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Mechanism of Disease & Patient Impact

Mike, a patient living with gMG. Mike has received compensation from Alexion Pharmaceuticals, Inc. and has a relative who works for Alexion.

Understanding pathophysiology, disease education, diagnosis, and treatment approaches

Generalized myasthenia gravis (gMG) is a rare autoimmune disorder that creates a fluctuating weakness of the voluntary muscles due to disrupted neuromuscular transmission. It is the most common type of myasthenia gravis (MG) and typically the most severe.1

A normal functioning complement system plays an important role in helping the body fight off infections. However, in gMG, the complement system attacks the area where the patient’s body sends signals to their muscles. This is known as impaired neuromuscular transmission, which can lead to weakness and fatigue of the muscles.1,2

Mechanism of Disease: In gMG, the complement cascade causes damage at the neuromuscular junction (NMJ)

WATCH: Understanding the Role of Complement in gMG


Learn more about the complement cascade

In gMG, the mechanisms that control the adaptive immune system do not function properly, as the adaptive immune system targets healthy tissues. With gMG, the pathology includes the generation of antibodies against acetylcholine receptors (AChRs). Anti-AChR antibodies disrupt signal transmission at the NMJ by blocking and reducing the number of functioning AChRs.3

  • AChRs are found on the surface of muscle cells and are important for the generation of muscle contraction3
  • On average, approximately 82% of patients with gMG are anti-AChR antibody positive4-8

At least three pathogenic mechanisms are believed to be responsible for disrupting the NMJ in anti-AChR antibody-positive gMG1,9:

  1. Complement-mediated postsynaptic membrane destruction
  2. Antigenic modulation
  3. Blockage of AChRs

Overview1,9,10: All three mechanisms are believed to be active in anti-AChR antibody-positive gMG, but complement-mediated postsynaptic membrane destruction could be a cause of functional AChR loss and consequent failure of neuromuscular transmission.

Anti-AChR antibody binding to AChRs activates the complement cascade, resulting in the downstream production of terminal complement components, including protein C5a (leading to inflammation) and C5b. C5b is the first protein included in the formation of the membrane attack complex (MAC) at the postsynaptic membrane.

MAC is composed of complement proteins C5b through C9 and damages the postsynaptic membrane and its associated structures, such as the membrane folds and dense clusters of AChRs. This causes a simplification and distortion of the postsynaptic membrane that reduces the overall number of AChRs.

Alteration of folds in the muscle membrane reduces the efficiency of neuromuscular transmission.

Healthy NMJ1,11,12

Microbiology image of typical folds in the muscle membrane

Typical folds in the muscle membrane

Complement
cascade leading to NMJ damage

NMJ With Complement-Mediated Damage1,11,13

Neuromuscular junction with complement-mediated damage

Simplified membrane morphology

Circled areas indicate deposition of C9 (MAC component).

Healthy NMJ image: Reprinted from Mayo Clin Proc, 52(5), Engel AG, et al. 267-280. © 2009, with permission from Elsevier.

NMJ With Complement-Mediated Damage image: Sahashi K, et al. J Neuropathol Exp Neurol. 1980;39(2):160-172. © 1980 by permission of Oxford University Press.

Learn About a Treatment Option

How gMG impacts patients


Prevalence of myasthenia gravis14,15:

Recent studies indicate that ~76% of diagnosed MG cases are generalized.

  • Prevalence numbers may underestimate the true number of gMG cases, as the disease is underdiagnosed
  • Generally prevalence is higher in females than in males, but reverses in older people; females often have an earlier age of onset compared to males
    • The peak of incidence is between 20 and 40 years in females and between 60 and 80 years in males

Muscle damage caused by gMG can make daily activities and physical functions challenging

Some patients may struggle with16:


Vision

Breathing

Speech

Eating

Mobility

Common symptoms of gMG include11,17,18:

  • Speech problems
  • Difficulty chewing and swallowing
  • Double vision/eyelid droop
  • Altered facial expressions
  • Difficulty holding one’s head up
  • Trouble lifting the arms
  • Weak grip
  • Difficulty walking long distances or climbing stairs
  • Trouble in rising from a sitting position
  • Difficulty breathing
Mike, a patient living with gMG. Mike has received compensation from Alexion Pharmaceuticals, Inc. and has a relative who works for Alexion.

See how a treatment option for gMG works

Learn About a Treatment Option

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

ULTOMIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)] Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.

  • Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.
  • Patients receiving ULTOMIRIS are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected.

Because of the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2)].

CONTRAINDICATIONS

  • Initiation in patients with unresolved serious Neisseria meningitidis infection.

WARNINGS AND PRECAUTIONS

Serious Meningococcal Infections

ULTOMIRIS, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors.

Revaccinate patients in accordance with ACIP recommendations considering the duration of ULTOMIRIS therapy. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent ULTOMIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including ULTOMIRIS. The benefits and risks of treatment with ULTOMIRIS, as well as those associated with antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis.

Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination.

Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if they occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection depending on the risks of interrupting treatment in the disease being treated.

ULTOMIRIS and SOLIRIS REMS
Due to the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS.

Prescribers must enroll in the REMS, counsel patients about the risk of serious meningococcal infection, provide patients with the REMS educational materials, assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of ULTOMIRIS. Antibacterial drug prophylaxis must be prescribed if treatment must be started urgently, and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ULTOMIRIS. Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card at all times during and for 8 months following ULTOMIRIS treatment.

Further information is available at www.UltSolREMS.com or 1-888-765-4747.

Other Infections
Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.

ULTOMIRIS 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. Patients receiving ULTOMIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.

Thromboembolic Event Management
The effect of withdrawal of anticoagulant therapy during treatment with ULTOMIRIS has not been established. Treatment should not alter anticoagulant management.

Infusion-Related Reactions
Administration of ULTOMIRIS may result in systemic infusion-related reactions, including anaphylaxis and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1 to 7% of patients, including lower back pain, abdominal pain, muscle spasms, drop or elevation in blood pressure, rigors, limb discomfort, drug hypersensitivity (allergic reaction), and dysgeusia (bad taste). These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS and institute appropriate supportive measures.

ADVERSE REACTIONS
Most common adverse reactions in adult patients with gMG (incidence ≥10%) were diarrhea and upper respiratory tract infection. Serious adverse reactions were reported in 20 (23%) of patients treated with ULTOMIRIS and in 14 (16%) patients receiving placebo. The most frequent serious adverse reactions were infections reported in at least 8 (9%) patients treated with ULTOMIRIS and in 4 (4%) patients treated with placebo. Of these infections, one fatal case of COVID-19 pneumonia was identified in a patient treated with ULTOMIRIS and one case of infection led to discontinuation of ULTOMIRIS.

DRUG INTERACTIONS
Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins
Concomitant use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ULTOMIRIS.

Neonatal Fc Receptor Blockers
Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod) may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS.

USE IN SPECIFIC POPULATIONS
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ULTOMIRIS during pregnancy. Healthcare providers and patients may call 1-833-793-0563 or go to www.UltomirisPregnancyStudy.com to enroll in or to obtain information about the registry.

To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

INDICATION
ULTOMIRIS is indicated for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive.

Please see full Prescribing Information for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening or fatal meningococcal infections.

References:

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