New clinical and safety results from a phase Ib/II trial in recurrent metastatic head and neck cancer, presented at the annual meeting of the European Society for Medical Oncology – ESMO 2018, shows that danvatirsen (formerly known as IONIS-STAT3-2.5Rx and also known as AZD9150), a Generation 2.5 antisense therapy targeting signal transducer and activator of transcription 3 (STAT3) being developed by Ionis Pharmaceuticals, in combination with durvalumab (Imfinzi?; AstraZeneca), a programmed death ligand (PD-L1) blocking antibody, shows that 7% of patients being treated with the combination achieved a complete tumor response and 23% achieved either a partial response (PR) or complete response (CR).

These results, estimated to be double that with durvalumab alone compared to previous studies in this difficult to treat patient populations, provide additional evidence that? danvatirsen can address previously undruggable targets and can access targets in difficult to reach cell (tumor) types, demonstrating the potential to treat intractable cancers.

Danvatirsen is an antisense therapy containing Generation 2.5 chemistry which was developed to increase the potency of antisense drugs. The investigational agent inhibits the production of signal transducer and activator of transcription 3 (STAT3), a previously undruggable target and an important regulator of immune responses to cancer cells. Inhibition of STAT3 has been shown to broadly enhance the activity of several immune check point therapies in preclinical studies.

The results presented during the 2018 ESMO congress are building on study results presented during the 2017 annual meeting of the European Society of Medical Oncology. Those study results confirmed that the combination treatment resulted in encouraging anti-tumor activity with a safety and tolerability profile supportive of continued development.

“We are encouraged by the results observed in the SCORES trial of patients with head and neck cancer and remain excited about the potential for this combination,” said Susan Galbraith, Senior Vice President and Head of Oncology, Innovative Medicines and Early Development Biotech Unit at AstraZeneca.

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“We are exploring new modalities such as antisense oligonucleotides to expand the range of druggable targets. Our strategy is also to develop novel combinations to overcome key immunosuppressive mechanisms, and thereby expand the potential for anti-tumor activity of immune checkpoint inhibition,” she added.

“AstraZeneca has made important progress in advancing the danvatirsen clinical program. The clinical responses observed in this study along with the strong safety profile exhibited by danvatirsen hold great promise for patients with head and neck cancer and other intractable cancers,” noted Brett P. Monia, Ph.D., Ionis’ chief operating officer.

“The results from this study provide additional evidence that our antisense platform can address previously undruggable targets and difficult to reach cell types in the tumor microenvironment. We believe that our Generation 2.5 chemistry will one day deliver new, potent treatment options to patients suffering from a variety of cancers,” he further added.

AstraZeneca is evaluating danvatirsen in a range of cancer types as part of a broader oncology partnership evaluating Generation 2.5 antisense therapies against undruggable targets either alone or in combination with immuno-oncology agents, including in non-small cell lung cancer, bladder cancer and head and neck cancer.

Ionis earned a $17.5 million milestone payment from AstraZeneca for advancing the phase II program for danvatirsen. The company is eligible for additional developmental and regulatory milestone payments from AstraZeneca, plus royalties on commercial sales of the drug.

Clinical trials
Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck – NCT02499328

Last Editorial Review: October 22, 2018

Featured Image: Annual Congress of ESMO 2018. Courtesy: ? 2018 European Society for Medical Oncology. Used with permission.

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