Isis Pharmaceuticals announced today that AstraZeneca has initiated a Phase 1 clinical study of ISIS-ARRx in patients with cancer.  Isis earned a $15 million milestone payment associated with the clinical advancement of ISIS-ARRx.  ISIS-ARRx is an antisense drug designed to treat patients with prostate cancer by inhibiting the production of the androgen receptor (AR).  AstraZeneca is planning to develop ISIS-ARRx broadly to treat patients under a variety of settings during the course of prostate cancer treatment, including both as a single agent and in combination therapy.

"This important milestone takes us another step further to understanding how we can develop ISIS-ARRx to better treat prostate cancer - both as a single agent or in combination with other agents in the AstraZeneca portfolio.  We look forward to building our close collaboration with Isis Pharmaceuticals to complete this study and to evaluate the broader therapeutic potential of the Isis antisense technology," said Susan Galbraith, Vice President, Head of Oncology Innovative Medicines, AstraZeneca.

"AR is a well-validated target in prostate cancer, and as such, has been a target of interest for many years.  Our antisense approach may allow us to avoid the limitations, including the emergence of resistance, characteristic of other AR-targeted therapeutic approaches.  Furthermore, ISIS-ARRx is designed to reduce the production of all known AR variants and, as such, could be effective in patients with prostate cancer regardless of the type of AR they produce," said Brett Monia, Ph.D., senior vice president, antisense drug discovery at Isis.

"AstraZeneca's extensive experience in successfully developing and commercializing drugs to treat hormone-related cancers, like prostate cancer, is a significant advantage for program success.  Together with AstraZeneca, we have expanded our efforts in developing drugs to treat patients with prostate cancer.  We look forward to working closely with AstraZeneca to complete this study and to evaluate the broader therapeutic potential of ISIS-ARRx," said B. Lynne Parshall, chief operating officer at Isis.

The open-label, dose-escalation Phase 1 study will evaluate the safety and efficacy of ISIS-ARRx in patients with advanced solid tumors, such as metastatic castrate resistant prostate, breast, bladder and ovarian cancers, where the androgen receptor pathway is potentially a contributing factor.  The endpoints for the study include measurements of anti-tumor activity and AR and AR-variant levels in tumor biopsies.  The study will also evaluate safety.

ISIS-ARRx, also referred to as AZD5312, is an antisense drug designed to inhibit the production of AR for the treatment of patients with prostate cancer.  Prostate cancer is the second leading cause of cancer deaths in men in the United States.  Prostate cancer growth, proliferation and progression are all androgen-dependent, and AR function is involved in disease progression at all stages of prostate cancer.  For patients diagnosed with metastatic prostate cancer, current treatments largely involve opposing the action of androgens by blocking the androgen receptor or removing circulating androgens.
Although androgen deprivation therapy approaches are initially effective in delaying disease progression in patients with metastatic prostate cancer, over time the course of the disease will progress in many of these patients.  Resistance to current therapies is frequent and can occur through a variety of mechanisms including the activation of AR signaling in tumor cells through the amplification, over expression and mutation of the AR gene.

ISIS-ARRx is designed to reduce the production of all known forms of AR, including variants of the AR gene, and therefore has the potential to be an effective treatment for all stages of prostate cancer, including prostate cancer patients who are resistant to current therapies.  ISIS-ARRx is the second drug to enter clinical development in Isis' pipeline that incorporates Isis' generation 2.5 chemistry.

Isis developed its generation 2.5 chemistry to increase the potency of antisense drugs thereby creating opportunities for drugs like ISIS-STAT3Rx and ISIS-ARRx to be effective in more difficult to treat cancers.
Isis and AstraZeneca are collaborating to discover and develop antisense drugs to treat cancer.  The collaboration combines AstraZeneca's experience and expertise in developing anti-cancer agents with Isis' antisense technology platform to broaden Isis' cancer franchise.  With the initiation of the Phase 1 study for ISIS-ARRx, Isis has earned $57 million in upfront and milestone payments from its relationship with AstraZeneca and is eligible to earn additional milestone payments as the drug progresses in development as well as royalties on sales of ISIS-ARRx if it is commercialized.