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Urticaria and Angioedema
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Jenny M Stitt, Stephen C Dreskin
Access to on demand therapy for acute attacks is effective and should be provided for all patients with HAE (Maurer et al. 2018). Prophylactic therapy should also be considered in HAE patients, particularly those with frequent or laryngeal attacks (Maurer et al. 2018). Androgens such as danazol, purified or recombinant C1 inhibitor and the kallekrein inhibitor lanedelumab have been shown to reduce the number of acute angioedema episodes in double-blind, placebo-controlled trials of HAE (Dreskin 2012, Hiragun et al. 2013, Maurer et al. 2018, Banerji et al. 2018). Attenuated androgens do carry the risk of unwanted side-effects, and the lowest therapeutic dose should be targeted. Liver transaminases must be monitored at intervals and patients must be aware of possible masculinization (Dreskin 2012, Hiragun et al. 2013). C1 inhibitor preparations and lanadelumab have fewer side effects but are more costly (Maurer et al. 2018).
The importance of recognizing and managing a rare form of angioedema: hereditary angioedema due to C1-inhibitor deficiency
Published in Postgraduate Medicine, 2021
A recombinant, human monoclonal antibody long-acting inhibitor of kallikrein formulated for SC administration, lanadelumab-flyo (TAKHZYROTM; DX-2930; Shire, now part of Takeda; Lexington, MA) [106] was approved by the FDA in August 2018 for prophylaxis to prevent HAE attacks [94]. The recommended dose of lanadelumab is 300 mg every 2 weeks; dosing every 4 weeks can be considered in patients who are well-controlled (eg, attack free) for more than six months [94]. In a 26-week, phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients 12 years of age or older with HAE (HELP study; NCT02586805), all lanadelumab treatment regimens were more effective than placebo in reducing the number of HAE attacks during the 26-week treatment period. When given at the FDA approved dose (300 mg SC given every 2 weeks), lanadelumab reduced the monthly HAE attack rate by 87% versus placebo (mean rate ratio 0.13 [95% CI, 0.07–0.24]; P < 0.001) [107]. Post hoc analyses of the HELP study found that attack prevention was evident within the initial 2 weeks of treatment, and sustained, even among patients who had a high baseline attack frequency [108]. A phase 3 long-term/extension study was conducted (NCT02741596; N = 212; median [range] 33 [1.4, 34.2] months of therapy), and reported that efficacy was sustained without emergence of any new safety concerns [109,110].
A focus on the use of subcutaneous C1-inhibitor for treatment of hereditary angioedema
Published in Expert Review of Clinical Immunology, 2020
Maria Fernanda Villavicencio, Timothy Craig
SC-C1-INH has added significantly to the armamentarium of physicians that treat HAE. The ability to achieve a steady state of C1-INH above 40% function is key to the success of the drug. Many individuals at the 60 IU/kg dose will achieve normal functional levels of C1-INH and with this have minimal if any attacks. The safety is evident from 40 years of use of C1-inhibitor in Europe. The drug burden is a subcutaneous (SC) injection twice a week that exceeds the newly approved lanadelumab, which is a small SC injection twice to once a month. There may be some benefit of SC-C1-INH in that the protein that is deficient in HAE is replaced and with this the complement, fibrinolytic, and coagulation pathways are also regulated, as well as the contact system; however, evidence for this is still lacking.
Antibodies to watch in 2018
Published in mAbs, 2018
Hélène Kaplon, Janice M. Reichert
Lanadelumab (SHP643, DX-2930), a human IgG1 mAb that targets plasma kallikrein and thereby prevents production of bradykinin, is in Phase 3 studies designed to assess the mAb's ability to treat hereditary angioedema attacks (HAE), a rare debilitating disease characterized by attacks of swelling that can occur anywhere in the body. The FDA has granted lanadelumab Breakthrough Therapy and orphan drug designations, and lanadelumab has been granted orphan drug designation in the EU, for treatment of hereditary angioedema attacks. In May 2017, Shire reported key results from the 26-week Phase 3 HELP study (NCT02586805), which evaluated the efficacy and safety of lanadelumab in preventing acute angioedema attacks in patients with Type I and Type II HAE.49 Patients were administered 300 mg lanadelumab every 2 weeks or every 4 weeks, or 150 mg lanadelumab every 4 weeks, or placebo. The primary and all secondary endpoints for all lanadelumab treatment arms compared to placebo. The monthly attack rate reduction compared to placebo was 87%, 73% and 76% for the 300 mg every 2 weeks, 300 mg every 4 weeks and 150 mg every 4 weeks treatment arms, respectively, with P < 0.001 for all analyses.49 A Phase 3 open-label, long term safety and efficacy study (NCT02741596) to evaluate lanadelumab in preventing acute angioedema attacks in patients with Type I and Type II HAE has a primary completion date in February 2018. Shire has indicated that their current expectation is for BLA submission in late 2017 to early 2018, and potential marketing application submission in Europe in the first half of 2018, pending discussions with the relevant regulatory agencies.