We have conducted five Phase 2 clinical trials to evaluate the ability of custirsen sodium (OGX-011), our lead product candidate, to enhance the effects of therapy in prostate, non-small cell lung and breast cancers. Data from these Phase 2 studies demonstrates the potential benefit of adding OGX-011, a second-generation antisense molecule, to existing cancer therapies. Based on our Phase 2 results in 294 patients, we believe that registration trials for market approval of OGX-011 are warranted in Castrate Resistant Prostate Cancer (CRPC) and Nonsmall Cell Lung Cancer (NSCLC). Our initial registration trials will focus on the CRPC indication.
OGX-011 is designed to block production of clusterin, a cell survival protein that is over-produced in several cancer indications and in response to many cancer treatments, including hormone ablation therapy, chemotherapy and radiation therapy. Increased clusterin production is observed in several human cancers, including prostate, non-small cell lung, breast, ovarian, bladder, renal, pancreatic, anaplastic large cell lymphoma and colon cancers and melanoma. Increased clusterin production is linked to faster rates of cancer progression, treatment resistance and shorter survival duration.
Clusterin expression is linked to disease progression, treatment resistance, poor prognosis and survival in scientific publications. For example, increased expression of clusterin in prostate cancer is closely correlated with increasing Gleason score, which is a strong prognostic factor for poor survival of patients with prostate cancer.
OGX-011 is being developed to work in combination with therapies that are broadly used by clinicians and considered effective in the treatment of each cancer indication that we are targeting with the intent of delaying treatment resistance to those therapies. Since production of clusterin and the resulting treatment resistance occurs in an array of cancer indications and in response to a variety of cancer treatments, we believe that our development options for OGX-011 are numerous.
A broad range of preclinical studies show that OGX-011 decreases clusterin levels and sensitizes tumor cells to standard chemotherapeutic drugs, resulting in increased rates of tumor cell death. Preclinical results also show that reducing clusterin production sensitizes prostate tumor cells to hormone ablation therapy and sensitizes prostate and non-small cell tumor cells to radiation therapy.
The Clinical program for OGX-011 is summarized below.
Two Phase 1 clinical trials and on one Phase 1/2, involving a total of 75 patients, have been completed with OGX-011. In all of these clinical trials, OGX-011 was well tolerated by the patients.
In the first Phase 1 clinical trial, OGX-011 was intravenously administered once per week in combination with hormone ablation therapy to patients with localized prostate cancer in advance of surgery to remove the prostate gland. This clinical trial showed that once weekly administration of OGX-011 reduced clusterin mRNA levels by approximately 92 percent in prostate cancer tissue and approximately 98 percent in lymph node tissue, and more than doubled the rate of prostate tumor cell death compared to hormone ablation therapy alone.
In the second Phase 1 clinical trial, OGX-011 was intravenously administered once per week in combination with docetaxel chemotherapy to patients with solid tumors known to express clusterin. This clinical trial showed that serum clusterin levels dropped in patients while on treatment with 640 mg OGX-011 in combination with docetaxel.
In the third Phase 1 portion of the clinical trial, OGX-011 was intravenously administered once per week in combination with two commonly used chemotherapeutic agents to patients with advanced non-small cell lung cancer.
We have conducted five phase 2 clinical trials to evaluate the ability of OGX-011 to enhance the effects of therapy in prostate, non-small cell lung and breast cancer.
Data is available from each of the five phase 2 studies which demonstrate that adding OGX-011 to therapy shows potential benefit of OGX 011:
- longer survival duration when adding OGX-011 to first-line docetaxel compared to first-line docetaxel alone in patients with CRPC within a randomized phase 2 trial;
- longer survival duration when adding OGX-011 to either mitoxantrone or docetaxel as second-line chemotherapy compared to survival duration observed in two published studies of CRPC patients receiving second-line chemotherapy;
- increased frequency and duration of pain palliation when adding OGX-011 to either mitoxantrone or docetaxel as second-line chemotherapy compared to the frequency and duration of pain palliation observed in the TAX 327 Study for first-line chemotherapy alone in patients with CRPC; and
- longer survival duration when adding OGX-011 to gemcitabine and a platinum-containing chemotherapy compared to the survival duration reported in prior published results from randomized clinical trials in NSCLC patients receiving gemcitabine and a platinum-containing chemotherapy.
Final results of a randomized phase 2 trial, noted above, that evaluated the benefit of combining OGX-011 with first-line docetaxel chemotherapy were presented during an oral presentation at the American Society of Clinical Oncology (“ASCO”) 2009 Annual Meeting. Analyses indicating a survival benefit in patients treated with OGX-011 in combination with first-line docetaxel compared to docetaxel alone, the latter of which being the current standard care for patients with advanced, progressive metastatic prostate cancer, are described below:
- The median overall survival in patients with advanced metastatic prostate cancer who were treated with OGX-011 plus docetaxel in a randomized phase 2 trial was 23.8 months compared to 16.9 months for patients treated with docetaxel alone, indicating a 6.9 month survival advantage in the OGX-011 arm;
- The unadjusted hazard ratio (“HR”), a measure used to compare the death rates between treatment groups, was 0.61, representing a 39% lower rate of death for patients treated with OGX-011;and
- A prospectively defined multivariate analysis indicated that the significant predictors of overall survival were treatment arm, performance status and presence of metastases other than in bone or lymph nodes. In the multivariate analysis, patients treated with OGX-011 had a rate of death of 51% lower than patients treated with docetaxel alone (HR=0.49; p=0.012).