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Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies.
BioDrugs 2019; 33(1):33-43B

Abstract

Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.

Authors+Show Affiliations

Division of Clinical Immunology and Allergy, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Room 11-20, New York, NY, 10029, USA. paula.busse@mssm.edu.Hungarian Angioedema Reference Center, 3rd Department of Internal Medicine, Semmelweis University, Kutvolgyi ut 4, Budapest, 1125, Hungary.Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Cox 201, Boston, MA, 02114, USA.Allergy and Asthma Research Associates, 10100 N. Central Expressway, Suite 100, Dallas, TX, 75231, USA.Department of Immunology, Addenbrookes Hospital Cambridge University NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK.Shire, 300 Shire Way, Lexington, MA, 02421, USA.Division of Rheumatology, Allergy and Immunology, University of California, San Diego, 8899 University Center Lane, Suite 230, San Diego, CA, 92122, USA.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

30539362

Citation

Busse, Paula J., et al. "Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema With C1 Inhibitor Deficiency: a Review of Preclinical and Phase I Studies." BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy, vol. 33, no. 1, 2019, pp. 33-43.
Busse PJ, Farkas H, Banerji A, et al. Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies. BioDrugs. 2019;33(1):33-43.
Busse, P. J., Farkas, H., Banerji, A., Lumry, W. R., Longhurst, H. J., Sexton, D. J., & Riedl, M. A. (2019). Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies. BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy, 33(1), pp. 33-43. doi:10.1007/s40259-018-0325-y.
Busse PJ, et al. Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema With C1 Inhibitor Deficiency: a Review of Preclinical and Phase I Studies. BioDrugs. 2019;33(1):33-43. PubMed PMID: 30539362.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies. AU - Busse,Paula J, AU - Farkas,Henriette, AU - Banerji,Aleena, AU - Lumry,William R, AU - Longhurst,Hilary J, AU - Sexton,Daniel J, AU - Riedl,Marc A, PY - 2018/12/13/pubmed PY - 2019/7/17/medline PY - 2018/12/13/entrez SP - 33 EP - 43 JF - BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy JO - BioDrugs VL - 33 IS - 1 N2 - Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE. SN - 1179-190X UR - https://www.unboundmedicine.com/medline/citation/30539362/Lanadelumab_for_the_Prophylactic_Treatment_of_Hereditary_Angioedema_with_C1_Inhibitor_Deficiency:_A_Review_of_Preclinical_and_Phase_I_Studies_ L2 - https://dx.doi.org/10.1007/s40259-018-0325-y DB - PRIME DP - Unbound Medicine ER -