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New Immunological Treatments in Skin Allergy

Prepared by: Pavel Kolkhir, member of the WINiT: Skin Allergy Committee and member of the JM Steering Committee
Marcus Maurer, Scientific chair of the WINiT: Skin Allergy Committee

Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema

Aygören-Pürsün E, Bygum A, Grivcheva-Panovska V, Magerl M, Graff J, Steiner UC, Fain O, Huissoon A, Kinaciyan T, Farkas H, Lleonart R, Longhurst HJ, Rae W, Triggiani M, Aberer W, Cancian M, Zanichelli A, Smith WB, Baeza ML, Du-Thanh A, Gompels M, Gonzalez-Quevedo T, Greve J, Guilarte M, Katelaris C, Dobo S, Cornpropst M, Clemons D, Fang L, Collis P, Sheridan W, Maurer M, Cicardi M. N Engl J Med. 2018 Jul 26;379(4):352-362. doi: 10.1056/NEJMoa1716995.

Reasons for recommending the article:

  • There are no effective and safe drugs for the oral prophylactic treatment of hereditary angioedema (HAE). BCX7353 is a new potent, synthetic oral small molecule inhibitor of plasma kallikrein that prevents HAE attacks.
  • In a randomized placebo-controlled trial, once-daily administration of BCX7353 at a dose of 125 mg or more led to significantly lower rates of HAE attacks as compared to placebo.
  • BCX7353 showed a good safety profile, with mild gastrointestinal symptoms in some patients. 


Background: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks.

Methods: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life.

Results: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups.

Conclusions: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 number, NCT02870972 .).

Efficacy and safety of the histamine H4 receptor antagonist ZPL-3893787 in patients with atopic dermatitis.

Werfel T, Layton G, Yeadon M, Whitlock L, Osterloh I, Jimenez P, Liu W, Lynch V, Asher A, Tsianakas A, Purkins L. J Allergy Clin Immunol. 2018 Nov 9. pii: S0091-6749(18)31578-1. doi: 10.1016/j.jaci.2018.07.047. [Epub ahead of print]

Reasons for recommending the article:

  • There is the need for new oral treatments of atopic dermatitis (AD) that safely and effectively target both the inflammatory and pruritic components of this condition.
  • H4 is the most recently discovered histamine receptor subtype, and its role in mediating histamine-induced inflammation and pruritus is well documented.
  • ZPL-3893787 (formerly PF-3893787) is a potent and highly selective histamine H4 receptor antagonist, which showed to be effective for the treatment of moderate-to-severe AD.
  • In this randomized, double-blind, placebo-controlled, parallel-group study, the drug was well tolerated. ZPL-3893787 reduced SCORAD and EASI scores in patients with AD, confirming H4 receptor antagonism as a novel therapeutic option.


Background: H4 receptor antagonists are potential novel treatments for inflammatory skin diseases, including atopic dermatitis (AD).

Objective: We sought to study the efficacy and safety of ZPL-3893787 (a selective H4 receptor antagonist) in patients with moderate-to-severe AD.

Methods: A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate ZPL-3893787 (30 mg) once-daily oral therapy in adults with moderate-to-severe AD. Patients were randomized (2:1) to ZPL-3893787 (n = 65) or placebo (n = 33) for 8 weeks. Patients had a history of AD for more than 12 months, Eczema Area and Severity Index (EASI) scores of 12 or greater and 48 or less, Investigator's Global Assessment (IGA) scores of 3 or greater, pruritus scores of 5 or greater (0- to 10-point scale), and AD on 10% or greater of body surface area. Efficacy parameters included EASI, IGA, SCORAD, and pruritus assessment.

Results: Treatment with oral ZPL-3893787 showed a 50% reduction in EASI score compared with 27% for placebo. The placebo-adjusted reduction in EASI score at week 8 was 5.1 (1-sided P = .01). Clear or almost-clear IGA scores were 18.5% with ZPL-3893787 versus 9.1% with placebo. SCORAD scores exhibited 41% reduction with ZPL-3893787 versus 26% with placebo (placebo-adjusted reduction of 10.0, P = .004). There was a 3-point reduction (scale, 1-10) in pruritus with ZPL-3893787, but there was a similar reduction with placebo, resulting in a nonsignificant difference (P = .249). Patient-reported pruritus subscores obtained from SCORAD were reduced with ZPL-3893787 compared with placebo at week 8 (nonsignificant). ZPL-3893787 was well tolerated.

Conclusion: For the first time, these results showed that ZPL-3893787 improved inflammatory skin lesions in patients with AD, confirming H4 receptor antagonism as a novel therapeutic option.

Nemolizumab in patients with moderate-to-severe atopic dermatitis: Randomized, phase II, long-term extension study.

Kabashima K, Furue M, Hanifin JM, Pulka G, Wollenberg A, Galus R, Etoh T, Mihara R, Nakano M, Ruzicka T. J Allergy Clin Immunol. 2018 Oct;142(4):1121-1130.e7. doi: 10.1016/j.jaci.2018.03.018. Epub 2018 May 10.

Reasons for recommending the article:

  • Despite the recent approval of the anti–IL-4 receptor mAb, dupilumab, for the treatment of atopic dermatitis (AD) inadequately controlled by topical therapy, treatment options for patients with AD remain limited, and there is an unmet need for novel therapies with minimal long-term side effects.
  • Nemolizumab (CIM331) is an anti–IL-31 receptor A humanized mAb that blocks signaling mediated by IL-31, a proinflammatory cytokine associated with AD and pruritus.
  • In this randomized, double-blind, placebo-controlled study, long-term treatment with nemolizumab was efficacious and well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy.


Background: Nemolizumab, an anti-IL-31 receptor A mAb, improved pruritus, dermatitis, and sleep in adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments in a phase II, 12-week, randomized, double-blind, placebo-controlled study (part A; NCT01986933).

Objective: We sought to assess the long-term efficacy and safety of nemolizumab injected subcutaneously every 4 weeks (Q4W) or every 8 weeks (Q8W) in a 52-week, double-blind extension (part B).

Methods: During part B, patients continued the previous nemolizumab dose (0.1, 0.5, or 2.0 mg/kg Q4W or 2.0 mg/kg Q8W). Part B end points included percentage improvement from baseline in pruritus visual analog scale and dermatitis scores (including the Eczema Area and Severity Index).

Results: Overall, 216 of 264 patients completed part A, and 191 entered part B; 131 completed part B. In 153 patients randomized to nemolizumab in part A, improvement from baseline in pruritus visual analog scale score was maintained/increased from weeks 12 to 64, with greatest improvement in the 0.5-mg/kg Q4W group (percentage change from baseline at week 64: -73.0, -89.6, -74.7, and -79.1 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Improvement from baseline in dermatitis scores was also maintained/increased to week 64 (percentage change in Eczema Area and Severity Index score: -68.5, -75.8, -78.9, and -69.3 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Over 64 weeks, 83% to 89% had 1 or more adverse events, with no new safety concerns identified.

Conclusion: Nemolizumab for up to 64 weeks was efficacious and overall well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy.

Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: Efficacy and safety observations.

Broesby-Olsen S, Vestergaard H, Mortz CG, Jensen B, Havelund T, Hermann AP, Siebenhaar F, Møller MB, Kristensen TK, Bindslev-Jensen C; Mastocytosis Centre Odense University Hospital (MastOUH). Allergy. 2018 Jan;73(1):230-238. doi: 10.1111/all.13237. Epub 2017 Jul 27.

Reasons for recommending the article:

  • Conventional mast cell mediator‐blocking agents can be insufficient to control symptoms in patients with systemic mastocytosis (SM), and there is an unmet need for efficient and safe treatment options.
  • Omalizumab, a monoclonal anti-IgE antibody, was shown to be effective and safe for the treatment of patients with allergic asthma and chronic spontaneous urticaria.
  • So far, only single case reports have described the efficacy of omalizumab in SM, and no controlled studies or larger case‐series have been published.
  • This is first study that assessed the efficacy of omalizumab as an add‐on, off‐label therapy in patients with SM and severe, recalcitrant mast cell mediator‐related symptoms and recurrent anaphylaxis. Omalizumab effectively prevented anaphylaxis and improved chronic mast cell mediator-related symptoms, insufficiently controlled by conventional therapy.
  • The mechanism by which omalizumab works in these apparently non-IgE mediated anaphylactic episodes is not clear.


Background: Patients with systemic mastocytosis (SM) may suffer from mast cell (MC) mediator-related symptoms insufficiently controlled by conventional therapy. Omalizumab is an established treatment in other MC-driven diseases, but experiences in SM are limited.

Objective: To assess the efficacy and safety of omalizumab in SM.

Methods: In our patient cohort, we evaluated all SM patients treated with omalizumab. A physician global assessment of type and severity of symptoms was performed at baseline, at 3 and 6 months and at latest follow-up. Quality of life was assessed by visual analogue scale. S-tryptase and KIT D816V allele burden were monitored.

Results: A total of 14 adult SM patients (10 ISM, 2 BMM, 1 SSM, and 1 ASM-AHN) received omalizumab with a median duration of 17 months (range: 1-73 months). One patient was excluded due to concomitant cytoreductive therapy. In the remaining 13 patients, we observed a significant reduction in symptoms, with complete symptom control in five (38.5%), major response in three (23.1%), and a partial response in three (23.1%) patients, whereas two patients (15.4%) withdrew due to subjective side-effects at first dose. The treatment was most effective for recurrent anaphylaxis and skin symptoms, less for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms. Patient-reported quality of life showed significant improvement. No significant changes in s-tryptase/KIT D816V allele burden were observed. No severe adverse events were recorded.

Conclusions: Omalizumab appears to be a promising treatment option in SM, effectively preventing anaphylaxis and improving chronic MC mediator-related symptoms, insufficiently controlled by conventional therapy. Controlled studies are needed to substantiate findings.

Molecular genetic investigation, clinical features, and response to treatment in 21 patients with Schnitzler syndrome.

Rowczenio DM, Pathak S, Arostegui JI, Mensa-Vilaro A, Omoyinmi E, Brogan P, Lipsker D, Scambler T, Owen R, Trojer H, Baginska A, Gillmore JD, Wechalekar AD, Lane T, Williams R, Youngstein T, Hawkins PN, Savic S, Lachmann HJ. Blood. 2018 Mar 1;131(9):974-981. doi: 10.1182/blood-2017-10-810366. Epub 2017 Dec 28.

Reasons for recommending the article:

  • Schnitzler syndrome (SchS) is a rare entity with a strong clinical resemblance of cryopyrin-associated periodic syndrome (CAPS), and SchS has been linked to somatic NLRP3 mutations.
  • This study reports the results of systematic genetic investigations in 21 patients with SchS.
  • The findings do not support a role for somatic NLRP3 mosaicism in SchS.
  • SchS was characterized by elevated levels of the extracellular apoptosis-associated speck-like protein and proinflammatory cytokines (IL-6 and IL-18), confirming that inflammasome activation is relevant in its pathogenesis.
  • IL-1 antagonists remain the mainstay of SchS treatment and ninety-five percent of the cohort achieved a complete response to treatment with the recombinant IL-1 receptor antagonist anakinra.


To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1β (IL-1β) production, although interest in the contribution of genetic factors has been fueled by detection of somatic NLRP3 mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ. Patients underwent searches for germ line and somatic mutations using next-generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic NLRP3, TNFRSF1A, NLRC4, or NOD2 mutations, apart from 1 patient with a germ line NLRP3 p.V198M substitution. The proinflammatory cytokines and extracellular apoptosis-associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic NLRP3 mosaicism in disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients.

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