New molecules in management of atopic dermatitis

Target 1: Epidermal barrier repair and restoration of the skin microbiome imbalance (dysbiosis)

Target 2: Modify the itch-scratch cycle at the central and peripheral levels

Itch is one of the key symptoms of AD. The itch-scratch cycle is a dynamic pathological process consisting of chronic itch sensations and its accompanying scratching behaviors. Scratching intensifies the sensation of itch by causing damage to skin epithelial cells. The underlying mechanism beneath the itch-scratch cycle is complex and involves activation of the peripheral sensory nerves through multiple mediators.^[13] As neurons express receptors for IL-4 and IL-13, it is suggested that targeted therapies such as dupilumab, tralokinumab, or lebrikizumab has a direct effect on nerve endings, resulting in the rapid relief of itch observed with these drugs.^[1]

IL-31 is an essential pruritogenic cytokine in the pathophysiology of AD and correlates with severity of the disease. Therapeutic strategies that targets IL-31 and its receptors aim at better itch control. Produced by Th2 cells, IL-31 works through the heterodimerization of IL-31Ra and the oncostatin M receptor- b (OSMRb).^[14,15] In a phase 2 clinical trial, the anti-IL-31Ra antibody nemolizumab significantly decreases itch at the end of a 12-week study period, with 53% having a >4 point decrease in pruritus score (vs. 26% in placebo), although the clinical measurements of AD severity did not improve significantly.^[4] In an extension study, of up to 52 weeks, similar effect on itch was observed, with clinical improvement achieved in a dose-dependent manner.^[16] In addition, nemolizumab in combination with topical corticosteroids showed greater reduction in itch and severity compared with placebo plus topical corticosteroids.^[17]

Another IL-31 targeted therapy that is currently in the pipeline is vixarelimab, which targets the other receptor subunit for IL-31, OSMRb. In particular, vixarelimab was shown to be efficacious in prurigo nodularis, demonstrating rapid reduction of itch and achievement of clear to almost clear skin in one-third of the patients in a phase 2a study.^[18] In a first-in-human study for AD, vixarelimab induced a rapid and sustained itch relief, although there was no significant effect on the clinical severity scores.^[19]

The initiation and transmission of itch is mediated by substance P through the neurokinin 1 receptor (NK1R) and the Mas-related G protein-coupled receptor.^[20] Pruritic conditions such as AD have been shown to have overexpression of substance P, suggesting that his signaling pathway can be targeted to modulate the sensation of itch and neurogenic inflammation.^[21] The NK1R antagonist serlopitant has demonstrated efficacy in reducing itch for patients with refractory prurigo nodularis in a phase II study.^[22] However, in a larger trial (ClinicalTrials.gov identifier: NCT02975206) studying serlopitant for itch control in AD, the reduction in pruritus was not statistically significant compared to placebo.^[23]

Other development of therapies targeting the itch-scratch cycle is the selective P2X3 antagonist BLU-5937, which acts on the cation channels P2X purinoreceptors 3, expressed in sensory neurons that potentially play an essential role in itch.^[1] Four types of histamine receptors have been identified, which are G protein-coupled receptors (H1R – H4R). Among these, H4R is of interest as a target for immunomodulation due to its effects on leukocyte activity. In the skin, H1R has immunomodulatory potential as well as induces pruritis.^[24] Mouse AD model study revealed synergistic effect of combination therapy of H1R antagonist mepyramine and H4R antagonist JNJ-39758979, with results of less severe skin lesions, reduced inflammation, and lower levels of IL-33 in lesional skin.^[25] A phase 2a proof of concept clinical trial evaluating the H4R antagonist adriforant in AD showed clinical significant anti-inflammatory effect with a reduction of 50% in Eczema Area and Severity Index (EASI) score in the treatment group compared to placebo 27% and clear/almost clear Investigator’s Global Assessment (IGA) scores with 19% in treatment group versus placebo 9% at week 8, although decrease in pruritus score was not significant.^[26] More research is needed to evaluate the efficacy of targeting histamine receptors, either as monotherapy or in combination.

Target 3: Modulate the dysregulated innate immunity

Given the efficacy of blocking both IL-4 and IL-13 by dupilumab, which targets the IL-4a receptor, it is now evident that the key driver of AD are type 2 cytokines.

1. The next therapeutic targets are upstream mechanisms that induce type 2 cytokines in the skin, which include IL-33, TSLP, and IL-1a that are released by the stressed keratinocytes.

   These cytokines act as alarmins that induce the production of IL-4, IL-5, and IL-13 from ILC2 and Th2 cells.

2. OX 40 receptor – OX 40 ligand interaction.

OX40 belongs to the TNF receptor family and is a costimulatory molecule.

It is transiently expressed on activated T cells.

T-cell survival and proliferation are enhanced in AD when the OX40 ligand, which is produced by TSLP-activated dendritic cells, interacts with the OX40 receptor on T cells. Clinical trials targeting upstream cytokines and receptors such as TSLP, IL-33, OX40 receptor, and OX40 ligand are already in progress. However, blocking the upstream processes might result in an increase in adverse effects such as infection; thus, we need caution in their use.

Despite preclinical data supporting IL-33 and TSLP inhibition in AD, clinical trial results have been disappointing. A phase IIb clinical study on the anti-TSLP monoclonal antibody, Tezepelumab, was terminated due to a lack of efficacy (NCT03809663). In this trial, after 12 weeks of treatment, a higher number of patients in the treatment arm (64.7% vs. 48.2% in the placebo arm) reached the primary endpoint of achieving EASI50 at week 12, but the results failed to reach statistical significance.^[27]

Etokimab, an anti-IL-33 mAb, was also removed from the AD development pipeline, much as TSLP, after a phase IIb trial showed no statistically significant benefit when compared to a placebo.^[28] Given the upstream mechanism of action of TSLP and IL-33, a longer treatment period may reveal greater improvements in AD symptoms.

An alternative approach involves targeting the T-cell costimulatory molecule OX40-OX40L to prevent clonal expansion, survival, and memory. This strategy may allow for broad inhibition across T-cell effector subsets.

Initial trials involving antibodies directed against OX40 or its ligand OX40L expressed on DCs demonstrate that these treatments are well tolerated and provide support for further research with larger trials.

Three OX40-OX40L inhibitors, rocatinlimab, telazorlimab, and amlitelimab, are being developed for the treatment of AD. Rocatinlimab, an anti-OX40 antibody, was evaluated in phase 2b, a randomized, placebo-controlled clinical trial. At week 16, rocatinlimab groups with different dosage regimens achieved a greater reduction in the EASI percentage change from the baseline (−48.3–−61.1%) against the placebo (−15.0%; P < 0.001), and clinical response was maintained 20 weeks after the treatment had ceased.^[29]

HORIZON is a phase 3, 24-week, randomized, placebo-controlled, double-blind study to assess the efficacy, safety, and tolerability of rocatinlimab monotherapy in adults with moderate-to-severe AD. Statistically significant improvement was observed in co-primary endpoints: 32.8% of rocatinlimab-treated subjects achieved an EASI-75 response at week 24 versus 13.7% placebo (19.1% difference, P < 0.001).

Telazorlimab is another anti-OX40 monoclonal immunoglobulin G1 antibody that has undergone a phase IIa trial with encouraging results. In this trial, intravenous GBR 830 was well tolerated and significantly improved the lesions with an EASI 50 at Day 71 in 76.9% of patients who received the antibody, compared with 37.5% in the placebo group.^[30] Amlitelimab, an anti-OX40L antibody, was studied in a 12-week treatment phase 2a clinical trial, with a significant efficacy response observed within 2 weeks. At week 16, patients treated with both low and high doses of amlitelimab achieved reductions in EASI scores of 80.1% and 69.9%, respectively, compared to a 49.4% reduction in the placebo group. Notably, 68% of patients who responded to the treatment maintained their improvement for 24 weeks after the last dose, suggesting a long-lasting and sustained effect. In addition, the incidence of adverse events was low and comparable between the treatment and placebo groups, supporting its safety profile.^[31] The phase 2b trial of amlitelimab also shows the same sustained, long-lasting benefit. In the first part of the study, patients were randomly assigned to receive placebo or subcutaneous amlitelimab doses of 250 mg with a 500 mg loading dose, 250 mg without a loading dose, 125 mg without a loading dose, or 62.5 mg without a loading dose every 4 weeks. In this second part of the study, patients who previously achieved a 75% improvement in EASI 75 or IGA 0 or 1 were randomly assigned to continue amlitelimab or withdraw from the drug. IGA 0 or 1 was maintained by 71.9% of patients who continued treatment and 57% of patients who stopped treatment, according to a pooled analysis of all the dosage groups. In addition, 69% and 61.6% of these groups, respectively, maintained EASI 75.^[32]

Target 4: Modulate the dysregulated adaptive immunity (Th2-IL4-IL13 pathway)

The core immunopathological pathway of AD involves Th2 responses, which include IL-4, IL-13, and their associated receptors. Dupilumab, an IL-4Ra receptor antagonist, acts on both IL-4 and IL-13 by binding to the common chain.

Dupilumab has been approved in many countries for use in AD, with various real-world data supporting its efficacy. Dupilumab is also one of the few newer molecules that are extensively studied in the pediatric population, with phase 3 trial of children aged as young as 6 months–5–years old showing significant improvement in clinical measurements by week-4 and sustained response by week-16, with 14.3% achieving IGA ≤ 1 versus 1.6% in placebo group and 46% achieving EASI-75 versus 6.6% in placebo group at the end of the 16 weeks study period. There was also a significant improvement in the dupilumab group in other endpoints, namely, pruritis numerical rating scale (NRS), skin pain NRS, quality of sleep NRS, and quality of life index. Overall, adverse events were similar between the groups, conferring an acceptable safety profile.^[33] Dupilumab is also approved for treating atopic comorbidities such as allergic asthma and nasal polyposis, highlighting its broad therapeutic profile.

Another key cytokine involved in Th2 immune responses is IL-13, and the development of new therapies targeting IL-13 is in motion. Tralokinumab acts on IL-13, which blocks its binding to both IL-13Ra1 and IL-13a2 receptor chains. In phase 2 studies (ECZTRA 1 and 2), tralokinumab demonstrated significant improvement at week-16, with 15.8% achieving an IGA score of 0/1 (vs. 7.1% in placebo group) in ECZTRA 1 and 22.2% (vs. 10.8% in placebo group) in ECZTRA 2. The majority of the responders had sustained response at week 52, without needing any rescue medications, including a topical corticosteroid.^[34]

Lebrikizumab is another anti-IL-13 antibody that exerts its effect by impairing the heterodimerization of IL-4Ra and IL-13Ra1, thus blocking signal transduction. In a phase 2b trial, this high-affinity monoclonal antibody has demonstrated dose-dependent efficacy. Rapid relief in pruritus was seen as early as Day 2 in the high dose (250 mg) lebrikizumab group, and 72% improvement in clinical responses versus 41% in placebo and an overall favorable safety profile.^[35]

Target 5: Modulate the dysregulated adaptive immunity (Th17-IL23 pathway)

Although mainly implicated in psoriasis, there is increasing evidence that the Th-17-IL-23 pathway may have a role in AD pathogenesis, particularly in intrinsic and Asian phenotypes. Increased Th17 activation, and a strong Th2 component with increased hyperplasia and parakeratosis were demonstrated in the skin of Asian patients with AD.^[36] However, this hypothesis is yet to be tested, as few studies to date have not shown favorable responses. An investigator-initiated, phase 2 study evaluating secukinumab, integrating clinical measurements with extensive cellular and genomic biomarkers in the skin of patients with AD, showed no significant changes in all assessments, concurring that targeting IL-17A is not a valid therapeutic option.^[37]

Fezakinumab, an anti-IL-22 antibody, is postulated to inhibit a feedforward mechanism of keratinocyte-driven inflammation. In a phase 2a study of patients with moderate-to-severe AD, there was no significant improvement in clinical outcomes in patients treated with fezakinumab, although significance was primarily obtained in patients with severe disease.^[38] However, a follow-up study investigating the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD found that fezakinumab therapy reversed transcriptomic changes associated with AD lesional skin in patients with elevated basal IL-22 expression.^[39]

In a phase 2 trial evaluating the IL-23 inhibitor rizankizumab for AD, no significant proportion of patients achieved the primary endpoints of EASI-75 at week 16, with either the 300 mg or 150 mg dose versus placebo.^[40]

To date, most clinical studies generally showed limited clinical efficacy in targeting the Th17-IL22/IL23 pathway for AD, compared with Il-4 or IL-13. This suggests that targeting Th17-IL-22/23 alone might not be a promising therapeutic strategy for the treatment of AD. Further research is warranted to fully understand the role of IL-22/23 in AD and to determine if specific patient populations might benefit from IL-22/23 blockade in combination with other therapies.

Target 6: Modify the dysregulated intracellular signaling pathways

C-AMP modulators

To date, there are still unmet needs for topical anti-inflammatory agents that are available to treat children under 2 years with AD. A topical non-steroidal option is crisaborole ointment 2%, which is a phosphodiesterase-4 (PDE-4) inhibitor that is used to treat mild-to-moderate AD.^[51] It is USFDA-approved for use in infants aged 3 months and older. The phase IV CrisADe CARE 1 is the first trial to assess the safety, effectiveness, and pharmacokinetics of crisaborole administered twice daily to infants aged 3–<24 months with mild-to-moderate AD. Among treatment-emergent adverse events, application site pain (n = 5; 3.6%), application site discomfort (n = 4; 2.9%), and redness were the most reported (≥2.5%). At the first post-baseline assessment on day 8, 20.0% of patients in the entire study population had achieved Investigator’s Static Global Assessment (ISGA) success, and at day 29, 30.2% had similar success. Furthermore, on days 8 and 29, 40.7% and 47.3% of patients, respectively, obtained an ISGA of clear or nearly clear. In this open-label study, infants with mild-to-moderate AD aged 3–<24 months showed good tolerance to crisaborole. Crisaborole’s safety and effectiveness were in line with those found in earlier research involving patients older than 2 years.

Roflumilast cream 0.3% is a very effective once-daily topical PDE4 inhibitor that is authorized to treat plaque psoriasis.^[52] Once-daily roflumilast cream at 0.15% and roflumilast cream 0.05% showed good safety and tolerability profiles in a phase 2 proof-of-concept trial, suggesting that they could be useful in treating mild-to-moderate AD. The effectiveness and safety of roflumilast cream 0.15% applied once daily for 4 weeks in patients aged 6 years and above with mild-to-moderate AD were assessed in the phase 3 randomized clinical trials reported in the Interventional Trial Evaluating Roflumilast Cream for the Treatment of AD 1 and 2 (INTEGUMENT-1 and INTEGUMENT-2). AD patients treated with roflumilast cream 0.15% showed improvement in several efficacy end points, including a reduction in pruritus within 24 h of application, in the INTEGUMENT-1 and INTEGUMENT-2 phase 3 randomized clinical trials. The patients also showed favorable safety and tolerability.^[53]