Novel and upcoming targeted AD treatment

“The therapeutic drought is finally coming to an end in atopic dermatitis (AD),” Prof. Emma Guttman-Yassky (Icahn School of Medicine at Mount Sinai, NY, USA) announced. The armamentarium of therapeutic agents to treat AD is rapidly expanding. Currently being investigated are not only different agents, such as lebrikizumab and nemolizumab, but entirely new targets, such as OX40.

The recent development of novel and upcoming AD treatments has been made possible by new insights into the pathogenesis, leading to a paradigm shift. Prof. Guttman Yassky pointed out that perpetuators of the disease towards chronic AD are immune abnormalities that already start to increase at a non-lesional stage in acute disease and occur even more so in chronic AD. Furthermore, it has to be taken into account that there might be various subphenotypes in AD, which e.g. exhibit different immune polarisations. So, although all types of AD include Th2 activation, specific pathways may play a role in the development of medications for subphenotypes.

Dupilumab, which has been in use for some years now, has demonstrated an effect on barrier dysfunction as well as inflammation. “Studies showed that IL-4 and IL-13 are pathogenic cytokines in AD, cementing the disease as being reversible and immune-driven, exactly like psoriasis,” Prof. Guttman-Yassky explained. Presently, dupilumab is approved for both adults and children in the USA and Europe, among others.

Instead of dual inhibition of IL-4 and IL-13, studies have been investigating whether solely targeting IL-13 would be efficacious, for example with tralokinumab and lebrekizumab. In the phase 3 ECZTRA 3 trial (NCT03363854), tralokinumab demonstrated significant superiority over placebo in Eczema Area and Severity Index (EASI) 75 and Investigator Global Assessment (IGA) 0/1 with an overall good safety profile [2]. A phase 2 study on monotherapy lebrekizumab in various regimens revealed dose-dependent efficacy with a good safety profile as well [3]. “The results are definitely in the ballpark of dupilumab, perhaps even slightly higher,” commented Prof Guttman-Yassky on lebrekizumab.

The IL-31 receptor inhibitor nemolizumab was also evaluated for AD in several trials. In phase 2b (NCT03100344), the agent showed significant but rather modest efficacy versus placebo (both in combination with topical steroids), but a substantial reduction of the pruritus [1,4]. In the safety evaluation, asthma exacerbations and peripheral oedema were observed, which will likely be further assessed in future trials.

Promising news is coming from a novel target for AD treatment: OX40. “OX40 is important in type 2 immunity but also important for T-regulatory cells,” emphasised Prof. Guttman-Yassky. As results from phase 1 were very encouraging for the anti-OX40 antibody KHK4083, the drug was taken forward and she presented the results of the successful phase 2 results in a separate lecture (see Long-term disease control in AD could be in reach with anti-OX40 antibody KHK4083).

The IL-1-alpha antagonist bermekimab will be assessed in larger studies against placebo, after an open-label, phase 2 pilot trial (NCT03512275) showed marked reductions in EASI 75 as well as IGA improvements [5].

“I mentioned that AD is heterogeneous, and in some patients, it is beneficial to target more than 1 cytokine axis as is achieved by Janus kinases, particularly JAK1 inhibitors, which target multiple cytokines that are important in AD, such as IL-13, IL-22, IL-31 and so on," Prof. Guttman-Yassky further elaborated (see Table) [1,6]. In the phase 3 Measure Up 1 and 2 trials (NCT03569293 and NCT03607422), monotherapy with JAK1 inhibitor upadacitinib achieved EASI 75 in 79.7% and 72.9% (both 30 mg) as well as 69.6% and 60.1% of participants (both 15 mg), respectively [7]. In terms of safety data for upadacitinib, Prof. Guttman-Yassky pointed out that its profile in AD is much cleaner than in other indications such as rheumatoid arthritis and psoriasis, but long-term data and larger studies are still needed.

Table: JAK inhibitors targeting key cytokines in atopic dermatitis [1,6]
IFN-γ, interferon gamma; IL, interleukin; JAK, Januse kinase; TSLP, thymic stromal lymphopoietin;  TYK, tyrosine kinase.

Lastly, the selective sphingosine-1-phospate receptor modulator etrasimod has advanced to phase 2 testing for AD. After 12 weeks, 29.8% of participants (n=140) in the ADVISE trial (NCT04162769) on etrasimod 2 mg achieved a validated IGA 0/1 and ≥2-point reduction from baseline, and additional studies with etrasimod are planned [8].

“I think we see that AD is now on a very exciting medical and scientific path,” stated Prof. Guttman-Yassky. “I believe that in the next few years we will have many more options to treat our patients with AD,” she concluded.

 

1. 
   
   1. Guttman-Yassky E. New targeted therapies in atopic dermatitis. D3T01.4D, EADV Congress 2021, 29 Sept–2 Oct.
   2. Silverberg JI, et al. Br J Dermatol. 2021;184(3):450–463.
   3. Guttman-Yassky E, et al. JAMA Dermatol. 2020;156(4):411–420.
   4. Silverberg JI, et al. J Allergy Clin Immunol. 2020;145(1):173–182.
   5. Gottlieb AB, et al. J Invest Dermatol. 2020 Aug;140(8):1538–1545.e2.
   6. Gadina M, et al. Rheumatology (Oxford). 2019;58 (Suppl1):i4–i16.
   7. Guttman-Yassky E, et al. Lancet. 2021;397(10290):2151–2168.
   8. Guttman-Yassky E, et al. S033, AAD VMX 2021, 23–25 April.

 

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Posted on 18 November, 202115 February, 2024