Emapalumab

Introduction to Emapalumab

Emapalumab (brand name: Gamifant) is a monoclonal antibody that binds to and neutralizes interferon gamma (IFNγ). It was developed by Novimmune SA and later acquired by Sobi (Swedish Orphan Biovitrum AB). Emapalumab received FDA approval in 2018 and EMA approval in 2020.

Emapalumab is primarily used for the treatment of primary hemophagocytic lymphohistiocytosis (HLH), a rare and life-threatening syndrome of excessive immune activation. It is particularly important in pediatric medicine as HLH often affects infants and young children.

Mechanism of Action

Emapalumab's mechanism of action is centered on its ability to neutralize interferon gamma (IFNγ):

  • High-affinity binding to both free and receptor-bound forms of human IFNγ
  • Prevents IFNγ from interacting with its cell surface receptors
  • Inhibits IFNγ-mediated signaling and downstream effects

In HLH, excessive production and action of IFNγ play a central role in the hyperinflammation and immune dysregulation characteristic of the disease. By neutralizing IFNγ, emapalumab aims to:

  • Reduce activation and proliferation of T cells and macrophages
  • Decrease production of pro-inflammatory cytokines
  • Mitigate the excessive immune response seen in HLH

Pharmacokinetics

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

  • Distribution: The volume of distribution of emapalumab is 4.2 L (CV=64%).
  • Metabolism: As a protein, emapalumab is expected to be degraded into small peptides and amino acids via catabolic pathways.
  • Elimination:
    • The elimination half-life of emapalumab is approximately 22 days (CV=55%).
    • Clearance is 0.007 L/h (CV=78%) in patients weighing 50 kg.
  • Dose linearity: Emapalumab exhibits dose-proportional pharmacokinetics over a wide dose range (1-10 mg/kg).
  • Special populations:
    • No significant differences based on age, sex, or race.
    • Body weight-based dosing accounts for size differences.
    • No formal studies in renal or hepatic impairment.

Indications and Clinical Use

Emapalumab is indicated for:

  • Treatment of adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy.

Clinical use considerations:

  • Primary HLH is a rare, life-threatening syndrome characterized by excessive immune activation and inflammation.
  • Emapalumab is used as a second-line therapy when first-line treatments (typically including dexamethasone and etoposide) are ineffective or poorly tolerated.
  • It can be used as a bridge to hematopoietic stem cell transplantation (HSCT), which is the only curative treatment for primary HLH.
  • While not approved for secondary HLH, case reports suggest potential efficacy in some forms of secondary HLH.

Dosage and Administration

The recommended dosing regimen for emapalumab is:

  • Initial dose: 1 mg/kg as an intravenous infusion over 1 hour twice per week (every 3-4 days).
  • Subsequent doses may be increased based on clinical response:
    • 3 mg/kg
    • 6 mg/kg
    • 10 mg/kg
  • Administer until HSCT is performed or unacceptable toxicity.
  • Doses up to 10 mg/kg may be administrered on a daily basis for up to 3 days in the presence of severe disease or life-threatening conditions.

Administration guidelines:

  • Administer as an intravenous infusion over 1 hour.
  • Use a 0.2 micron in-line filter for administration.
  • Do not mix with other medications or administer as an intravenous push or bolus.
  • Dilute to a final concentration between 0.25 mg/mL and 2.5 mg/mL with 0.9% Sodium Chloride Injection, USP.

Emapalumab is available as a 50 mg/10 mL (5 mg/mL) solution in a single-dose vial.

Clinical Efficacy

The efficacy of emapalumab was established in a clinical trial of 34 pediatric patients with suspected or confirmed primary HLH with either refractory, recurrent, or progressive disease during conventional HLH therapy or who were intolerant to conventional HLH therapy.

Key efficacy outcomes:

  • Overall Response Rate (ORR): 65% (22/34 patients) achieved a response
  • Complete Response: 21% of patients achieved complete response
  • Partial Response: 44% of patients achieved partial response
  • 70.6% (24/34) of patients proceeded to HSCT

Response criteria included normalization of HLH disease markers such as:

  • Fever
  • Splenomegaly
  • Cytopenias
  • Hyperferritinemia
  • Hypertriglyceridemia
  • Hypofibrinogenemia
  • Central nervous system symptoms

Adverse Effects

Common adverse reactions (incidence ≥20%) include:

  • Infections (56%): including CMV and Candida
  • Hypertension (41%)
  • Infusion-related reactions (27%)
  • Pyrexia (24%)

Other important adverse effects:

  • Serious infections: Increased risk due to IFNγ neutralization
  • Stem cell transplantation (SCT) complications: Increased risk of graft failure
  • Elevated liver enzymes: Monitor hepatic function

Most adverse effects are manageable with appropriate monitoring and intervention. The benefits of emapalumab in this life-threatening condition often outweigh the risks.

Precautions and Contraindications

Contraindications:

  • None specifically listed in the prescribing information

Precautions:

  • Infections:
    • Increased risk of serious infections due to IFNγ neutralization
    • Test for latent tuberculosis
    • Consider prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections
  • Stem Cell Transplantation (SCT) Complications:
    • Increased risk of graft failure with pre-transplant emapalumab use
    • Closely monitor for SCT complications
  • Pregnancy: Limited data available; animal studies show no harm to fetus
  • Lactation: No data on presence in human milk; consider developmental and health benefits of breastfeeding along with mother's clinical need for emapalumab

Pediatric Considerations

Emapalumab is particularly important in pediatric medicine as primary HLH often affects infants and young children. Key pediatric considerations include:

  • Safety and efficacy have been established in pediatric patients (newborns and older)
  • The majority of clinical trial participants were pediatric patients
  • Weight-based dosing allows for use across a wide range of pediatric ages and sizes
  • Special attention to infection prevention is crucial in pediatric patients
  • Long-term effects on the developing immune system are not fully known
  • Impact on growth and development should be monitored

Pediatricians should consider:

  • Early diagnosis and treatment of primary HLH is critical for improved outcomes
  • Coordination with pediatric hematology-oncology and immunology specialists
  • Family education and support, given the serious nature of HLH and its treatment
  • Long-term follow-up post-HSCT to monitor for late effects of both the disease and its treatment

Monitoring and Follow-up

Patients on emapalumab require close monitoring. Key aspects include:

  • HLH disease activity:
    • Clinical symptoms (fever, hepatosplenomegaly, CNS symptoms)
    • Laboratory markers (ferritin, fibrinogen, triglycerides, cytopenias)
  • Infections:
    • Regular screening for bacterial, viral, and fungal infections
    • Particular attention to opportunistic infections
  • Liver function:
    • Monitor ALT and AST prior to each infusion
    • Consider dose adjustment if significant elevation occurs
  • Stem cell transplantation preparation and follow-up:
    • Close coordination with transplant team
    • Monitoring for graft failure or other transplant-related complications

Follow-up recommendations:

  • Frequent clinical assessments during active treatment (often multiple times per week)
  • Regular laboratory monitoring as indicated by clinical status
  • Long-term follow-up post-HSCT to monitor for disease recurrence and late effects of therapy
  • Genetic counseling for families, given the hereditary nature of primary HLH

Drug Interactions

While formal drug interaction studies have not been conducted with emapalumab, several important considerations exist:

  • Increased risk of infection with concomitant use of immunosuppressants:
    • Emapalumab is often used in combination with other immunosuppressive agents (e.g., dexamethasone, cyclosporine) as part of HLH treatment protocols
    • Close monitoring for infections is essential
  • Potential interaction with IFNγ-inducing therapies:
    • Emapalumab may counteract the effects of therapies that rely on IFNγ induction (e.g., certain immunotherapies)
    • Clinical significance is not well established
  • Vaccines:
    • Avoid live or live attenuated vaccines during emapalumab treatment
    • Efficacy of non-live vaccines may be reduced
  • Cytochrome P450 substrates:
    • Formation of CYP450 enzymes may be suppressed by increased cytokine levels in chronic inflammation
    • As emapalumab reduces inflammation, it may normalize CYP450 enzyme formation
    • This could potentially affect the metabolism of drugs that are CYP450 substrates
    • Monitor for potential changes in efficacy or toxicity of concomitant CYP450 substrate medications

Given the complex nature of HLH treatment and the potential for multiple medications, close collaboration between hematology-oncology, clinical pharmacology, and other specialties is crucial for optimal patient management.



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