Lanadelumab

Identification

Summary

Lanadelumab is a monoclonal antibody targeted against kallikrein which is used to treat attacks of hereditary angioedema.

Brand Names
Takhzyro
Generic Name
Lanadelumab
DrugBank Accession Number
DB14597
Background

Lanadelumab, also known as DX-2930, is a human IgG1 monoclonal antibody designed for subcutaneous self-injection.6 It is a fully human immunoglobulin, k-light-chain made in recombinant Chinese Hamster Ovary cells.5 It has been granted priority review, breakthrough therapy, and orphan drug designations for rare diseases based on the results of clinical trials.1 Lanadelumab was approved for use in patients with hereditary angioedema by the FDA in August 2018,5 followed by Health Canada in October 201812 and the EMA in November 2018.11

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Protein Chemical Formula
C6468H10016N1728O2012S47
Protein Average Weight
146000.0 Da
Sequences
>Heavy chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYIMMWVRQAPGKGLEWVSGIYSSGGITVY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAYRRIGVPRRDEFDIWGQGTMVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
>Light chain
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASTLESGVPS
RFSGSGSGTEFTLTISSLQPDDFATYYCQQYNTYWTFGQGTKVEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. Health Canada Approved Drug Products: Takhzyro (lanadelumab) solution for subcutaneous injection [Link]
Download FASTA Format
Synonyms
  • Lanadelumab
  • Lanadelumab-flyo
External IDs
  • DX-2930

Pharmacology

Indication

Lanadelumab is indicated for prophylaxis to prevent attacks in adult and pediatric patients aged 2 years and older with hereditary angioedema.9,11 In Canada, it is indicated for use only in adults and adolescents.12

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Prophylaxis ofHereditary angioedema attack•••••••••••••••••••••
Prophylaxis ofHereditary angioedema attack•••••••••••••••••••••
Prophylaxis ofHereditary angioedema attack••••••••••••••••••••••••••••••
Prophylaxis ofHereditary angioedema attack•••••••••••••••••• ••••••••••••••••••
Prevention ofRecurrent angiodema•••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In phase 1 studies, the level of kininogen, the substrate of kallikrein, was studied as a marker of kallikrein activity. In patients with C1 deficiency, the level of cleaved kininogen is 4-fold higher when compared with C1-normal individuals. When lanadelumab was administered, the levels of cleaved kininogen were significantly reduced with a dose of 300 and 400 mg of lanadelumab with a maximum reduction at day 22 corresponding with time for maximum concentration. This maximum reduction corresponded with the normal levels of cleaved kininogen. Similarly, the decreases of cleaved kininogen corresponded with reductions in the levels of the activated factor XII.2

Clinically, the attacks of angioedema completely vanished in the patients receiving a dose of 300 mg of lanadelumab. In other doses such as 400 mg and combo 300/400 mg the attack reduction reached 90%.2 In phase 3 clinical trials, lanadelumab showed an attack rate reduction of over 70% for all studied regimens.1

Mechanism of action

Hereditary angioedema (HEA) is an autosomal dominant disorder resulting from the presence of C1 deficiency. This condition manifests as attacks of subcutaneous or submucosal edema in the face, larynx, GI tract, limbs or genitalia, with laryngeal edema being the most serious due to the potential to compromise the airways. Attacks may be accompanied by pain and considerable dysfunction.4

Lanadelumab is a plasma kallikrein inhibitor. This enzyme works by cleaving high molecular weight kininogen to generate the pro-inflammatory peptide bradykinin, a potent vasodilator. Because the activity of plasma kallikrein is regulated by C1 esterase inhibitor, patients deficient in C1 esterase inhibitor may be at risk of excessive production of bradykinin leading to serious angioedema.3 Lanadelumab occludes the proteolytic active site of plasma kallikrein, preventing the cleavage of kininogen to bradykinin. It is a selective inhibitor and does not bind to prekallikrein or inhibit other serine proteases.4

TargetActionsOrganism
APlasma kallikrein
inhibitor
regulator
Humans
Absorption

Drug levels of lanadelumab are dose-dependent and the maximum plasma concentration increases correspondingly with increasing dosage. The Cmax and AUC ranged from 3800 - 45000 ng/ml and 64000 - 762000 ng.day/ml, respectively, across a dosing range of 30 to 400 mg. A sustained quantifiable drug concentration was observed through day 120.2 The bioavailability of lanadelumab is approximately 66% with a time to reach peak drug concentration of approximately 7 days.9,4

Volume of distribution

The apparent volume of distribution of lanadelumab is approximately 14 - 16 L depending on the dose administered.9

Protein binding

Not Available

Metabolism

As with other therapeutic proteins, the degradation of lanadelumab likely occurs via catabolism to smaller peptides and amino acids.

Route of elimination

Not Available

Half-life

Lanadelumab has a half-life of approximately 2 weeks after subcutaneous administration.9

Clearance

The apparent clearance of lanadelumab ranges from 0.667 to 0.809 L/day depending on the administered dose.9

Adverse Effects
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Toxicity

No significant toxicities related to the administration of lanadelumab have been reported.4

Studies regarding the carcinogenic potential or overdosage effect have not been performed. Published literature supports bradykinin, which is elevated in HAE, as a pro-tumorigenic molecule. However, the malignancy risk in humans from an antibody that inhibits plasma kallikrein activity, such as lanadelumab-flyo, which lowers bradykinin levels, is currently unknown.9 There are no available data on lanadelumab use in pregnant women to inform of any drug-associated risks. Monoclonal antibodies such as lanadelumab-flyo are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. An enhanced pre-and postnatal development (ePPND) study conducted in pregnant monkeys at doses resulting in exposures of up to 33 times the exposure achieved (on an AUC basis) at the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus.9

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Lanadelumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Lanadelumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Lanadelumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Lanadelumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Lanadelumab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TakhzyroInjection, solution300 mgSubcutaneousTakeda Pharmaceuticals International Ag Ireland Branch2021-01-28Not applicableEU flag
TakhzyroSolution150 mg/1mLSubcutaneousTakeda Pharmaceuticals America, Inc.2023-02-03Not applicableUS flag
TakhzyroSolution300 mg / 2 mLSubcutaneousTakeda2018-10-31Not applicableCanada flag
TakhzyroInjection, solution150 mgSubcutaneousTakeda Pharmaceuticals International Ag Ireland Branch2023-11-28Not applicableEU flag
TakhzyroInjection, solution300 mgSubcutaneousTakeda Pharmaceuticals International Ag Ireland Branch2021-01-28Not applicableEU flag

Categories

ATC Codes
B06AC05 — Lanadelumab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans

Chemical Identifiers

UNII
2372V1TKXK
CAS number
1426055-14-2

References

General References
  1. Kaplon H, Reichert JM: Antibodies to watch in 2018. MAbs. 2018 Feb/Mar;10(2):183-203. doi: 10.1080/19420862.2018.1415671. Epub 2018 Jan 16. [Article]
  2. 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: Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med. 2017 Feb 23;376(8):717-728. doi: 10.1056/NEJMoa1605767. [Article]
  3. Reichert JM: Antibodies to watch in 2017. MAbs. 2017 Feb/Mar;9(2):167-181. doi: 10.1080/19420862.2016.1269580. Epub 2016 Dec 14. [Article]
  4. Chyung Y, Vince B, Iarrobino R, Sexton D, Kenniston J, Faucette R, TenHoor C, Stolz LE, Stevens C, Biedenkapp J, Adelman B: A phase 1 study investigating DX-2930 in healthy subjects. Ann Allergy Asthma Immunol. 2014 Oct;113(4):460-6.e2. doi: 10.1016/j.anai.2014.05.028. Epub 2014 Jun 26. [Article]
  5. FDA news [Link]
  6. Globalnews [Link]
  7. NIH [Link]
  8. FDA Approved Drug Products: TAKHZYRO (lanadelumab-flyo) injection [Link]
  9. FDA Approved Drug Products: TAKHZYRO® (lanadelumab-flyo) injection, for subcutaneous use (February 2023) [Link]
  10. EMA Summary of Product Characteristics: Takhzyro (lanadelumab) solution for subcutaneous administration [Link]
  11. EMA EPAR: Takhzyro (lanadelumab) [Link]
  12. Health Canada Approved Drug Products: Takhzyro (lanadelumab) solution for subcutaneous injection [Link]
  13. WHO sequence of lanadelumab [File]
RxNav
2055640
Wikipedia
Lanadelumab
FDA label
Download (73.1 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
3CompletedPreventionCoronavirus Disease 2019 (COVID‑19) / Hereditary Angioedema (HAE)1somestatusstop reasonjust information to hide
3CompletedPreventionHereditary Angioedema (HAE)2somestatusstop reasonjust information to hide
3CompletedTreatmentAngioedema1somestatusstop reasonjust information to hide
3CompletedTreatmentAngioedema / Coronavirus Disease 2019 (COVID‑19)1somestatusstop reasonjust information to hide
3CompletedTreatmentCoronavirus Disease 2019 (COVID‑19)1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionParenteral; Subcutaneous300 MG
Injection, solutionSubcutaneous150 mg
Injection, solutionSubcutaneous300 mg
Injection, solutionSubcutaneous300 mg/2mL
SolutionSubcutaneous150 mg/1mL
SolutionSubcutaneous300 mg/2mL
SolutionSubcutaneous300 mg / 2 mL
Injection, solution300 mg/2ml
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)80-90 ºC (based on IgG properties)McConnell A., et al. (2014). MAbs. Sep-Oct; 6 (5); 1274-1282
boiling point (°C)Fab and Fc domains denaturates at 60 and 70 ºC respectivelyArnoldus W. et al. (2000). Biophysical Journal. Vol 78. 394-404
water solubility50 mg/mlHuman IgG purified. Product Information
isoelectric point6.1-8.5 Agrisera Information about IgG antibodies.

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Regulator
General Function
Serine-type endopeptidase activity
Specific Function
The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen an...
Gene Name
KLKB1
Uniprot ID
P03952
Uniprot Name
Plasma kallikrein
Molecular Weight
71369.205 Da
References
  1. Reichert JM: Antibodies to watch in 2017. MAbs. 2017 Feb/Mar;9(2):167-181. doi: 10.1080/19420862.2016.1269580. Epub 2016 Dec 14. [Article]
  2. Riedl MA, Bernstein JA, Craig T, Banerji A, Magerl M, Cicardi M, Longhurst HJ, Shennak MM, Yang WH, Schranz J, Baptista J, Busse PJ: An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension. Clin Transl Allergy. 2017 Oct 6;7:36. doi: 10.1186/s13601-017-0172-9. eCollection 2017. [Article]
  3. 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: Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med. 2017 Feb 23;376(8):717-728. doi: 10.1056/NEJMoa1605767. [Article]
  4. Wu MA: Lanadelumab for the treatment of hereditary angioedema. Expert Opin Biol Ther. 2019 Dec;19(12):1233-1245. doi: 10.1080/14712598.2019.1685490. Epub 2019 Nov 4. [Article]

Drug created at August 24, 2018 16:28 / Updated at December 13, 2023 13:52