The Race to Treat Atopic Dermatitis - Everything you need to know

Posted by Graham Hamilton on Sep 9, 2019 10:09:52 AM

The race to treat Atopic dermatitis (AD) is crowded so this has led to a lot of experience in Longboat on AD studies. The second installment in our therapeutic area series therefore centers on AD. Also known as atopic eczema - AD is a common chronic skin disease, and evidence suggests its lifetime prevalence is, for the most part, increasing worldwide. It most often develops in childhood; however, it can persist to, or even begin to develop in, adulthood.

It is an inflammatory disease characterized by recurrent, intensely itchy, eczematous lesions (i.e. red patches/blisters with oozing in early stages and dry, thickened skin in later stages), which can affect any part of the body, and typically shows an age-related morphology and distribution. It is linked not only with other atopic diseases, such as asthma and allergic rhinitis, but also food allergies.

A recent report has estimated the annual cost of AD in the United States alone to be in excess of $5.297 billion.

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Current Diagnosis and Treatment 

Currently, there are no specific diagnostic tests for AD, and therefore diagnosis is based on criteria that take in to account the patient’s history and clinical features. There are several proposed sets of diagnostic criteria, and the ‘Hanifin and Rajka criteria’ - one of the earliest and most recognized criteria - is still widely used. Guidelines for diagnosis can be found here.

Disease severity is established following diagnosis. Both objective signs and subjective symptoms are evaluated and graded. As with diagnosis, there are a variety of scoring systems for this, and two of the most commonly used in clinical trials are the ‘Eczema Area Severity Index’, or EASI, and the ‘Scoring of Atopic Dermatitis’, or SCORAD index.

AD is not currently curable, and so therapy centers around alleviating symptoms and establishing disease control through a multistep approach. This can include: restoring the skin barrier, trigger avoidance, anti-inflammatory therapy, and treatment of skin infections - therapy selection largely depends on the extent and severity of the disease.

However, current treatments demonstrate limited efficacy in cases of severe AD.

 

Treatments on the Horizon?

Recently, the understanding of AD has made major advances, particularly with respect to pathogenesis. While this pathogenesis is not yet fully understood, it is known to be complex and multifactorial - involving skin barrier disruption, immunologic factors, and environmental factors.

Driven by this new understanding, therapies that act on specific molecular targets are emerging with many at advanced stages of development.

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IL-4 and IL-13

Interleukin (IL)-4 and IL-13 are important Th2 cytokines, and their downstream effects are prominent in AD. Th2 cytokines have pleiotropic effects on both the innate and adaptive systems.

Dupilumab is a humanized monoclonal antibody (mAb) that targets the α-subunit of the IL-4 receptor, preventing IL-4 and IL-13 from binding to it, therefore modifying both the IL-4 and IL-13 pathways. In 2017, Dupilumab was designated ‘breakthrough therapy’ status and approved by the FDA,  becoming the first approved targeted therapy for AD.

Lebrikizumab is a humanized mAb that specifically targets and binds to IL-13. It has been studied in Phase 2 trials for AD, and is also currently under study for other conditions.

IL-17A

IL-17A is a Th17 cytokine that is known to play a role in AD development. This role has not been fully elucidated; however, it is thought to contribute to inflammation in AD.

Secukinumab is a humanized mAb that selectively binds to IL-17A. This prevents interaction with the IL-17 receptor, which is thought to limit the generation of pro-inflammatory chemokines and cytokines. It is under study in Phase 2 trials for AD, and is also approved for treatment in plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.

IL-22

IL-22 is thought to hinder proteins that mediate keratinocyte differentiation, contributing to epidermal hyperplasia and skin barrier defects. Additionally, it has been linked to act synergistically with IL-17. Increased levels of cytokine IL-22 have been shown in lesions of chronic AD patients.

Fezakinumab is a mAb that targets IL-22, blocking its actions. It has recently completed a Phase 2 trial in AD, and is also under study in clinical trials in rheumatoid arthritis and psoriasis.

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TSLP and OX40

TSLP (Thymic stromal lymphopoietin) is involved in cytokine secretion linked to AD and is highly expressed on keratinocytes in lesions of patients with AD. Additionally, TSLP causes OX40L expression, which interacts with OX40 – a key process in the generation of Th2 responses and in the development of allergic inflammation. Together, these may be pivotal for the exacerbation of Th2 immune activation in AD.

Tezepelumab is a mAb that binds to TSLP, preventing receptor interaction. It is currently under study in Phase 2 trials for AD, as well as asthma, bronchial diseases, and respiratory tract diseases, amongst others.

GBR 830 is a mAb, OX40 antagonist. It is currently under study for AD and was the first OX40 antagonist to complete Phase 1 trials globally.

JAK-STAT pathway

The JAK-STAT (Janus Kinase – Signal Transducer and Activator of Transcription) signalling pathway is hypothesized to play a critical role in the dysregulation of a range of immune responses in AD, including; disrupting the skin barrier, amplifying the Th2 response, and suppressing regulatory T-cells.

Baricitinib is a small molecule JAK 1 and JAK 2 inhibitor. It was recently evaluated as an oral treatment in a Phase 3 trial in patients with moderate-to-severe AD. It is approved for treatment in adults with moderate-to-severe rheumatoid arthritis.

NK1R

Substance P stimulates the NK1R (Neurokinin-1) receptor, inducing pruritis in skin nerve fibres. In AD patients, the expression of substance P is elevated, therefore increasing pruritis.

Trapidant is a small molecule, NK1R antagonist that blocks substance P interaction with NK1R. It has been studied in pruritic conditions such as eczema, chronic pruritus, and AD - in AD it is currently undergoing a Phase 3 trial.

PDE-4

PDE-4 (Phosphodiesterase-4) is an enzyme that is involved in the degradation of cyclic adenosine monophosphate (cAMP). Reduced levels of cAMP are associated with increased levels of pro-inflammatory cytokines - accelerating functions involved in acute and chronic inflammation. Levels of PDE-4 are increased in AD patients.

Crisaborole is a small-molecule, topical, non-steroidal, PDE-4 inhibitor. It was approved by the FDA for AD in 2016 as the first drug in its class

Apremilast is a small-molecule, orally-available, PDE-4 inhibitor. It has recently completed Phase 2 trials for AD, and is approved for the treatment of psoriatic arthritis in adults and moderate-to-severe plaque psoriasis.

 

Challenges in Developing Drugs for AD

AD is a heterogenous disease - shown both clinically and by the absence of distinct, reliable biomarkers that apply to all patients. However, it is still largely considered to be a single disease and treated as such, and while this is effective for some, other patients remain refractory to this treatment model.

Research to identify and characterise subtypes is therefore required, and would allow stratification of the disease in to more homogenous subgroups. This stratification would help to build on current targeted therapies already in the pipeline, potentially allowing a more personalized approach – delivering therapies that are more effective, with fewer side effects than those currently available.

 

The Future Clinical Landscape 

The understanding of AD has made major advances, particularly with respect to its complex pathogenesis. Novel insights have led to thriving drug development; the pipeline is crowded with many biologics and small molecules that target different pathways all in the hope of improving the lives of AD patients. If approved, they will provide new and exciting options for AD management.

 

Clinical Trial Leaders Interviews

 

Topics: Clinical Reseach, Clinical Trials, New Drug Applications, Drug Development, Indication Overview Series