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About gMG

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

About generalized myasthenia gravis (gMG)

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 your body sends signals to the patient’s 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

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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

Diagnosing gMG1,10,14

gMG diagnosis begins with a review of the patient’s medical history and physical examination, but clinicians must be careful as signs and symptoms of gMG can look similar to other conditions. Once gMG is suspected, several tests are used to confirm the diagnosis.

If gMG is suspected, testing for anti-acetylcholine receptor (AChR) antibodies is a key step toward confirming diagnosis

  • Blood tests are used to detect the presence of anti-AChR and other antibodies. However, the absence of anti-AChR does not exclude gMG
  • Additional tests can include ice pack tests, especially if ptosis is a key symptom (ice packs are placed over the eye for 2 to 5 minutes to assess ptosis improvement). There may be benefit in testing the recovery of muscle strength after rest and the ability to look upward for a sustained period
  • Diagnostic testing is preferred to help confirm diagnosis, as unofficial measures/additional testing options may not yield the most accurate results

All patients with confirmed gMG should undergo diagnostic imaging to exclude the presence of a thymoma, as thymomas have been reported in up to 30% of patients with MG.

gMG symptoms in patients are commonly measured by the MG-ADL and QMG scales

The Myasthenia Gravis Activities of Daily Living scale (MG-ADL scale) is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. The total score ranges from 0 to 24, with the higher scores indicating more impairment.17

The Quantitative Myasthenia Gravis scale (QMG scale) is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. The total score ranges from 0 to 39, where higher scores indicate more severe impairment.19

Alexion has compiled a variety of assessment tools that are available for download below.

Download the Assessment Tool Booklet

Review a common classification method utilized to group MG patients based on symptom severity20

Per the MGFA Clinical Classification, symptoms are divided into different classes based on severity:

Class I: Any ocular muscle weakness; may have weakness of eye closure. All other muscle strength is normal.

Class II: Mild weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

IIa. Prominently affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.

IIb. Mainly affecting oropharyngeal, respiratory muscles, or both; and potentially lesser or equal involvement of limb, axial muscles, or both.

Class III: Moderate weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

IIIa. Mainly affecting limb, axial muscles, or both; with potentially less impact of oropharyngeal muscles.

IIIb. Mainly affecting oropharyngeal, respiratory muscles, or both; with lesser or equal involvement of limb, axial muscles, or both.

Class IV: Severe weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

IVa. Primarily affecting limb, axial muscles, or both; with lesser impact of oropharyngeal muscles.

IVb. Predominantly affecting oropharyngeal, respiratory muscles, or both; with potentially lesser or equal impact of limb, axial muscles, or both.

Class V: Defined as intubation, with or without mechanical ventilation, except when employed during routine postoperative management. Using a feeding tube without intubation classifies a patient as IVb.

Treating gMG

Today there are several treatment options that allow healthcare providers to individualize treatment plans for gMG patients. These options range from conventional therapies to FDA-approved branded therapies, such as C5 inhibitors.


Treatment goals include21,22:

  • Reduced symptomatology, specifically muscle weakness
  • Reduced need for medications, ideally allowing patients to reduce/control symptoms with the lowest dose possible

Some strategies include1:

  • Symptomatic therapies (eg, AChE inhibitors such as pyridostigmine)
  • Long-term immunosuppressive therapies (ISTs) (eg, prednisone and related corticosteroids, azathioprine, and mycophenolate mofetil)
  • Short-term ISTs (eg, PLEX and IVIg)
  • Surgery (eg, thymectomy)
  • Biologic therapies (eg, complement inhibitors, etc.)

AChE, acetylcholinesterase; IVIg, intravenous immunoglobulin; MGFA, Myasthenia Gravis Foundation of America; PLEX, plasma exchange.

See how a treatment option for gMG works

Learn About a Treatment Option

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

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)].

SUPPORT

Connect with Alexion

Connect with a live ULTOMIRIS representative by calling 1-833-445-2111, emailing gMGSupport@astrazeneca.com, or via our online form

Support

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.

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

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.

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

References:

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  3. Röth A, Rottinghaus ST, Hill A, et al. Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv. 2018;2(17):2176-2185.
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