Psoriasis

XBiotech has completed a multicenter, phase II study of its True Human™ therapeutic antibody MABp1 in subjects with moderate to severe plaque psoriasis. This clinical trial was launched after a dramatic response was observed in a psoriasis patient who was treated with MABp1 on a compassionate basis. The phase II study was headed by internationally recognized expert in dermatology research, Johann Gudjonsson MD, Ph.D., Assistant Professor Department of Dermatology, University of Michigan. Patients received subcutaneous injections of the antibody and numerous efficacy assessments were made, including the Psoriasis Area and Severity Index (PASI).

Psoriasis, an inflammatory disease that primarily involves the skin, and secondarily the joints, affects about 2-3% percent of the population in the USA. Disease severity can vary substantially among individuals, from thin plaques involving limited areas, to thick lesions over large areas of the body. Treatments such as topical corticosteroids, topical vitamin D analogs, and emollients are used to treat mild disease; light based therapies, oral medications with anti-inflammatory or immunosuppressive medications can be used to treat more severe disease.

Four biological therapies have been approved for the treatment of psoriasis: etanercept (a TNF-α receptor analog), infliximab (a chimeric TNF-α antibody), adulimumab (a humanized monoclonal tnf α antibody), and ustekinumab (a recombinant monoclonal antibody to IL-12 and IL-23 p40 subunit). These biologic drugs are not without side effects, which are sometimes serious. Moreover, these medications exhibit loss of effectiveness over time, probably due to neutralizing antibody against the drugs that form in patients. These biologics are also very costly.

IL-1α has been identified as a key mediator of sterile inflammation and is abundantly present in psoriatic skin lesions. Skin cells, or keratinocytes, are in fact a large reservoir for preformed, intracellular, and biologically active IL-1α. Excess IL-1 activity promotes the production of adhesion molecules by endothelial cells and release of chemokines, both of which lead to infiltration of the tissues by white blood cells. Once in the dermis, some of these white blood cells can differentiate into macrophages and dendritic cells, which can induce psoriatic skin changes through further production of proinflammatory cytokines. This cycle of inflammation and infiltration by white blood cells likely plays a significant role in the chronic inflammatory component of psoriasis.

Mouse models have been used to illustrate the importance of IL-1α in the development of psoriasis. Animals genetically lacking a single mechanism used to naturally regulate the effects of IL-1α spontaneously develop psoriasis-like disease. Interestingly, these mice also develop atherosclerosis- and arthritis-like disease.

Cutaneous inflammation, in terms of both macro and microscopic features, looks markedly like psoriatic lesions. Similar results have been seen in mice that are bred to over-express IL-1α in the skin. Mice that overproduce IL-1α in basal keratinocytes, develop sparse hair and fine, scaly skin. These mice often progress to develop inflammatory psoriatic-like skin lesions. Studies using human keratinocyte cultures show that IL-1α induces similar genetic changes as in the skin of subjects with psoriasis.

XBiotech's antibody directed against IL-1α has been found to be not only effective in treating psoriasis, but could be safer and better tolerated than the existing front line therapies for the disease. MABp1 therapy is potent and fast acting, offering the potential for an important and novel treatment option for the disease.