Dr. Neal Walker: Targeting the immune system in dermatology

Oct 03, 2017 | Focus on Patients

Skin, the largest organ of the human body,[1] plays a critical role in the immune system, providing a physical barrier against foreign substances and acting as an immunologic organ.[2] Human skin contains an estimated 20 billion T cells – a white blood cell that is an important part of the body’s immune response – far greater than the number of T cells found circulating in blood.[3]

Unfortunately, despite the amazing efficiency and precision with which the skin and immune systems work together, things sometimes do go wrong. These “errors” can lead to autoimmune dermatological disorders such as a type of hair loss known as alopecia areata, and other conditions including eczema, psoriasis and vitiligo.

As our understanding of the immune systems grows, one of the most exciting areas of dermatology research is the development of highly targeted immuno-therapeutics that have the potential to change approaches to managing skin disorders. Aclaris Therapeutics is working in this cutting-edge field of immunodermatology, working with several families of immunomodulators targeting Janus kinase (JAK), interleukin-2 inducible kinase (ITK) or the p38/MK2 pathway. These intracellular signaling pathways are involved with many aspects of the body’s immune responses, including skin inflammation.[4]

The first of the four JAK enzymes was discovered in the early 1990s by researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Subsequent studies showed that genetic defects in a particular JAK, JAK3, can cause severe combined immunodeficiency (SCID).[5] In fact, many of you may be familiar with the medical case of David Vetter, dubbed “the bubble boy,” who suffered from SCID. It was his case that ultimately led to the discovery of JAK and spawned the idea that drugs blocking these proteins might be protective against the damaging inflammation of certain autoimmune diseases.[6]

At Aclaris, we are diligently working on oral and topical JAK inhibitor candidates, which are in clinical testing for conditions including alopecia areata. Our research and development team also is actively looking at the application of JAK inhibitors for the potential treatment of androgenetic alopecia, also known as male/female pattern baldness.

We find the potential for immunodermatology so promising that we recently acquired Confluence Life Sciences, Inc., a company focused on discovery of new kinase inhibitors. The Confluence acquisition expands our anti-inflammation and immunology pipeline. Confluence has developed a family of complementary JAK inhibitors, including unique, skin-targeted JAK1/3 inhibitors that we will evaluate for the potential treatment of alopecia areata and, possibly, other skin disorders. These skin-targeted, “soft” JAK inhibitors are designed to be active in the skin but rapidly metabolized in the circulation.

ITK inhibitors, a second category of kinase inhibitors was acquired by us as part of the acquisition of Confluence. This kinase is involved with T cell signaling, and it has a particularly potent influence on Th17 cells and their expression of interleukin-17. We have plans to evaluate ITK inhibitors in psoriasis and related pathologies.

A third drug class that has come to Aclaris via Confluence is called p38/MK2 pathway inhibitors. One can think of these drugs as “oral anti-TNFα and anti-IL1β” agents. P38/MK2 is the central pathway involved in all chronic inflammation.

Finally, with the Confluence acquisition, we not only expanded our inflammation and immunology pipeline, but also gained a drug discovery engine led by some of the leading researchers in the field.

As a dermatologist-led biopharmaceutical company focused on identifying, developing and commercializing innovative and differentiated therapies to address significant unmet needs in medical and aesthetic dermatology, we are proud to be on the front lines of immunodermatology.

[1] Swann, G. Editorial. Journal of Visual Communication in Medicine. 2010; 4:148-149
[2] Salmon JK, Armstrong CA, Ansel JC. The skin as an immune organ. Western Journal of Medicine. 1994;160(2):146-152.
[3] Seneschal J, Clark RA, Gehad A, Baecher-Allan CM, Kupper TS. Human Epidermal Langerhans Cells Maintain Immune Homeostasis in Skin by Activating Skin Resident Regulatory T Cells. Immunity. 2012;36(5):873-884. doi:10.1016/j.immuni.2012.03.018.
[4] Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nature Reviews Rheumatology. 2016;12(1):25-36. doi:10.1038/nrrheum.2015.167.
[5] Notarangelo LD, Mella P, Jones A, de Saint Basile G, Savoldi G, Cranston T, Vihinen M, Schumacher RF. Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat. 2001 Oct;18(4):255-63.
[6] Cossu F. Genetics of SCID. Italian Journal of Pediatrics. 2010;36:76. doi:10.1186/1824-7288-36-76.