Lanadelumab

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Lanadelumab
Monoclonal antibody
Type Whole antibody
Source Human
Target Kallikrein
Clinical data
Trade names Takhzyro
Other nameslanadelumab-flyo
AHFS/Drugs.com Monograph
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
Formula C6468H10016N1728O2012S47
Molar mass 145684.18 g·mol−1

Lanadelumab, sold under the brand 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 people 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 attacks. [4] [10] Lanadelumab is the first treatment for hereditary angioedema prevention made by using cells within a lab, not human plasma. [11]

Contents

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

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] [10] [13]

Medical uses

In the United States, lanadelumab is indicated for the prophylaxis of hereditary angioedema attacks. [4] [12] [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. [17]

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. [7] [17] Poor regulation of the C1 inhibitor results in increased levels of kallikrein and subsequent proteolysis of kininogen. [7] [17] 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] [17]

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. [7] [18] [19] [20] 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, and orphan drug designations by the Food and Drug Administration. [12] [10] [21] The phase 3 HELP study evaluated efficacy and safety of lanadelumab. This drug was produced by Dyax Corp and currently under development by Shire. [22]

There were 125 participants studied over a 26-week period in the randomized, double-blind, parallel-group, placebo-controlled trial. [22] [15] Participants were randomized to receive either lanadelumab treatment or placebo in a 1:2 ratio. [22] [15] 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. [22] [15] Participants on the medication had a statistically significant reduction in hereditary angioedema attack rates per month. [22] [15] Participants 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. [22] [15]

Related Research Articles

<span class="mw-page-title-main">Bradykinin</span> Chemical compound

Bradykinin (BK) (from Greek brady- 'slow' + -kinin, kīn(eîn) 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins.

<span class="mw-page-title-main">Enalapril</span> ACE inhibitor medication

Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure, diabetic kidney disease, and heart failure. For heart failure, it is generally used with a diuretic, such as furosemide. It is given by mouth or by injection into a vein. Onset of effects are typically within an hour when taken by mouth and last for up to a day.

<span class="mw-page-title-main">Hereditary angioedema</span> Disorder resulting in severe swelling

Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction and trouble breathing. Without preventive treatment, attacks typically occur every two weeks and last for a few days.

<span class="mw-page-title-main">Angioedema</span> Disease characterized by rapid swelling

Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.

The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.

<span class="mw-page-title-main">C1-inhibitor</span> Mammalian protein found in humans

C1-inhibitor is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the contact system. C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during inflammation. C1-inhibitor irreversibly binds to and inactivates C1r and C1s proteases in the C1 complex of classical pathway of complement. MASP-1 and MASP-2 proteases in MBL complexes of the lectin pathway are also inactivated. This way, C1-inhibitor prevents the proteolytic cleavage of later complement components C4 and C2 by C1 and MBL. Although named after its complement inhibitory activity, C1-inhibitor also inhibits proteases of the fibrinolytic, clotting, and kinin pathways. Note that C1-inhibitor is the most important physiological inhibitor of plasma kallikrein, FXIa, and FXIIa.

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.

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Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication from the ACE inhibitor class.

Ecallantide is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which was developed from a Kunitz domain through phage display to mimic antibodies inhibiting kallikrein.

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<span class="mw-page-title-main">Berotralstat</span> Medication

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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. 1 2 3 "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. 17 October 2018. 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): 23596–23608. doi: 10.1074/jbc.M114.569061 . PMC   4156074 . PMID   24970892.
  7. 1 2 3 4 5 6 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 31 October 2021. Retrieved 2 September 2019.
  8. ↑ Statement On A Nonproprietary Name Adopted By The USAN Council - Lanadelumab Archived 2 April 2016 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 7 August 2020. Retrieved 5 October 2020.
  10. 1 2 3 4 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  11. 1 2 3 "www.takhzyro.com". Archived from the original on 3 August 2021. Retrieved 1 July 2022.
  12. 1 2 3 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  13. ↑ "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.
  14. ↑ "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.
  15. 1 2 3 4 5 6 "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.
  16. ↑ 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.
  17. 1 2 3 4 5 "Clinical Pharmacology Database". Archived from the original on 31 October 2021. Retrieved 1 July 2022.
  18. ↑ 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.
  19. ↑ Clinical trial number NCT01923207 for "A Single Increasing Dose Study to Assess Safety and Tolerability of DX-2930 in Healthy Subjects" at ClinicalTrials.gov
  20. ↑ 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
  21. ↑ "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.
  22. 1 2 3 4 5 6 "Lanadelumab - Takeda". Adis Insight. Springer Nature Switzerland AG. Archived from the original on 25 March 2017. Retrieved 24 March 2017.
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