Isis Pharmaceuticals Reports Encouraging Data on ISIS-STAT3rx in Patients With Cancer

Isis Pharmaceuticals, Inc.

announced that data from the Phase 1 study of ISIS-STAT3[Rx] in patients with cancer were presented today at the American Society of Clinical Oncology in Chicago.  Results of the initial dose escalation study in patients with metastatic cancer showed that ISIS-STAT3[Rx] treatment resulted in partial responses that were durable and prolonged in two out of three patients with diffuse large B-cell lymphoma (DLBCL) who were refractory to prior chemotherapy treatments.  Isis and AstraZeneca are currently evaluating ISIS-STAT3[Rx], in two clinical studies in patients with advanced lymphoma and metastatic liver cancer. "STAT3 activation has been shown to be associated with the growth, invasiveness and metastases of many types of cancer making it an attractive anti-cancer target.  However, STAT3 has proven to be a difficult target to inhibit.  ISIS-STAT3[Rx] is one of the new molecules in development that inhibit STAT3," said David S. Hong, M.D., associate professor, department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center.  "Patients with advanced cancer often have failed multiple therapies and have few other chemotherapeutic options.  For these patients there is a desperate need for new therapies that can halt their disease progression.  The clinical responses observed to date suggest that inhibition of STAT3 could provide benefit to some of these cancer patients.   The early clinical data on ISIS-STAT3[Rx ]is impressive because it suggests that this drug can produce durable responses in patients with advanced cancer who have failed to respond to other therapies." ISIS-STAT3[Rx], also referred to as AZD9150, is the first drug in Isis' pipeline that incorporates Isis' Generation 2.5 chemistry, which Isis developed to increase potency of antisense drugs, thereby creating opportunities for drugs like ISIS-STAT3[Rx] to be effective in more difficult-to-treat cancers, like DLBCL.  The open-label, dose-escalation Phase 1 study evaluated ISIS-STAT3[Rx] in 15 patients with advanced solid tumors and lymphoma who had relapsed or were refractory to multiple chemotherapy regimens. Signals of tumor responses were observed in four patients, including objective partial responses in two of three patients with DLBCL.  One patient with a partial response with DLBCL, who had previously failed ten different chemotherapy regimens, experienced a 50 percent reduction in tumor burden and has maintained a partial response for longer than one year and continues to receive weekly ISIS-STAT3[Rx] therapy.   Another patient with DLBCL experienced a partial response with a 65 percent reduction in tumor burden and, as a result, was well enough to receive an autologous stem cell transplant.   This patient successfully completed a bone marrow transplant and remains disease free.  Isis and AstraZeneca are currently evaluating ISIS-STAT3[Rx] in two other clinical studies, including a study in patients with advanced lymphomas, like DLBCL, and a study in patients with advanced metastatic hepatocellular carcinoma.  "AstraZeneca's considerable expertise in developing anti-cancer drugs has enabled us to rapidly advance the clinical development of ISIS-STAT3[Rx].  We believe that ISIS-STAT3[Rx] may be applicable to many different types of cancer.  As such, together with AstraZeneca, we plan to evaluate ISIS-STAT3[Rx] in a broad Phase 2 program," said Brett Monia, Ph.D., senior vice president, antisense drug discovery at Isis.  "We are very pleased and encouraged with the safety and efficacy observed in our initial clinical study of ISIS-STAT3[Rx] and look forward to the results from the two ongoing clinical studies in patients, which we plan to report next year." ISIS-STAT3[Rx] is designed to inhibit the production of signal transducer and activator of transcription 3 (STAT3), a protein critical for tumor cell growth and survival.  In addition, STAT3 is an important mediator of signaling in the JAK2/STAT3 pathway, which has been previously shown to be an important target for drug development.  Because STAT3 is activated in numerous types of cancer, ISIS-STAT3[Rx] has the potential to be broadly useful for both solid and hematologic tumors.  ISIS-STAT3[Rx] has been shown to reduce STAT3 levels in preclinical tumor models and produce anti-tumor activity.  Inhibition of STAT3 has also been shown to block the induction of tumor-associated cytokines involved in the progression of cancer, such as IL-6, IL-1, TGF, and IL-10, which could serve as important biomarkers in clinical studies.