MECHANISM OF ACTION
ZILBRYSQ is a first-of-its-kind complement C5 inhibitor approved for the treatment of gMG in adult patients who are anti-AChR Ab+1,2
Complement activation
in gMG
Generalized myasthenia gravis (gMG) is a chronic, unpredictable, autoimmune disease2
In gMG, pathogenic immunoglobulin G (IgG) autoantibodies attack key proteins, most commonly the acetylcholine receptor (AChR), in the neuromuscular junction (NMJ). This prevents AChR binding, reduces receptor density, and activates the complement system.1,2
In anti-AChR antibody positive (Ab+) gMG, binding of pathogenic autoantibodies to the AChR initiates complement activation2
- Complement activation results in the cleavage of complement component 5 (C5) into C5a and C5b by C5 convertase1-3
- C5a is a potent proinflammatory mediator, while C5b initiates the terminal complement pathway2
Formation of the membrane attack complex (MAC) damages the NMJ2
- Activation of C5b within the complement cascade contributes to MAC formation
- This leads to the deposition of MAC on the post-synaptic membrane of the NMJ leading to damage and subsequent impaired synaptic transmission
Complement inhibition
with ZILBRYSQ
ZILBRYSQ is a first-of-its-kind small peptide C5 inhibitor for the treatment of anti-AChR Ab+ gMG1,2
Small macrocyclic peptide2
ZILBRYSQ is a first-of-its-kind, macrocyclic peptide that specifically targets the complement cascade.
Prevents assembly of MAC2,3
ZILBRYSQ binds to C5 with high affinity and specificity, preventing C5 cleavage into C5a and C5b by C5 convertase. This prevents the subsequent assembly and activity of the MAC, providing complement inhibition.
The precise mechanism through which ZILBRYSQ exerts therapeutic effects in gMG is unknown.1
ZILBRYSQ Mechanism of Action
ZILBRYSQ (zilucoplan) is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.
Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors; ZILBRYSQ is a complement inhibitor. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Complete or update meningococcal vaccination at least 2 weeks prior to administering the first dose of ZILBRYSQ, unless the risk of delaying therapy outweighs the risk of developing a meningococcal infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccinations in patients receiving a complement inhibitor. Persons receiving ZILBRYSQ are at increased risk for invasive disease caused by N. meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected. ZILBRYSQ is available only through a restricted program called ZILBRYSQ REMS. ZILBRYSQ is contraindicated in patients with unresolved Neisseria meningitidis infection. Additional important warnings and precautions associated with ZILBRYSQ include an increased susceptibility to infections and pancreatitis and pancreatic cysts. The most common adverse reactions (≥10%) were injection site reactions, upper respiratory tract infection, and diarrhea.
Please see Important Safety Information at the end of this video, including Boxed Warning for serious meningococcal infections.
[MOA]
ZILBRYSQ® (zilucoplan) is a first-of-its-kind complement C5 inhibitor for the treatment of adult patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis or gMG.
ZILBRYSQ is a small, macrocyclic peptide that specifically targets the complement pathway to prevent the formation of the membrane attack complex, or MAC to provide complement inhibition.
In gMG, pathogenic immunoglobulin G (IgG) autoantibodies attack key receptors of proteins on the postsynaptic membrane involved in signal transmission at the neuromuscular junction (NMJ). This impairs signal transduction and muscle contraction, which leads to the debilitating muscle weakness and fatigue experienced by patients with gMG.
The acetylcholine receptor (AChR) is the most common target of autoantibodies in gMG. And pathogenic autoantibodies to AChR are found in approximately 80%-88% of people living with gMG.
AChR autoantibodies result in pathology via any of the following 3 mechanisms:
- Preventing acetylcholine from binding to its receptor and thus inhibiting neurotransmission.
- Reducing receptor density because of cross-linking and subsequent AChR endocytosis, leading to lower signaling capacity.
- Activating the complement system leads to the formation of a MAC, essentially puncturing the postsynaptic membrane promoting an influx of ions that cause damage.
AChR autoantibody activation of the complement pathway is the primary cause of damage to the postsynaptic membrane and a key mechanism of signal impairment in gMG.
Binding of pathogenic autoantibodies to the AChR initiates complement activation, resulting in the cleavage of C5 in C5a and C5b by C5 convertase. C5a is a potent proinflammatory mediator, while C5b initiates the terminal complement pathway by binding to additional complement proteins to form the MAC, triggering an influx of ions that cause damage.
In gMG, MAC formation and deposition causes structural damage to the postsynaptic membrane of the neuromuscular junction, ultimately resulting in impaired neuromuscular signal transmission.
ZILBRYSQ is a first-of-its-kind complement C5 inhibitor for the treatment of gMG in adult patients who are anti-acetylcholine receptor antibody-positive.
ZILBRYSQ is a small macrocyclic peptide that binds to C5 with high affinity and specificity, preventing the cleavage of C5 to C5a and C5b by C5 convertase. This prevents the subsequent assembly and activity of the MAC, a key contributor in the destruction of the neuromuscular junction and resulting signal impairment in gMG.
ZILBRYSQ is a first-of-its kind small peptide for complement inhibition.
The exact mechanism by which ZILBRYSQ exerts its effect is unknown.
Please listen to the following Important Safety Information for ZILBRYSQ.
INDICATION
ZILBRYSQ (zilucoplan) is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.
IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors; ZILBRYSQ is a complement inhibitor. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.
- Complete or update meningococcal vaccination (for serogroups A, C, W, and Y, and serogroup B) at least 2 weeks prior to administering the first dose of ZILBRYSQ, unless the risk of delaying therapy outweighs the risk of developing a meningococcal infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccinations in patients receiving a complement inhibitor.
- Persons receiving ZILBRYSQ are at increased risk for invasive disease caused by N. meningitidis, even if they develop antibodies following vaccination. Monitor patients for signs of meningococcal infections and evaluate immediately if infection is suspected.
Because of the risk of serious meningococcal infections, ZILBRYSQ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ZILBRYSQ REMS.
CONTRAINDICATIONS
ZILBRYSQ is contraindicated in patients with unresolved Neisseria meningitidis infection.
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections
Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors; ZILBRYSQ is a complement inhibitor. The use of ZILBRYSQ increases a patient’s susceptibility to serious and life-threatening meningococcal infections (septicemia and/or meningitis) caused by any serogroup, including non-groupable strains.
Complete or update meningococcal vaccination (for both serogroups A, C, W, and Y [MenACWY] and serogroup B [MenB]) at least 2 weeks prior to administering the first dose of ZILBRYSQ, according to current ACIP recommendations for meningococcal vaccinations in patients receiving a complement inhibitor.
If urgent ZILBRYSQ therapy is indicated in a patient who is not up to date with both MenACWY and MenB vaccines according to ACIP recommendations, administer meningococcal vaccine(s) as soon as possible and provide the patient with antibacterial drug prophylaxis.
Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Withhold administration of ZILBRYSQ in patients who are undergoing treatment for meningococcal infection until the infection is resolved.
ZILBRYSQ REMS
Due to the risk of meningococcal infections, ZILBRYSQ is available only through a restricted program under a REMS called ZILBRYSQ REMS.
Under the ZILBRYSQ REMS, prescribers must enroll in the program. Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccines. Additional information on the REMS requirements is available at www.ZILBRYSQREMS.com or 1-877-414-8353.
Other Infections
ZILBRYSQ blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. Persons receiving ZILBRYSQ are at increased risk for infections due to these bacteria, even after vaccination.
Pancreatitis And Other Pancreatic Conditions
Pancreatitis and pancreatic cysts have been reported in patients treated with ZILBRYSQ. Patients should be informed of this risk before starting ZILBRYSQ. Obtain lipase and amylase levels at baseline before starting treatment with ZILBRYSQ. Discontinue ZILBRYSQ in patients with suspected pancreatitis and initiate appropriate management until pancreatitis is ruled out or has resolved.
ADVERSE REACTIONS
In a placebo-controlled study, the most common adverse reactions (reported in at least 10% of gMG patients treated with ZILBRYSQ) were injection site reactions, upper respiratory tract infections, and diarrhea.
Please refer to the full Prescribing Information at www.ZILBRYSQHCP.com
For US Healthcare Professionals Only.
ZILBRYSQ® is a registered trademark of the UCB Group of Companies.
©2024 UCB, Inc., Smyrna, GA 30080. All rights reserved.
References:
- ZILBRYSQ [Prescribing Information]. Smyrna, GA: UCB, Inc.
- Howard JF Jr, Bresch S, Genge A, et al; RAISE Study Team. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, Phase 3 study. Lancet Neurol. 2023;22(5):395-406. doi:10.1016/S1474-4422(23)00080-7
- Mantegazza R, Vanoli F, Frangiamore R, et al. Complement inhibition for the treatment of myasthenia gravis. ImmunoTargets Ther. 2022;9:317-331. doi:10.2147/ITT.S261414
