Baricitinib in AD: Efficacy paired with consistent long-term results

In the phase 3 BREEZE-AD3 trial, baricitinib demonstrated reliable long-term response maintenance in patients with moderate-to-severe atopic dermatitis (AD) for up to 68 weeks.

The oral JAK1/JAK2 inhibitor baricitinib has shown significant efficacy in improving signs and symptoms of AD in the 2 independent monotherapy trials BREEZE-AD1 (NCT03334396) and BREEZE-AD2 (NCT03334422) [1]. Patients completing these studies were eligible for enrolment into the presented BREEZE-AD3 (NCT03334435), a double-blind, long-term extension trial to assess baricitinib in patients with moderate-to-severe AD up to 68 weeks [2].

The trial design differed depending on the participant’s outcome at the end of the parent studies. Responders and partial responders, identified by a validated Investigator´s Global Assessment (IGA) for AD of 0, 1, or 2 at week 16, would continue receiving the same agent as in BREEZE-AD1 and BREEZE-AD2. As a result, there were 4 arms with either placebo or 1 mg, 2 mg, or 4 mg of baricitinib. Non-responders, who ended the previous studies with an validated IGA AD score of 3 or 4, were re-randomised and switched from once daily placebo, 1 mg, or 2 mg of baricitinib to either 2 mg or 4 mg of baricitinib in the extension study. Non-responders in the 4 mg baricitinib group continued their previous dosage. Efficacy outcomes were measured by the rate of patients achieving a validated IGA AD of 0/1 (i.e. clear or almost clear) as the primary endpoint and an Eczema Area and Severity Index (EASI) 75 improvement up to 68 weeks. The investigators used 2 different approaches for imputing missing data: last observation carried forward (LOCF) and non-responder imputation (NRI). Results were compared between both methods.

Independent of the applied approach, baricitinib 4 mg accounted for an overall consistent efficacy that was more or less maintained from week 16 on, with a validated IGA AD 0/1 starting at 45.7% at week 16 and reaching 47.1% (LOCF) and 40.0% (NRI) at week 68. Furthermore, the EASI 75 of 70.0% at week 16 decreased slightly to 55.7% (LOCF) and 51.4% (NRI) at week 68 (see Figure). Similar outcomes were seen in the evaluation of itch NRS (≥4-point improvement), skin pain NRS (≥4-point improvement), and AD symptom score (ADSS) item 2 (≥1.5-point improvement) with baricitinib 4 mg. “You see a consistent pattern across all those endpoints regardless of using LOCF or NRI,” said Prof. Jonathan Silverberg (George Washington University School of Medicine and Health Sciences, USA). The rates measured at week 32 (LOCF) were: 45.9% (itch NRS), 54.5% (skin pain NRS), and 71.4% (ADSS item 2) versus 52.5%, 61.8%, and 75.0%, respectively, at week 16. In the baricitinib 2 mg treatment arms, validated IGA AD and EASI 75 percentages at week 16 were 46.3% and 74.1%, and even mounted to 59.3% and 81.5% (both with LOCF) at week 68. Also, the patient-related outcomes were suggestive of stable response through week 32.

Figure: Results for validated IGA AD 0/1 and EASI 75 with baricitinib 4 mg from week 16 to 68 [2]



*Total weeks includes the 16 weeks of treatment in the original studies BREEZE-AD1 and BREEZE-AD2.
EASI, Eczema Area and Severity Index; LOCF, last observation carried forward; NRI, non-responder imputation; vIGA-AD, validated Investigator’s Global Assessment for atopic dermatitis.

 

Reassuring safety data in over 2,500 treated patients

Since the patients enrolled in BREEZE-AD3 originated from different parent studies, Prof. Silverberg presented a unique safety summary that was published, which contained integrated data from 2,531 patients from 8 clinical trials (7 phase 3 trials and a phase 2 trial) [2,3]. The data includes adverse event information from responders, partial responders, and non-responders within the placebo-controlled data sets until week 16, as well as the extended analyses. All AD trial patients treated with baricitinib equalled a total of 2247.4 patient-years of exposure. “What you can appreciate overall is that the safety is pretty consistent to what we have seen in the individual studies, but now in the pooled analyses there is maybe a little bit of an increase in terms of any treatment-related adverse events with baricitinib 2 mg and 4 mg doses, although we don’t see any kind of dose-dependent responses,” Prof. Silverberg pointed out. Especially in the placebo-controlled treatment phase up to week 16, there were no deaths, no gastro-intestinal perforations, and no major adverse cardiovascular events. In all patients treated with baricitinib (n=2,531), herpes zoster had a study size-adjusted incidence rate of 2.3 and herpes simplex an incidence rate of 10.3. All in all, authors of the safety analysis observed no new safety concerns. In conclusion, Prof. Silverberg highlighted that baricitinib 2 mg and 4 mg demonstrated sustained long-term efficacy in moderate-to-severe AD.

 

1. 
   
   1. Simpson EL, et al. Br J Dermatol. 2020;183:242-55.
   2. Silverberg JI, et al. Long-term efficacy of baricitinib in patients with moderate-to-severe atopic dermatitis enrolled in the phase 3 long-term extension study BREEZE-AD3. D3T03.4a, EADV 2020 Virtual Congress, 29-31 Oct.
   3. Bieber T, et al. J Eur Acad Dermatol Venereol. 2020 Sep 14. Doi: 10.1111/jdv.16948.

 



Posted on 17 December 202018 December 2020