Lanadelumab

Identification

Name

Lanadelumab

Accession Number

DB14597

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

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

Download FASTA Format

Synonyms

lanadelumab-flyo

External IDs

DX-2930

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

Acute attack of hereditary angioedema

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 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.

Target	Actions	Organism
APlasma kallikrein	inhibitor	Humans

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

Adverse Effects

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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.

Drug	Interaction
Unlock Additional Data
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Lanadelumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Lanadelumab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Lanadelumab.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Lanadelumab.
Anthrax immune globulin human	The risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Lanadelumab.
Antilymphocyte immunoglobulin (horse)	The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Lanadelumab.
Antithymocyte immunoglobulin (rabbit)	The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Lanadelumab.
Asfotase alfa	The risk or severity of adverse effects can be increased when Asfotase alfa is combined with Lanadelumab.
Atezolizumab	The risk or severity of adverse effects can be increased when Atezolizumab is combined with Lanadelumab.
Atoltivimab	The risk or severity of adverse effects can be increased when Lanadelumab is combined with Atoltivimab.

Additional Data Available

Extended Description

Available for Purchase

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

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A severity rating for each drug interaction, from minor to major.

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Evidence Level

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A rating for the strength of the evidence supporting each drug interaction.

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Action

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An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

Not Available

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Unlock Additional Data
Takhzyro	Solution	300 mg	Subcutaneous	Shire Pharma Canada Ulc	Not applicable	Not applicable
Takhzyro	Solution	300 mg	Subcutaneous	Shire Pharma Canada Ulc	2018-10-31	Not applicable
Takhzyro	Injection, solution	300 mg/2mL	Subcutaneous	Dyax Corp.	2018-08-24	Not applicable

Additional Data Available

Application Number

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

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Product Code

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

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Chemical Identifiers

UNII: 2372V1TKXK
CAS number: 1426055-14-2

References

General References

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]
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]
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]
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]
FDA news [Link]
Globalnews [Link]
NIH [Link]
WHO sequence of lanadelumab [File]

External Links

RxNav: 2055640
Wikipedia: Lanadelumab

AHFS Codes

92:32.00 — Complement Inhibitors

FDA label

Download (73.1 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Prevention	Hereditary Angioedema (HAE) / Novel Coronavirus Infectious Disease (COVID-19)	1
3	Completed	Prevention	Hereditary Angioedema (HAE)	2
3	Not Yet Recruiting	Treatment	Angioedema	1
3	Recruiting	Treatment	Angioedema / Novel Coronavirus Infectious Disease (COVID-19)	1
3	Recruiting	Treatment	Hereditary Angioedema (HAE)	1
2	Recruiting	Treatment	Hereditary Autoinflammatory Disease	1
1	Active Not Recruiting	Treatment	Healthy Volunteers	1
1	Completed	Treatment	Healthy Volunteers	2
1	Completed	Treatment	Hereditary Angioedema	1
1	Completed	Treatment	Hereditary Angioedema (HAE)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Cutaneous	300 MG
Injection, solution	Subcutaneous	300 mg/2mL
Solution	Subcutaneous	300 mg

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
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 respectively	Arnoldus W. et al. (2000). Biophysical Journal. Vol 78. 394-404
water solubility	50 mg/ml	Human IgG purified. Product Information
isoelectric point	6.1-8.5	Agrisera Information about IgG antibodies.

Targets

Details1. Plasma kallikrein

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

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]
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]
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]