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Updates in AD: New Treatment Options

In this podcast, Ramiz Hamid, MD, reviews some of the newer therapeutic options in the pipeline for atopic dermatitis.

Dr Hamid is a resident physician in the Department of Dermatology at Wake Forest School of Medicine.


Melissa: Hello. Welcome to another “Updates in Atopic Dermatitis” podcast. Today, Dr Hamid, resident physician in dermatology at Wake Forest School of Medicine, will discuss the latest therapies in the pipeline for atopic dermatitis.

Let’s start with some of the newer options in later‑phase clinical trials. What are these therapies, and can you tell us a little bit about their mechanisms of action? Let’s start with some of the newer options in later phase clinical trials. What are some of the latest therapies under investigation?

Dr Ramiz Hamid: It’s an exciting time in the world of atopic dermatitis. For many years, corticosteroids and systemic immunosuppression were the only options for patients with severe disease. A growing realization of the economic burden of eczema and the success of some of the newer treatments has really spurred development and has transformed this into a hot area of research.

There are several new biologic therapies in the pipeline, and a few of these include nemolizumab, which is an IL‑31 receptor antagonist developed by Galderma. There’s lebrikizumab, which is Eli Lilly’s monoclonal antibody targeting IL‑13 and tralokinumab, which is also a IL‑13 inhibitor, by LEO Pharma that is currently under review by the FDA and may hit the market as early as 2021.

Melissa: For nemolizumab, what does the data show in regards to safety and efficacy, and what can clinicians expect for patients with this option?

Dr Hamid: Yes. Nemolizumab is a monoclonal antibody that blocks the IL‑31 receptor. IL‑31 is an important pruritus‑inducing cytokine, so blocking that signaling pathway in peripheral neuron could relieve the sensation of itch.

Phase II trials demonstrated that monthly subcutaneous dosing of the medication significantly improved pruritus in patients with moderate to severe atopic dermatitis. It’s currently in phase III trials, and results of one phase III study were published in the New England Journal of Medicine in July.

It was a 16‑week trial with 215 patients in Japan. It was comparing the use of nemolizumab in addition to topical agents to placebo plus topical agents in improving the itch associated with atopic dermatitis. Pruritus was measured on the visual analog scale, so from zero, which is no itch, to 100, or the worst imaginable itch.

Interestingly, the mean baseline score was 75, which just highlights the severity of this symptom in eczema patients. At week 16, the mean visual analog scale score was reduced by 42% in the nemolizumab group compared to 21% in the placebo group. That’s a 21‑percentage‑point difference, which was a statistically significant reduction.

There were injection‑related reactions in about 8% of patients who received nemolizumab compared to only 3% in placebo. Phase II trials also showed a dose‑dependent increase in mild asthma exacerbations in some subjects.

We know that itch is the most burdensome symptom for eczema patients, and these studies show some promising results for symptomatic relief and potential quality‑of‑life improvements. However, longer and larger trials are going to be necessary to really determine whether nemolizumab has a durable effect and if it’s safe for atopic dermatitis.

It’s important to keep in mind that since the target’s only a symptom of the disease, it would likely need to be used in conjunction with other therapies. It is also under investigation for use in, I think, prurigo nodularis, and it may have applications in many other disorders that cause pruritus.

Melissa: Can you tell us a little bit more about the latest data regarding lebrikizumab, in terms of its safety and efficacy?

Dr Hamid: Sure. The amazing clinical success of dupilumab underscores the importance of these type 2 immune cytokines in atopic dermatitis. Dupilumab inhibits both IL‑4 and IL‑13, whereas lebrikizumab selectively blocks the IL‑13 receptor. A recent phase II‑b trial examined the efficacy of lebrikizumab in a variety of different dosing regimens.

The primary endpoint of the study was the percent change in the Eczema Area and Severity Index, or EASI score, from baseline to week 16. Lebrikizumab demonstrated a statistically significant dose‑dependent response across the endpoints.

At the highest dose of 250 mg every two weeks, 66% of patients had a 75% decrease in their EASI scores. 44% of patients had a 90% decrease in their EASI score. These trials suggest that IL‑13 may be an essential pathogenic mediator in atopic dermatitis and that targeting it alone could achieve a therapeutic response.

Phase II clinical trials are currently evaluating lebrikizumab in adults and adolescents with moderate to severe atopic dermatitis. Results are expected in 2021, but there may be delays due to the pandemic.

Melissa: For tralokinumab, this was accepted as a new biologic by the FDA for atopic dermatitis. Could you discuss the data regarding this efficacy and what it’s going to bring to the table for patients with atopic dermatitis if it gets approved?

Dr Hamid: Yeah. Tralokinumab is currently under FDA review after showing efficacy and safety in treatment of moderate to severe atopic dermatitis in phase III trials. It’s an IL‑13 inhibitor, could come to the market within the next year.

There were three phase III trials for tralokinumab, and they were called ECZTRA 1 through 3. ECZTRA 1 and 2 were 52‑week, multinational monotherapy studies with a total of almost 1,600 enrollees. The endpoints were the Investigator Global Assessment score of clear or almost clear skin plus at least a 75% improvement in the EASI score at week 16.

In ECZTRA 1 and 2, this was accomplished in 16% and 22% of patients on 300 mg of tralokinumab every two weeks, compared with only 7% and 11% of placebo‑treated controls.

The ECZTRA 3 trial was a smaller trial, and that was examining tralokinumab plus topical therapy. In that trial, about 39% of patients achieved the IGA zero mark of clear skin by week 16. Roughly 56% of patients achieved a 75% improvement of their EASI score from baseline at that same week 16 point.

Regarding reduction of itch, about 45% of patients achieved a 4‑point response in their worst daily itch. The safety profile of tralokinumab was similar to placebo, and there may be lower risk of conjunctivitis compared to dupilumab. The biggest unknown is how this therapy will stand up against dupilumab in terms of efficacy.

There have been no head‑to‑head comparisons with dupilumab in the trials, so it remains to be seen how that will turn out. Dupilumab allows patients to achieve a mean EASI reduction of about 80%, it seems, in clinical practice, so that’s a pretty high bar to tackle.

Melissa: Are there any new topical therapies being investigated for AD?

Dr Hamid: I’m particularly intrigued by new topical therapies that are targeting changes in the skin microbiome in patients with eczema. The underlying pathology of atopic dermatitis consists not only of the defective skin barrier function, but there’s also increased susceptibility to Staph aureus skin infection as well as immune imbalance.

Treatment with a topical commensal gram‑negative bacteria called Roseomonas mucosa could be a potential treatment modality, and it’s currently being investigated. There have only been very small studies of 10 to 20 adults and children with atopic dermatitis for this treatment.

For that limited sample, results show that four months of treatment resulted in some improvement in disease symptoms, as well as improvements in epithelial barrier function, the amount of Staph aureus growing on the skin and quality of life for children and their families.

These improvements persisted for up to eight months after cessation of the Roseomonas mucosa treatment. I think this is another great area of exploration that’s only in its infancy, but it holds great potential for new treatments in atopic dermatitis and other inflammatory skin conditions.

Melissa: Are there any other therapeutic targets being considered for atopic dermatitis?

Dr Hamid: Several agents targeting the janus kinase family of proteins are currently in trials and are showing promising results. These JAK inhibitors were discussed by Dr Bowers in a prior episode. Then the anti‑OX40 antibody is also being studied. That’s a monoclonal IGG antibody targeting OX40, also called CD134.

OX40 is expressed on activated antigen‑presenting cells, and it’s essential for T‑cell expansion. There’s a phase II‑b clinical trial that’s currently recruiting for that.

Melissa: Are there any other thoughts about new therapies you would like to add or share with our audience?

Dr Hamid: I just want to reemphasize my excitement at all the new developments in the field of atopic dermatitis. As a clinician, you always want more options to have for tailoring therapy to particular patients.

These new biologics may allow for a more targeted approach to treatment that decreases the risk of side effects, and increased competition may also lead to a decrease in price of these biologic medications. I think it’s a really interesting time.

Melissa: Thank you for joining us today, Dr Hamid.

Dr Hamid: Thank you.

Melissa: Thank you for listening. If you have any questions or comments, please submit them in the feedback box below.

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