Lanadelumab

Introduction to Lanadelumab

Lanadelumab (brand name: Takhzyro) is a fully human monoclonal antibody (IgG1/κ-light chain) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. It was developed by Dyax Corp. (now part of Takeda Pharmaceutical Company) and received FDA approval in 2018. Lanadelumab is primarily used for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older.

Hereditary angioedema is a rare genetic disorder characterized by recurrent episodes of severe swelling (edema) in various parts of the body, including the limbs, face, intestinal tract, and airway. These attacks can be painful, disabling, and potentially life-threatening if they affect the airway.

Mechanism of Action

Lanadelumab is a highly specific, long-acting inhibitor of plasma kallikrein. Its mechanism of action includes:

  • Binding to active plasma kallikrein with high affinity and specificity
  • Inhibiting plasma kallikrein proteolytic activity
  • Decreasing plasma kallikrein-mediated bradykinin production

In HAE, uncontrolled activation of the contact system leads to overproduction of bradykinin, causing increased vascular permeability and the characteristic angioedema attacks. By inhibiting plasma kallikrein, lanadelumab reduces bradykinin production and helps prevent HAE attacks.

Pharmacokinetics

Understanding the pharmacokinetics of lanadelumab is crucial for its effective use:

  • Absorption: After subcutaneous administration, lanadelumab reaches maximum plasma concentrations (Cmax) in approximately 5 days.
  • Distribution: The volume of distribution is approximately 14.5 L, suggesting distribution mainly in the vascular compartment.
  • Metabolism: As a protein, lanadelumab is expected to be catabolized into small peptides and individual amino acids.
  • Elimination: The elimination half-life is approximately 14 days.
  • Steady-state: Achieved after approximately 70 days of dosing.

Notably, lanadelumab exhibits dose-proportional pharmacokinetics, and its long half-life allows for less frequent dosing compared to other HAE prophylaxis options.

Indications and Clinical Use

Lanadelumab is indicated for:

  • Routine prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients aged 12 years and older.

It is particularly useful in:

  • Patients with frequent HAE attacks (e.g., ≥1 attack per month)
  • Cases where on-demand treatment is insufficient to manage the disease burden
  • Patients with a history of laryngeal attacks
  • Those with significant disease-related quality of life impairment

Lanadelumab is not indicated for treatment of acute HAE attacks.

Dosage and Administration

The recommended dosing regimen for lanadelumab is:

  • 300 mg subcutaneously every 2 weeks
  • A dosing interval of 300 mg every 4 weeks may be considered if the patient is well-controlled (e.g., attack-free) for more than 6 months

Administration guidelines:

  • Subcutaneous injection in the abdomen, thigh, or upper arm
  • Rotation of injection sites is recommended
  • Can be self-administered or given by a caregiver after proper training
  • The solution should be clear to slightly opalescent, colorless to slightly yellow

Lanadelumab is available as a 300 mg/2 mL (150 mg/mL) solution in a single-dose vial.

Clinical Efficacy

The efficacy of lanadelumab was established in the HELP study, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial:

  • Significant reduction in HAE attack rate compared to placebo
  • 76.2% reduction in monthly attack rate for 300 mg every 2 weeks dosing
  • Reduction in moderate to severe attacks and attacks requiring acute treatment
  • Improvement in quality of life measures

Long-term efficacy data from the HELP OLE study showed:

  • Sustained efficacy over an extended treatment period (median 29.6 months)
  • 87.4% reduction in attack rate compared to baseline
  • Approximately 93% of patients experienced ≥70% reduction in attacks

Adverse Effects

Common adverse reactions (occurring in ≥10% of patients) include:

  • Injection site reactions (pain, erythema, bruising)
  • Upper respiratory infections
  • Headache
  • Rash
  • Myalgia
  • Dizziness
  • Diarrhea

Less common but important adverse effects:

  • Hypersensitivity reactions
  • Elevated liver enzymes (transient and generally mild)

Most adverse effects are mild to moderate in severity and do not lead to treatment discontinuation.

Precautions and Contraindications

Contraindications:

  • Known hypersensitivity to lanadelumab or any of its excipients

Precautions:

  • Hypersensitivity reactions: Monitor for signs and symptoms of hypersensitivity reactions
  • Concomitant use of substrates of CYP3A4 and CYP2B6 (as lanadelumab may increase their levels)
  • Use in pregnancy: Limited data available; animal studies show no harm to the fetus
  • Use in lactation: No data on presence in human milk; benefits of breastfeeding should be considered along with mother's clinical need for lanadelumab

Pediatric Considerations

Lanadelumab is approved for use in patients 12 years and older. Specific pediatric considerations include:

  • Efficacy and safety in the 12-17 year age group were similar to adult patients in clinical trials
  • No dosage adjustment is required for adolescents
  • Safety and efficacy in children under 12 years have not been established
  • Ongoing studies are evaluating its use in younger children (2-11 years)

Pediatricians should consider:

  • Impact of long-term prophylaxis on quality of life and school attendance
  • Potential effect on growth and development (current data show no adverse effects)
  • Importance of training adolescents in self-administration techniques
  • Psychological impact of chronic medication use in young patients

Monitoring and Follow-up

Patients on lanadelumab should be monitored for:

  • Frequency and severity of HAE attacks
  • Injection site reactions
  • Signs of hypersensitivity reactions
  • Liver function tests (periodically)
  • Quality of life measures

Follow-up recommendations:

  • Regular clinic visits (e.g., every 3-6 months) to assess treatment response
  • Maintain an attack diary to track frequency and severity of breakthrough attacks
  • Assess need for dose adjustment or interval changes based on clinical response
  • Ensure patient has an on-demand treatment plan for breakthrough attacks
  • Annual review of treatment plan and consideration of attempt to extend dosing interval in well-controlled patients

Drug Interactions

While lanadelumab has limited drug interactions, clinicians should be aware of the following:

  • No formal drug interaction studies have been conducted
  • Potential interaction with CYP3A4 and CYP2B6 substrates:
    • Chronic administration of lanadelumab may increase systemic exposure of these substrates
    • Examples include hormonal contraceptives, certain antidepressants, and some anticonvulsants
    • Monitor for increased effects or consider dose adjustment of these medications if necessary
  • No known interactions with common medications used in HAE management (e.g., tranexamic acid, danazol)
  • No interaction expected with on-demand treatments for acute HAE attacks (e.g., icatibant, C1-INH concentrates)

Always review the patient's complete medication list to assess for potential interactions.



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