Lebrikizumab shows potential for atopic dermatitis

The novel, high-affinity, monoclonal antibody lebrikizumab demonstrated significant efficacy in a dose-dependent manner across a range of clinical manifestations of moderate-to-severe atopic dermatitis (AD), including pruritus and quality of life (QoL), a phase IIb study has shown.

Pruritus is deemed the most burdensome symptom of AD that substantially impairs QoL. [J Invest Dermatol 2017;137:26-30; Immunol Allergy Clin North Am 2017;37:113-122; Dermatol Clin 2017;35:373-394] “[The] reduction in itch severity was observed by day 2 in high-dose lebrikizumab-treated patients [highlighting its rapid, robust efficacy] … The rapid onset of itch relief suggests that lebrikizumab may help ameliorate the substantial burden of itch, [thereby improving QoL],” said the researchers.

A total of 280 participants (mean age 39 years, 59 percent female) were randomized 2:3:3:3 to receive placebo Q2W or subcutaneous injections of lebrikizumab at three doses*: 125 mg Q4W (L1), 250 mg Q4W (L2), or 250 mg Q2W (L3). The study comprised a 16-week treatment phase and a 16-week safety follow up phase. [JAMA Dermatol 2020;doi:10.1001/jamadermatol.2020.0079]

At week 16, significant improvements were observed in terms of the primary endpoint (percentage change in Eczema Area and Severity Index) with all doses of lebrikizumab vs placebo (least squares mean, -62 percent; p=0.02 [L1], -69 percent; p=0.002 [L2], and -72 percent; p<0.001 [L3] vs -41 percent [placebo]).

The similar improvements between the once- and twice-monthly dosing underscores the convenience of the once-monthly dosing schedule, noted the researchers.

Moreover, a greater fraction of participants in the L3 arm achieved at least a 4-point improvement in the pruritus numeric rating scale score at week 16 (70 percent vs 27 percent [placebo]; p<0.001). This improvement was seen as early as day 2 (15 percent vs 5 percent), suggesting its rapid onset of action.

Despite the higher incidence of treatment-emergent adverse events** with lebrikizumab (ranging from 49 to 61 percent vs 46 percent [placebo]), most were mild to moderate in intensity and none led to study discontinuation.

 

The role of IL-13 inhibition

Evidence has shown the role of interleukin(IL)-13 in inflammation, skin barrier dysfunction, infections, pruritus, and the allergic responses that characterize AD. [Allergy Asthma Proc 2019;40:84-92; Allergy 2020;75:54-62]

“Lebrikizumab … selectively targets IL-13,” said the researchers. Therefore, the current findings, along with previous evidence on lebrikizumab and another IL-13 inhibitor tralokinumab, [J Am Acad Dermatol 2018;78:863-871.e11; J Allergy Clin Immunol 2019;143:135-141] suggest that IL-13 may be the central pathogenic mediator in AD, they added. “[Our findings] provide additional clinical support for the central role of IL-13 in AD pathophysiology … IL-13 inhibition alone may be sufficient for therapeutic responses in patients with AD.”

 

Keeping an eye

Another monoclonal antibody, dupilumab, has been proven effective in this setting, noted the researchers. However, dupilumab-induced conjunctivitis has emerged as a notable tolerability issue in AD treatment. [J Eur Acad Dermatol Venereol 2019;33:1224-1231] This could be due to the interferon γ–mediated goblet cell apoptosis and reduced mucin production brought about by IL-4 inhibition, leading to dry eye and conjunctivitis. [Sci Rep 2018;8:12162; Exp Eye Res 2013;117:118-125; Invest Ophthalmol Vis Sci 2015;56:4186-4197]

In the current study however, the rate of conjunctivitis across all lebrikizumab arms was only 2.6 percent. Nonetheless, the researchers recommended further exploration to ascertain the mechanisms underlying drug-induced conjunctivitis in AD.

 

Key therapeutic agent

Taken together, the robust improvements in AD clinical manifestations and the favourable safety profile suggest that it may be an effective and tolerable treatment alternative for moderate-to severe-AD that does not respond well to standard topical remedies, said the researchers.

“If these findings replicate in phase III studies, lebrikizumab may meaningfully advance the standard of care for moderate-to-severe AD … [L]ebrikizumab could be an important addition to the AD treatment landscape and a central therapeutic agent in the treatment paradigm,” they said.

The phase III programme is underway to evaluate the long-term efficacy and safety of lebrikizumab and maintenance regimens, as well as its therapeutic potential in children.