demonstrate that ARV-102 broadly biodistributes across deep brain regions to degrade LRRK2 and early clinical data demonstrates that ARV-102 crosses the blood-brain barrier.

Diseases of Interest for Development:
Progressive supranuclear palsy (PSP) and Parkinson’s disease are neurodegenerative diseases characterized by abnormal protein misfolding and have overlapping clinical phenotypes associated with movement disorders. LRRK2 is genetically linked to PSP, where higher levels of LRRK2 are associated with faster PSP disease progression. Similarly, mutations in LRRK2 are known to cause Parkinson’s disease, and elevated LRRK2 protein levels and kinase activity play a role in Parkinson’s disease more broadly.

In both PSP and Parkinson’s disease, elevated LRRK2 contributes to neuroinflammation and impairs protein homeostasis by disrupting the endolysosomal system, directly contributing to the accumulation of aggregated tau and alpha-synuclein in PSP and Parkinson’s disease, respectively. LRRK2 may also phosphorylate tau through direct and indirect mechanisms. Currently, there is no cure for either disease and treatment options are limited.

Clinical Status:
ARV-102 is currently under investigation with additional clinical studies planned for 2026.

Mechanism of Action:
ARV-027 is an investigational oral, peripherally restricted PROTAC degrader designed to selectively target and eliminate toxic polyglutamine-expanded androgen receptor (polyQ-AR) in skeletal muscle. PolyQ-AR is the root cause of motor dysfunction in spinal bulbar muscular atrophy (SBMA) or Kennedy’s disease due to the toxic gain of function imparted by the polyQ expansion on the AR. PolyQ-AR misfolds and aggregates in a ligand-dependent manner, disrupts normal transcription, and impairs muscle and mitochondrial function, ultimately driving progressive neuromuscular degeneration.

ARV-027 is a clinical candidate specifically selected for potent in vitro reduction of cytosolic and nuclear polyQ-AR and for favorable skeletal-muscle exposure following oral administration. Preclinical data demonstrated that ARV-027 showed robust pharmacokinetic (PK)/pharmacodynamic (PD)–driven degradation of muscle polyQ-AR in a rapidly progressing polyQ-AR overexpression model where ARV-027 induced polyQ-AR degradation in muscle tissues and rescued both strength and endurance.

Diseases of Interest for Development:
SBMA, also known as Kennedy’s disease, is a rare, X-linked, genetically defined neuromuscular disease caused by a CAG trinucleotide repeat expansion (polyQ) in the AR gene, causing protein misfolding and leading to progressive degeneration of the neuromuscular system primarily in men. There are currently no approved disease-modifying therapies for SBMA.

Clinical Status:
ARV-027 is currently under investigation in a Phase 1 clinical study in healthy male participants:

• ARV-027-101: EUCT 2025-523469-79-00

Mechanism of Action:
ARV-393 is an investigational, orally bioavailable PROTAC designed to specifically target and degrade the B-cell lymphoma 6 (BCL6) protein. BCL6 is a master regulator of germinal center (GC) B-cell development, an established oncogenic driver in multiple non-Hodgkin lymphomas (NHLs), and more recently implicated in nodal T-follicular helper cell lymphoma of angioimmunoblastic type (nTFHL-AI, formerly AITL). BCL6 has long been considered “undruggable” due to the inability of inhibitors to achieve sustained pathway suppression. ARV-393 leverages a catalytic, event-driven mechanism of action to counteract the rapid resynthesis rate of the BCL6 protein resulting in potent, sustained degradation and robust single agent and combination activity across aggressive preclinical NHL models.

Diseases of Interest for Development:
Despite significant progress made with treating B-cell NHL and nTFHL, many patients will ultimately experience disease progression or relapse. Thus, there remains an unmet need for novel mechanisms (like BCL6 degradation) and drug combinations that may be able to improve clinical outcomes.

Clinical Status:
ARV-393 is currently being evaluated in a Phase 1 trial as a monotherapy in patients with relapsed or refractory NHL as well as in combination with glofitamab in DLBCL (NCT06393738).

Mechanism of Action:
ARV-6723 is an investigational, oral PROTAC designed to degrade hematopoietic progenitor kinase 1 (HPK1) in solid malignancies and is Arvinas’ first clinical candidate in the immuno-oncology (IO) space. HPK1 acts as a negative regulator in T-cell receptor signaling, and therefore degrading HPK1 has the potential to unleash an immune response with potent anti-tumor effects and minimal off-target toxicity. Preclinically, ARV-6723 as a single agent and in combination with immune checkpoint inhibitors has shown potent, selective HPK1 degradation and anti-tumor immune responses in low- and high-immunogenic tumor models, as well as in IO-resistant models.

Diseases of Interest for Development:
Solid malignancies such as non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC), where dysfunctional tumor microenvironment contributes to immune suppression and resistance to IO therapy. New therapies are needed to address the immunosuppressive activities of HPK1 driven by a dysfunctional tumor microenvironment.

Clinical Status:
A Phase 1 trial is planned to begin in 2026.

Mechanism of Action:
ARV-806 is an investigational novel PROTAC designed to selectively target and degrade mutant Kirsten rat sarcoma (KRAS) G12D in solid tumors.

KRAS is one of the most frequently mutated human oncogenes and G12D is the most common mutation of the KRAS protein. KRAS exists in both an “ON” and “OFF” form and most inhibitors target one state or the other. However, the ternary complex formed by PROTAC degraders between the protein of interest and the E3 ligase allows ARV-806 to target both “ON” and “OFF” forms of KRAS G12D. By using the body’s own disposal system to eliminate the KRAS G12D protein, rather than inhibiting its activity, ARV-806 aims to directly block oncogenic signaling and disrupt pathways that drive tumor growth and survival.

Diseases of Interest for Development:
Pancreatic, colorectal, and non-small cell lung cancer (NSCLC) are solid tumor cancers frequently driven by KRAS G12D mutations. There are currently no approved therapies that specifically target KRAS G12D mutations.

Clinical Status:
ARV-806 is currently being evaluated in a Phase 1/2 clinical trial in patients with advanced solid tumors harboring KRAS G12D mutations (NCT07023731). Arvinas plans to complete the ongoing Phase 1 monotherapy dose escalation clinical trial for ARV-806 and seek an out-licensing agreement for any additional clinical trials, including dose expansion or combination clinical trials.

Vepdegestrant is an orally bioavailable PROTAC, a type of heterobifunctional protein degrader therapy, under investigation for additional uses in treating advanced or metastatic breast cancer. Arvinas and Pfizer are responsible for current ongoing development activities. Future development plans will be determined by Rigel Pharmaceuticals following a license agreement in May 2026.

Luxdegalutamide is an investigational, orally bioavailable PROTAC androgen receptor (AR) degrader. In the second quarter of 2024, Arvinas completed a transaction with Novartis Pharma AG, which included a global license agreement with Novartis for the development and commercialization of luxdegalutamide for the treatment of prostate cancer. Novartis is progressing luxdegalutamide in Phase 2 trials in combination with PLUVICTO® in metastatic castrate-resistant prostate cancer (mCRPC), tulmimetostat in mCRPC, and abiraterone in metastatic hormone-sensitive prostate cancer. Learn more.