Biotherapies are expanding the ways we can intervene in disease, increasingly targeting the underlying biological processes rather than focusing primarily on the manifestations of disease.
While cellular therapies use living cells to achieve therapeutic effects, other emerging approaches act on specific components of the immune system, including antibodies and the pathways that regulate them. This broader landscape is creating important connections among cellular therapy, immunology, transfusion medicine and laboratory practice.
In this sponsored edition of "Cell Notes," Christina Celluzzi, AABB's director of biotherapies, and Leona Ling, PhD, senior director of clinical science at Johnson & Johnson, explore FcRn-blocker therapies and what this evolving approach may mean for professionals across the biotherapies field.
I'm Leona Ling, PhD, senior director of clinical science supporting Johnson & Johnson's autoantibody disease area. My team focuses on translating the science of neonatal Fc receptor (FcRn) blockade with IMAAVY (nipocalimab-aahu) into meaningful clinical programs for diseases driven by pathogenic immunoglobulin G (IgG) autoantibodies or alloantibodies. What drives me is the opportunity to study more targeted options for patients who often have significant unmet needs.
FcRn blockers like IMAAVY are an evolving class of therapies designed to reduce circulating IgG, including pathogenic autoantibodies, by interrupting the normal recycling pathway that keeps high concentrations of IgG in circulation.1 IMAAVY is indicated for the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients 12 years of age and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive, and for warm autoimmune hemolytic anemia (wAIHA) in adult and pediatric patients 12 years of age and older who are currently or previously treated with corticosteroids. IMAAVY may increase the risk of infections and may cause hypersensitivity and infusion-related reactions.2 Please see Important Safety Information below.
The field has moved quickly from concept to clinical practice in diseases such as generalized myasthenia gravis (gMG) and wAIHA,2, 3 demonstrating the clinical potential of targeting the FcRn pathway.
There is overlap in that both are immunologically driven approaches, but they work very differently. IMAAVY is a fully human monoclonal antibody that reduces pathogenic IgG autoantibodies.1 Cellular therapies typically involve collecting, modifying or expanding living cells - often immune cells - and returning them to the patient to exert a therapeutic effect.4
IMAAVY is indicated for the treatment of gMG in adult and pediatric patients 12 years of age and older who are AChR or MuSK antibody positive, and for wAIHA in adult and pediatric patients 12 years of age and older who are currently or previously treated with corticosteroids.2
What is different about FcRn blockers like IMAAVY is the fact that they act in an immunoselective manner.1 IMAAVY is engineered with an aglycosylated Fc domain, resulting in no effector function activities.1 This means that through their mechanism of action, FcRn blockers are designed to reduce circulating levels of IgG, including disease-driving autoantibodies, while preserving B-cell function.1 This is based on in vivo and in vitro data. The clinical significance of this is unknown.
Transfusion medicine professionals and laboratories play a critical role in antibody-driven diseases. In wAIHA, laboratories help detect and characterize autoantibodies that can contribute to diagnosis, support differential diagnosis and inform treatment decisions.5-7 Their expertise is essential to connecting pathogenic antibody biology with real-world clinical decision-making, particularly as new targeted therapies continue to emerge.
From a developer's standpoint, access starts well before approval. We rely on strong evidence generation, clear diagnostic pathways, appropriate monitoring standards, and close collaboration with clinicians, laboratories, regulators, payers and patient communities. This facilitates understanding of disease biology and unmet need and enables drug discovery and clinical development. Especially in rare or complex diseases, partnerships are essential to ensure the right patients can be identified, offered novel treatment options and provided supportive care.
I'd want them to see FcRn blockade as part of a broader shift toward targeted intervention in gMG and wAIHA - not just managing downstream consequences, but targeting the IgG antibody biology underlying these diseases. Transfusion medicine professionals are uniquely positioned to help make that shift happen because of their central role in antibody identification, monitoring and patient care pathways.
IMAAVY® (nipocalimab-aahu) is a neonatal Fc receptor (FcRn) blocker indicated for the treatment of:
IMAAVY® (nipocalimab-aahu) is contraindicated in patients with a history of serious hypersensitivity reaction to nipocalimab-aahu or to any of the excipients in IMAAVY. Reactions have included anaphylaxis and angioedema.
Infections
IMAAVY may increase the risk of infection. In the gMG Study 1 and its extension (gMG studies), 132 (71%) out of 186 patients treated with IMAAVY reported 360 events of infection and serious infections were reported in 7% of patients. The infections included upper respiratory tract infection (46%), respiratory tract infections (28%; including pneumonia, bronchitis, COVID-19), urinary tract infection (15%), herpes (8%; including herpes simplex, herpes zoster, herpes zoster oticus), influenza (8%), oral infection (8%; including candidiasis and dental infections), and skin infection (7%; including cellulitis). Two cases of infections (1%; including cellulitis and urinary tract infection) led to discontinuation of IMAAVY.
In the wAIHA Study and its extension (wAIHA studies), 80 (71%) out of 113 patients treated with IMAAVY reported 184 events of infection and serious infections were reported in 12% of patients. The infections included upper respiratory tract infection (34%), respiratory tract infection (33%), urinary tract infection (12%), and gastroenteritis (5%). Three (2.7%) cases of infections (pneumonia, salmonella sepsis and spontaneous bacterial peritonitis) led to discontinuation of IMAAVY.
Delay IMAAVY administration in patients with an active infection until the infection is resolved. During treatment with IMAAVY, monitor for clinical signs and symptoms of infection. If serious infection occurs, administer appropriate treatment and consider withholding IMAAVY until the infection has resolved.
Patients treated with IMAAVY may be at an increased risk of activation of latent viral infections. Follow standard vaccination guidelines.
Immunization: The safety of immunization with live vaccines and the immune response to vaccination during treatment with IMAAVY are unknown. Live vaccines are not recommended during treatment with IMAAVY. Evaluate the need to administer age-appropriate vaccinations before initiation of treatment with IMAAVY.
Hypersensitivity Reactions
Administration of IMAAVY may result in hypersensitivity reactions, including angioedema, anaphylaxis, rash, urticaria, and eczema. In gMG Study 1 and the wAIHA Study, hypersensitivity reactions were mild to moderate. In gMG Study 1, all hypersensitivity reactions occurred within 1 hour to 2 weeks of administration. In the gMG studies, 30 (16%) out of 186 patients treated with IMAAVY experienced hypersensitivity reactions.
In the wAIHA Study, 76% of the hypersensitivity reactions occurred within 2 weeks of administration. In the wAIHA studies, 9 (8%) out of 113 patients treated with IMAAVY experienced hypersensitivity reactions.
Management of hypersensitivity reactions depends on the type and severity of the reaction. Monitor the patient during treatment and for 30 minutes after administration. If a hypersensitivity reaction occurs during administration, discontinue IMAAVY infusion and institute appropriate supportive measures if needed.
Infusion-Related Reactions
Administration of IMAAVY may result in infusion-related reactions (IRRs), including headache, influenza-like illness, rash, nausea, fatigue, dizziness, chills, and erythema. In gMG Study 1 and the wAIHA Study, IRRs were mild to moderate in severity. In gMG Study 1, all IRRs occurred within 1 hour to 2 days of administration. In the gMG studies, 20 (11%) out of 186 patients treated with IMAAVY, experienced IRRs.
In the wAIHA Study, 89% of IRRs occurred within 2 days of administration. In the wAIHA studies, 12 (11%) out of 113 patients treated with IMAAVY, experienced IRRs.
Monitor patients during treatment and for 30 minutes after each infusion. If a severe infusion-related reaction occurs, discontinue IMAAVY infusion and initiate appropriate therapy. Consider the risks and benefits of readministering IMAAVY following a severe infusion-related reaction. If a mild to moderate infusion-related reaction occurs, patients may be rechallenged with close clinical observation, slower infusion rates, and pre-medication.
In the gMG studies:
The most common (≥10% of patients) adverse reactions associated with IMAAVY include: respiratory tract infection, peripheral edema, and muscle spasms.
Adverse reactions in ≥5% of patients taking IMAAVY include: urinary tract infection, herpes zoster and herpes simplex infection, oral infection, hypersensitivity reaction, abdominal pain, back pain, pyrexia, diarrhea, cough, anemia, dizziness, nausea, hypertension, and insomnia.
In the wAIHA studies:
The most common (≥10% of patients) adverse reactions associated with IMAAVY include: peripheral edema, diarrhea, and pyrexia.
Adverse reactions in ≥5% of patients taking IMAAVY include: dizziness, urinary tract infection, and headache.
Laboratory Findings
Lipid Increases in the gMG Study: Patients treated with IMAAVY had elevations from normal to high of fasting total cholesterol and LDL cholesterol and decreases from normal to low of fasting HDL cholesterol.
Lipid Increases in the wAIHA Study: Patients treated with IMAAVY had elevations from normal to high of fasting total cholesterol and LDL cholesterol remained <160 mg/dL.
Pediatric Patients 12 Years of Age and Older
Adverse reactions in pediatric patients age 12 to 16 with gMG were consistent with those observed in adult patients.
Pregnancy: There are limited data on the use of IMAAVY in pregnant women. IMAAVY reduces maternal serum IgG concentration and impedes placental IgG transfer to the fetus. Passive immunity in the infant may be reduced for 6 months or more. Monitor for the development of serious infections. Effectiveness of vaccines may be reduced. Risks and benefits should be considered prior to administering live vaccines to infants exposed to IMAAVY in utero.
Lactation: Nipocalimab-aahu is excreted in human colostrum and breastmilk. There are insufficient data on the effect of IMAAVY in the breastfed infant. There are no data on the effect of nipocalimab-aahu on milk production.
Pediatric Use: The safety and effectiveness of IMAAVY for the treatment of gMG or wAIHA in pediatric patients below the age of 12 years have not been established.
Please see the full Prescribing Information and Patient Information for IMAAVY. Provide the Patient Information to your patients and encourage discussion.
Dosage Form and Strengths: IMAAVY is supplied as a 300 mg/1.62 mL (185 mg/mL) and a 1,200 mg/6.5 mL (185 mg/mL) single-dose vial per carton for intravenous use after dilution.
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