Neurogen is evaluating data from the Phase IIa trial and profiling additional C5a antagonist compounds.

Inflammatory and autoimmune conditions are debilitating diseases including many different forms of arthritis, autoimmune diseases, and pulmonary disorders. Rheumatoid arthritis (RA) involves inflammation in the lining of the joints and/or other internal organs. It is a systemic disease affecting the entire body and is one of the most common forms of arthritis, characterized by the inflammation of the membrane lining the joint, resulting in pain, stiffness, warmth, redness and swelling. Industry surveys indicate that this disease affects 2.6 million Americans.

Key to the body’s immune system is a biological response called the complement cascade, with the primary function of guarding against invading microorganisms by actually promoting inflammation to fight infection. C5a protein functions to attract the white blood cells that attack the invading cells, but in many patients, it may also trigger the immune system to start attacking the body's own tissues. This inappropriate reaction is central to autoimmune and inflammatory diseases.

Neurogen’s inflammation program is based on the hypothesis that blocking the activation of the C5a receptor of the immune system’s complement cascade may work to treat inflammation in RA and other autoimmune diseases.

Development Status
A Phase IIa clinical trial using NGD 2000-1, one of the first oral C5a antagonists to be tested in humans, for the treatment of RA encompassed 48 patients who were dosed twice daily with either placebo, 10 mg, 60 mg, or 100 mg of NGD 2000-1. The study’s primary endpoint was change in C-reactive protein (CRP), a biomarker of disease activity which is measured from patient blood samples; secondary endpoints addressed clinical signs and symptoms.

In June 2004, we reported data indicating that NGD 2000-1 did not affect the study’s primary endpoint but, in a post hoc analysis, did produce a statistically significant (p=0.014) result at the highest dose tested with American College of Rheumatology Criteria (ACR). NGD 2000-1 demonstrated a 20 percent improvement or an ACR 20 score.

The study’s primary and secondary endpoints were chosen to provide the component data to calculate an ACR score. The ACR is a standard outcome measure used in clinical trials to determine the effectiveness of new agents. The ACR criteria, which were not a predetermined endpoint of the study, require an improvement in three of five of the following variables: patient global assessment, physician global assessment, C-reactive protein, pain scale, and a health assessment questionnaire. Improvement is denoted as ACR 20, ACR 50, or ACR 70 reflecting an improvement to the 20percent, 50 percent, or 70 percent level, respectively, in the parameters outlined.

Phase I studies of NGD 2000-1 identified that the compound inhibits cytrochrome P450 3A4 (3A4), a metabolic enzyme found in the liver, which metabolizes many drugs. At the 100 mg dose, where statistically significant results occurred, this characteristic would severely limit the use of NGD 2000-1 by patients also taking other medications which are metabolized by the 3A4 enzyme.

We are tabling further development of NGD 2000-1 pending further analysis of data, but will continue the inflammation program, profiling additional C5a antagonist compounds with the intent to develop those with greater commercial potential. To date, Neurogen has retained all rights to its C5a antagonist program.