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
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 ...
(HAE) attacks.
[ ] Lanadelumab is the first treatment for
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 ...
(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
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 ...
(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
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 ...
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,
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 ...
, 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
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 ...
in the plasma of particpants 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 ...
and decrease the number of particpants experiencing attacks 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 ...
.
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
*
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