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. 2019 Nov 12;34(2):239–250. doi: 10.1111/jdv.15973

Table 1.

Products approved or in development that have potential to manage itch in AD

Target Compound Status Key clinical data Magnitude of effect on itch Reference
Small molecule products
JAK1 Upadacitinib Phase 2b Significantly reduced itch in moderate‐to‐severe AD by Week 1 throughout Week 16 and further to Week 32 Mean percent change from baseline in pruritus Numerical Rating Scale (NRS):

  • Week 1: −19–36% (range for 7.5, 15 and 30 mg upadacitinib) vs. 1% with placebo; P < 0.001 vs. placebo

  • Week 16: −40–69% vs. −10%; P < 0.01 (7.5 mg) and P < 0.001 (15 and 30 mg) vs. placebo

  • Week 32: At all doses, treatment cohorts who continued to receive treatment rather than placebo after week 16 achieved further reduction in pruritus (NRS −44 to −53%), compared to treatment cohorts randomized to placebo (NRS +3 to +13%). Placebo cohorts randomized to treatment after Week 16 achieved −94% NRS

 AbbVie 201867; AbbVie 201869; ClinicalTrials.gov identifier: NCT02925117
JAK1, JAK3 Tofacitinib Phase 2a Significantly reduced itch in mild‐to‐moderate AD by Day 2 throughout Week 4 Least squares (LS) mean percent change from baseline in Itch Severity Item:

  • Day 2 to Day 14 (diary‐based LS mean) and Weeks 2 and 4 (clinical‐based LS mean): P < 0.001 with 2% tofacitinib vs. placebo

 Bissonnette 201640
JTE‐052 Phase 2 Significantly reduced itch in moderate‐to‐severe AD by Day 1 (night‐time) and Week 1 Mean percent change from baseline in pruritus NRS:

  • Day 1 (night‐time score): P < 0.001 for the 0.5%, 1%, and 3% JTE‐052 groups vs. placebo

  • Week 1 (night‐time and daytime: P < 0.001 for the 0.5%, 1% and 3% groups vs. placebo

 Nakagawa 201870
PDE4 Crisaborole Approved (mild‐to‐moderate AD) Significantly improved itch in mild‐to‐moderate AD as early as Day 2 through Day 29 Proportions of patients achieving improvement in pruritus score 0 or 1 and ≥1‐grade reduction (scale 0–4) from baseline:

  • Day 2: 34.3% vs. 27.3%; P = 0.013; crisaborole vs. placebo‐treated patients, respectively

  • Day 6: 56.6% vs. 39.5%; P < 0.001; crisaborole vs. placebo‐treated patients, respectively

 Yosipovitch 201868
Roflumilast

Approved (COPD)

Phase 2a

 Significant improvement in patient assessment of itch in moderate AD by Day 15 Mean difference in pruritus score between the roflumilast‐ and placebo‐treated groups:

  • Day 15: 1.56, P = 0.013

 ClinicalTrials.gov Identifier: NCT01856764
Apremilast Approved (psoriasis and PsA); Phase 2 in AD Significant improvement in itch in AD in an open‐label trial by Week 2 Reduction in pruritus visual analog scale (VAS) by Week 2:

  • P = 0.045 (20 mg apremilast) and P = 0.059 (30 mg apremilast)

 Samrao 201271
Non‐significant improvement in itch in moderate‐to‐severe AD by Week 12 Mean percent change from baseline in pruritus VAS at Week 12:

  • −3.9 and −16.2 vs. −9.8 (P = not significant) with 40 mg and 30 mg apremilast vs. placebo, respectively

 Simpson 201872
E6005/RVT‐501 Phase 2 Non‐significant reduction in itch in AD by Week 12 Mean percent difference (95% confidence interval [CI]) in Itch Behavioral Rating Scale score between the E6005 group and placebo:

  • Week 4: −0.9 (−19.9 to 18.2); P = NS

  • Week 12: P = 0.462

 Furue 201473
NGF (TrkA) Pegcantratinib (CT327†) Phase 2b Significantly reduced itch in adults with mild‐to‐moderate psoriasis Significant reductions from baseline at Week 8 in pruritus VAS and Psoriasis Area Severity Index with 0.05% and 0.1% CT327 vs. placebo, respectively Roblin 201574
α2δ‐1 subunit of spinal N‐type Ca2+ channels Gabapentin†, Pregabalin† Approved (pain) Significantly reduced itch of neuropathic origin Commencement of pregabalin 75 mg twice daily and increased to 150 mg twice daily resulted in a more than 70% reduction in itch 5–8 weeks after treatment initiation Ehrchen 200875
NK‐1 receptor (antagonist) Aprepitant† (oral) Phase 1 Anti‐pruritic effect observed as early as Day 2 in severe refractory chronic pruritus associated with several non‐malignant conditions, including atopic diathesis and prurigo nodularis 16 out of 20 patients (80%) with chronic pruritus responded to short‐term aprepitant monotherapy

  • Pruritus intensity on the VAS before treatment ranged from 5 to 10 (mean, 8.4; SD ± 21.7; median VAS, 8)

  • After treatment with aprepitant, pruritus intensity was reduced to a mean of 4.9 points (standard deviation [SD] ± 3.2; P < 0.001; CI, 1.913 to 5.187)

 Ständer 201076
Serlopitant (oral)† Phase 2 Significantly reduced itch in patients with severe refractory chronic pruritus of various aetiologies Mean percent changes from baseline in pruritus NRS at Week 6:

  • −41.4 and −42.5 vs. −28.3 (P = 0.022 and P = 0.013) with 1 mg and 5 mg serlopitant, respectively, vs. placebo (primary endpoint)

 Yosipovitch 201877
Non‐significant reduction of itch in a phase 2 trial in adolescents and adults with a history of AD Mean absolute change from baseline in pruritus NRS at Week 6:

  • Treatment effect with 1 mg and 5 mg serlopitant, respectively vs. placebo: −0.32 and −0.23 (P = 0.11 and P = 0.17)

 Menlo Therapeutics 201878; ClinicalTrials.gov Identifier: NCT02975206
Significantly reduced several measures of itch in patients with prurigo nodularis
LS mean difference (95% CI) in average itch VAS scores between the serlopitant and placebo group:
  • Week 2: −0.9 (−1.5 to −0.2); P = 0.0110
  • Week 8: −1.0 (−1.8 to −0.1); P < 0.0001
Mean difference (95% CI) in average itch NRS scores between the serlopitant and placebo group:
  • Week 2: −0.9 (−1.6 to −0.2); P = 0.009
  • Week 8: −1.4 (−2.3 to −0.4); P = 0.007
 Ständer 201979
Tradipitant (oral) Phase 2 Significant and clinically meaningful improvements in several measures of itch in AD

Improvements were observed in the measurement of Worst Itch VAS (P = 0.019) with tradipitant vs. placebo

More tradipitant‐treated vs. placebo‐treated patients achieved ≥40 points improvement from baseline in Worst Itch VAS scores (P = 0.037) or ≥30 points (P = 0.049)

More tradipitant‐treated patients showed improvement in Average Itch VAS over placebo‐treated patients, but this improvement was not significant

 Vanda Pharmaceuticals 201780; ClinicalTrials.gov Identifier: NCT02651714
Serotonin norepinephrine reuptake inhibitor Mirtazapine† Case series Significant reduction in chronic nocturnal pruritus Two of three cases had underlying AD, both reported itch symptom alleviation within 1 week on mirtazapine Hundley 200481
μ‐opioid receptor (antagonist) Naltrexone Placebo‐controlled case series Non‐significant decrease in allokinesis and duration of acetylcholine‐induced acute itch in AD patients Heyer 200282
Nalmefene (SRD174; topical) Phase 2 Non‐significant reduction in itch after two 7‐day periods of treatment in adults with persistent moderate‐to‐severe pruritus associated with AD

The LS mean difference (95% CI) in sum of pruritus intensity difference from 0 to 4 h (SPID0–4) between the SRD174 cream and placebo group was −1.3 (−25.9 to 23.3); P = 0.914

The LS mean difference (95% CI) in average daily pruritus score between the SRD174 cream and placebo group was −0.1 (−0.2 to 0.0); P = 0.095

 Herzog 201183
κ‐opioid receptor (agonist) Nalfurafine (oral)† Approved in Japan for uraemic pruritus Significant reduction in pruritus in patients with liver disease in a phase 3 randomized, placebo‐controlled trial
The changes in pruritus scores at Week 4 were:
  • 0.74 (95% CI, 0.59 to 0.90), 1.09 (0.94 to 1.24) and 1.01 (0.86 to 1.16) in the placebo, 2.5 μg and 5 μg nalfurafine groups, respectively

The difference between the 2.5 μg group vs. placebo was 0.35 (0.13 to 0.56, P = 0.0007), and between 5 μg vs. placebo, 0.26 (0.05 to 0.47, P = 0.0071)

 Kumada 201784
κ‐opioid receptor (full agonist) and μ‐opioid receptor (partial agonist) Nalbuphine/Nubain† (extended‐release tablet formulation) Phase 2/3 Significant reduction in severe chronic uraemic pruritus in haemodialysis patients The mean NRS (±SE) declined by 3.5 (2.4) and 2.8 (2.2) in the 120 mg nalbuphine and placebo groups, respectively (P = 0.017 vs. placebo) from a baseline NRS of 6.9 (1.5) Mathur 201785; ClinicalTrials.gov Identifier: NCT02373215
Successfully completed a phase 2 trial for pruritus in patients with prurigo nodularis Among the 12 of 18 enrolled patients who completed the 10‐week study, the proportion who reported > 50% reduction in 7‐day worst itch NRS vs. baseline achieved significance (P = 0.028) Trevi Therapeutics 201686; ClinicalTrials.gov Identifier: NCT02174419
κ‐opioid receptor (agonist) and μ‐opioid receptor (antagonist) Butorphanol† Significantly reduced itch in 5 patients with severe, chronic intractable pruritus No specific data are reported (anecdotal only) Dawn 200687
Spinal cannabinoid 1 receptor (agonist) WIN 55,212‐2† Preclinical Dose‐dependently decreased serotonin‐induced scratching in an animal study Bilir 201888
Spinal cannabinoid 2 receptor (agonist) N‐palmitoyl ethanolamine (PEA)† Open application observation Reduced itch by 86.4% in 14/22 patients with prurigo, lichen simplex, and pruritus The average reduction in itch was 86.4% Ständer 200689
S‐777469† Preclinical Significantly reduced scratching behaviour induced by histamine or substance P in animal studies Haruna 201590
Histamine 4 receptor (H4R) ZPL‐3893787 Phase 2 Non‐significant decrease in pruritus in both treatment and control groups at Week 8; clinical implications unclear Worst pruritus NRS mean change (SD) from baseline to Week 8 was −3.03 (2.186) with ZPL‐3893787 and −2.66 (2.057) with placebo (P = 0.249); TCS permitted as rescue (75.4% ZPL‐3893787 and 84.8% placebo patients received rescue) Werfel 201991
Biologics
TSLP Tezepelumab (monoclonal antibody) Phase 2a Marginal reduction in itch in moderate‐to‐severe AD

Adjusted mean percentage improvement (±SE) in pruritus NRS from baseline to Week 12 with tezepelumab + TCS vs. placebo + TCS was 35.53 (5.9) vs. 21.05 (5.9); P = 0.050 vs. placebo

Adjusted mean percentage improvement (±SE) in peak pruritus NRS from baseline to Week 12 with tezepelumab + TCS vs. placebo + TCS was 33.54 (6.0) vs. 25.41 (6.1); P = 0.258 vs. placebo

 Simpson 201992
IL‐33 (ST2) IL‐33 mouse antibody† Preclinical Scratching behaviour was reduced in an animal model Peng 201893
IL‐4Rα (IL‐4 and IL‐13) Dupilumab (monoclonal antibody) Approved (moderate‐to‐severe AD) Significantly reduced itch in moderate‐to‐severe AD for up to 52 weeks in phase 3 studies; reduction in itch was reported as early as Day 2 in a post‐hoc analysis
LS mean percent change from baseline (±SE) in peak pruritus NRS score:
  • At Day 2 (pooled LIBERTY AD SOLO 1 and 2 phase 3 studies): −4.0% (0.1) and −4.5% (1.0) vs. −0.6% (1.0); P = 0.0110 and P = 0.0033; qw and q2w vs. placebo, respectively
LS mean percent change from baseline (±SE) in peak pruritus NRS score:
  • At Week 52 (LIBERTY AD CHRONOS): −54.4% (2.6) and −56.2% (4.4) vs. −27.1% (2.7); P ≤ 0.0001; qw + TCS and q2w + TCS vs. placebo + TCS, respectively
Proportions of patients achieving peak pruritus NRS ≥3‐point improvement from baseline:
  • At Week 52 (LIBERTY AD CHRONOS phase 3 study): 43% and 56% vs. 16%; P < 0.0001; dupilumab 300 mg qw and 300 mg q2w vs. placebo, respectively
 Silverberg 2017 (pooled SOLO 1 and 2)41; Blauvelt 2017 (CHRONOS)8; Simpson 20167
IL‐22 Fezakinumab (monoclonal antibody) Phase 2a Non‐significant difference in itch in moderate‐to‐severe AD by Week 12 No significant differences in SCORing Atopic Dermatitis VAS pruritus score, but a sustained treatment effect was observed among patients with baseline pruritus > 5 after Week 12 vs. placebo Guttman‐Yassky 201894
IL‐13 Lebrikizumab (monoclonal antibody) Phase 2; phase 2b Numerical reduction in itch in moderate‐to‐severe AD by Week 12 (phase 2); no itch data available yet from phase 2b study Adjusted mean percent reductions from baseline pruritus VAS at Week 12 were:

  • Placebo response group 27.5%

  • Lebrikizumab 125 mg single dose 34.9% (P = 0.40), 250 mg single dose 32.8% (P = 0.54), 125 mg q4w 40.7% (P = 0.13)

 Simpson 201895; ClinicalTrials.gov Identifier: NCT03443024 (phase 2b)
Tralokinumab (monoclonal antibody) Phase 2b Significant reduction in itch in moderate‐to‐severe AD by Week 12 Improvements (95% CI) with tralokinumab‐treated patients vs. placebo for pruritus NRS at Week 12:

  • 45 mg tralokinumab adjusted mean difference, −0.77 (−1.52 to −0.02); nominal P = 0.04, and 300 mg tralokinumab −1.14 (−1.88 to −0.41); nominal P = 0.002

 Wollenberg 201996
IL‐17A Secukinumab (monoclonal antibody) Phase 2; approved for psoriasis A placebo‐controlled trial assessing the efficacy and safety of secukinumab in moderate‐to‐severe AD is currently in recruitment No data available yet Clinicaltrials.gov Identifier: NCT02594098
IL‐17A Ixekizumab (monoclonal antibody) Phase 3 Significant, rapid reduction in itch in moderate‐to‐severe psoriasis by Week 12

Greater differences in time to pruritus NRS ≥4‐point improvement for patients treated with ixekizumab every 2 weeks or every 4 weeks vs. placebo (P < 0.001)

The median time for 50% of patients to achieve a ≥4‐point reduction in pruritus NRS was shorter for ixekizumab‐treated patients (2 weeks, with both 80 mg ixekizumab every 4 weeks and every 2 weeks) compared with placebo‐treated patients (> 12 weeks)

 Leonardi 201797
IL‐31RA Nemolizumab (monoclonal antibody) Phase 2; phase 2 long‐term extension Significantly decreased itch in moderate‐to‐severe AD by Week 12 (phase 2 randomized trial) and Week 64 (open‐label extension) Changes on the pruritus VAS were:

  • At Week 12: −43.7% (0.1 mg q4w nemolizumab group), −59.8% (0.5 mg q4w group), and −63.1% (2.0 mg q4w group), vs. −20.9% with placebo (P < 0.01 for all comparisons)

  • At Week 64: −73.0% (0.1 mg q4w nemolizumab group), −89.6% (0.5 mg q4w group), −74.7% (2.0 mg q4w group), and −79.1% (2.0 mg q8w group)

 Ruzicka 201710; Kabashima 201811

†Agents effective in itch but not tested in AD.

AD, atopic dermatitis; CI, confidence interval; COPD, chronic obstructive pulmonary disease; GABA, gamma‐aminobutyric acid; LS, least squares; NGF, nerve growth factor; NRS, numerical rating scale; PsA, psoriatic arthritis; q2w, every 2 weeks; q4w, every 4 weeks; qw, every week; SD, standard deviation; SE, standard error; VAS, visual analog scale.