Sustained deep clinical and itch responses with novel IL-13 inhibitor

An analysis of the phase 3 trials ADvocate 1 (NCT04146363) and ADvocate 2 (NCT04178967) demonstrated that deep responses achieved at week 16 were maintained or even increased through week 52 with continuous lebrikizumab treatment. Deep responses might be a step towards disease modification. The ADvantage study further demonstrated lebrikizumab’s efficacy for patients with an inadequate response to cyclosporin.

In 2 phase 3 trials, the investigational IL-13 inhibitor lebrikizumab documented efficacy and a positive benefit-risk profile as monotherapy for moderate-to-severe AD over 52 weeks [1]. Prof. Eric Simpson (Oregon Health & Science University, OR, USA) emphasised that deep responses provide additional quality-of-life improvements and benefits for the patient [2]. Therefore, he and his colleagues evaluated the maintenance of deep responses through week 52 in lebrikizumab responders, defined as those who had achieved Investigator´s Global Assessment (IGA) 0/1 with a ≥2-point improvement or an Eczema Area and Severity Index improvement by 75% (EASI75) at week 16. A deep response was defined as achieving clear skin according to the Investigator´s Global Assessment (IGA), EASI100 responses, and no or minimal itch. Topical corticosteroids were not allowed in the double-blind phase but were allowed as rescue mediation in the maintenance phase.

At week 16, only 20% of responders had an EASI100 response. “Even for responders, it is hard to get clear skin,” Prof. Simpson commented. However, participants who achieved deep responses at week 16 showed a maintained or even increased response through 1 year with continuous lebrikizumab. At 52 weeks, 44% of participants treated with lebrikizumab 250 mg every 2 weeks and 39% treated every 4 weeks achieved an IGA (0) response. The corresponding results for EASI100 were 32% and 27%. No or minimal itch was achieved by 39% of participants treated with lebrikizumab every 2 weeks and 41% treated every 4 weeks.

Long-term deep response is achievable in a chronic disease such as AD. “Potentially, this means we can start modifying this disease in the future,” Prof. Simpson concluded.

Lebrikizumab is also effective in patients with inadequate response to cyclosporin

The phase 3 ADvantage study (NCT05149313) assessed the efficacy and safety of lebrikizumab combined with low- or mid-potency topical corticosteroids in adolescents (≥12 years) and adults with moderate-to-severe AD not adequately controlled or non-eligible for cyclosporine A (CsA) [3].

The participants had an EASI≥16, IGA≥3, and ≥10% body surface area of AD involvement which was not adequately controlled or who were non-eligible for CsA therapy. They received either a loading dose of lebrikizumab of 500 mg followed by 250 mg at baseline and week 2 or a placebo every 2 weeks. All participants received concomitant mid-potency topical steroids through week 16 until lesions were clear or almost clear. The primary efficacy endpoint was the percentage of participants who achieved a 75% reduction from baseline in EASI (EASI75) at week 16.

After 16 weeks, 68.4% of the lebrikizumab + topical steroids treated participants compared with 40.8% of those on placebo achieved an EASI75 response (P<0.001). “Because of the topical steroids, we see this high placebo response; thus, it is important to look at the delta, namely the difference between the placebo arm and the active arm,” Prof. Richard Warren (University of Manchester, UK) explained. In addition, a higher percentage of participants achieved clear or almost clear skin according to the IGA (42.0% vs 24.5%; nominal P<0.01) and a clinically relevant pruritus improvement (≥4-points in a numerical rating scale; 49.9% vs 29.7%; nominal P<0.05).

“We would expect and anticipate a signal of conjunctivitis and that was there,” Prof. Warren said. Accordingly, nasopharyngitis (12.7% vs 12.6%) and conjunctivitis (11.4% vs 1.8%) were the most common treatment-emergent side effects. “In Europe, where cyclosporine is one of the few approved drugs for atopic dermatitis, this is particularly relevant data,” Prof. Warren concluded.

The European Medicines Agency (EMA) has accepted the filing of the Marketing Authorization Application for lebrikizumab for the treatment of moderate-to-severe atopic dermatitis, the first step of the regulatory process in Europe.

1. 
   
   1. Blauvelt A, et al. Br J Dermatol 2023;188:740–748.
   2. Simpson E. Raising the bar of efficacy in atopic dermatitis: lebrikizumab provides sustained deep clinical and itch responses up to 52 weeks. FC06.6, EADV Congress 2023, 11–14 October, Berlin, Germany.
   3. Warren RB. Lebrikizumab improves signs and symptoms of moderate-to-severe atopic dermatitis in patients inadequately controlled or ineligible for cyclosporine: a placebo-controlled, randomized phase 3 clinical study (ADvantage). FC06.7, EADV Congress 2023, 11–14 October, Berlin, Germany.

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Posted on 28 November, 202322 February, 2024