Clinical

CLINICAL PLATFORM: BLOCKING CHRONIC (STERILE) INFLAMMATION

Chronic or sterile inflammation has been long associated with disease. XBiotech is using True Human™ antibody technology to block one of the body’s key regulators of inflammation—IL-1α. The Company believes that there is a tremendous unmet medical need—in multiple diseases—that may be addressed by blocking the activity of IL-1α and interrupting chronic (sterile) inflammation.

Tissue injury and cell death (necrosis) leads to inflammation. Tissue injury and necrosis do not necessarily involve infectious agents (ie. blunt trauma, blood clot, etc.), but are yet able to potently induce inflammatory responses. This non-infectious activation of an inflammatory response can be termed sterile inflammation. When we refer to chronic inflammation we are often speaking of sterile inflammation, since in many chronic diseases there is no known infectious cause. In cases of chronic viral infections, such as some forms of hepatitis, a virus cause is known. In these circumstances, it may be difficult to distinguish between chronic and sterile inflammation. In any event, chronic inflammation is a culprit in tissue destruction and disease progression.

White blood cells fight infection and repair injured tissue. Acute inflammation is thus helpful and even essential in fighting infection and healing tissue after injury. Unchecked, however, inflammation can lead to tissue destruction and provide the basis of disease.

Indeed, wherever there is ongoing disease, a process of chronic inflammation ensues. For many diseases, in fact, the unwanted effects of chronic inflammation may explain some or all of the disease process. For many conditions, the effect of chronic inflammation is virtually all that is known of the disease process.

For example, in rheumatoid arthritis the underlying cause is not known. However, inflammation in an affected joint is quite obviously a source of pain and joint destruction. Curing joint inflammation would effectively “cure” the disease, even though whatever underlying problem caused the inflammation may be unknown.

As another example, different situations can predispose to atherosclerosis, such as smoking or obesity. But the pathological process that results in atherosclerosis appears to be the same: white blood cell infiltration (e.g. inflammation) into the lining of the artery, with the eventual formation of plaques and blockage. If the process of white blood cell infiltration into the artery wall could be stopped, disease progression would be effectively treated. While chronic inflammation may not be the cause of atherosclerosis, blocking this inflammation could effectively represent a cure.

One final example, in the case of skin disease, such as psoriasis, the underlying cause is not well understood. It is clear, however, that white blood cell infiltration into skin results in the formation of lesions, often appearing over much of the body surface. If white blood cells could be effectively stopped from entering the skin, there would be no evidence of disease, regardless of the underlying process that normally causes this problem.

In the broadest sense, therefore, disease may often be thought of as inflammation in a given tissue: the joint in arthritis; the artery in atherosclerosis; and the skin, in the case of psoriasis.

In other situations, the relationship of chronic inflammation to progression of the underlying disease is more complex. In the case of cancer, the cancerous tumor “tricks” white blood cells, drawing them into the tumor environment. There the white blood cells can stimulate growth of new blood vessels and remodel tissue to enable nutrient supply for tumor growth and room for expansion, respectively. This form of chronic inflammation may be essential in some cases for the growth and spread of cancer. We believe that the anti-tumor activity that we have seen in our clinical study with advanced cancer patients evidences the importance of inflammation in tumor growth and supports a role for targeting IL-1α to block this process.

Targeting a crucial mediator of chronic inflammation thus holds promise to treat many important disease processes. XBiotech believes that IL-1α represents a crucial mediator of chronic and sterile inflammatory processes. We thus believe that our product candidate holds promise as a significant breakthrough in the management of unmet medical needs.