Pipeline – Dazostinag (TAK-676)

Overview^1-5

Dazostinag (TAK-676) is a novel small-molecule IV STING agonist optimized for systemic delivery that ignites the innate immune system and mobilizes adaptive immunity

Mechanism of Action^1-5

- Dazostinag is a systemic STING agonist, leading to production of type I interferons and proinflammatory cytokines.

- These proinflammatory cytokines aim to activate dendritic cells, macrophages, and natural killer cells, and subsequently mobilize adaptive immune cells against tumor cells

- Combining dazostinag with radiation and/or checkpoint inhibitors has shown enhanced anti-tumor activity in preclinical studies

- Dying tumor cells release tumor antigens and tumor-derived cGAMP, which continue to activate the STING pathway

cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; STING, stimulatory of interferon genes

TAK-676 is an investigational therapy. The mechanism of action is based on preclinical data. Clinical efficacy and safety have not been determined.

CD8, cluster of differentiation 8; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; IFN, interferon; IP-10, interferon gamma-induced protein 10; IRF-3, interferon regulatory factor 3; NK, natural killer; PD-L1, programmed cell death-ligand 1; PD-1, programmed cell death protein 1; STING, stimulator of interferon genes; TNF, tumor necrosis factor

Clinical Trials

Study Name

An Open-label, Dose Escalation, Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-676 as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Advanced or Metastatic Solid Tumors

Study Name

An Open-label, Phase 1 Dose Escalation Study to Evaluate the Safety and Preliminary Antitumor Activity of TAK-676 with Pembrolizumab following Radiation Therapy in the Treatment of Non-small Cell Lung Cancer, Triple-negative Breast Cancer, or Squamous-cell Carcinoma of the Head and Neck that has Progressed on Checkpoint Inhibitors

References

1. Carideo Cunniff E, Sato Y, Mai D, et al. TAK-676: A novel stimulator of interferon genes (STING) agonist promoting durable IFN-dependent antitumor immunity in preclinical studies. Cancer research communications. 2022;2(6):489-502. Web Link

2. Appleman V, Matsuda A, Ganno M, et al. PRECLINICAL ACTIVITY OF C-C CHEMOKINE RECEPTOR 2 (CCR2)-TARGETED IMMUNE STIMULATING ANTIBODY CONJUGATE (ISAC), MOTIVATING CLINICAL TESTING OF TAK-500. Journal for ImmunoTherapy of Cancer. 2022;10:A1194. Web Link

3. Cooper B, Chmura SJ, Luke JJ, et al. Phase 1 study of TAK-676 + pembrolizumab following radiation therapy in patients with advanced nonsmall-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN). Cancer Res. 2022;82(12). Web Link

4. Knelson EH, Ivanova EV, Tarannum M, et al. Activation of Tumor-Cell STING Primes NK-Cell Therapy. Cancer Immunol Res. 2022;10(8):947-961. Web Link

5. Yum S, Li M, Chen ZJ. Old dogs, new trick: classic cancer therapies activate cGAS. Cell Res. 2020;30(8):639-648. doi:10.1038/s41422-020-0346-1