Lanadelumab, sold under the brand name Takhzyro, is a human

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ...

(class IgG1 kappa) that targets plasma

kallikrein Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by '' KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a ...

(pKal) in order to promote prevention of

angioedema 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 ...

in people with

hereditary angioedema 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 vomitin ...

. Lanadelumab, was approved in the United States as the first monoclonal antibody indicated for prophylactic treatment to prevent

(HAE) attacks. Lanadelumab is the first treatment for

(HEA) prevention made by using cells within a lab, not human plasma. Common side effects include pain associated with

injection site reaction Injection site reactions are allergic reactions that result in cutaneous necrosis that may occur at sites of medication injection, typically presenting in one of two forms, (1) those associated with intravenous infusion or (2) those related to intra ...

s, injection site

bruising A bruise, also known as a contusion, is a type of hematoma of tissue, the most common cause being capillaries damaged by trauma, causing localized bleeding that extravasates into the surrounding interstitial tissues. Most bruises occur clos ...

, upper respiratory infection, headache,

rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

, myalgia,

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

, and

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

. The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) 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 (HEA).

Medical uses

In the United States, lanadelumab is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the prophylaxis of

(HAE) attacks.

Adverse events

In a phase III randomized controlled trial, which examined the efficacy and safety of lanadelumab in preventing hereditary angioedema attacks, the most common

adverse event An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can ther ...

s noted in patients being treated were: * Injection site pain in 42.9% of patients * Viral

upper respiratory tract infection An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore thro ...

in 23.8% of patients * Headache in 20.2% of patients * Injection site

erythema Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not asso ...

in 95% of patients * Injection site

in 7.1% of patients *

Dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

in 6.0% of patients

Mechanism of action

Lanadelumab works by binding to an enzyme within the plasma,

, to inhibit its activity. Kallikrein is a

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

that functions to cleave

kininogen 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. Types o ...

, subsequently creating kininogen and

bradykinin 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 ...

, a potent vasodilator. People have hereditary angioedema (HAE) because of a deficiency or dysfunctional C1 inhibitor, which is an enzyme that regulates the activity of the kallikrein-kinin cascade. Poor regulation of the C1 inhibitor results in increased levels of kallikrein and subsequent proteolysis of kininogen. The proteolysis of the kininogen forces an upscaled production of bradykinin and kininogen within the patient. Increased bradykinin levels cause

vasodilation Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstrictio ...

, increased

vascular permeability Vascular permeability, often in the form of capillary permeability or microvascular permeability, characterizes the capacity of a blood vessel wall to allow for the flow of small molecules (drugs, nutrients, water, ions) or even whole cells (lymph ...

, and the succeeding angioedema and pain associated with hereditary angioedema attacks.

History

In phase I

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s Lanadelumab was well tolerated and was reported to reduce cleavage of

in the plasma of particpants with

and decrease the number of particpants experiencing attacks of

. 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. Through this trial, lanadelumab was given

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...

, and orphan drug designations by the FDA. The phase 3 HELP study evaluated efficacy and safety of lanadelumab. This drug was produced by Dyax Corp and currently under development by Shire. There were 125 participants studied over a 26-week period in the randomized, double-blind, parallel-group, placebo-controlled trial. Particpants were randomized to receive either lanadelumab treatment or placebo in a 1:2 ratio. 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. Particpants on the medication had a statistically significant reduction in hereditary angioedema attack rates per month. Particpants that took lanadelumab every 2 weeks had 83% less moderate to severe attacks. The study results proved that all three dosing regimens for lanadelumab were more effective than placebo.

References

External links

* {{Portal bar , Medicine Breakthrough therapy Monoclonal antibodies Orphan drugs