DESTIN, FLA. — A safety and efficacy trial is underway of an agent designed to treat dermatomyositis or polymyositis in adults via the novel approach of blocking interferon-alpha or its receptor.
Dr. Steven A. Greenberg reported that he and his colleagues are currently assessing the safety and tolerability of multidose, intravenously administered MEDI-545 (a fully human anti-interferon-alpha monoclonal antibody) in adult patients with dermatomyositis or polymyositis. The agent is being tested in study MI-CP151, a phase IB clinical trial sponsored by the drug manufacturer, MedImmune Inc.
“This is a true personalized-medicine trial, in that patients have to have a pattern of type I interferon-inducible gene activation in their blood by microarray studies to be enrolled,” said Dr. Greenberg, a neurologist at Brigham and Women's Hospital in Boston. He noted that in a rank-order listing of blood gene expression of patients with active disease who are enrolled in the study thus far, 90% of the genes are type I interferon transcripts, confirming that “these are biomarkers of active disease.”
Microarray and protein studies are identifying long-overlooked immune system cell types and processes that are involved in muscle damage in these diseases; such findings open channels for more targeted drug development and clinical trials of existing drugs that act on these immune pathways.
For example, dermatomyositis is characterized by progressive proximal muscle inflammation and weakness, as well as associated skin changes. “The way people have thought about this disease for a couple of decades is that the muscle injury is an end product of capillary injury,” said Dr. Greenberg at the Congress of Clinical Rheumatology. “It has largely been believed that dermatomyositis is a disease in which antibodies are binding to an endothelial cell antigen, causing complement-mediated injury in capillaries, and that the capillary injury eventually causes ischemia to muscle. According to this model, the characteristic perifascicular atrophy is thought to simply be a result of lack of blood supply to muscle.”
There are a number of problems with this theoretical model, Dr. Greenberg explained. “Importantly, no antigens or antibodies have been demonstrated and, in experimental models of ischemia, perifascicular atrophy doesn't occur. Experimental ischemic myopathy actually affects the central portions of fascicles, not the peripheral portions,” he said. “Nor does one ever see perifascicular atrophy in vasculitis, the one disease in which we do know there is muscular ischemia.”
Plasmacytoid dendritic cells, which produce alpha and beta interferons, have recently been identified in the muscle and skin of patients with dermatomyositis. Gene-expression profiling of these cells shows significant up-regulation of type I interferon-alpha/-beta-inducible genes that correlates with disease activity. These findings suggest a different mechanistic model, said Dr. Greenberg. “One potential way to think about this disease is that the overproduction of type I interferon-usable proteins, regardless of the mechanism, may be separately injuring both capillaries and the perifascicular muscle fibers,” he said.
“There are muscle fibers that appear to be dying for no apparent reason. There are no immunoglobulin molecules; there are no T cells touching them,” said Dr. Greenberg. “The question that arises is whether the production of some interferon-inducible transcript or protein within myofibers themselves could injure the muscle fibers,” he said.
“Is this an autoimmune disease in which tissue injury results from the intracellular proteins of the innate immune system, rather than by-products of the adaptive immune system, either in the immunoglobulin molecules secreted by plasma cells or effector cytotoxic molecules secreted by CD8 plasma T cells?”
Given this possibility, “it is very reasonable to try blocking interferon-alpha or its receptor for the treatment of dermatomyositis,” said Dr. Greenberg. The paradigm for muscle injury in inclusion body myositis (IBM) and polymyositis should also be revisited in light of recent “surprises,” according to Dr. Greenberg. Both diseases have long been considered “classic intramuscular CD8 T-cell-mediated diseases.” However, recent research has demonstrated an abundance of both myeloid dendritic cells (which are implicated in triggering the adaptive immune system) and differentiated B cells (in the form of CD138+ plasma cells) in the inflamed muscle tissue of patients with either IBM or polymyositis.
These findings, taken together, broaden the pool of potential therapeutic agents. “There are at lease 15 [Food and Drug Administration]-approved drugs targeting these molecules of interest,” said Dr. Greenberg.
He disclosed having a sponsored-research agreement with MedImmune for support of his research laboratory, but noted that all data discussed in this presentation were obtained prior to this agreement.