CCR9 Program

Our lead product candidate, Traficet-EN™, or CCX282, which targets the CCR9 chemokine receptor, recently completed a Phase II/III clinical trial in 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.

Traficet-EN is intended to control the inappropriate immune system response that underlies Crohn's disease by inhibiting the CCR9 chemokine receptor. In adults, CCR9 is a highly specific receptor expressed predominately by T cells, a subset of the body's immune cells that migrate selectively to the digestive tract. Studies have shown that when CCR9, or its chemokine ligand CCL25 (previously known as TECK), are over-expressed, the migration of T cells to the small and large intestine causes persistent inflammation. CCR9 positive T cells have been shown to play a role in Crohn's disease and ulcerative colitis.

We believe Traficet-EN, if approved for marketing by the FDA and other regulatory agencies, will provide physicians with a new and attractive option for the treatment of patients with moderate-to-severe Crohn's disease.

We have completed eight clinical trials to date with Traficet-EN. These trials include five Phase I clinical trials of Traficet-EN among healthy volunteers to evaluate safety and pharmacokinetics with single-dose and multiple-dose administration. In these trials, Traficet-EN was well tolerated and was found to be appropriate for once- or twice-daily oral dosing. We subsequently conducted a 28-day Phase II clinical trial in 74 patients with moderate-to-severe Crohn's disease, in which Traficet-EN was demonstrated safe and well tolerated. In this trial, we observed indications of clinical activity based on a reduction in Crohn's Disease Activity Index (CDAI) scores and lower C-reactive protein (CRP) levels in patients treated with Traficet-EN.

In 2006, we initiated a multinational, multi-center Phase II/III clinical trial, called PROTECT-1, 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 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 active treatment period to either Traficet-EN or placebo.

We recently 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.

Another investigational new drug in clinical trials is CCX025 which is the second orally administered compound that inhibits the CCR9 chemokine receptor.

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:

• Excellent safety profile, as it is designed to avoid the broad immunosuppressive effects of 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. Improved 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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