ZymoGenetics, Inc (SEATTLE, Washington) and Serono (GENEVA, Switzerland) announced the start of a phase II clinical trial of their investigational therapeutic atacicept (formerly TACI-Ig) in patients with rheumatoid arthritis (RA). The randomized, double-blind, placebo-controlled, multicenter, dose-finding study will investigate the efficacy of atacicept in patients with an inadequate disease response to prior treatment with TNF inhibitors. The primary endpoint of the study will be clinical improvement as evaluated by ACR 20 response at week 26. Secondary objectives include further characterizing the efficacy, safety, tolerability, and pharmacologic profile of atacicept at each of three dose levels. ACR 50 and ACR 70 responses and DAS 28 will be used as secondary measures of efficacy.

The study will enroll 320 patients who have had active RA for more than 1 year and who have had an inadequate response to at least 3 months of TNF inhibitor therapy. Patients will be randomized into groups receiving one of three dose levels (25 mg, 75 mg, or 150 mg) of atacicept or placebo, in addition to background methotrexate therapy, and they will be treated for 25 weeks. Loading doses will be given twice weekly for 4 weeks, followed by 21 weekly maintenance doses. A follow-up visit will occur 13 weeks after the last dose.

ZymoGenetics and Serono are developing atacicept for the treatment of several autoimmune diseases and B-cell malignancies. Earlier this year, the companies completed phase Ib studies with atacicept in RA and systemic lupus erythematosus (SLE). The RA clinical study was an exploratory dose-escalating, single and repeat dose phase Ib clinical trial with atacicept in 73 adult patients with active, moderate-to-severe RA. The patients in this multicenter, randomized, double-blind, placebo-controlled trial received subcutaneous administration of single or multiple doses of either atacicept or placebo for a maximum period of 3 months. Atacicept appeared to possess a favorable safety and tolerability profile and demonstrated exposure-dependent biological activity in line with its mechanism of action, including up to a 30% to 40% reduction in the levels of total and mature B cells, and reduced immunoglobulin (IgM, IgA, and IgG) and rheumatoid factor. There were also positive trends of effect on disease activity/progression (ACR 20, DAS 28).

The primary objective of the dose-escalating phase Ib clinical SLE trial, which included 49 patients with SLE in six cohorts, was to determine the safety and tolerability of atacicept administered subcutaneously. Secondary objectives included examining the effects of various dose and schedule regimens on markers of biologic activity and disease activity. The results showed that atacicept was well tolerated across all dose levels and schedules in the study. In addition, atacicept therapy was associated with clear biologic activity, as shown by dose-dependent reductions in IgM, IgA, and IgG, and B-cell levels, consistent with atacicept's proposed mechanism of action. Although the study was not designed to evaluate efficacy, compared to placebo an overall positive trend in SELENA-SLEDAI (SLE Disease Activity Index) scores and complement levels was seen in patients treated with multiple doses of atacicept. ZymoGenetics and Serono are in dialogue with the US FDA regarding the SLE phase II clinical development program. The companies are planning to initiate the trial in SLE in mid-2007.

The two companies will also pursue a clinical trial program with atacicept in multiple sclerosis (MS), and plan to initiate a clinical trial in MS in 2007.

Atacicept is a soluble, recombinant fusion protein formed between the extracellular, ligand-binding domain of a novel cytokine receptor, human TACI (transmembrane activator and CAML [calcium-modulator and cyclophilin ligand]-interactor]) and the Fc domain of human IgG that neutralizes BLyS (B-Lymphocyte Stimulator, also known in the literature as zTNF4, BAFF, TALL-1 and THANK) and APRIL (A Proliferation-Inducing Ligand), TNF family cytokines that promote normal and autoimmune B-cell maturation, proliferation, and survival. Levels of BLyS and APRIL are elevated in patients with SLE, RA, and B-cell malignancies. Atacicept has been shown to affect several stages of B-cell development and may inhibit the survival of cells responsible for making antibodies.

—A. Techman

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