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Mechanism of Action

ULTOMIRIS® binds specifically to C5 to inhibit terminal complement activity1

The precise mechanism by which ULTOMIRIS (ravulizumab-cwvz) exerts its therapeutic effect in gMG patients is not known.1

In gMG, the complement cascade causes damage at the NMJ2-4

Healthy NMJ3-5

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 Damage3,4,6

Neuromuscular junction with complement mediated damage

Simplified membrane morphology

Circled areas indicate deposition of C9 (MAC component).



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

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

ULTOMIRIS is the first and only long-acting complement C5 inhibitor1,7,8

ULTOMIRIS inhibits the complement protein C5—a key driver of damage to the NMJ in generalized myasthenia gravis (gMG).1,9

Mechanism of disease in gMG4,9

illustration of C5, C5b, and C5b-9 (MAC)
  • Binding of anti-AChR antibodies to the AChR triggers activation of the complement system4
  • Terminal complement activation results in cleavage of C5 into C5a and C5b9
  • C5a leads to inflammation, while C5b binds to other complement proteins to form the MAC9
  • MAC formation results in destruction to the NMJ4,9

ULTOMIRIS mechanism of action1

Illustration of C5 – magnified

Images are magnified for clarity.

  • ULTOMIRIS is a monoclonal antibody that inhibits C5, preventing cleavage into C5a and C5b1
  • This prevents formation of MAC1

The precise mechanism by which ULTOMIRIS exerts its therapeutic effect in gMG patients is not known1

ULTOMIRIS Mechanism of Action Video

Watch how this targeted gMG treatment inhibits the complement protein C5.1

Engineered for once-every-8-week dosing1,10

ULTOMIRIS is built on the foundation of eculizumab but is designed for extended inhibition and elimination of C5 through lysosomal degradation10,11

ULTOMIRIS was engineered through modification of eculizumab. Four amino acid changes resulted in 4-times-longer half-life compared with eculizumab.10,11

The precise mechanism by which ULTOMIRIS and eculizumab exert their therapeutic effect in gMG patients is not known.1

Fab regions10-12

2 amino acid modifications to promote the release of C5 in the endosome

Two amino acid modifications increase the ULTOMIRIS half-life to ~4x that of eculizumab, enabling maintenance dosing once every 8 weeks

Fc region

2 amino acid modifications to enhance FcRn binding

Advantages of the ULTOMIRIS modifications10,11

ULTOMIRIS is less likely to be degraded with C5

ULTOMIRIS is more likely to be recycled back into circulation, increasing its half-life

The recycling of ULTOMIRIS could occur multiple times, further extending its half-life

AChR, acetylcholine receptor; Fab, fragment antigen-binding; Fc, fragment crystallizable; FcRn, neonatal Fc receptor; gMG, generalized myasthenia gravis; MAC, membrane attack complex; NMJ, neuromuscular junction.

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IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

Life-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a meningococcal infection. See Warnings and Precautions for additional guidance on the management of the risk of meningococcal infection.
  • Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of 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 REMS.

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CONTRAINDICATIONS

  • Patients with unresolved Neisseria meningitidis infection.
  • Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection.

WARNINGS AND PRECAUTIONS

Serious Meningococcal Infections

Life-threatening meningococcal infections have occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.

Vaccinate or revaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Immunize patients without history of meningococcal vaccination at least 2 weeks prior to the first dose of ULTOMIRIS. Patients who initiate ULTOMIRIS treatment less than 2 weeks after receiving meningococcal vaccine(s) must receive appropriate prophylactic antibiotics until 2 weeks after vaccination.

In clinical studies, 2 adult patients with gMG were treated with ULTOMIRIS less than 2 weeks after meningococcal vaccination. All of these patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established. Consider discontinuation of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection.

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

Under the ULTOMIRIS REMS, prescribers must enroll in the program. Prescribers must counsel patients about the risk of meningococcal infection/sepsis, 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.ultomirisrems.com or 1-888-765-4747.

Other Infections
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. If ULTOMIRIS is administered to patients with active systemic infections, monitor closely for worsening infection.

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
Intravenous 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% of patients treated with ULTOMIRIS. These events included lower back pain, drop in blood pressure, elevation in blood pressure, limb discomfort, drug hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS infusion 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.

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 meningococcal infections/sepsis.

References:

Reference:

  1. ULTOMIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.
  1. Data on file. Alexion Pharmaceuticals, Inc.
  2. ULTOMIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.
  1. ULTOMIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.
  2. Data on file. Alexion Pharmaceuticals, Inc.
  3. Howard JF Jr, et al. Poster presented at: AAN 2022 Annual Meeting; April 2-7, 2022; Seattle, WA.
  4. Vu T, et al. NEJM Evid. 2022;1(5):1-22. doi:10.1056/EVIDoa2100066
  1. Data on file. Alexion Pharmaceuticals, Inc.
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  3. Muppidi S, et al; MG Composite and MG-QOL 15 Study Group. Muscle Nerve. 2011;44(5):727-731.
  4. Howard JF Jr, et al. Poster presented at: AAN 2022 Annual Meeting; April 2-7, 2022; Seattle, WA.
  5. Kulasekararaj AG, et al. Blood. 2019;133(6):540-549.
  6. Lee JW, et al. Blood. 2019;133(6):530-539.
  7. Vu T, et al. NEJM Evid. 2022;1(5):1-22.
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  2. Kusner LL, et al. Ann N Y Acad Sci. 2012;1274(1):127-132.
  3. Meriggioli MN, et al. Lancet Neurol. 2009;8(5):475-490.
  4. Conti-Fine BM, et al. J Clin Invest. 2006;116(11):2843-2854.
  5. Engel AG, et al. Mayo Clin Proc. 1977;52(5):267-280.
  6. Sahashi K, et al. J Neuropathol Exp Neurol. 1980;39(2):160-172.
  7. Kulasekararaj AG, et al. Blood. 2019;133(6):540-549.
  8. Lee JW, et al. Blood. 2019;133(6):530-539.
  9. Howard JF Jr. Ann N Y Acad Sci. 2018;1412(1):113-128.
  10. Sheridan D, et al. PLoS One. 2018;13(4):e0195909.
  11. Röth A, et al. Blood Adv. 2018;2(17):2176-2185.
  12. Rother RP, et al. Nat Biotechnol. 2007;25(11):1256-1264.
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  2. Centers for Disease Control and Prevention. Updated February 17, 2022. Accessed April 27, 2022. https://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf
  3. Centers for Disease Control and Prevention. Updated October 12, 2021. Accessed April 27, 2022. https://www.cdc.gov/vaccines/vpd/mening/public
  4. Mbaeyi SA, et al; Advisory Committee on Immunization Practices. Centers for Disease Control and Prevention; 2020. Accessed August 6, 2022. https://www.cdc.gov/mmwr/volumes/69/rr/pdfs/rr6909a1-H.pdf
  5. Transition from Menactra to MenQuadfi Meningococal Conjugate Vaccine; 2022. Accessed October 13, 2022. https://portal.ct.gov/-/media/Departments-and-Agencies/DPH/dph/infectious_diseases/immunization/CVP-2020/2022-CVP-Communications/update-menactra-discontinuation-2-24-22.pdf
  6. Centers for Disease Control and Prevention. Updated October 12, 2021. Accessed August 6, 2022. https://www.cdc.gov/vaccines/vpd/mening/hcp/administering-vaccine.html
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  2. Howard JF Jr, et al. Poster presented at: AAN 2022 Annual Meeting; April 2-7, 2022; Seattle, WA.
  3. Data on file. Alexion Pharmaceuticals, Inc.
  4. Vu T, et al. NEJM Evid. 2022;1(5):1-12. doi:10.1056/EVIDoa2100066
  5. Jaretzki A III, et al. Neurology. 2000;55(1):16-23.
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  2. Data on file. Alexion Pharmaceuticals, Inc.
  1. ULTOMIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.
  2. Conti-Fine BM, et al. J Clin Invest. 2006;116(11):2843-2854.