Over the last two decades, biologics have improved the management of patients with psoriasis and advanced melanoma, many of whom either did not respond to traditional treatments or experienced severe side effects from them. With their success in deadly forms of melanoma and more common chronic inflammatory conditions such as psoriasis, drug developers are now targeting rarer indications with their biologics.
Also called biopharmaceuticals, biologics include a wide range of medical products that are produced from or contain components of living organisms and modify natural cellular and intracellular processes. There are several types of biologics such as vaccines, blood and blood components, insulins, cytokines, somatic cells, stem cells, growth factors, gene therapy, tissues, and recombinant proteins. The more contemporary connotation of the term “biologics” is drugs produced by biotechnology, often using recombinant DNA methods.
It is monoclonal antibodies (ending in -mab), fusion antibody proteins (ending in -cept), and small molecule inhibitors of kinase enzymes (ending in -nib) that are seeing the greatest success in the field of dermatology.[1] Although expensive when compared with oral systemic drugs, these biologics can succeed when all other treatments fail. Likewise, their more specific action generally produces fewer side effects and an improved quality of life compared with traditional systemic treatments.
Of all specialties, dermatology represents a growing proportion of FDA-approved therapeutic proteins in the last five years. A 2016 report found that biologics accounted for some 37 percent of dermatology products in development.[2]
Early Biologics in Dermatology
The early development of biologics for melanoma in the 2000s played an important role in demonstrating the efficacy of biologics for dermatology. The two main types of biological therapy for melanoma are targeted treatments, which target gene changes, and immunotherapy drugs. Examples of targeted treatments include BRAF-inhibitors such as vemurafenib, dabrafenib, and sorafenib, while immunotherapy products for melanoma include ipilimumab, pembrolizumab, and nivolumab.
In 2003, alefacept for plaque psoriasis became the first FDA-approved biologic for any non-melanoma dermatologic condition. Since then it has been withdrawn from the market and more than a dozen new biologics have been approved for the treatment of psoriasis and its many manifestations, such as psoriatic arthritis.
More Than Melanoma and Psoriasis
Since alefacept, biologics are bringing relief to an increasing number of other skin diseases with approved therapies for advanced basal cell carcinoma (hedgehog signaling pathway inhibitors, vismodegib, and sonidegib), atopic dermatitis (dupilumab), pemphigus vulgaris (rituximab), chronic spontaneous urticaria (omalizumab), and hidradenitis suppurativa (adalimumab). Most of these have been extensions of indications — frequently first approved for other conditions than skin diseases— rather than novel therapies targeting a single disease alone.
Biologics for a number of other indications are also in development, including the following.
Behçet Disease
Behçet disease is a chronic, relapsing, vasculitis (inflammation of blood vessels) that affects the mouth and skin and many other systems within the body, including the eyes, bowels, lungs, joints, heart, and even the brain. Painful mouth ulcers are usually the first visible sign of Behçet disease and occur in most patients. Other common manifestations include dermatological manifestations. They include painful and scarring lesions on the genitals, skin nodules, acne-like sores on arms, trunk and legs.
Partly because anti-TNF therapies have had success in treating inflammatory bowel disease — which shares many similarities with the intestinal manifestations of Behçet’s — doctors have considered biologic treatment options for this condition.
Earlier this year, the European League Against Rheumatism updated its recommendations for the management of Behçet disease in its many manifestations.[3] In it, they noted the apparent efficacy of IL-1 blockade with the newer biologics anakinra and canakinumab in patients with mucocutaneous Behçet. However, they also highlighted that other IL-17 and -6 blockers, such as secukinumab and tocilizumab respectively, are not recommended, with the first drug being ineffective and the latter drug worsening lesions.
Several other biologics are used off-label or are in clinical development for different manifestations of Behçet disease, such as infliximab and adalimumab for eye involvement and ustekinumab and apremilast for oral ulcers.[4]
Alopecia Areata
Also called spot baldness, alopecia areata (AA) is an autoimmune disorder wherein the immune system attacks the hair follicles, resulting in hair loss and characteristic exclamation mark hairs. This usually manifests as small patches of missing hair, but total baldness can occur in severe cases. Although usually most noticeable on the scalp, AA can also affect facial and body hair. AA is often found in conjunction with other dermatologic conditions.
There are currently no FDA-approved treatment options for severe cases, which makes AA an attractive indication for biologic drug developers. Additionally, the frequent use of broad immunosuppressants has severe side effects and can’t be used long term.
There have been numerous case reports of effective off-label use of alefacept and efalizumab. Unfortunately, this effect failed to be reproduced in double-blind trials. There have also been reports of recurrence of AA in patients undergoing biologic therapy for other conditions.
The lack of good treatment options for AA may change in coming years with Janus kinase inhibitors (JAKis), abatacept and Phosphodiesterase 4 (PDE4) inhibitors.[5] JAKis, including tofacitinib, ruxolitinib, and baricitinib, have already shown to beneficially treat AA in small proof-of-concept studies. Abatacept, a fusion protein that modulates T-cell costimulation, is in clinical development for moderate to severe AA. PDE4 is highly increased in human AA scalp lesions, representing a potential therapeutic target. Apremilast, a PDE4 inhibitor, is currently in development for severe AA.
Palmoplantar Pustulosis
Palmoplantar pustulosis (PPP) is a chronic, recalcitrant disorder where neutrophil-filled aseptic pustules form on the palms and soles of the feet that can cause major difficulties in manual occupations and impedes walking. PPP occurs usually on its own but is associated with psoriasis in 10 to 20 percent of cases.[6]
The first-line treatment for PPP is the same as for psoriasis, including topical drugs and phototherapy, followed by systemic medications. However, many cases of PPP are highly resistant to these strategies, and some patients experience severe side effects from these drugs.
Unfortunately, biologic therapies have yet to conclusively work for PPP. Etanercept and ustekinumab were not found to be superior to placebo. Treatment with infliximab has shown 100 percent clinical improvement in some case studies.[7] More recently, guselkumab, an anti-IL-23 antibody, showed promising efficacy in palmoplantar pustulosis.[8]
Hidradenitis Suppurativa
Also called acne inversa, hidradenitis suppurativa (HS) is a chronic, inflammatory disease that affects the apocrine sweat glands. The sweat glands are found in the axillary (armpits), breast and inguino-perineal (groin, peri-genital, peri-anal) regions.
In HS, the development of apocrine sweat glands during puberty causes occlusion and inflammation of the hair follicles and painful nodules and abscesses that rupture, leaking pus and leading to scars. HS has been historically very difficult to treat with systemic antibiotics, retinoids, anti-androgens, immunosuppressive agents, analgesics and surgery.
In 2015, adalimumab (Humira) became the first and thus far only FDA-approved treatment for moderate to severe disease. Dermatologists have noted that adalimumab treatment in HS patients resulted in relatively few infections compared with what was anticipated.
Although there is some reported success with off-label use of TNF inhibitors, such as infliximab and etanercept, pP trials, Phase 3 trials are not currently planned.
A number of biologics targeting IL-1 (anakinra, canakinumab, bermekimab) and IL-17 (secukinumab, bimekizumab) are also in the pipeline for HS.
Pediatric Indications
Although biologics have lagged in approval for pediatric patients, even for psoriasis, etanercept was approved to treat severe plaque psoriasis in children eight years of age or older by the European Medicines Agency in 2009 (and subsequently approved for those six years of age and under); in 2016, it was approved by the FDA for children as young as four.
In 2017, ustekinumab was approved by the FDA for psoriasis patients 12 and older. Multiple other biologics already approved for use in adults with psoriasis are now following pediatric investigation plans.
This shift is important for pediatric patients. In psoriatic children, methotrexate is one of the most common systemic treatments and can have severe side effects. One 2017 retrospective study using over two decades of data found that 48 percent of pediatric patients on the drug had at least one adverse event, primarily gastro-intestinal.[9] By comparison, biologic agents (TNF inhibitors) resulted in fewer adverse effects in pediatric psoriasis patients, mainly injection site reactions.
Biologics are also being considered for pediatric patients with atopic dermatitis. Dupilumab trials for patients ages 12 to 17 are ongoing, with one key phase 3 trial reportedly meeting primary and certain important secondary endpoints in May 2018. The trial thus far reported similar rates of adverse events between drug and placebo combined with a 75 percent greater improvement in the drug group than in the placebo group.
Shifting Focus
There is a clear shift in dermatology drug development towards biologics, targeted treatments, and rare skin diseases and away from topicals and symptomatic treatments. Despite their high potential, however, biologics have a greater risk than most topical treatments and require a good knowledge of the diseases, their management and the regulatory environment. The solution? Researchers with the right experience.
[1] Sorting Through the Confusion of Biologic Drug Names – Medscape – Aug 19, 2016.
[2] MarketResearchReports.biz. (2016, August 8). Global Dermatology Market to 2022 – Innovative Pipeline and Increasing Uptake of Biologics to Diversify Treatment Options and Drive Strong Growth. Retrieved from https://www.marketresearchreports.biz/reports/725316/global-dermatology-to-innovative-market-research-reports
[3] Hatemi G, Christensen R, Bang D, et al. 2018 update of the EULAR recommendations for the management of Behçet’s syndrome. Annals of the Rheumatic Diseases Published Online First: 06 April 2018. doi: 10.1136/annrheumdis-2018-213225
[4] INSERM. Orphanet: Behçet disease. Orphanet: About orphan drugs. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=117. Published December 2012. Accessed November 20, 2018.
[5] Renert-Yuval Y, Guttman-Yassky E. The Changing Landscape of Alopecia Areata: The Therapeutic Paradigm. Advances in Therapy. 2017;34(7):1594-1609. doi:10.1007/s12325-017-0542-7.
[6] British Association of Dermatologists – Patient Information Leaflets (PILs). British Association of Dermatologists healthy skin for all. https://www.bad.org.uk/for-the-public/patient-information-leaflets/palmoplantar-pustulosis/?showmore=1&returnlink=https://www.bad.org.uk/for-the-public/patient-information-leaflets#.W_Q0-HtKipo. Published April 2018. Accessed November 20, 2018.
[7] Sanchez IM, Sorenson E, Levin E, Liao W. The efficacy of biologic therapy for the management of palmoplantar psoriasis and palmoplantar pustulosis: a systematic review. Dermatol Ther. 2017;7(4):425-446. doi:10.1007/s13555-017-0207-0
[8] Terui T, Kobayashi S, Okubo Y, Murakami M, Hirose K, Kubo H. Efficacy and Safety of Guselkumab, an Anti–interleukin 23 Monoclonal Antibody, for Palmoplantar Pustulosis. JAMA Dermatology. 2018;154(3):309-316. doi:10.1001/jamadermatol.2017.5937.
[9] Bronckers IMGJ, Seyger MMB, West DP, et al. Safety of Systemic Agents for the Treatment of Pediatric Psoriasis. JAMA Dermatol. 2017;153(11):1147–1157. doi:10.1001/jamadermatol.2017.3029