Mechanism of action: Signal transducer and activator of transcription 3 (STAT3) antisense

Preclinical pharmacology

AZD9150 is a 16 oligonucleotide antisense molecule (ASO) targeting the 3’ untranslated part of STAT3 thereby preventing the production of the protein. AZD9150 knocks down mRNA and protein in multiple tumour cell screens, and demonstrated a good correlation between mRNA knockdown and protein knockdown in vitro. Control ASOs did not impact STAT3 mRNA or protein levels at any dose. STAT3 inhibition leads to apoptosis in lymphoma cells. In vivo, a dose dependent and time dependant knockdown of STAT3 mRNA and protein were shown in multiple xenografts and explants. In vivo tumour growth inhibition (TGI) has been shown in xenografts and explants, with TGI shown predominately in explants.

Safety and tolerability

AZD9150 has been administered IV to DLBCL and HCC patients in multiple doses up to 3 mg/kg. AZD9150 is given as a three-hour IV infusion on Cycle 0 Days 1, 3, 5, and weekly three-hour IV infusions in Cycles 1 and beyond, on Days 1, 8, and 15 of each cycle. The most frequent and dosing limiting adverse effect is thrombocytopenia.

Clinical pharmacology

Responses have been seen in the DLBCL study and enrollment continues. Escalation continues in the HCC study and knockdown of STAT3 in PBMCs has been shown.

Suitable for and exclusions

Suitable for clinical studies that investigate the mode of action of AZD9150, e.g. tumour STAT3 knock down and or immunomodulatory effects.

See for a list of exclusions.

Additional Information

Clinical trials for this compound

See all of the clinical trials currently associated with this compound:

Publications for this compound

Find out more about this compound by reading related publications:

ASCO University 

A phase I study of ISIS 481464 (AZD9150), a first-in-human, first-in-class, antisense oligonucleotide inhibitor of STAT3, in patients with advanced cancers

2013 NCRI Cancer Conference

AZD9150, a next generation antisense oligonucleotide targeting STAT3

Gene information from the NCBi

This compound works on the following genes: