Power & potential
PIPELINE
(Phase 1)
(Phase 2)
(Phase 3)
ONCOLOGY
VVD-037
KEAP1 Activator
Solid tumors
VVD-850
STAT3 Inhibitor
Solid & hematologic tumors
VVD-214
WRN Inhibitor
Solid tumors with microsatellite instability
RAS-PIK3CA Inhibitor
Solid tumors
Undisclosed Targets
Solid tumors
IMMUNOLOGY
KEAP1 Inhibitor
Immunology
STAT3 Inhibitor
Immunology
Undisclosed Targets
Immunology
NEUROLOGY
Undisclosed Targets
Neurology
PROGRAMS / ONCOLOGY
Oncology program
KEAP1 Activator
Early Clinical (Phase 1)
TARGET SELECTION
KEAP1 is an E3 ligase that degrades NRF2, a master regulatory transcription factor that coordinates antioxidant, detoxification and cytoprotective gene programs. Gain-of-function mutations in NRF2 or loss-of-function mutations in KEAP1 lead to pathway activation, which can promote malignant tumor growth and resistance to many standard-of-care therapies. These mutations are most frequently detected in solid cancers, such as non-small cell lung cancer, esophageal squamous cell carcinoma, and head and neck squamous cell carcinoma.
SMALL MOLECULE APPROACH
VVD-037 is a highly selective, first-in-class small molecule activator of KEAP1 that allosterically enhances the ability of this E3 ligase to degrade its natural cellular target, NRF2. In preclinical models of NRF2-hyperactivated tumors, VVD-037-induced NRF2 depletion robustly inhibits tumor growth, as either a single agent or in combination with common chemotherapeutic agents and radiotherapy. Therapeutic targeting of NRF2 has the potential to dramatically shift the treatment paradigm of NRF2-activated cancers.
DEVELOPMENT STAGE
VVD-037 is currently being evaluated in a Phase 1 clinical trial (NCT05954312).
Oncology program
STAT3 Inhibitor
Early Clinical (Phase 1)
TARGET SELECTION
STAT3 is a transcription factor and oncogenic driver that has eluded traditional drug discovery approaches. Abnormal STAT3 activation is thought to contribute to tumor progression by promoting cellular proliferation, survival, metabolic realignment, angiogenesis, and immune evasion. In solid tumors, STAT3 may also directly interfere with immunotherapy treatment.
SMALL MOLECULE APPROACH
VVD-850 is an orally bioavailable, highly selective, small molecule inhibitor of STAT3 that allosterically prevents the transcription factor from binding DNA and driving downstream gene expression. Given the important role that STAT3 plays in both hematological cancers and solid tumors, Vividion’s approach to inhibiting STAT3 has the potential for broad utility across many different cancer types.
DEVELOPMENT STAGE
VVD-850 is being evaluated in a Phase 1 clinical trial (NCT06188208).
Oncology program
WRN Inhibitor
Early Clinical (Phase 1)
TARGET SELECTION
WRN helicase is an enzyme that maintains genomic stability and integrity. Cancer cells that are defective in a specific type of DNA repair exhibit microsatellite instability (MSI) in their genomic DNA and depend on this enzyme for growth and viability. WRN inhibition could be used to specifically target MSI-positive cancers.
SMALL MOLECULE APPROACH
VVD-214 is a WRN inhibitor designed to prevent MSI repair without harming healthy cells to treat MSI-positive cancers, including subsets of colorectal, endometrial, and gastric cancers.
DEVELOPMENT STAGE
Roche is currently evaluating VVD-214 (also known as RO7589831) in a phase 1 clinical trial (NCT06004245).
Oncology program
RAS-PIK3CA Inhibitor
IND Enabling
TARGET SELECTION
RAS proteins are membrane-bound GTPases that can cause multiple types of cancers by activating two signaling pathways, MAPK and PI3Kα. In preclinical models, it has been shown that simultaneous inhibition of these two signaling arms can effectively inhibit disease progression, but it has been difficult to implement this strategy clinically due to tolerability issues associated with the existing small molecules, which can disrupt homeostatic signaling through inhibition of the protein’s active site.
SMALL MOLECULE APPROACH
Vividion has discovered small molecules that inhibit RAS-dependent PIK3CA oncogenic signaling by specifically blocking the interaction between RAS and PIK3CA, without disrupting homeostatic signaling. Our molecules show dramatic benefit in pre-clinical models of RAS-driven cancers when combined with therapies targeting the MAPK pathway. In addition, we have found that this same mechanism is effective at countering adaptive resistance to RAS inhibitors. We therefore anticipate that our RAS-PIK3CA inhibitors will have broad clinical utility, particularly as part of rational combination therapies in RAS-driven cancers.
DEVELOPMENT STAGE
The RAS-PI3Kα program is currently in IND enablement.
PROGRAMS / IMMUNOLOGY
Immunology program
KEAP1 Inhibitor
IND Enabling
TARGET SELECTION
KEAP1 is an E3 ligase that degrades NRF2, a master regulatory transcription factor that protects tissues from damage by upregulating antioxidant, detoxification, and cytoprotective gene programs. In addition, NRF2 has important roles in tempering ongoing inflammatory responses by interfering with pro-inflammatory signaling, decreasing cytokine and chemokine production, and reducing leukocyte trafficking. Blocking NRF2 degradation could have a protective role in autoimmune disease.
SMALL MOLECULE APPROACH
Vividion has discovered a series of highly selective small molecule inhibitors of KEAP1 that allosterically block this E3 ligase from degrading NRF2, leading to the rapid accumulation of NRF2 in the nucleus and subsequent activation of its target genes. Vividion’s KEAP1 inhibitors have demonstrated significant inhibition of inflammatory cytokines and chemokines as well as restoration of epithelial healing in multiple preclinical models. This distinct, anti-inflammatory and cytoprotective mechanism holds substantial promise in various inflammatory and autoimmune indications, especially inflammatory bowel disease, by simultaneously inhibiting inflammation while promoting cellular resilience and healing.
DEVELOPMENT STAGE
The KEAP1 immunology program is currently in IND enablement.
Immunology program
STAT3 Inhibitor
IND Enabling
TARGET SELECTION
Within the immune system, STAT3 plays a critical role in relaying pathogenic signaling from certain cytokines (including IL-23 and IL-6 family members), which can drive many autoimmune conditions. Disrupting STAT3 activity can improve immunological pathologies by reducing inflammatory signaling, restoring balance to certain T cell populations, and interfering with stromal-immune amplification loops present in many chronic inflammatory diseases.
SMALL MOLECULE APPROACH
Vividion has discovered a series of highly selective, orally bioavailable, small molecule inhibitors of STAT3 that allosterically prevent this traditionally undruggable transcription factor from binding DNA and driving downstream gene expression. Vividion’s STAT3 inhibitors have demonstrated significant efficacy in preclinical models of Th17- and IL-6 mediated disease and restore balance between regulatory and pathogenic T-cells. Given STAT3’s central role in pathogenic cytokine signaling, Vividion’s inhibitors have the potential to treat a diverse range of autoimmune diseases such as inflammatory bowel disease, psoriasis, psoriatic arthritis, lupus, and fibrosis while leaving the anti-viral and tumor immune-surveillance response mediated by interferons intact.
DEVELOPMENT STAGE
The STAT3 immunology program is currently in IND enablement.
