Isis Pharmaceuticals, Inc. has initiated a phase 1b/2a clinical study of ISIS-STAT3Rx in patients with advanced metastatic hepatocellular carcinoma (HCC).  HCC is a tumour of the liver and is one of the most common cancers worldwide with at least one million new cases diagnosed each year.  ISIS-STAT3Rx is an antisense drug discovered by Isis and being developed to treat patients with cancers with a strong link to STAT3, such as HCC.  Isis licensed ISIS-STAT3Rx to AstraZeneca as part of a strategic alliance in cancer. AstraZeneca is conducting this newly initiated study in patients with HCC.

"We are pleased to be working with AstraZeneca on the development of ISIS-STAT3Rx.  AstraZeneca's considerable resources, expertise and development capabilities to develop anti-cancer drugs strengthen substantially our ability to broadly evaluate ISIS-STAT3Rx across a range of cancer types. Given the role of STAT3 in the growth and survival of tumours, we believe that ISIS-STAT3Rx could be beneficial in the treatment of many different types of cancers.  As such, together with AstraZeneca, we have designed a broad development program to explore the effects of ISIS-STAT3Rx in a number of different cancers," said B. Lynne Parshall, chief operating officer at Isis.  "Our early work showed that ISIS-STAT3Rx treatment resulted in clear responses in patients with advanced cancer who were refractory to prior chemotherapy treatment, with an acceptable safety profile.  The new study builds on this early work and expands our evaluation of ISIS-STAT3Rx into liver cancer where STAT3 inhibition could also provide therapeutic benefit."

The phase 1b/2a study will evaluate the safety and efficacy of ISIS-STAT3Rx in patients with HCC who have failed first-line therapy.  The endpoints for the study include measurements of anti-tumour activity, STAT3 protein levels in tumour biopsies and STAT3-related biomarkers.  The study will also evaluate safety.   Although HCC is common, it is considered a very difficult to treat cancer that does not respond well to chemotherapy.

"STAT3 is important for the growth, invasiveness and metastases of many types of cancer, which makes it a very attractive target. The potency we have observed in our preclinical cancer studies and the early evidence of clinical activity we observed in our phase 1 study suggest that ISIS-STAT3Rx could be an effective anti-tumour agent that is broadly applicable to many different types of cancer," said Brett Monia,  senior vice president, antisense drug discovery at Isis.

ISIS-STAT3Rx, also referred to as AZD9150, is designed to specifically reduce the production of signal transducer and activator of transcription 3 (STAT3).  STAT3 is a gene that blocks natural cell death and is critical for tumour cell growth and survival.  Inhibition of STAT3 has been shown to block the induction of tumour-associated cytokines involved in the progression of cancer, such as IL-6, IL-1, TGFb, and IL-10, which could serve as important biomarkers in clinical studies.  ISIS-STAT3Rx is the first drug in Isis' pipeline that incorporates Isis' Generation 2.5 chemistry, which was developed to increase potency of antisense drugs thereby creating opportunities for drugs like ISIS-STAT3Rx to be effective in more difficult to treat cancers.  In a phase 1 safety study, ISIS-STAT3Rx treatment produced an acceptable safety profile and resulted in sustained responses in two of three patients with advanced diffuse large B cell lymphoma who were refractory to multiple prior chemotherapy treatments.  Isis and AstraZeneca are currently evaluating ISIS-STAT3Rx in two phase 1b/2a clinical studies in patients with HCC and advanced lymphomas.  Because STAT3 is over expressed in numerous types of cancers, ISIS-STAT3Rx has the potential to be broadly useful for both solid and haematological tumours.

Isis is exploiting its leadership position in antisense technology to discover and develop novel drugs for its product pipeline and for its partners.