Arvinas doses first patient with oral HPK1 PROTAC degrader ARV-6723 in advanced solid tumors
核心洞察
Arvinas has dosed the first participant in a Phase 1/2 trial of ARV-6723 (搜索), an oral PROTAC degrader of HPK1 (搜索), in adults with advanced solid tumors (搜索).
ARV-6723 (搜索) is Arvinas' first immuno-oncology clinical candidate and the first HPK1 (搜索) PROTAC degrader to enter clinical testing in the United States.
The global, multicenter ARV-6723 (搜索)-101 trial will assess safety, pharmacokinetics, pharmacodynamics and preliminary antitumor activity as monotherapy and with pembrolizumab.
Arvinas has dosed the first participant in a Phase 1/2 clinical trial of ARV-6723 (搜索), an investigational oral PROteolysis TArgeting Chimera (PROTAC) designed to degrade hematopoietic progenitor kinase 1 (HPK1 (搜索)) in advanced solid tumors (搜索). The candidate is Arvinas' first clinical program in immuno-oncology and, according to the company, the first HPK1 PROTAC degrader to enter the clinic in the United States.
HPK1 (搜索) acts as a negative regulator of immune activation and is expressed across multiple cell types, including T cells, B cells, natural killer cells and dendritic cells. The company states that HPK1 also plays an important role in shaping the tumor microenvironment. ARV-6723 (搜索) is designed to degrade and remove the HPK1 protein together with its signaling scaffolding, a mechanism intended to address functions of HPK1 that may not be fully covered by traditional inhibitors.
Trial Design and Endpoints
The ARV-6723 (搜索)-101 trial (NCT07749586) is a global, multicenter Phase 1/2 study assessing the safety, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of orally administered ARV-6723 as a monotherapy or in combination with pembrolizumab in adults with advanced solid tumors (搜索).
The first-in-human study will initially evaluate the safety of ARV-6723 (搜索) as monotherapy and subsequently in combination with an anti-PD-1 therapy. It will also examine whether deep and sustained HPK1 (搜索) degradation translates into meaningful antitumor effects in patients. The initial monotherapy cohort is enrolling patients who have received a prior immune checkpoint inhibitor and have no suitable standard treatment options.
Preclinical Rationale
In preclinical studies, ARV-6723 (搜索) demonstrated potent and selective HPK1 (搜索) degradation, enhanced immune activity and antitumor activity both as a single agent and in combination with an immune checkpoint inhibitor. These effects were observed across tumor models with differing levels of immune responsiveness, including multiple anti-PD-1-resistant models.
In seven preclinical models, ARV-6723 (搜索) showed meaningful single-agent activity where neither an HPK1 (搜索) inhibitor nor anti-PD-1 therapy showed benefit. Arvinas states that these data support clinical evaluation of the compound as both monotherapy and in combination with an anti-PD-1 therapy.
"The advancement of ARV-6723 (搜索) into the clinic represents an important step in expanding the application of targeted protein degradation into immuno-oncology," said Randy Teel, Ph.D., President and Chief Executive Officer at Arvinas. "Resistance to immunotherapy remains a significant challenge; to date, combinations targeting other immune pathways have not provided a reliable way to prevent or reverse it. The encouraging preclinical data for ARV-6723, including activity in models resistant to immune checkpoint inhibitors, support clinical investigation of its potential to address this unmet need for patients."
Degrader Mechanism Versus Inhibition
By removing HPK1 (搜索) rather than inhibiting its kinase activity, ARV-6723 (搜索) may address both kinase-dependent and kinase-independent functions of the protein and enhance antitumor immune activity, according to the company. Arvinas positions this as a potential differentiation from traditional inhibitors, which act on enzymatic activity alone.
Broader Protein Degradation Pipeline
Arvinas is advancing several investigational drugs through clinical development. These include ARV-393, targeting BCL6 for relapsed or refractory non-Hodgkin lymphoma (搜索); ARV-102, targeting LRRK2 (搜索) for neurodegenerative disorders; ARV-027 (搜索), targeting the polyglutamine-expanded androgen receptor (搜索) (polyQ-AR) in skeletal muscle for spinal-bulbar muscular atrophy (搜索), also known as Kennedy's disease; and ARV-6723 (搜索), targeting HPK1 (搜索) for advanced solid tumors (搜索). The company has also advanced ARV-806 (搜索), targeting KRAS G12D (搜索) for solid tumors, into the clinic and has previously announced plans to seek an out-licensing agreement for any additional clinical trials of ARV-806, including dose expansion or combination studies.
Arvinas, with its partner Pfizer, developed the first FDA-approved PROTAC, a type of heterobifunctional protein degrader, which has been out-licensed to Rigel Pharmaceuticals for exclusive global development, manufacturing and commercialization. Arvinas is headquartered in New Haven, Connecticut.