Wikipedia

Lanadelumab

Lanadelumab, sold under the brand name Takhzyro, is a human monoclonal antibody (class IgG1 kappa)[7] that targets plasma kallikrein (pKal)[8] in order to promote prevention of angioedema in people with hereditary angioedema.[9][10] Lanadelumab, was approved in the United States as the first monoclonal antibody indicated for prophylactic treatment to prevent hereditary angioedema attacks.[5][11] Lanadelumab is the first treatment for hereditary angioedema prevention made by using cells within a lab, not human plasma.[12]

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

Common side effects include pain associated with injection site reactions, injection site bruising, upper respiratory infection, headache, rash, myalgia, dizziness, and diarrhea.[12]

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.[13][11][14]

Medical uses

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In the United States, lanadelumab is indicated for the prophylaxis of hereditary angioedema attacks.[5][13][15]

Adverse events

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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:[16][17]

  • Injection site reactions, such as pain, redness, and bruising in 42.9% of patients
  • Viral upper respiratory tract infection in 23.8% of patients
  • Headache in 20.2% of patients
  • Injection site erythema in 95% of patients
  • Injection site bruising in 7.1% of patients
  • Dizziness in 6.0% of patients

Mechanism of action

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Lanadelumab works by binding to an enzyme within the plasma, kallikrein, to inhibit its activity.[18] Kallikrein is a protease that functions to cleave kininogen, subsequently creating kininogen and bradykinin, a potent vasodilator.[18]

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.[8][18] Poor regulation of the C1 inhibitor results in increased levels of kallikrein and subsequent proteolysis of kininogen.[8][18] The proteolysis of the kininogen forces an upscaled production of bradykinin and kininogen within the patient.[8] Increased bradykinin levels cause vasodilation, increased vascular permeability, and the succeeding angioedema and pain associated with hereditary angioedema attacks.[8][18]

History

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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.[8][19][20][21] 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.[8][11] Through this trial, lanadelumab was given priority review, breakthrough therapy, and orphan drug designations by the Food and Drug Administration.[13][11][22] The phase 3 HELP study evaluated efficacy and safety of lanadelumab. This drug was produced by Dyax Corp and currently under development by Shire.[23]

There were 125 participants studied over a 26-week period in the randomized, double-blind, parallel-group, placebo-controlled trial.[23][16] Participants were randomized to receive either lanadelumab treatment or placebo in a 1:2 ratio.[23][16] 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.[23][16] Participants on the medication had a statistically significant reduction in hereditary angioedema attack rates per month.[23][16] Participants that took lanadelumab every 2 weeks had 83% less moderate to severe attacks.[12] The study results proved that all three dosing regimens for lanadelumab were more effective than placebo.[23][16]

References

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  1. ^ "Lanadelumab (Takhzyro) Use During Pregnancy". Drugs.com. 19 September 2018. Archived from the original on 20 October 2020. Retrieved 4 September 2020.
  2. ^ https://www.tga.gov.au/resources/prescription-medicines-registrations/takhzyro-takeda-pharmaceuticals-australia-pty-ltd
  3. ^ "Takhzyro Product information". Health Canada. 25 April 2012. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
  4. ^ "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.
  5. ^ a b c "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.
  6. ^ "Takhzyro EPAR". European Medicines Agency. 17 October 2018. Archived from the original on 19 October 2021. Retrieved 30 May 2022.
  7. ^ 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): 23596–23608. doi:10.1074/jbc.M114.569061. PMC 4156074. PMID 24970892.{{cite journal}}: CS1 maint: overridden setting (link)
  8. ^ a b c d e f g 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 31 October 2021. Retrieved 2 September 2019.{{cite journal}}: CS1 maint: overridden setting (link)
  9. ^ Statement On A Nonproprietary Name Adopted By The USAN Council - Lanadelumab Archived 2 April 2016 at the Wayback Machine, American Medical Association.
  10. ^ 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 7 August 2020. Retrieved 5 October 2020.
  11. ^ a b c d "FDA approves new treatment for rare hereditary disease". U.S. Food and Drug Administration. 30 September 2021. Archived from the original on 19 January 2021. Retrieved 15 March 2021.   This article incorporates text from this source, which is in the public domain.
  12. ^ a b c "www.takhzyro.com". Archived from the original on 3 August 2021. Retrieved 1 July 2022.
  13. ^ a b c "FDA approves new treatment for rare hereditary disease". U.S. Food and Drug Administration (Press release). 30 September 2021. Archived from the original on 7 February 2023. Retrieved 10 February 2023.   This article incorporates text from this source, which is in the public domain.
  14. ^ "Drug Trials Snapshots: Takhzyro". U.S. Food and Drug Administration (FDA). 9 February 2019. Archived from the original on 30 September 2022. Retrieved 10 February 2023.
  15. ^ "U.S. FDA Approves Takeda's Takhzyro (lanadelumab-flyo) to Prevent Hereditary Angioedema (HAE) Attacks in Children 2 Years of Age and Older" (Press release). Takeda. 4 February 2023. Archived from the original on 6 February 2023. Retrieved 10 February 2023.
  16. ^ a b c d e f "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.
  17. ^ Banerji A, Riedl MA, Bernstein JA, Cicardi M, Longhurst HJ, Zuraw BL, et al. (November 2018). "Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial". JAMA. 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.{{cite journal}}: CS1 maint: overridden setting (link)
  18. ^ a b c d e "Clinical Pharmacology Database". Archived from the original on 31 October 2021. Retrieved 1 July 2022.
  19. ^ 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.{{cite journal}}: CS1 maint: overridden setting (link)
  20. ^ Clinical trial number NCT01923207 for "A Single Increasing Dose Study to Assess Safety and Tolerability of DX-2930 in Healthy Subjects" at ClinicalTrials.gov
  21. ^ 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
  22. ^ "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 25 March 2017. Retrieved 24 March 2017.
  23. ^ a b c d e f "Lanadelumab - Takeda". Adis Insight. Springer Nature Switzerland AG. Archived from the original on 25 March 2017. Retrieved 24 March 2017.
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