What is lebrikizumab?
The US Food and Drug Administration (FDA) granted lebrikizumab Fast Track designation for atopic dermatitis (AD) in Dec 2019. In July 2022, there were one phase II and eight phase III clinical trials assessing the use of lebrikizumab in moderate to severe AD, with expected submission for approval in 2023 in the United States and the European Union.
Lebrikizumab has shown promising efficacy and a favourable safety profile in moderate to severe AD, including pruritus improvement as early as two days after commencing treatment.
What is lebrikizumab used for?
Clinical trials for the use of lebrikizumab in the following conditions are currently underway:
- Atopic dermatitis (AD)
- Idiopathic pulmonary fibrosis
- Chronic obstructive pulmonary disease (COPD).
Preliminary clinical trial results suggest that lebrikizumab may significantly improve AD disease severity when used in conjunction with topical steroids. It should also be used in combination with standard aspects of AD management such as moisturisers and emollients.
How does lebrikizumab work?
Lebrikizumab is thought to work by downregulating inflammatory processes that contribute to atopic dermatitis.
- The immune pathogenesis of AD is characterised by type 2 and type 22 immune responses in the skin and serum.
- Type 2 immune response cytokines involve interleukin 4 (IL-4) and interleukin 13 (IL-13). It is thought that IL-4 initiates while IL-13 maintains the T helper (Th) type 2 (Th2) response.
- IL-13 also plays a crucial role in immunoglobulin E (IgE) recruitment and synthesis.
- IL-13 cytokines contribute to barrier impairment. Research demonstrates that IL-13 downregulates filaggrin and loricrin, two proteins expressed in the skin barrier. By downregulating these proteins, the skin barrier’s ability to protect against pathogens and allergens and maintain adequate moisture on the skin surface is compromised.
- The inflammation caused by the IL-13 pathway leads to skin barrier dysfunction causing itching, skin thickening, and infection.
Lebrikizumab is an IL-13 antagonist. It is understood to inhibit IL-13 by neutralizing the cytokine and preventing binding and heterodimerization of receptor subunits IL-13Rα1 and IL-4Rα. Lebrikizumab binds to IL-13 with high affinity and blocks downstream signalling, reducing inflammation and thereby helping to relieve symptoms of AD and improve the barrier function of the skin.
Pharmacokinetics and dosing
- Lebrikizumab is administered as a subcutaneous injection.
- Dosing in clinical trials includes single dose 125mg, single dose 250mg, 125mg every four weeks, 250mg every four weeks, and 250mg every two weeks.
- Dose-dependent pharmacokinetic profile and efficacy was demonstrated for AD symptoms.
- Mean elimination half-life: 18.5–25 days.
- In the TREBLE study by Simpson et al, serum lebrikizumab levels gradually tapered down following single-dose treatment, while patients given 125mg lebrikizumab four weekly gradually increased their minimum serum concentration over twelve weeks.
- The linear pharmacokinetic profile and long half-life allow for dosing of lebrikizumab every four weeks, and might enable less frequent dosing during maintenance therapy.
What are the benefits of lebrikizumab?
Clinical trials have demonstrated promising results for lebrikizumab, including rapid improvement in atopic dermatitis symptoms and severity, and high rates of sustained itch relief and skin clearance at one year of treatment.
- Reduction in pruritus as early as two days after commencing treatment.
- A placebo-controlled phase II B clinical trial (280 patients) found that at 16 weeks, 60.6% of those given lebrikizumab 250mg every two weeks and 56.1% of those given 250mg every four weeks achieved a 75% improvement in Eczema Area and Severity Index (EASI) score from baseline.
- Preliminary results from two phase III trials for AD found that ~80% of patients who achieved clinical response to lebrikizumab at 16 weeks (EASI score improvement of 75%) maintained itch relief and skin clearance through one year of treatment.
Other benefits include:
- Potentially lower rates of conjunctivitis (1.4–3.8%) in lebrikizumab-treated patients compared to dupilumab (an IL-4 and IL-13 inhibitor) in some studies
- Therapeutic benefit for patients already on maximal topical therapy for AD
- Effective in some patients with AD for whom dupilumab therapy was not successful.
What are the side effects and risks of lebrikizumab?
Lebrikizumab seems to be generally well tolerated.
Reported adverse events include:
Data on drug-to-drug interactions are limited.
See also immunisation in immunosuppressed dermatology patients for information on vaccination.
What are the contraindications to lebrikizumab?
- Hypersensitivity to lebrikizumab or any of its constituents.
If you are not based in New Zealand, we suggest you refer to your national drug approval agency for further information about medicines (eg, the Australian Therapeutic Goods Administration and the US Food and Drug Administration) or a national or state-approved formulary (eg, the New Zealand Formulary and New Zealand Formulary for Children and the British National Formulary and British National Formulary for Children).