JAK inhibitor upadacitinib a clear winner in comparative study with dupilumab

The development of innovative drugs for the treatment of atopic dermatitis (AD) is increasingly focused on targeted therapies that selectively interfere with disease-causing signaling pathways [1]. That the Janus kinase (JAK) inhibitor upadacitinib can counteract the symptoms of moderate-to-severe AD faster and better than the IL-4/IL-13 inhibitor dupilumab was shown by the results of the Heads Up comparative study presented at the^11th Georg Rajka International Symposium on Atopic Dermatitis (ISAD 2021) [2].

(red) AD is a hitherto incurable chronic inflammatory skin disease, which is associated with episodes of eczema and severe itching. Lifetime prevalence is up to 20% and standard therapy is predominantly skin care, anti-inflammatories and systemic immunosuppressants. However, the latter often have severe side effects [3]. Therefore, the development of new drugs is increasingly focused on biologics and targeted small molecules that directly interfere with inflammatory signaling pathways [4]. Since its Swissmedic approval in April 2019, the IL-4/IL-13 inhibitor dupilumab has established itself as an effective injectable treatment option for moderate-to-severe AD [5–7]. Another promising candidate is upadacitinib. The orally administered, selective and reversible JAK inhibitor is already approved in moderate-to-severe rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis and was also shown to be effective and well tolerated in moderate-to-severe AD in a placebo-controlled phase IIb study [8,9].

Faster and more effective relief from eczema and itching

The phase IIIb Heads Up study presented at ISAD 2021 compared the efficacy and safety of upadacitinib and dupilumab (each as monotherapy) in adults with moderate-to-severe AD over 24 weeks. For this, upadacitinib was administered in tablet form (30 mg 1× daily plus placebo injections), while dupilumab was injected (600 mg initial dose at baseline followed by 300 mg every two weeks plus placebo tablets). The primary endpoint of the multicenter, randomized, double-blind comparative study was the proportion of 629 patients with at least a 75% improvement in the Eczema Area Severity Index (EASI 75) at week 16. With respect to this parameter, the results of the study showed significant superiority of upadacitinib over dupilumab (Table 1). Furthermore, there was also significant improvement in all secondary endpoints with upadacitinib compared with dupilumab. For example, itching was reduced more quickly and effectively (Tab. 1). In addition, more than one and a half times as many patients achieved an EASI 90 response and more than three times as many patients achieved an EASI 100 response with upadacitinib than with dupilumab after 16 weeks (Table 1). The superior efficacy of upadacitinib compared with dupilumab was seen after one (EASI 75, EASI 90, Worst Pruritus NRS) and after four (EASI 100) weeks, respectively, and persisted, numerically, until week 24 of treatment [2].

Safety profiles of upadacitinib and dupilumab.

In general, upadacitinib was well tolerated throughout the study period of 24 weeks. Here, the safety profile observed in Heads Up was consistent with the results of the three Phase III studies, Measure Up 1, Measure Up 2, and AD Up, and no new important safety risks were observed. The proportion of serious adverse events that were potentially related to the investigational drugs was low in both study arms (1.4% with upadacitinib vs. 1.2% with dupilumab). More serious infections occurred with upadacitinib than with dupilumab, but these were observed infrequently overall (1.1% vs. 0.6%). Herpes zoster was also recorded more frequently in the upadacitinib group than in the dupilumab group (3.4% vs. 1.2%), although none of the cases were severe and most involved a single dermatome. Hepatic disorders mostly manifested as asymptomatic elevation of transaminase levels in both treatment groups and were not severe in any case. And anemia, neutropenia, or elevated creatine phosphokinase levels, which were more common with upadacitinib, were never serious or led to study discontinuation.

Venous thromboembolism, serious cardiovascular events, active tuberculosis, or gastrointestinal perforation were not observed in any of the treatment groups. The most common adverse event was mild to moderate acne (18.4%) in the upadacitinib arm and conjunctivitis (10.2%) in dupilumab. Both the observed acne and conjunctivitis were not severe nor did they lead to discontinuation of the investigational drugs [2].

Promising treatment option for the future

Overall, the selective and reversible JAK inhibitor upadacitinib clearly prevailed over the IL4/IL13 inhibitor dupilumab in the treatment of adult patients with moderate-to-severe AD in the Heads Up direct comparison study. Thus, significantly more patients achieved complete or near-complete relief from eczema as well as greater relief of itching with upadacitinib. In addition, a faster response was observed than under the established biologic. In addition, upadacitinib is characterized by oral administration and generally good tolerability, thus offering a promising treatment option that could provide patients with moderate-to-severe AD with significant relief of their symptoms in the future [2].

Source: Congress:^11th Georg Rajka International Symposium on Atopic Dermatitis (ISAD 2021); AbbVie

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