With the approaching launch of two novel therapies that have shown substantial clinical promise to date, the coming decade is set to be a very exciting time for individuals suffering from chronic and/or severe atopic dermatitis. This form of dermatitis, literally meaning ‘atypical inflammation of the skin,’ is in many ways similar to contact dermatitis, which commonly occurs upon contact of the skin with an irritant. Atopic dermatitis, however, is characterized by a far more nefarious course and presentation: an often high degree of body surface area involvement and, because its cause nearly always goes unidentified, persistent eczema and uncontrollable itching that can continue for decades. While contact dermatitis generally clears rapidly after identification and subsequent avoidance of the irritant, the eczema characteristic of atopic dermatitis usually continues unabated, often persisting even after treatment. Also, unlike the itch caused by mosquito bites, for example, a growing body of evidence suggests that atopic dermatitis itch does not appear to be driven by histamine, thus rendering anti-histamines relatively ineffective in controlling atopic dermatitis itch.

For years, the treatment landscape of atopic dermatitis has remained relatively static, with non-moisturizing agents and two classes of prescription topical treatments, glucocorticosteroids and calcineurin inhibitors, dominating the market. While the wide array of generically available glucocorticosteroids and their proven efficacy in controlling symptoms of atopic dermatitis underlie their extensive use for the indication, risks of skin thinning after long-term use and a pervasive “steroid phobia” limit patients’ and physicians’ comfort with the class, especially in cases of high body surface area involvement or breaks in the skin that could lead to systemic absorption. The calcineurin inhibitors tacrolimus (Astellas’s Protopic and generics) and pimecrolimus (Valeant’s Elidel) are efficacious alternatives to topical steroids, but carry black box warnings of lymphoma risk, also substantially limiting their use. Indeed, research has shown that adherence to prescribed topical therapies is extremely low in atopic dermatitis, which is likely due, at least in part, to safety concerns.

Patients with severe atopic dermatitis that cannot be adequately managed by topical treatment, whether due to safety concerns or a lack of efficacy, have very few options to turn to. At present, these patients tend to cycle through systemic immunosuppressants, such as azathioprine, cyclosporine, or mycophenolate mofetil, which are often likened to “sledge hammers” because of their broad and potent suppression of the immune system. While these systemic treatments can control disease in patients, many are unable to tolerate the side effects of long-term use.

While topical treatments are largely efficacious in helping control eczema and itching, the continuing concerns over the safety and side effects of both topical and systemic treatment highlight two niche populations of atopic dermatitis patients that require better treatment options—patients with severe, widespread eczema that is not adequately controlled by topicals or systemic immunosuppressants, and patients who are not comfortable with, or are intolerant of, existing topicals. These unmet needs, coupled with the high prevalence of atopic dermatitis in the major markets (estimated at a combined 50 million in the United States and major European markets), have fueled a great degree of interest and investment into the development of new atopic dermatitis therapies over the past several years.

These investments now appear set to bear fruit, with two emerging agents—crisaborole and dupilumab—forecast to reach the market in 2017, each addressing a key niche population of patients who are not adequately served by current treatment options. Crisaborole, a topical PDE-4 inhibitor, is being developed by Anacor, whose acquisition by Pfizer is set to be completed in Q3 2016. Crisaborole was submitted for FDA approval earlier this year and currently has a PDUFA goal date of January 7, 2017. Dupilumab, an injectable biologic targeting the receptor of two inflammatory cytokines involved in driving eczema, is being developed by Regeneron and Sanofi. Sanofi and Regeneron expect to file dupilumab, which has received breakthrough status, for FDA review in Q3 2016.

Both therapies appear to be very safe and well-tolerated in clinical trials, and are widely expected to transform the AD treatment landscape in the coming years. Crisaborole, set to be the first non-steroidal topical to become available since the launch of Elidel in 2005, will provide a much-needed alternative to glucocorticosteroids and calcineurin inhibitors, over which safety concerns abound. The large size of the prevalent atopic dermatitis population targeted by a safe, effective topical will drive sales, which was likely factored into Pfizer’s $5.2 billion bid for Anacor earlier this year. Dupilumab, in contrast, is expected to target the individuals suffering from severe disease with high body surface area involvement for whom current therapies are inadequate. Despite some concern over its subcutaneous route of delivery, the agent has shown exceptional results in clinical trials. We believe that, in patients with incurable itch and severe eczema who have exhausted other treatment options, an injection will not be a significant hurdle to dupilumab’s uptake, owing to the great degree of unmet need for effective therapies to treat severe atopic dermatitis.

The launch of these targeted therapies for the treatment of AD shares many parallels with psoriasis, a skin disease which, like AD, is characterized by a high prevalence and chronic nature. Until about fifteen years ago, the psoriasis treatment landscape was dominated by topical agents and systemic immunosuppressants such as methotrexate and cyclosporine. However, driven in part by a great degree of unmet need for more-effective therapies, the psoriasis market has since exploded, being driven from under $1 billion in 2003 to over $5 billion in 2014 with a number of targeted drugs spanning several classes now available to treat psoriasis. Importantly, commercial interest in this space has yet to taper off, a strong suggestion that the market continues to be ripe for agents that offer improved efficacy, safety, or dosing. The evolution of the psoriasis market over the past decade and a half raises the possibility that launch of crisaborole and dupilumab in the atopic dermatitis market represent the first of several waves of targeted AD drugs. Launch of these targeted therapies will mark the beginning of the materialization of a lucrative market for drug developers (for more information on continued therapeutic development in the psoriasis market, please see the DRG blog post entitled “Biologics continue to flare up the psoriasis market, indicating opportunities in the larger dermatology space”).

For the first time, physicians and patients are offered hope that severe atopic dermatitis for which no satisfactory treatments currently exist could soon become a manageable condition. While crisaborole, with its potential as a steroid-free maintenance therapy, and dupilumab will revolutionize atopic dermatitis treatment, their respective launches may only be the beginning of a new era of therapeutic development. A strong pipeline and continued research into the pathological processes that drive eczema and itch in atopic dermatitis, in combination with the expected commercial success of crisaborole and dupilumab, will drive the continued development of novel therapeutics for atopic dermatitis patients, many of whom have suffered for years without any adequate treatment options.

 

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