Lanadelumab Explained

Type:mab
Mab Type:mab
Source:u
Target:Kallikrein
Tradename:Takhzyro
Dailymedid:Lanadelumab
Pregnancy Au:B1
Pregnancy Au Comment:[1]
Routes Of Administration:Subcutaneous
Atc Prefix:B06
Atc Suffix:AC05
Legal Au:S4
Legal Ca:Rx-only
Legal Ca Comment:/Schedule D[2]
Legal Uk:POM
Legal Uk Comment:[3]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[4]
Cas Number:1426055-14-2
Drugbank:DB14597
Chemspiderid:none
Unii:2372V1TKXK
Kegg:D11094
Synonyms:lanadelumab-flyo
C:6468
H:10016
N:1728
O:2012
S:47

Lanadelumab, sold under the brand name Takhzyro, is a human monoclonal antibody (class IgG1 kappa)[5] that targets plasma kallikrein (pKal)[6] in order to promote prevention of angioedema in people with hereditary angioedema.[7] [8] Lanadelumab, was approved in the United States as the first monoclonal antibody indicated for prophylactic treatment to prevent hereditary angioedema attacks.[9] [10] Lanadelumab is the first treatment for hereditary angioedema prevention made by using cells within a lab, not human plasma.[11]

Common side effects include pain associated with injection site reactions, injection site bruising, upper respiratory infection, headache, rash, myalgia, dizziness, and diarrhea.

The US Food and Drug Administration approved the use of lanadelumab in August 2018, for people that are 12 years and older and have either type I or type II hereditary angioedema.[12] [13]

Medical uses

In the United States, lanadelumab is indicated for the prophylaxis of hereditary angioedema attacks.[14]

Adverse events

In a phase III randomized controlled trial, which examined the efficacy and safety of lanadelumab in preventing hereditary angioedema attacks, the most common adverse events noted in patients being treated were:[15] [16]

Mechanism of action

Lanadelumab works by binding to an enzyme within the plasma, kallikrein, to inhibit its activity.[17] Kallikrein is a protease that functions to cleave kininogen, subsequently creating kininogen and bradykinin, a potent vasodilator.

People have hereditary angioedema because of a deficiency or dysfunctional C1 inhibitor, which is an enzyme that regulates the activity of the kallikrein-kinin cascade. Poor regulation of the C1 inhibitor results in increased levels of kallikrein and subsequent proteolysis of kininogen. The proteolysis of the kininogen forces an upscaled production of bradykinin and kininogen within the patient. Increased bradykinin levels cause vasodilation, increased vascular permeability, and the succeeding angioedema and pain associated with hereditary angioedema attacks.

History

In phase I clinical trials Lanadelumab was well tolerated and was reported to reduce cleavage of kininogen in the plasma of participants with hereditary angioedema and decrease the number of participants experiencing attacks of angioedema.[18] Lanadelumab's approval in the United States was spearheaded by the data presented in the phase 1b, multicenter, double blind, placebo controlled, multi-ascending-dose trial. Through this trial, lanadelumab was given priority review, breakthrough therapy, and orphan drug designations by the Food and Drug Administration.[19] The phase 3 HELP study evaluated efficacy and safety of lanadelumab. This drug was produced by Dyax Corp and currently under development by Shire.[20]

There were 125 participants studied over a 26-week period in the randomized, double-blind, parallel-group, placebo-controlled trial. Participants were randomized to receive either lanadelumab treatment or placebo in a 1:2 ratio. Subjects randomized to receive lanadelumab were further randomized 1:1:1 ratio to receive doses of either 150 mg every 4 weeks, 300 mg every 4 weeks, or 300 mg every 2 weeks. Participants on the medication had a statistically significant reduction in hereditary angioedema attack rates per month. Participants that took lanadelumab every 2 weeks had 83% less moderate to severe attacks. The study results proved that all three dosing regimens for lanadelumab were more effective than placebo.

Notes and References

  1. Web site: Lanadelumab (Takhzyro) Use During Pregnancy . Drugs.com . 19 September 2018 . 4 September 2020 . 20 October 2020 . https://web.archive.org/web/20201020215529/https://www.drugs.com/pregnancy/lanadelumab.html . live .
  2. Web site: Takhzyro Product information . Health Canada . 25 April 2012 . 29 May 2022 . 30 May 2022 . https://web.archive.org/web/20220530062338/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=97159 . live .
  3. Web site: Takhzyro 300 mg solution for injection in pre-filled syringe - Patient Information Leaflet (PIL) . (emc) . 1 July 2022 . 1 July 2022 . 19 April 2021 . https://web.archive.org/web/20210419164046/https://www.medicines.org.uk/emc/product/12051/pil . live .
  4. Web site: Takhzyro EPAR . European Medicines Agency . 17 October 2018 . 30 May 2022 . 19 October 2021 . https://web.archive.org/web/20211019225258/https://www.ema.europa.eu/en/medicines/human/EPAR/takhzyro . live .
  5. Kenniston JA, Faucette RR, Martik D, Comeau SR, Lindberg AP, Kopacz KJ, Conley GP, Chen J, Viswanathan M, Kastrapeli N, Cosic J, Mason S, DiLeo M, Abendroth J, Kuzmic P, Ladner RC, Edwards TE, TenHoor C, Adelman BA, Nixon AE, Sexton DJ . 6 . Inhibition of plasma kallikrein by a highly specific active site blocking antibody . The Journal of Biological Chemistry . 289 . 34 . 23596–23608 . August 2014 . 24970892 . 4156074 . 10.1074/jbc.M114.569061 . free .
  6. Banerji A, Busse P, Shennak M, Lumry W, Davis-Lorton M, Wedner HJ, Jacobs J, Baker J, Bernstein JA, Lockey R, Li HH, Craig T, Cicardi M, Riedl M, Al-Ghazawi A, Soo C, Iarrobino R, Sexton DJ, TenHoor C, Kenniston JA, Faucette R, Still JG, Kushner H, Mensah R, Stevens C, Biedenkapp JC, Chyung Y, Adelman B . 6 . Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis . The New England Journal of Medicine . 376 . 8 . 717–728 . February 2017 . 28225674 . 10.1056/NEJMoa1605767 . 2 September 2019 . live . free . 54486011 . 31 October 2021 . https://web.archive.org/web/20211031094205/https://air.unimi.it/retrieve/handle/2434/550555/962524/2017%20Lana%20in%20HAE.pdf . 2434/550555 .
  7. http://www.ama-assn.org/resources/doc/usan/x-pub/lanadelumab.pdf Statement On A Nonproprietary Name Adopted By The USAN Council - Lanadelumab
  8. ((World Health Organization)) . International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 114 . WHO Drug Information . 29 . 4 . 2015 . World Health Organization . 5 October 2020 . 7 August 2020 . https://web.archive.org/web/20200807134332/https://www.who.int/medicines/publications/druginformation/innlists/PL114.pdf . live .
  9. Web site: Takhzyro- lanadelumab-flyo solution Takhzyro- lanadelumab-flyo injection, solution . DailyMed . 17 February 2022 . 30 May 2022 . 20 January 2022 . https://web.archive.org/web/20220120101824/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=15f99d8c-efe7-4f7d-aa20-0d0f1e30c6e8 . live .
  10. Web site: FDA approves new treatment for rare hereditary disease. . 30 September 2021. live. 15 March 2021. 19 January 2021. https://web.archive.org/web/20210119192609/https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-new-treatment-rare-hereditary-disease.
  11. Web site: www.takhzyro.com. live. 1 July 2022. 3 August 2021. https://web.archive.org/web/20210803024224/https://www.takhzyro.com/.
  12. FDA approves new treatment for rare hereditary disease . . 30 September 2021 . 10 February 2023 . 7 February 2023 . https://web.archive.org/web/20230207213133/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-rare-hereditary-disease . live .
  13. Web site: Drug Trials Snapshots: Takhzyro . U.S. Food and Drug Administration (FDA) . 9 February 2019 . 10 February 2023 . 30 September 2022 . https://web.archive.org/web/20220930041220/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-takhzyro . live .
  14. U.S. FDA Approves Takeda's Takhzyro (lanadelumab-flyo) to Prevent Hereditary Angioedema (HAE) Attacks in Children 2 Years of Age and Older . Takeda . 4 February 2023 . 10 February 2023 . 6 February 2023 . https://web.archive.org/web/20230206131343/https://www.takeda.com/newsroom/newsreleases/2023/us-fda-approves-takedas-takhzyro-lanadelumab-flyo-to-prevent-hereditary-angioedema-hae-attacks-in-children-2-years-of-age-and-older/ . live .
  15. Web site: Efficacy and Safety Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE. 13 May 2021. live. 24 March 2017. 19 April 2021. https://web.archive.org/web/20210419150425/https://clinicaltrials.gov/ct2/show/NCT02586805.
  16. Banerji A, Riedl MA, Bernstein JA, Cicardi M, Longhurst HJ, Zuraw BL, Busse PJ, Anderson J, Magerl M, Martinez-Saguer I, Davis-Lorton M, Zanichelli A, Li HH, Craig T, Jacobs J, Johnston DT, Shapiro R, Yang WH, Lumry WR, Manning ME, Schwartz LB, Shennak M, Soteres D, Zaragoza-Urdaz RH, Gierer S, Smith AM, Tachdjian R, Wedner HJ, Hebert J, Rehman SM, Staubach P, Schranz J, Baptista J, Nothaft W, Maurer M . 6 . Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial . JAMA . 320 . 20 . 2108–2121 . November 2018 . 30480729 . 6583584 . 10.1001/jama.2018.16773 . 15 March 2021 . live . 53757796 . https://web.archive.org/web/20200807014319/https://jamanetwork.com/journals/jama/fullarticle/2716564 . 7 August 2020 .
  17. Web site: Clinical Pharmacology Database. live. 1 July 2022. 31 October 2021. https://web.archive.org/web/20211031094206/https://www.clinicalkey.com/pharmacology/login.
  18. Chyung Y, Vince B, Iarrobino R, Sexton D, Kenniston J, Faucette R, TenHoor C, Stolz LE, Stevens C, Biedenkapp J, Adelman B . 6 . A phase 1 study investigating DX-2930 in healthy subjects . Annals of Allergy, Asthma & Immunology . 113 . 4 . 460–6.e2 . October 2014 . 24980392 . 10.1016/j.anai.2014.05.028 . free .
  19. News: Dyax Corp. Receives FDA Breakthrough Therapy Designation for DX-2930 for Prevention of Attacks of Hereditary Angioedema. 24 March 2017. www.businesswire.com. 7 July 2015. en. 25 March 2017. https://web.archive.org/web/20170325112936/http://www.businesswire.com/news/home/20150707005320/en/Dyax-Corp.-Receives-FDA-Breakthrough-Therapy-Designation. live.
  20. Web site: Lanadelumab - Takeda. 24 March 2017. Adis Insight. Springer Nature Switzerland AG. 25 March 2017. https://web.archive.org/web/20170325024313/http://adisinsight.springer.com/drugs/800038587. live.

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