Lanadelumab

Identification

Summary

Lanadelumab is a plasma kallikrein inhibitor 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 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
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

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Drug Discovery

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Associated Conditions

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

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
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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.
Aducanumab	The risk or severity of adverse effects can be increased when Aducanumab 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.
Amivantamab	The risk or severity of adverse effects can be increased when Lanadelumab is combined with Amivantamab.
Ansuvimab	The risk or severity of adverse effects can be increased when Lanadelumab is combined with Ansuvimab.
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.

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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
Takhzyro	Solution	300 mg / 2 mL	Subcutaneous	Takeda	2018-10-31	Not applicable
Takhzyro	Injection, solution	300 mg	Subcutaneous	Shire	2021-01-28	Not applicable
Takhzyro	Injection, solution	300 mg	Subcutaneous	Shire	2021-01-28	Not applicable
Takhzyro	Injection, solution	300 mg	Subcutaneous	Shire	2021-01-28	Not applicable
Takhzyro	Injection, solution	300 mg	Subcutaneous	Shire	2021-01-28	Not applicable
Takhzyro	Injection, solution	300 mg/2mL	Subcutaneous	Dyax Corp.	2018-08-24	Not applicable
Takhzyro	Injection, solution	300 mg	Subcutaneous	Shire	2021-01-28	Not applicable
Takhzyro	Solution	300 mg / 2 mL	Subcutaneous	Takeda	2021-01-18	Not applicable
Takhzyro	Injection, solution	300 mg	Subcutaneous	Shire	2021-01-28	Not applicable

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

External Links

RxNav: 2055640
Wikipedia: Lanadelumab

FDA label

Download (73.1 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Prevention	Coronavirus Disease 2019 (COVID‑19) / Hereditary Angioedema (HAE)	1
3	Active Not Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
3	Completed	Prevention	Hereditary Angioedema (HAE)	2
3	Recruiting	Treatment	Angioedema	1
3	Recruiting	Treatment	Angioedema / Coronavirus Disease 2019 (COVID‑19)	1
3	Recruiting	Treatment	Hereditary Angioedema	1
3	Recruiting	Treatment	Hereditary Angioedema (HAE)	1
2	Recruiting	Treatment	Hereditary Autoinflammatory Disease	1
1	Completed	Treatment	Healthy Volunteers	3
1	Completed	Treatment	Hereditary Angioedema (HAE)	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Parenteral; Subcutaneous
Injection, solution	Subcutaneous	300 mg/2mL
Injection, solution	Subcutaneous	300 mg
Solution	Subcutaneous	300 mg / 2 mL

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

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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. [Article]
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]
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]

Drug created on August 24, 2018 16:28 / Updated on July 24, 2021 14:58

Lanadelumab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References