Lanadelumab

What is it hereditary angioedema?

Hereditary angioedema is a rare autosomal dominant disease associated with a deficiency or dysfunction of the activity of the C1-esterase inhibitor (C1-INH). Hereditary angioedema causes spontaneous, recurrentand life-threatening inflammation in various regions of the body, including the larynx.

What is lanadelumab?

Lanadelumab (also called lanadelumab-flyo) is a prescription biologic medicine used in patients 12 years of age and older to prevent attacks of severe inflammation due to hereditary angioedema. It is the first one monoclonal antibody available for hereditary angioedema.

Lanadelumab was approved by the United States Food and Drug Administration (FDA) in August 2018, in Canada in September 2018 and by the European Commission in November 2018. Regulatory applications for the marketing of lanadelumab are also being considered in Australia. Lanadelumab is not currently available in New Zealand.

Lanadelumab is marketed under the brand name Takhzyro ™ by Dyax Corp (a subsidiary of Shire) based in Burlington, MA, USA.

How does lanadelumab work?

Lanadelumab is completely human immunoglobulin G1, kappa light chain monoclonal antibody that provides inhibition of plasma kallikrein, a critical regulator of hereditary angioedema attacks.

• The activity of plasma kallikrein is regulated by the activity of C1-INH.
• C1-INH deficiency or dysfunction leads to uncontrolled increases in plasma kallikrein activity.
• Plasma kallikrein is a protease that works by dividing the height molecular kininogen weight (a coagulation protein) to generate theinflammatory peptide bradykinin Bradykinin is a potent vasodilator and increases vascular permeability, which is the cause of the swelling and pain associated with hereditary angioedema.
• Lanadelumab clogs the proteolytic active site of plasma kallikrein, preventing the division of kininogen into bradykinin.
• Lanadelumab therefore decreases plasma kallikrein and bradykinin activity in patients with hereditary angioedema.

What is the indication for lanadelumab?

Lanadelumab is indicated to prevent recurrent attacks of hereditary angioedema in patients 12 years of age and older.

• It is not intended for the treatment of acute attacks of hereditary angioedema.
• Treatment should be started under the supervision of a physician experienced in treating patients with hereditary angioedema.

How is lanadelumab administered?

Lanadelumab can be self-administered by the patient or administered by a caregiver after receiving training on subcutaneous injection technique by a healthcare professional.

• The recommended starting dose is 300 mg lanadelumab by subcutaneous injection every 2 weeks.
• Injection should be restricted to the recommended injection sites: the abdomen, thighs, and upper outer arms, with the injection site rotating as necessary.
• In patients who do not have attacks of swelling during treatment, the dose can be reduced to 300 mg every 4 weeks.
• If a dose of lanadelumab is missed, the missed dose should be administered as soon as possible, ensuring at least 10 days between doses.

Contraindications to lanadelumab

The main contraindication Lanadelumab is hypersensitivity the active substance or any of the excipients.

Warnings and precautions

Traceability

To improve the traceability of biological medicinal products, the name and batch number of the administered lanadelumab should be clearly recorded.

Hypersensitive reactions

Hypersensitivity reactions to lanadelumab have been observed. In the event of a severe hypersensitivity reaction, administration of lanadelumab should be stopped immediately and appropriate treatment initiated.

general

Lanadelumab is not intended for the treatment of acute attacks of hereditary angioedema. In the case of breakthrough angioedema, individualized treatment should begin with approved rescue medication.

There are no clinical data available on the use of lanadelumab in patients with hereditary angioedema with normal C1-INH activity.

Dose modification

Patients with renal disability

There have been no studies in patients taking lanadelumab who have severe kidney failure. Renal impairment is not expected to affect Lanadelumab exposure or its safety profile. No dose adjustment is required in patients with renal impairment.

Patients with hepatic disability

No dosage adjustment is required in patients taking lanadelumab who have hepatic impairment. Hepatic impairment is not expected to affect exposure to lanadelumab. There are no studies in patients with moderate or severe hepatic impairment.

Old people

No dose adjustment is required for patients over 65 years of age because age is not expected to affect exposure to lanadelumab.

Children

Safety and effectiveness Lanadelumab in children under 12 years of age has not been established. No data available.

Use of lanadelumab in specific populations.

Pregnant women

There are no data available on the use of lanadelumab in pregnant women to inform the risks associated with the medications. Monoclonal antibodies like lanadelumab it can cross the placenta during the third trimester of pregnancy with potentially harmful effects on the fetus. Studies of lanadelumab in pregnant women cynomolgus monkeys, treated with 33 times the maximum recommended dose for humans, revealed no evidence of harm to the developing fetus.

Nursing mothers

It is not known whether lanadelumab or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, mothers should stop breastfeeding before using lanadelumab. Available pharmacokinetics Data in cynomolgus monkeys have demonstrated the excretion of lanadelumab in milk at approximately 0.2% of the maternal plasma level.

Children

The safety and efficacy of lanadelumab in children under 12 years of age have not been established.

Old people

In clinical trials, no overall differences in safety or effectiveness have been observed between patients over 65 years of age and younger patients treated with lanadelumab.

Individuals of childbearing age

The effect of lanadelumab on fertility has not been evaluated in humans. Lanadelumab had no effect on male or female fertility in cynomolgus monkeys.

What are the possible drug interactions with lanadelumab?

No dedicated drug-drug interaction studies have been performed with lanadelumab. Based on their characteristics, pharmacokinetic interactions with co-administered drugs are not expected.

Interaction with the aPPT assay

• Lanadelumab may increase activated partial thromboplastin time (aPTT) due to an interaction with the aPTT assay.
• Reagents used in the laboratory test aPTT initiates intrinsic coagulation through the activation of plasma kallikrein in the contact activation system.
• Inhibition of plasma kallikrein by lanadelumab may increase aPTT in this assay.

What are the possible side effects of lanadelumab?

The most common side effects in patients receiving lanadelumab in clinical trials are described below.

Side effects with more than one 10% incidence

At a dose of lanadelumab 300 mg every 2 weeks, the following Adverse reactions where seen:

• Injection site reactions, including pain erythemaand bruising (56%)
• Upper respiratory tract infection (44%)
• Headache (33%)
• Myalgia (11%).

At a dose of lanadelumab 300 mg every 4 weeks, the following adverse reactions were observed:

• Injection site reactions (45%)
• Upper respiratory tract infection (31%)
• Headache (21%).

Side effects from 1 to 10% incidence

Adverse reactions of incidence 1 to 10% observed with lanadelumab include:

• Alanine transferase increased (ALT) and aspartate transferase (AST) liver enzymes (2%)

• Hypersensitivity (1%): symptoms of a serious illness. allergic reaction include urticaria, itching / swelling (especially of the face, tongue and throat), severe dizziness, and trouble breathing.

At a dose of 300 mg lanadelumab every 2 weeks, the following adverse reactions were observed:

• Eruption (4%)
• Dizziness (4%)
• Diarrhea (4%).

At a dose of lanadelumab 300 mg every 4 weeks, the following adverse reactions were observed:

• Rash (10%)
• Dizziness (10%).

Immunogenicity

Lanadelumab treatment has been associated with the development of anti-drug antibodies in 10 of 84 patients (11.9%). All antibody titers were low. The anti-drug antibody response was transient in the 20% of the subjects positive for anti-drug antibodies; two of 84 patients treated with lanadelumab (2.4%) tested positive for neutralizing antibodies.

The development of anti-drug antibodies, including neutralizing antibodies against lanadelumab, did not appear to adversely affect the pharmacokinetics and pharmacodynamics profiles or clinical response.