Identification

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Name
Lanadelumab
Accession Number
DB14597
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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 The FDA and EU granted the designation of priority review, breakthrough therapy and orphan drug for rare diseases based on the results of the reported clinical trials.1 Lanadelumab was developed by Shire and FDA approved on August 28, 2018.5

Protein structure
Db14597
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
Download FASTA Format
Synonyms
  • lanadelumab-flyo
External IDs
DX-2930
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TakhzyroInjection, solution300 mg/2mLSubcutaneousDyax Corp.2018-08-24Not applicableUs
TakhzyroSolution300 mgSubcutaneousShire Pharma Canada Ulc2018-10-31Not applicableCanada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
2372V1TKXK
CAS number
1426055-14-2

Pharmacology

Indication

Lanadelumab is indicated for the prophylaxis treatment to prevent attacks in patients 12 years and older with hereditary angioedema.5

The hereditary angioedema (HEA) is an autosomal dominant disorder resulted from the presence of C1 deficiency. Some reports have indicated a high prevalence of cases that result from spontaneous mutations which can be inherited. This condition is manifested by attacks of subcutaneous or submucosal edema in the face, larynx, GI tract, limbs or genitalia. From all the types of attacks, the most serious is the laryngeal as it can compromise the airway. The rest of the attacks are accompanied by pain and considerable dysfunction.4

Associated Conditions
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 as well 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 (HELP study, lanadelumab showed an attack rate reduction of over 70% for all three different dose regimes.1

Mechanism of action

Lanadelumab is a plasma kallikrein inhibitor. This enzyme works by cleaving high molecular weight kininogen to generate the pro-inflammatory peptide bradykinin which is a potent vasodilator. The activity of plasma kallikrein is regulated by the activity of C1-inhibitor and thus, the patients that are deficient in C1 are known to be correlated to excessive production of bradykinin which will further lead to fatal angioedema.3 Hence, lanadelumab occludes the proteolytic active site of plasma kallikrein, preventing the cleavage of kininogen to bradykinin. It is a selective inhibitor as it has been reported that lanadelumab does not bind to prekallikrein or to inhibit any other serine proteases.4 The activity of lanadelumab works as an additional checkpoint for the patients suffering from C1 deficiency.

TargetActionsOrganism
APlasma kallikrein
inhibitor
Humans
Additional Data Available
Adverse Effects

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Contraindications

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Blackbox Warnings

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Absorption

The drug levels of lanadelumab are dose-dependent and thus, the maximum plasma concentration increased correspondingly with an increased dosage. The Cmax and AUC ranged from 3800 to 45000 ng/ml and from 64000 to 762000 ng.day/ml respectively for concentrations from 30 to 400 mg. As well, sustained quantifiable drug concentration was observed through day 120.2 The bioavailability of lanadelumab is of approximately 66% with a time to reach peak drug concentration of approximately 7 days.4

Volume of distribution

The reported volume of distribution of lanadelumab is in the range of 12 to 16 L which variates according to the dose administered.4

Protein binding

General information on plasma protein binding is not available but it is considered that, as the site of action is with plasma proteins, the percentage of protein binding should be significant.

Metabolism

Because lanadelumab is a protein, it is expected to be degraded into small peptides and amino acids by proteolytic enzymes.

Route of elimination

The main excretion is thought to be done in the urine but this has not been confirmed and further studies are required.

Half life

Lanadelumab has a prolonged half-life which is typical of a human monoclonal antibody and it ranged from 13.8 to 15 days.2

Clearance

The apparent total plasma clearance after extravascular administration ranges between 18 and 25 ml/h.2

Toxicity

In clinical trials, the apparition of antidrug antibodies was nos significant and from those who expressed it, none were neutralizing.2 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. Fertility studies show no effect on reproductive organs.Label

Affected organisms
  • Humans
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.
AbituzumabThe risk or severity of adverse effects can be increased when Abituzumab is combined with Lanadelumab.
AbrilumabThe risk or severity of adverse effects can be increased when Lanadelumab is combined with Abrilumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Lanadelumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Lanadelumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Lanadelumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab 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.
AmatuximabThe risk or severity of adverse effects can be increased when Amatuximab is combined with Lanadelumab.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
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Food Interactions
Not Available

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. [PubMed:29300693]
  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. [PubMed:28225674]
  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. [PubMed:27960628]
  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. [PubMed:24980392]
  5. FDA news [Link]
  6. Globalnews [Link]
  7. NIH [Link]
  8. WHO sequence of lanadelumab [File]
External Links
Wikipedia
Lanadelumab
ATC Codes
B06AC05 — Lanadelumab
AHFS Codes
  • 92:32.00 — Complement Inhibitors
FDA label
Download (73.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentHereditary Angioedema1
1CompletedTreatmentHereditary Angioedema (HAE)1
1RecruitingTreatmentHealthy Volunteers1
3Active Not RecruitingPreventionHereditary Angioedema / Hereditary Angioedema (HAE)1
3CompletedPreventionHereditary Angioedema / Hereditary Angioedema (HAE)1
3Not Yet RecruitingTreatmentHereditary Angioedema (HAE)1
3RecruitingPreventionHereditary Angioedema (HAE)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous300 mg/2mL
SolutionSubcutaneous300 mg
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.

Taxonomy

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

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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. [PubMed:27960628]
  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. [PubMed:29043014]
  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. [PubMed:28225674]

Drug created on August 24, 2018 10:28 / Updated on December 10, 2019 15:54