Lanadelumab

Lanadelumab (INN; trade name Takhzyro) is a human monoclonal antibody (class IgG1 kappa)[6] that targets plasma kallikrein (pKal)[7] in order to promote prevention of angioedema in patients with hereditary angioedema.[8][9] Lanadelumab, was approved in the United States as the first monoclonal antibody indicated for prophylactic treatment to prevent hereditary angioedema (HAE) attacks.[4][10] Takhzyro is the first treatment for hereditary angioedema (HEA) prevention made by using cells within a lab, not human plasma.[11] The US Food and Drug Administration approved the use of lanadelumab on 23 August 2018 for patients that are 12 years and older and have either type I or type II hereditary angioedema (HEA).[10] Administration of the medication is done through 1 subcutaneous injection at a dose of 300 milligrams every 2 weeks (every 4-week dosing can be considered in specific patients).[4]

Lanadelumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetKallikrein
Clinical data
Trade namesTakhzyro
Other nameslanadelumab-flyo
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6468H10016N1728O2012S47
Molar mass145684.18 g·mol−1

In phase 1 clinical trials Lanadelumab was well tolerated and was reported to reduce cleavage of kininogen in the plasma of patients with hereditary angioedema and decrease the number of patients experiencing attacks of angioedema.[7][12][13][14] 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.[7][10] Through this trial, Lanadelumab was given Priority Review, Breakthrough Therapy, Orphan Drug designation by the FDA.[10][15] The phase 3 HELP study evaluated efficacy and safety of lanadelumab. This drug was produced by Dyax Corp and currently under development by Shire.[16]

Common side effects include pain associated with injection site reactions, injection site bruising, upper respiratory infection, headache, rash, myalgia, dizziness, and diarrhea.[11]

Medical use

In the United States, lanadelumab is indicated for patients 12 years and older for the prophylaxis of hereditary angioedema (HAE) attacks.[4] There is no data on the efficacy or safety of lanadelumab in patients under the age of 12 years old.[11] Lanadelumab was not studied in pregnant or breastfeeding women.[11]

Adverse events

In a phase 3 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:[17][18]

Mechanism of action

Lanadelumab works by binding to an enzyme within the plasma, kallikrein, to inhibit its activity.[19] Kallikrein is a protease that functions to cleave kininogen, subsequently creating kininogen and bradykinin, a potent vasodilator.[19]

Patients have hereditary angioedema (HAE) because of a deficiency or dysfunctional C1 inhibitor, which is an enzyme that regulates the activity of the kallikrein-kinin cascade.[7][19] Poor regulation of the C1 inhibitor results in increased levels of kallikrein and subsequent proteolysis of kininogen.[7][19] The proteolysis of the kininogen forces an upscaled production of bradykinin and kininogen within the patient.[7] Increased bradykinin levels cause vasodilation, increased vascular permeability, and the succeeding angioedema and pain associated with hereditary angioedema attacks.[7][19]

Efficacy trial

The phase 3 trial that analyzed the efficacy of lanadelumab is called Effect of Lanadelumab compared with Placebo on Prevention of Hereditary Angioedema Attacks, also known as the HELP study. The objective of the randomized controlled trial was to examine the effectiveness of lanadelumab in preventing hereditary angioedema attacks.

There were 125 patients studied over a 26-week period in the randomized, double-blind, parallel-group, placebo-controlled trial.[16][17] Patients were randomized to receive either lanadelumab treatment or placebo in a 1:2 ratio.[16][17] 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.[16][17] Patients on the medication had a statistically significant reduction in hereditary angioedema attack rates per month.[16][17] Patients that took lanadelumab every 2 weeks had 83% less moderate to severe attacks.[11] The study results proved that all three dosing regimens for lanadelumab were more effective than placebo.[16][17]

References
  1. "Lanadelumab (Takhzyro) Use During Pregnancy". Drugs.com. 19 September 2018. Archived from the original on 20 October 2020. Retrieved 4 September 2020.
  2. "Takhzyro Product information". Health Canada. 25 April 2012. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
  3. "Takhzyro 300 mg solution for injection in pre-filled syringe - Patient Information Leaflet (PIL)". (emc). 1 July 2022. Archived from the original on 19 April 2021. Retrieved 1 July 2022.
  4. "Takhzyro- lanadelumab-flyo solution Takhzyro- lanadelumab-flyo injection, solution". DailyMed. 17 February 2022. Archived from the original on 20 January 2022. Retrieved 30 May 2022.
  5. "Takhzyro EPAR". European Medicines Agency. Archived from the original on 19 October 2021. Retrieved 30 May 2022.
  6. Kenniston JA, Faucette RR, Martik D, Comeau SR, Lindberg AP, Kopacz KJ, et al. (August 2014). "Inhibition of plasma kallikrein by a highly specific active site blocking antibody". The Journal of Biological Chemistry. 289 (34): 23596–608. doi:10.1074/jbc.M114.569061. PMC 4156074. PMID 24970892.
  7. Banerji A, Busse P, Shennak M, Lumry W, Davis-Lorton M, Wedner HJ, et al. (February 2017). "Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis" (PDF). The New England Journal of Medicine. 376 (8): 717–728. doi:10.1056/NEJMoa1605767. hdl:2434/550555. PMID 28225674. S2CID 54486011. Archived (PDF) from the original on 2021-10-31. Retrieved 2019-09-02.
  8. Statement On A Nonproprietary Name Adopted By The USAN Council - Lanadelumab Archived 2016-04-02 at the Wayback Machine, American Medical Association.
  9. World Health Organization (2015). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 114" (PDF). WHO Drug Information. 29 (4). Archived (PDF) from the original on 2020-08-07. Retrieved 2020-10-05.
  10. "FDA approves new treatment for rare hereditary disease". FDA. 30 September 2021. Archived from the original on 19 January 2021. Retrieved 15 March 2021.
  11. "www.takhzyro.com". Archived from the original on 2021-08-03. Retrieved 2022-07-01.
  12. Chyung Y, Vince B, Iarrobino R, Sexton D, Kenniston J, Faucette R, et al. (October 2014). "A phase 1 study investigating DX-2930 in healthy subjects". Annals of Allergy, Asthma & Immunology. 113 (4): 460–6.e2. doi:10.1016/j.anai.2014.05.028. PMID 24980392.
  13. Clinical trial number NCT01923207 for "A Single Increasing Dose Study to Assess Safety and Tolerability of DX-2930 in Healthy Subjects" at ClinicalTrials.gov
  14. Clinical trial number NCT02093923 for "Double-Blind, Multiple Ascending Dose Study to Assess Safety, Tolerability and Pharmacokinetics of DX-2930 in Hereditary Angioedema (HAE) Subjects" at ClinicalTrials.gov
  15. "Dyax Corp. Receives FDA Breakthrough Therapy Designation for DX-2930 for Prevention of Attacks of Hereditary Angioedema". www.businesswire.com. 7 July 2015. Archived from the original on 2017-03-25. Retrieved 2017-03-24.
  16. "Lanadelumab - Takeda". Adis Insight. Springer Nature Switzerland AG. Archived from the original on 2017-03-25. Retrieved 2017-03-24.
  17. "Efficacy and Safety Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE". 13 May 2021. Archived from the original on 19 April 2021. Retrieved 24 March 2017. {{cite journal}}: Cite journal requires |journal= (help)
  18. Banerji, Aleena; et al. (27 November 2018). "Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks A Randomized Clinical Trial". JAMA Network. 320 (20): 2108–2121. doi:10.1001/jama.2018.16773. PMC 6583584. PMID 30480729. S2CID 53757796. Archived from the original on 7 August 2020. Retrieved 15 March 2021.
  19. "Clinical Pharmacology Database". Archived from the original on 2021-10-31. Retrieved 2022-07-01.
  • "Lanadelumab". Drug Information Portal. U.S. National Library of Medicine.
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