Eculizumab is the First Drug Approved for the Treatment of Complement-Mediated Diseases : A Part from the Book Chapter : A Systematic Review of Infectious Complications of Eculizumab

“But however secure and well-regulated civilized life may become, bacteria, Protozoa, Viruses, infected fleas, lice, ticks, mosquitoes, and bed bugs will always lurk in the shadows ready to pounce when neglect, poverty, famine, or war lets down the defenses”- Hans Zinsser.

Eculizumab is the first drug approved for the treatment of complement-mediated diseases. It is a humanized monoclonal Antibody. Its heavy chains consist of portions derived from human IgG2 (constant region 1, the hinge and the very first part of constant region 2) and from human IgG4 (the remaining part of constant region 2 and the whole constant region 3). Eculizumab is approved by the United States Food and Drug Administration (FDA) for three indications: paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor-positive generalized myasthenia gravis (gMG), is a complement inhibitor that inhibits the complement C5 that normally mounts a defense response against the encapsulated bacteria, Neisseria meningitidis (N. meningitidis), causing the bacteria to take advantage of this vulnerable situation and lead to meningitis, septic shock, and severe end-organ damage.

PNH is a rare hematologic disorder with an incidence of 15.9 individuals per million worldwide with most of the patients falling in the range of 30-40 years. It is an X-linked disease with a mutation in the phosphatidylinositol glycan class A (PIGA) gene producing a deficiency in glycosylphosphatidylinositol (GPI) protein, which anchors protein moieties CD55 and CD59 that further block the activity of membrane attack complex (C5b-C9). Due to loss of complement inhibition, RBCs become vulnerable to destruction by membrane attack complex resulting in hemolytic anemia. Thus, PNH presents with hemolytic anemia, hemoglobinuria, thrombosis, renal insufficiency, and aplastic anemia.

Author(s) Details:

Ravneet K. Dhanoa
Department of Internal Medicine/Hematology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

Ramaneshwar Selvaraj
Department of Internal Medicine/Family Medicine/General Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

Shoukrie I. Shoukrie
Department of Orthopaedics/Traumatology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

Anam Zahra
Department of Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

Jyothirmai Malla
Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

Tharun Yadhav Selvamani
Department of General Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

Sathish Venugopal
Department of Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

Ranim K. Hamouda
Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

Pousette Hamid
Department of Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.

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Recent Global Research Developments in Long-Term Efficacy of Eculizumab: A Comprehensive Review

Paroxysmal Nocturnal Hemoglobinuria (PNH):

A study published in Blood by Terriou et al. (2021) investigated the long-term survival benefit of eculizumab treatment in patients with PNH. Eculizumab, the first C5 inhibitor approved for PNH, significantly improved survival to levels comparable to an age- and sex-matched general population¹. The study analyzed data from the International PNH Registry and included a large international cohort of eculizumab-treated patients. The baseline characteristics of patients were comparable between treated and untreated groups [1] .

Notably, eculizumab transformed PNH treatment by enhancing survival outcomes.

Generalized Myasthenia Gravis (gMG):

Eculizumab has also shown long-term efficacy in treating antiacetylcholine receptor antibody-positive refractory gMG. An open-label extension study evaluated eculizumab’s safety and efficacy over an extended period [2] . Patients who switched from eculizumab to ravulizumab (another complement inhibitor) also experienced success [2] .

Cold Agglutinin Disease (CAD):

In CAD, continuous therapy with eculizumab led to sustained reduction in hemolysis, elimination of transfusion requirements, and improvement in anemia, fatigue, and overall quality of life. Importantly, no exacerbations of the disease occurred since the initiation of eculizumab treatment [2] .

References

1. Terriou, L., Patriquin, C. J., Griffin, M., Lee, J. W., Gustovic, P., Patel, A. S., & Szer, J. (2021). Long-Term Survival Benefit of Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from the International PNH Registry. Blood, 138, 2188.
2. Long-Term Data Affirm Efficacy of Eculizumab in Refractory Generalized MG
   https://www.ajmc.com/view/long-term-data-affirm-efficacy-of-eculizumab-in-refractory-generalized-mg
3. Röth, A., Hüttmann, A., Rother, R. P., Dührsen, U., & Philipp, T. (2009). Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease. Blood, The Journal of the American Society of Hematology, 113(16), 3885-3886.

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