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
- Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More- 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 inhibitorHumans - 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
Learn about our commercial Adverse Effects data.
Learn More- 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 DataAbciximab 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. 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. 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. Additional Data Available- Extended DescriptionExtended DescriptionAvailable for Purchase
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - SeveritySeverityAvailable for Purchase
A severity rating for each drug interaction, from minor to major.
Learn more - Evidence LevelEvidence LevelAvailable for Purchase
A rating for the strength of the evidence supporting each drug interaction.
Learn more - ActionActionAvailable for Purchase
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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- Food Interactions
- Not Available
Products
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Unlock Additional DataTakhzyro Solution 300 mg Subcutaneous Shire Pharma Canada Ulc 2018-10-31 Not applicable Canada Takhzyro Injection, solution 300 mg/2mL Subcutaneous Dyax Corp. 2018-08-24 Not applicable US Takhzyro Solution 300 mg Subcutaneous Shire Pharma Canada Ulc Not applicable Not applicable Canada Additional Data Available- Application NumberApplication NumberAvailable for Purchase
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
Learn more - Product CodeProduct CodeAvailable for Purchase
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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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
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
- 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 Coronavirus Disease 2019 (COVID‑19) / Hereditary Angioedema (HAE) 1 3 Completed Prevention Hereditary Angioedema (HAE) 2 3 Not Yet Recruiting Treatment Angioedema 1 3 Not Yet Recruiting Treatment Hereditary Angioedema 1 3 Recruiting Treatment Angioedema / Coronavirus Disease 2019 (COVID‑19) 1 3 Recruiting Treatment Coronavirus Disease 2019 (COVID‑19) 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 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Parenteral; Subcutaneous 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
- 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]
Drug created on August 24, 2018 10:28 / Updated on January 26, 2021 22:46