D11: Other dermatological preparations
D11 holds the skin preparations that fit in no other D group: sweat-reducing preparations (antihidrotics), medicated shampoos, male sex hormones (androgens) for topical use, wart and anti-corn preparations, agents for skin inflammation (dermatitis) excluding corticosteroids (D11AH), and other dermatologicals. The notes below are about the agents for dermatitis, which include both topical preparations and drugs given by mouth or parenterally [1].
How do agents for dermatitis work?
- Topical calcineurin inhibitors, tacrolimus (D11AH01) and pimecrolimus (D11AH02), are used as steroid-sparing treatments on the skin [2].
- Crisaborole (D11AH06) is a nonsteroidal phosphodiesterase 4 inhibitor, applied as an ointment in mild to moderate eczema (atopic dermatitis) [3].
- Dupilumab (D11AH05) is a monoclonal antibody against the interleukin-4 (IL-4) receptor α subunit, and inhibits the signaling of IL-4 and IL-13, two type 2 cytokines [4].
- Nemolizumab (D11AH12) is a humanized monoclonal antibody that targets the IL-31 receptor α [5].
- Abrocitinib (D11AH08) is an oral, once-daily inhibitor selective for Janus kinase 1 [6].
Efficacy
The nemolizumab analysis scored atopic dermatitis with two investigator-reported measures and one patient-reported measure of itch [5]:
- The Eczema Area and Severity Index (EASI) is an investigator assessment of the extent and severity of disease, from 0 (clear) to 72 (very severe).
- The Investigator’s Global Assessment (IGA) grades global severity on an ordinal scale, from 0 (clear) to 4 (severe disease) on the 5-point version, or to 5 (very severe disease) on the 6-point version.
- The Peak Pruritus Numerical Rating Scale (PP NRS) is the patient’s own rating of itch, from 0 (no itch) to 10 (worst itch imaginable).
Trials can turn these scores into binary responder endpoints. In the two phase 3 trials of dupilumab, the primary outcome was an IGA of 0 or 1 together with a reduction of at least 2 points from baseline at week 16, and the proportion of patients with at least 75% improvement in EASI (EASI-75) was also reported [4].
In the nemolizumab analysis, each type of score got its own model: EASI and PP NRS were described with turnover models whose output was transformed onto the bounded scale of each score, and IGA with a continuous-time Markov model. Nemolizumab exposure decreased with increasing bodyweight, and the simulated median trough at week 16 was 2.51 µg/mL below 90 kg and 1.71 µg/mL at 90 kg or above. Even so, the simulated proportions of responders for EASI, PP NRS and IGA were similar in the two weight groups [5].
For rocatinlimab, an anti-OX40 antibody, EASI was grouped into four categories of improvement from baseline (below 50%, 50 to 75%, 75 to 90%, and 90% or more) and modeled with a four-state continuous-time Markov model. In that model the probability of dropout was highest in the category with less than 50% improvement, so dropout depended on the response state [7].
In phase 1 studies in healthy subjects, dupilumab lowered circulating total immunoglobulin E (IgE) and thymus- and activation-regulated chemokine (TARC), pharmacodynamic markers that indicated blockade of IL-4 receptor α signaling [8].
Safety
In pediatric trials of tacrolimus, the most frequently reported adverse events were a burning sensation, itching (pruritus) and skin infections. Two cohort studies found no significant increase in the risk of cancer (malignancy) with topical calcineurin inhibitors in children [2].
Crisaborole reaches the circulation: in a pooled analysis of six studies, systemic exposure at a given ointment dose was 2.5-fold higher in patients with atopic dermatitis or psoriasis than in healthy participants. Model predictions indicated that exposure in children aged 2 to 17 years is unlikely to exceed that in adults [3].
In the phase 3 trials of dupilumab, injection-site reactions and inflammation of the eye surface (conjunctivitis) were more frequent with dupilumab than with placebo [4].