PROteolysis TArgeting Chimera (PROTAC)

Rigel’s vepdegestrant is an oral PROteolysis Targeting Chimera (PROTAC).1

PROTACs are part of a new class of heterobifunctional protein degraders designed to harness the body’s natural machinery to selectively degrade, rather than inhibit, disease-causing proteins. They consist of two binding regions, one that binds to the target protein and one that binds to an E3 ubiquitin ligase, joined by a linker. PROTACs are designed to harness the body’s natural protein disposal machinery to target and eliminate specific proteins.

Vepdegestrant binds to an estrogen receptor (ER) and recruits an E3 ligase complex to tag the receptor with a chain of ubiquitin proteins. The ubiquitin-tagged estrogen receptor is then recognized and eliminated by the proteasome. Because vepdegestrant bonds transiently and reversible to both the E3 ligase complex and the estrogen receptor, it is able to repeat this process multiple times until metabolized. In preclinical models, vepdegestrant was associated with greater ER degradation and tumor growth inhibition vs. fulvestrant.2

Development of vepdegestrant:

  • In a Phase 1/2 clinical study (VERITAC) (NCT04072952), vepdegestrant was evaluated in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (mBC), including those that had an estrogen receptor 1 (ESR1) mutation.
  • In a Phase 3 clinical trial (VERITAC-2) (NCT05654623), vepdegestrant was evaluated in patients with ER+/HER2- mBC, including those with an ESR1 mutation.
  • Following the effective date of Rigel’s in-license of vepdegestrant, Arvinas and Pfizer will remain responsible for current clinical trials and Rigel will contribute up to $40 million for certain clinical activities over the next 4 years. The activities may provide key insights into additional development opportunities for vepdegestrant in the future. Clinical trials and studies include:
    • A PHASE 3, RANDOMIZED, OPEN-LABEL, MULTICENTER TRIAL OF ARV-471 (PF-07850327) VS FULVESTRANT IN PARTICIPANTS WITH ESTROGEN RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED BREAST CANCER WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE BASED TREATMENT FOR ADVANCED DISEASE (VERITAC-2) (NCT05654623)
    • A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, PARALLEL GROUP STUDY TO COMPARE THE PHARMACOKINETICS OF VEPDEGESTRANT (PF-07850327) IN ADULT PARTICIPANTS WITH MODERATE AND SEVERE HEPATIC IMPAIRMENT RELATIVE TO HEALTHY PARTICIPANTS WITH NORMAL HEPATIC FUNCTION (NCT07231991)
    • A PHASE I, OPEN-LABEL STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF ARV-471 (PF-07850327), A SINGLE AGENT IN JAPANESE PARTICIPANTS WITH ER+/HER2-LOCALLY ADVANCED OR METASTATIC BREAST CANCER (NCT05463952)
    • TACTIVE-U: AN INTERVENTIONAL SAFETY AND EFFICACY PHASE 1B/2, OPEN-LABEL UMBRELLA STUDY TO INVESTIGATE TOLERABILITY, PK, AND ANTITUMOR ACTIVITY OF ARV-471 (PF-07850327), AN ORAL PROTEOLYSIS TARGETING CHIMERA, IN COMBINATION WITH OTHER ANTICANCER TREATMENTS IN PARTICIPANTS AGED 18 YEARS AND OVER WITH ER+ ADVANCED OR METASTATIC BREAST CANCER
      • Sub-Study A (combination with abemaciclib) (NCT05548127)
      • Sub-Study B (combination with ribociclib (NCT05573555)
      • Sub-Study C (combination with samuraciclib) (NCT06125522)
    • AN INTERVENTIONAL SAFETY AND EFFICACY PHASE 1B/2, OPEN-LABEL STUDY TO INVESTIGATE TOLERABILITY, PK, AND ANTITUMOR ACTIVITY OF VEPDEGESTRANT (ARV-471/PF-07850327), AN ORAL PROTEOLYSIS TARGETING CHIMERA, IN COMBINATION WITH PF-07220060 IN PARTICIPANTS AGED 18 YEARS AND OLDER WITH ER+/HER2- ADVANCED OR METASTATIC BREAST CANCER (TACTIVE-K) (NCT06206837)

Note: The above trials are active, not enrolling, except for the hepatic impairment study (NCT07231991).

  1. In June 2026, Rigel entered intan exclusive, global licensing agreement with Arvinas and Pfizer tdevelop, manufacture and commercialize vepdegestrant.
  2. Gough, S, et al. Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models Open Access. Clin Cancer Res. August 15, 2024. Doi: https://doi.org/10.1158/1078-0432.CCR-23-3465