CCR9 Program

Our most advanced drug candidate, Traficet-EN™ (CCX282, now GSK'786) which targets the chemokine receptor known as CCR9, is currently in three pivotal Phase III clinical trials being conducted by our partner GSK for the treatment of patients with moderate-to-severe Crohn's disease, a chronic inflammatory condition of the gastrointestinal tract and one of two forms of inflammatory bowel disease (IBD). Inflammatory bowel disease refers to two diseases, Crohn's disease and ulcerative colitis, both characterized by inflammation of the gastrointestinal tract.

Traficet-EN is intended to control the inflammatory response underlying IBD by targeting the chemokine receptor known as CCR9. In adults, CCR9 is found primarily on a population of T cells, a subset of the body's inflammatory cells that migrate selectively to the digestive tract. It is believed that when CCR9's ligand, CCL25 (also known as TECK), is over-expressed, the migration of T cells to the small and large intestine causes persistent inflammation that may result in Crohn's disease or ulcerative colitis, the two forms of IBD. Traficet-EN is designed to prevent the migration of inflammatory cells to the digestive tract by blocking the function of CCR9. By interrupting CCR9 signaling, we believe Traficet-EN may hasten the elimination of inflammatory T cells from the intestines, thus potentially speeding recovery by reducing the longevity of flare-ups associated with IBD.

We believe this mechanism of action would allow Traficet-EN, if approved, to be a highly effective treatment with significantly fewer side effects than currently available immunosuppressive therapies, including TNF-a inhibitors, providing physicians with a new and attractive option for the treatment of patients with moderate-to-severe Crohn's disease.

We have completed nine clinical trials with Traficet-EN in a total of 785 subjects, including five Phase I clinical trials in a total of 151 subjects, one Thorough QT study in 57 subjects demonstrating cardiovascular safety, two Phase II clinical trials in 510 patients with Crohn's disease and one Phase II clinical trial in 67 patients with celiac disease. The largest of these Phase II clinical trials, PROTECT-1, was conducted in 436 patients with moderate-to-severe Crohn's disease. Results from this clinical trial indicated that Traficet-EN was effective in inducing a clinical response over a 12-week treatment period in these patients. Furthermore, the results indicated that Traficet-EN was also effective in maintaining clinical remission over a 36-week treatment period. Traficet-EN was safe and well tolerated in all clinical trials completed to date.

In 2006, we initiated PROTECT-1, a multinational, multi-center Phase II clinical trial to further assess the safety and efficacy of Traficet-EN for the induction of clinical response or remission in patients with moderate-to-severe Crohn's disease. Following the completion of a 12-week induction phase during which all subjects received either a placebo or one of three doses of Traficet-EN and a four-week open label active treatment phase during which all subjects received Traficet-EN, the study included a separate 36-week phase to evaluate Traficet-EN's utility as maintenance therapy for the response or remission in patients with Crohn's disease. This was accomplished by re-randomizing all subjects with a 70-point-or-greater drop in CDAI scores at the end of the four-week active treatment period to either Traficet-EN or placebo.

We completed the PROTECT-1 trial. Traficet-EN demonstrated evidence of clinical efficacy in the reduction of disease severity, as defined by a decrease from baseline in the Crohn's Disease Activity Index (CDAI) score of at least 70 points over the course of 12 weeks; the more stringent criterion of at least a 100 point decrease in the CDAI score was also met by week 12. In addition, Traficet-EN was safe and well-tolerated.

Data from the maintenance period of the PROTECT-1 clinical trial showed that more patients receiving Traficet-EN were in clinical remission by the end of 36 weeks compared to placebo.

In addition, we completed a Thorough QT study in healthy volunteers which showed that there was no deleterious effect on QT/QTc interval with Traficet-EN at either therapeutic or supratherapeutic doses.

In December 2009, GSK exercised its option to obtain an exclusive license to Traficet-EN and is now solely responsible for all further clinical development and commercialization expenditures worldwide. To date, three pivotal Phase III clinical trials have been initiated by GSK with Traficet-EN in Crohn's disease. The pivotal Phase III clinical trials are designed to support the use of Traficet-EN to induce clinical response or remission of Crohn's disease, and to provide maintenance of remission for Crohn's disease.

Phase III Clinical Program
GSK has initiated three pivotal Phase III clinical trials intended to obtain the clinical results necessary to apply for marketing approval for Traficet-EN in Crohn's disease. In general, the development approach of the Phase III program is modeled after the design of our PROTECT-1 clinical trial. The following pivotal Phase III clinical trials are currently ongoing:

• SHIELD-1 is a multi-national, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of two doses, 500mg once-daily and 500mg twice-daily, of Traficet-EN over 12 weeks of treatment in approximately 600 adult patients with moderate-to-severe Crohn's disease. Patient recruitment was initiated in December 2010.

• SHIELD-2 is a multi-national, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of two doses, 500mg once-daily and 500mg twice-daily, of Traficet-EN in maintaining disease remission over 52 weeks in approximately 750 adult patients with Crohn's disease. Eligible patients will have achieved disease improvement and/or remission in SHIELD-1. Patient recruitment was initiated in April 2011.

• SHIELD-3 is a multi-national, open-label clinical trial to evaluate the safety and effectiveness of 500mg twice-daily of Traficet-EN over 108 weeks in approximately 800 adult patients with Crohn's disease. Patients completing previous clinical trials with the drug or patients who withdraw early from the SHIELD-2 maintenance clinical trial may be eligible to participate. Patient recruitment was initiated in April 2011.

Traficet-EN Advantages
We believe that Traficet-EN may provide the following advantages over existing therapeutic approaches for the treatment of patients with Crohn's disease:

• Improved safety profile, as it is designed to avoid the broad immunosuppressive effects often seen in existing therapies by selectively targeting the CCR9 chemokine receptor.

• Oral administration as a more convenient option relative to injectable or infusible therapeutics such as TNF-α inhibitors as well as certain steroids and immunosuppressants. Patient compliance is particularly important in controlling chronic conditions such as Crohn's disease.

• Lower manufacturing costs, relative to TNF-α inhibitors, as a small molecule.

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