XBiotech Announces First Patient in Clinical Study to Evaluate Bermekimab in Systemic Sclerosis
Bermekimab Blocks Key Inflammatory Pathway in Systemic Sclerosis, a Devastating Disease with Currently No Approved Therapies
AUSTIN, Texas, Oct. 02, 2019 (GLOBE NEWSWIRE) -- XBiotech (NASDAQ: XBIT) announced the first patient was enrolled in a clinical study evaluating bermekimab therapy in adults with systemic sclerosis (SSc), otherwise known as scleroderma, a devastating inflammatory syndrome characterized by chronic inflammation in the blood vessels, skin, and other organs. The randomized double-blind, placebo-controlled trial will evaluate efficacy of weekly bermekimab monotherapy versus placebo. The primary endpoint of the study will be measured at 12 weeks, and will assess SSc disease severity using a combination of rheumatological, clinical, and physiological measures. The study will randomize patients 1:1 to receive either weekly subcutaneous injections of bermekimab or placebo. The study will also include an open label weekly bermekimab treatment regimen during weeks 13-24, where patients will continue to be evaluated using the same endpoints.
SSc is characterized by systemic inflammation that results in injury to blood vessels, and fibrosis of the skin and internal organs1. Skin lesions can be severe, resulting in disfiguration and debilitating pain. In addition, patients suffering from SSc have substantially reduced life expectancy due to the fibrosis that occurs in vital organs and chronic inflammation of the blood vessels2.
While the cause of SSc is unknown, pathogenesis of the disease is understood to involve errant activation of fibroblasts. In normal organs and tissues, fibroblast cells play a crucial role in building the structural framework of connective tissue that holds the organs and tissues together. Fibroblasts produce the extracellular matrix substances that actually enable the organ structure. When fibroblasts are errantly activated in SSc, they become hyperactive and produce excessive extracellular matrix, which is the basis for fibrosis.
An initial step in the SSc disease process is believed to be the release of the potent inflammatory cytokine interleukin-1 alpha (IL-1⍺) from keratinocytes in the epidermis3. The release of IL-1⍺ results in the production of a myriad of other inflammatory cytokines, including IL-6, TNF, IL-8, IL-10, and others from surrounding tissues4,5,6,7. Blocking IL-1⍺ could abrogate the pathological cascade that occurs in this disease. Bermekimab specifically binds and neutralizes IL-1⍺.
Errant IL-1⍺ production has been repeatedly shown to occur in cells of patients with SSc (8,9). IL-1⍺ levels are elevated in SSc patients10,11, including in the skin and in lung fluids of SSc patients with pulmonary fibrosis; and when IL-1⍺ production is induced in normal fibroblasts, these take on the characteristics of SSc fibroblasts12.
Evangelos Giamarellos-Bourboulis, MD, PhD, Professor of Internal Medicine, Attikon University Hospital and principle investigator of the study, commented, “We have long suspected a role for IL-1⍺ in the pathogenesis of systemic sclerosis. There are thus strong fundamental principles behind our use of bermekimab in treating the disease. We hope that this study will finally lead to an effective treatment approach for patients with systemic sclerosis.”
The most common affected organs in SSc are the skin, the gastrointestinal tract, the lungs, and the heart. Capillary endothelium is involved, leading to ischemia and digital necrosis. Patients develop an interstitial lung disease (ILD) prototype dominated by pulmonary hypertension (PHA) and failed gas exchange. Almost all patients also have signs of intestinal dysmotility leading to gastrointestinal reflux and bloating13. Hallmarks of SSc are fibrosis of the skin and internal organs and vasculopathy. SSc is the only rheumatic disorder accompanied by substantial lethality; so far no specific treatment targeting the mechanism of pathogenesis is available.
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