GI-4000 for mutated-Ras mediated cancers

The GI-4000 Tarmogen causes the targeted elimination of any cell containing mutations in the ras  oncogene. GI-4000 is broadly protected by both issued patents and pending patent applications.  In total, GI-4000 has patent coverage through at least December 2023. 

Ras proteins control signaling pathways that are key regulators of both normal cell growth and malignant transformation.  Mutations cause Ras proteins to remain longer in their active form, resulting in an overstimulation of the EGFR pathway.  Mutations in the ras  oncogene family are the most common oncogene-related mutations in human cancer.  Mutations in Ras proteins are found in approximately 30% of all human tumors, representing the cause of  >150,000 new cases of cancer annually in the US alone. 

Ras mutations occur in:

• ~90 of pancreatic cancers where approximately 31,800 people are diagnosed and 31,250 people die annually in the U. S.
• ~40% of colorectal cancers, with approximately 147,500 new diagnoses and over 56,000 patient deaths in the U. S. each year
• ~25% of non-small cell lung carcinomas (NSCLC), the second most common form of cancer in the U. S. with about 139,000 new cases and 128,000 deaths annually
• ~25% of ovarian cancers, with 25,500 new cases diagnosed annually, usually only after the disease has spread, with over 16,000 deaths annually.

Tumors caused by a mutation in the Ras protein represent cancers that may be resistant to current therapies.  For some cancers such as NSCLC or colorectal cancer, presence of a Ras mutation in the tumor has been associated with poor prognosis. 

• Studies have shown that NSCLC tumors with K-ras mutations are associated with a lack of response to EGFR tyrosine kinase inhibitors such as Tarceva and Iressa, and drug sensitivity is associated with the absence of a K-ras  mutation.  [Pao, ASCO 2007]
• Patients with NSCLC tumors containing mutated Ras have poorer survival after surgery than those without Ras mutations.  Further, patients with ras--mutated tumors do not appear to benefit from adjuvant chemotherapy, where patients with tumors containing wild-type (normal) ras  do. [Winton et al, NEJM 2005]
• Colorectal cancer patients with tumors characterized by mutated ras  show no benefit from cetuximab therapy where wild-type (normal) Ras show a survival benefit from therapy [Lievre et al, JCO January 2008] 

Because of the central role for Ras activation in tumor proliferation, targeted destruction of cells harboring mutant Ras proteins could result in remission of a broad range of human cancers.

Preclinical Studies

GI-4000 has demonstrated safety and efficacy in numerous prophylactic and therapeutic animal tumor models.  Products from the GI-4000 series have been shown in animals to be capable of inducing complete remission of tumors bearing the targeted mutations, and to do so in a mutation specific manner.  GI-4000 has been administered to animals in studies conducted under Good Laboratory Practices (GLP) with no observable systemic toxicity.  Other closely related products using the yeast-based platform have been administered to mice, rats, rabbits and rhesus macaque monkeys with no significant systemic toxicity. 

Clinical Studies

A phase 1 study of GI-4000 in 33 subjects with advanced colorectal and pancreas cancer was successfully completed in 2006 showing that GI-4000 was well-tolerated through the highest dose group tested, and demonstrated an antigen-specific immune response in the majority of subjects treated.  No Dose Limiting Toxicities (DLTs), therapy-related serious adverse events (SAEs), or therapy related clinically significant laboratory abnormalities were observed in the trial.  An antigen-specific T cell response was detected in 90% of subjects.  Several subjects experienced disease stabilization during the 29-day treatment phase based on investigator assessment of clinical status, biochemical markers, and/or imaging.  One subject with Stage IV pancreas cancer had stable disease for 85 days based on biochemical markers (CA 19-9), clinical stability for 8 months post-treatment, and on-treatment Ras specific immune responses.  There were five long term surviviors living between 1-2.5 years; four of the five subjects demonstrated strong T cell immune responses. 

The Company has initiated a phase 2 program to explore the potential of GI-4000 in various clinical indications with high rates of activating Ras mutations.  The first phase 2 study evaluating GI-4000 in subjects with newly diagnosed, resected pancreas cancer, is a randomized, double-blind, placebo-controlled trial in 100 subjects (50 subjects treated with adjuvant gemcitabine plus placebo versus 50 subjects treated with adjuvant gemcitabine plus GI-4000).  Endpoints for this trial include recurrence free survival, overall survival and changes in biochemical markers (CA19-9).  This study is being run at 50 centers in the US and 10 in India.  Click here for additional details on the study.   Additional phase 2 studies are being planned for both patients with locally-advanced pancreas cancer and NSCLC.