Autoimmune diseases - atacicept

One of the many factors that can cause tumours to develop is a malfunction in the proliferation of the B cells. These cells are important in the regulation of immune responses, and among their functions are the production of pro-inflammatory cytokines, the activation of T-cells, and it is also thought they may act as antigen presenting cells.

The maturation, proliferation and survival of B cells are modulated by the B cell activating factor, or BAFF, and APRIL, or A proliferation inducing ligand, which are both members of the tumour necrosis factor family. Both of these are also thought to be involved in the development of autoimmune diseases, and thus may provide targets for treating malignancies and autoimmune conditions that are associated with B cells.

A new biologic that inhibits the effects of BAFF and APRIL is atacicept, which is being developed by Merck Serono as a potential treatment for autoimmune diseases such as rheumatoid arthritis, lupus and multiple sclerosis. It is also at an earlier stage of development for multiple myeloma, chronic lymphocytic leukaemia and non-Hodgkin's lymphoma.

Atacicept is a soluble recombinant fusion protein made up of the extracellular ligand binding domain of the TACI receptor protein (which both BAFF and APRIL bind to) and the Fc region of human immunoglobulin G.

In a multicentre placebo-controlled, dose escalating study in patients with rheumatoid arthritis, a total of 73 subjects were given subcutaneous injections of atacicept or placebo, either as single doses of 70, 210 or 630mg, or repeated doses of 3 x 70, 3 x 210 or 7 x 420mg given at two week intervals.¹ They were assessed for 10 weeks of trial, and again three months after the final dose. It was well tolerated, with most adverse events being unrelated to the trial or a result of the injection process. Those given the active showed decreases in immunoglobulin and rheumatoid factor levels, and this was most pronounced in the group given 7 doses of 420mg. Disease activity scores showed that the drug gave an improvement in the signs and symptoms of rheumatoid arthritis.

It has also been looked at in systemic lupus erythematosus. Patients were given either 0.3, 1, 3 and 9mg/kg of the drug, or weekly doses of 1 or 3mg/kg for four weeks.² The drug caused dose-dependent reductions in immunoglobulin levels and total numbers of B cells, and was well tolerated.

Several early stage trials in various malignancies have also been carried out. These include one in a group of patients with relapsed and refractory non-Hodgkin's lymphoma.³ They were given weekly subcutaneous doses for five weeks of 2, 4, 7 or 10mg/kg. It was well tolerated up to this level, and the most common adverse events were fatigue and bruising at the injection site. While none of the patients achieved a complete or partial response, a quarter had stable disease eight weeks after administration of 2mg/kg, and the remainder had progressed. Trials continue, including several Phase II/III studies for autoimmune conditions.