Coley Pharmaceutical Group, Inc (WELLESLEY, Massachusetts), an international biopharmaceutical company having a pipeline of Toll-Like Receptor (TLR) therapeutic product candidates, announced that it has dosed its first subject in a phase I study of its novel, orally-available TLR Therapeuticâ„¢ drug candidate for the treatment of systemic lupus erythematosus (SLE). The drug candidate, CPG 52364, is a small molecule, first-in-class TLR antagonist designed to specifically inhibit TLRs 7, 8, and 9 and inhibit disease development in SLE and other autoimmune disorders in which the TLRs are inappropriately activated such as in rheumatoid arthritis (RA) and psoriasis. CPG 52364 has also been designed to treat the underlying cause of the disease without causing general suppression of immune function.

The phase I study is a double-blind, placebo-controlled, randomized clinical trial designed to examine the safety, tolerability, and pharmacokinetics of ascending doses (1 mg, 3 mg, 10 mg, 30 mg, and 100 mg) of the compound. The drug will be administered as a single oral dose as a liquid (1 mg dose) or a capsule (all other doses) in approximately 40 healthy volunteers at a single clinical center.

In SLE, autoantibodies bind to DNA and/or RNA, and their associated cellular proteins, forming immune complexes containing anti-DNA antibodies that activate TLR9, while immune complexes that contain RNA activate TLR7 and TLR8. Recent studies show that the development and progression of SLE are driven by the inappropriate activation of TLRs 7, 8, and 9. TLRs 7 and 9 are present within B-cells, which secrete high levels of interferon-α and contribute to disease severity. TLR8 is expressed in monocytes and other dendritic cells, which are thought to produce proinflammatory cytokines further contributing to the disease process. Other studies have indicated that autoimmunity in RA and psoriasis also is mediated through one or more of these TLRs.

Coley evaluated and selected TLRs 7, 8, and 9 as key targets by elucidating the therapeutic mechanism of action for the antimalarial medication hydroxychloroquine (HCQ, Plaquenil®), a disease modifying antirheumatic drug commonly used in treating both chronic discoid erythematosus and SLE in addition to treating acute or chronic RA. In SLE, HCQ has been found to relieve skin inflammation, hair loss, mouth sores, fatigue, and joint pains; it has also been found helpful in preventing relapses of active disease. The therapeutic mechanism for HCQ in these autoimmune diseases were unknown, until research from Coley and other scientists revealed that the compound is an antagonist of TLR9, to a lesser extent TLRs 7 and 8, and that the efficacy of HCQ appears to result from blocking the TLRs. Coley designed and developed CPG 52364 to inhibit the TLRs more effectively and in the company's preclinical studies, the compound showed a marked increase in therapeutic potency compared with HCQ, preventing the development of anti-DNA antibodies in SLE-prone mice as well as exhibiting an improved safety profile.

In addition to its activity as a monotherapy, preclinical data showed that the combination of CPG 52364 with HCQ delivers added efficacy, suggesting that the compound could be used clinically either in combination with HCQ or as a replacement therapy for HCQ in the first-line treatment of SLE.

Coley has product development, research and license agreements with Pfizer Inc, sanofi-aventis, GlaxoSmithKline, Merck & Co Inc, and Novartis Pharmaceuticals Corp in a variety of fields including cancer, asthma and allergy, autoimmune disorders and vaccines.