The Show Must Go On

An Update on Clinical Experiences and Clinical Studies on Novel Pharmaceutical Developments for the Treatment of Atopic Dermatitis

Tatjana Honstein; Thomas Werfel

Disclosures

Curr Opin Allergy Clin Immunol. 2020;20(4):386-394. 

In This Article

Targeting the IL-4 Receptor α Chain with Dupilumab for the Treatment of Atopic Dermatitis: What is New?

Dupilumab enables a targeted therapy inhibiting the action of the key type 2 cytokines IL-4 and IL-13 to their receptors by binding to the common α chain of their receptors. Following successful clinical trials in adults, the antibody was approved in the USA and the EU for the treatment of severe-to-moderate atopic dermatitis by the Food and Drug Administrarion (FDA) and the EMA in adults in 2017. The key studies showed efficacy of a reduction of the skin score EASI by 75% ('EASI75') after 16 weeks,[5] respectively 1 year[6] in approximately two-thirds of the study patients.

Clinical studies often do not reflect the situation in 'real world' where there is a need of treating patients with comorbidities, which are often defined as exclusion criteria in study settings. Therefore, data coming from disease-specific independent registries have gained increasing interest during the last years. The German registry for adult patients with atopic dermatitis was started more than 5 years ago and follows patients at least 2 years. The registry data show that after approval in the EU, dupilumab displaced cyclosporine and other immunosuppressing drugs and is now used as first-line systemic therapy in Germany in the majority of patients with atopic dermatitis. EASI75 was achieved in 57% of patients participating in the German registry after 3 months and in 52% after 6 months of patients, which is slightly less than in the placebo-controlled studies but overall also indicates a very good responsiveness to the antibody in 'real world'.[7,8] These data were confirmed by a registry from the Netherlands showing EASI-75 in 62% of all patients after 16 weeks. In addition severity-related serum biomarkers (TARC, PARC, periostin, and IL-22), eotaxin-1, and eotaxin-3 were determined in this registry study and shown to decrease significantly during dupilumab treatment.[9]

More recently, the application of dupilumab was also clinically evaluated for pharmacokinetics, long-term safety and efficacy in adolescents in a phase III study, which led to the FDA and EMA approval for this patient group. A significant change in EASI75 was seen in approximately 40% of adolescent patients, patients with a lower placebo response in this age group compared with adults.[10] The effect of the drug was sustained in an open label trial extension of 1 year.[11] Treatment was well tolerated – as seen before in adults only the incidence of conjunctivitis and injection site reactions were significantly higher in the dupilumab-treated group compared with placebo control.

Other phase III studies, which led to approval of dupilumab by health authorities addressed allergic asthma bronchiale and polyposis nasi, which may now be treated 'in label' as stand alone indication or in combination with atopic dermatitis.

As itch has an important impact on the burden of disease effects, all data on pruritus were reanalysed from all placebo-controlled phase III studies with dupilumab recently.[12] It was shown that across all phase III trials, dupilumab treatment showed rapid and sustained improvements in the magnitude of itch, starting with first dose. Responses on itch progressively increased and were sustained up to 1 year.

In terms of the risk of skin infections with herpes viruses or bacteria during therapy with dupilumab, a meta-analysis of study data from four controlled studies with 2706 patients came to a clear result.[13] Treatment with dupilumab reduces the risk of developing eczema herpeticatum by about 2/3 [risk ratio (RR) 0.34; 95% confidence interval (CI) 0.14–0.84]. No association was found for overall herpes recurrence during treatment with dupilumab (RR 1.16; 95% CI 0.78–1.74). Interestingly, the same evaluation also calculated a significant overall reduction in skin infections (RR 0.54; 95% CI 0.42–0.70), whereas dupilumab had no effect on overall (i.e. nonskin) infections in atopic dermatitis patients (RR 0.98; 95% CI 0.83–1.16). The result on severe herpes infection was recently confirmed by a comprehensive analysis of seven placebo-controlled clinical trials involving 2932 patients. Here, clinically important herpes virus infection rates (mainly eczema herpeticum) were markedly reduced after dupilumab treatment with a RR of 0.31.[14]

In clinical studies, 11% of patients treated with dupilumab experienced inflammatory eye symptoms at 16 weeks and 47% at 52 weeks. The inflammatory symptoms in the eye varied. Often conjunctivitis or blepharoconjunctivitis with inflammatory changes in the corneal limbus was observed, rarely in combination with keratitis. The severity was usually mild to moderate but in a few patients, it can be severe. Risk factors for the occurrence of inflammatory eye diseases are high severity of atopic dermatitis, a higher age, and a longer disease history. Both worsening and newly developed eye diseases have been reported during therapy with dupilumab, which usually disappear after discontinuation of medication. Interestingly, this side effect is only observed in patients with atopic dermatitis and not in patients with allergic asthma bronchial or in patients with polyposis nasi treated with dupilumab.[15,16] Numerous mechanisms have been discussed for atopic dermatitis-related ocular symptoms induced by dupilumab. One of them is that the availability of the therapeutic antibody at the conjunctiva may be reduced as it cannot diffuse as well as it is increasingly eliminated via nFcR-dependent mechanisms. This means that with simultaneously increased systemic availability of free IL-4 and IL-13 under the blockade of their receptors, these two cytokines could have stronger effects in loco.[17]

Another more recently decribed side effect is nonpruritic facial rash appearing after the injection of dupilumab sometimes remaining for a couple of days.[18,19] Rosacea-like reactions associated with the administration of dupilumab suggested that Th2 inhibition by dupilumab might support the lesions via increased IL-17 inflammation.[20] In two patients who developed itchy and painful facial flushing during dupilumab treatment, itraconazole led to improvement of the symptoms.[21]

It was speculated that Th1-associated or Th 17-associated inflammatory diseases might be induced or aggravated during the therapy with a Th2 blocker like dupilumab. So far, a few case reports or case histories have been published on patients developing arthritis or polyenthesitis during therapy with dupilumab.[22,23] It is not possible to decide if there was a causal relation or if this was coincidental.

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