Monoclonal antibody | |
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Type | Whole antibody |
Source | Human |
Target | Kallikrein |
Clinical data | |
Trade names | Takhzyro |
Other names | lanadelumab-flyo |
AHFS/Drugs.com | Monograph |
License data |
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Pregnancy category |
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Routes of administration | Subcutaneous |
ATC code | |
Legal status | |
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Identifiers | |
CAS Number | |
DrugBank | |
ChemSpider |
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Chemical and physical data | |
Formula | C6468H10016N1728O2012S47 |
Molar mass | 145684.18 g·mol−1 |
Lanadelumab, sold under the brand name Takhzyro, is a human monoclonal antibody (class IgG1 kappa) [6] that targets plasma kallikrein (pKal) [7] in order to promote prevention of angioedema in people with hereditary angioedema. [8] [9] Lanadelumab, was approved in the United States as the first monoclonal antibody indicated for prophylactic treatment to prevent hereditary angioedema attacks. [4] [10] Lanadelumab is the first treatment for hereditary angioedema prevention made by using cells within a lab, not human plasma. [11]
Common side effects include pain associated with injection site reactions, injection site bruising, upper respiratory infection, headache, rash, myalgia, dizziness, and diarrhea. [11]
The US Food and Drug Administration approved the use of lanadelumab in August 2018, for people that are 12 years and older and have either type I or type II hereditary angioedema. [12] [10] [13]
In the United States, lanadelumab is indicated for the prophylaxis of hereditary angioedema attacks. [4] [12] [14]
In a phase III randomized controlled trial, which examined the efficacy and safety of lanadelumab in preventing hereditary angioedema attacks, the most common adverse events noted in patients being treated were: [15] [16]
Lanadelumab works by binding to an enzyme within the plasma, kallikrein, to inhibit its activity. [17] Kallikrein is a protease that functions to cleave kininogen, subsequently creating kininogen and bradykinin, a potent vasodilator. [17]
People have hereditary angioedema because of a deficiency or dysfunctional C1 inhibitor, which is an enzyme that regulates the activity of the kallikrein-kinin cascade. [7] [17] Poor regulation of the C1 inhibitor results in increased levels of kallikrein and subsequent proteolysis of kininogen. [7] [17] The proteolysis of the kininogen forces an upscaled production of bradykinin and kininogen within the patient. [7] Increased bradykinin levels cause vasodilation, increased vascular permeability, and the succeeding angioedema and pain associated with hereditary angioedema attacks. [7] [17]
In phase I clinical trials Lanadelumab was well tolerated and was reported to reduce cleavage of kininogen in the plasma of participants with hereditary angioedema and decrease the number of participants experiencing attacks of angioedema. [7] [18] [19] [20] Lanadelumab's approval in the United States was spearheaded by the data presented in the phase 1b, multicenter, double blind, placebo controlled, multi-ascending-dose trial. [7] [10] Through this trial, lanadelumab was given priority review, breakthrough therapy, and orphan drug designations by the Food and Drug Administration. [12] [10] [21] The phase 3 HELP study evaluated efficacy and safety of lanadelumab. This drug was produced by Dyax Corp and currently under development by Shire. [22]
There were 125 participants studied over a 26-week period in the randomized, double-blind, parallel-group, placebo-controlled trial. [22] [15] Participants were randomized to receive either lanadelumab treatment or placebo in a 1:2 ratio. [22] [15] Subjects randomized to receive lanadelumab were further randomized 1:1:1 ratio to receive doses of either 150 mg every 4 weeks, 300 mg every 4 weeks, or 300 mg every 2 weeks. [22] [15] Participants on the medication had a statistically significant reduction in hereditary angioedema attack rates per month. [22] [15] Participants that took lanadelumab every 2 weeks had 83% less moderate to severe attacks. [11] The study results proved that all three dosing regimens for lanadelumab were more effective than placebo. [22] [15]
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins.
Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction and trouble breathing. Without preventive treatment, attacks typically occur every two weeks and last for a few days.
Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.
The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.
Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.
Mepolizumab, sold under the brand name Nucala by GlaxoSmithKline, is a humanized monoclonal antibody used for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis, and hypereosinophilic syndrome (HES). It recognizes and blocks interleukin-5 (IL-5), a signalling protein of the immune system.
Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication from the ACE inhibitor class.
Ecallantide is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which was developed from a Kunitz domain through phage display to mimic antibodies inhibiting kallikrein.
BioCryst Pharmaceuticals, Inc. is an American pharmaceutical company headquartered in Durham, North Carolina. The company is a late stage biotech company that focuses on oral drugs for rare and serious diseases. BioCryst's antiviral drug peramivir (Rapivab) was approved by FDA in December 2014. It has also been approved in Japan, Korea, and China.
Ixekizumab, sold under the brand name Taltz, is an injectable medication for the treatment of autoimmune diseases. Chemically, it is a form of a humanized monoclonal antibody. The substance acts by binding interleukin 17A and neutralizing it, reducing inflammation.
Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2.
Risankizumab, sold under the brand name Skyrizi, is a humanized monoclonal antibody used for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. It is designed to target interleukin 23A (IL-23A). It is given by subcutaneous injection.
Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.
Lecanemab, sold under the brand name Leqembi, is a monoclonal antibody medication used for the treatment of Alzheimer's disease. Lecanemab is an amyloid beta-directed antibody. It is given via intravenous infusion. The most common side effects of lecanemab include headache, infusion-related reactions and amyloid-related imaging abnormalities, a side effect known to occur with the class of antibodies targeting amyloid.
Lumasiran, sold under the brand name Oxlumo, is a medication for the treatment of primary hyperoxaluria type 1 (PH1).
Berotralstat, sold under the brand name Orladeyo, is a medication used to prevent attacks of hereditary angioedema (HAE) in people aged twelve years and older.
Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.
Tirzepatide, sold under the brand name Mounjaro among others, is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered through subcutaneous injection.
Vutrisiran, previously known as (ALN-TTRSC02), sold under the brand name Amvuttra, is a medication used for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double stranded small interfering RNA (siRNA) that interferes with the expression of the transthyretin (TTR) gene. Transthyretin is a serum protein made in the liver whose major function is transport of vitamin A and thyroxine. Rare mutations in the transthyretin gene result in accumulation of large amyloid deposits of misfolded transthyretin molecules most prominently in peripheral nerves and the heart. Patients with hATTR typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy which, if untreated, is fatal within 5 to 10 years.