New Treatment For Genetic CHAPLE Disease

I. Introduction to CHAPLE Disease

CHAPLE (Complement Hyperactivation, Angiopathic thrombosis, and Protein-Losing Enteropathy) disease, also known as CD55 deficiency, is a rare genetic condition that affects the immune system. It is an ultra-rare recessive condition caused by loss-of-function mutations in the CD55 gene, which is translated into the protein called decay-accelerating factor (DAF). There are fewer than 100 individuals worldwide known to have the disease. In the U.S., fewer than 10 patients with CHAPLE disease have been identified. [Regeneron, 2023]

It is characterized by severe protein-losing enteropathy (the loss of proteins from the intestines) leading to hypoproteinemia. The main symptoms of CHAPLE disease include: [Ozen, 2017]

➢    Gastrointestinal symptoms: These can include abdominal pain, nausea, vomiting, diarrhea, and loss of appetite.

➢    Weight loss: Due to the gastrointestinal symptoms and malabsorption.

➢    Edema: This is swelling caused by excess fluid trapped in your body’s tissues.

➢    Malabsorption: People with CHAPLE disease also have chronic malabsorption, which causes deficiencies in iron, ferritin, calcium, magnesium, folate, vitamin D and vitamin B12.

Additionally, individuals with CHAPLE disease are prone to experiencing lung infections and recurrent blood clots. These blood clots can occur in various blood vessels, including veins and arteries, and can lead to serious complications. This condition usually manifests in childhood and can be life-threatening.

The hyperactivation of the complement system, a part of the immune system responsible for clearing pathogens and damaged cells, is a characteristic feature of CHAPLE disease. [Dho, 2018] The excessive activation of the complement system contributes to inflammation, tissue damage, and the development of blood clots.

CHAPLE disease is ultra-rare making it challenging to diagnose, however non-functional or low levels of DAF protein could provide a clue. Genetic testing could confirm the presence of mutations in the CD55 gene that prevent functional DAF protein production. A diagnostic test that takes into account CD55 status at the DNA and protein level has been patented. [Lenardo, 2021]

Until recently, treatment for CHAPLE disease was mainly supportive and focused on managing symptoms, such as controlling gastrointestinal issues and preventing infections. Consulting with a healthcare professional is essential for individuals suspected of having CHAPLE disease to receive appropriate care and management.

II. Recent Treatment Innovations 

Very recent advances in the understanding of CHAPLE Disease have enabled new proactive treatment options. [Lavelle, 2017]

Eculizumab

Eculizumab is a recombinant humanized monoclonal antibody that specifically binds to the terminal complement component 5, or C5, which acts at a late stage in the complement cascade. When activated, C5 is involved in activating host cells, thereby attracting pro-inflammatory immune cells, while also destroying cells by triggering pore formation. [Eculizumab, 2020]

Eculizumab has been used off-label and shown to provide a dramatic benefit in CHAPLE Disease. [Prabhu, 2022] Thus Eculizumab provides a potent treatment option, however, one serious warning associated with Eculizumab is the risk of meningococcal infections, which may rapidly become life-threatening or fatal if not recognized and treated early. Therefore, it’s recommended to immunize patients with a meningococcal vaccine at least 2 weeks prior to administering the first dose of Eculizumab [Drugscom, 2022]

Pozelimab-bbfg

Pozelimab-bbfg, also known as Veopoz, is a treatment for CHAPLE disease in adult and pediatric patients 1 year of age and older, which was approved by the FDA on August 18, 2023. [CDER, 2023]

Pozelimab-bbfg is a fully human monoclonal antibody designed to block the activity of complement factor C5, a protein involved in complement system activation. By blocking the cleavage of C5 into C5a (anaphylatoxin) and C5b, Pozelimab-bbfg inhibits terminal complement activation, thereby blocking the formation of the membrane-attack complex (C5b-C9, a structure mediating cell lysis). This action helps to control the overactive complement system seen in CHAPLE disease. [Ramsey, 2023] [Pozelimab, 2023]

Veopoz's effectiveness and safety were assessed in a single-arm study (NCT04209634) in patients with active CD55-deficient protein-losing enteropathy (PLE) who had hypoalbuminemia. Ten individuals from ages 3 to 19, with a median age of 8.5 years, participated in the study. Veopoz was administered to patients at a loading dosage of 30 mg/kg, followed by a weekly maintenance dose calculated based on body weight. By week 12, every patient had a serum albumin content of at least 3.5 g/dL, which they kept for at least 72 weeks. Additionally, compared to the 48 weeks before therapy, all patients displayed a decrease in hospitalizations and albumin transfusions throughout the first 48 weeks of treatment. [CDER, 2023]

Upper respiratory tract infections, fractures, hives, and baldness are among the major side effects of the medicine Veopoz. Like Eculizumab there is a boxed warning for potentially fatal meningococcal infections. Based on medical advice, patients should update their vaccines at least two weeks before treatment. They need immunizations because they are more likely to get invasive Neisseria meningitidis and other bacterial diseases. [CDER, 2023]

III. CD55 Downregulation in Other Diseases

Beyond CHAPLE Disease there are other conditions where CD55 is downregulated. For instance, Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by the somatic mutation of X-linked gene PIG-A, required for glycosylphosphatidylinositol (GPI)-anchor biosynthesis. This results in absent or decreased expression of all membrane proteins normally anchored by GPI - including CD55 and CD59 - in all circulating cells, leading to an unusual sensitivity of red blood cells (RBCs) to complement lysis and subsequently intravascular hemolysis and hemoglobinuria. [Shah, 2023]

Additionally, the presence of CD55- and/or CD59-deficient erythrocytes has been observed in patients with rheumatic diseases. The aim of this study was to evaluate the presence of “PNH-like” red-cell populations in patients with rheumatic diseases and investigate possible correlations with clinical or laboratory parameters. [Meletis, 2014]

IV. Conclusion

CHAPLE Disease provides a paradigm for complement-mediated diseases through its involvement in pathogenic cross-activation of the coagulation system, leading to severe thrombosis. This characteristic is shared with other complement disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). [Lenardo, 2021] [Lavelle, 2017]

By understanding the mechanisms underlying CHAPLE Disease, specifically the pathogenic cross-activation of the coagulation system, researchers can gain insights into the broader processes involved in complement-mediated diseases. This knowledge can be applied to other conditions associated with dysregulated complement activation and thrombosis, potentially leading to improved diagnosis, treatment, and management strategies for patients with complement-mediated disorders.

V. Sources

■ CDER. “FDA Approves First Treatment for CD55-Deficient Protein-Losing Enteropathy (CHAPLE Disease).” U.S. Food and Drug Administration, FDA, 18 Aug. 2023, www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-cd55-deficient-protein-losing-enteropathy-chaple-disease.

■ Dho, So Hee, et al. “Beyond the role of CD55 as a complement component.” Immune Network, vol. 18, no. 1, Feb. 2018, p. e11, https://doi.org/10.4110/in.2018.18.e11.

■ Drugscom. “Eculizumab Side Effects: Common, Severe, Long Term.” Drugs.Com, 7 Dec. 2022, www.drugs.com/sfx/eculizumab-side-effects.html.

■ “Eculizumab.” Uses, Interactions, Mechanism of Action | DrugBank Online, Oct. 2020, go.drugbank.com/drugs/DB01257. 

■ Lavelle, Judith. “NIAID Scientists Identify Cause, Possible Treatment for Life-Threatening Gut Condition.” National Institutes of Health, U.S. Department of Health and Human Services, 29 June 2017, www.nih.gov/news-events/news-releases/niaid-scientists-identify-cause-possible-treatment-life-threatening-gut-condition.

■ Lenardo, Michael J., et al. “EP3512964B1 - Methods of Diagnosing and Treating CD55 Deficiency, Hyperactivation of Complement, Angiopathic Thrombosis and Protein Losing Enteropathy (Chaple), a Newly Identified Orphan Disease.” Google Patents, Google, 15 Dec. 2021, patents.google.com/patent/EP3512964B1/en?oq=PCT%2FUS2017%2F051413.

■ Meletis, John. “The presence of CD55- and/or CD59-deficient erythrocytic populations in patients with rheumatic diseases reflects an immune-mediated bone-marrow derived phenomenon.” Medical Science Monitor, vol. 20, 27 Jan. 2014, pp. 123–139, https://doi.org/10.12659/msm.889727.

■ Ozen, Ahmet, et al. “CD55 deficiency, early-onset protein-losing enteropathy, and thrombosis.” New England Journal of Medicine, vol. 377, no. 1, 6 July 2017, pp. 52–61, https://doi.org/10.1056/nejmoa1615887.

■ “Pozelimab.” Uses, Interactions, Mechanism of Action | DrugBank Online, 2 Sept. 2023, go.drugbank.com/drugs/DB15218.

■ Prabhu, Yogikala. “Methods of Diagnosing and Treating CHAPLE, A Newly Identified Orphan Disease: Collaborative Research and Licensing Opportunity.” Nature News, Nature Publishing Group, 2022, www.nature.com/articles/d43747-020-00626-y.

■ Shah, Nischay, and Harshil Bhatt. “Paroxysmal Nocturnal Hemoglobinuria .” StatPearls, NCBI, 31 July 2023, www.ncbi.nlm.nih.gov/books/NBK562292/.

■ Ramsey, Taylor, and Vesna Tosic. “Pozelimab (C5 Antibody) BLA for Treatment of Children and Adults with Ultra-Rare Chaple Disease Accepted for FDA Priority Review.” Regeneron Pharmaceuticals Inc., 21 Feb. 2023, investor.regeneron.com/news-releases/news-release-details/pozelimab-c5-antibody-bla-treatment-children-and-adults-ultra.  

■ Regeneron. “What Is Chaple Disease?” Whatischaple.Com, Regeneron Pharmaceuticals, June 2023, www.whatischaple.com/.

VI. About The Author

David  Orchard-Webb, Ph.D., is a technical writer with broad interests including  health & technology writing, plus extensive training and knowledge of  biomedicine and microbiology. My Ph.D. and postdoc were in oncology and  developing cancer medicines. I provide technical medical and other writing  services for projects ranging from “knowledge automation” to pure pharma, to  food safety, to the history of science, and everything in between. I also  provide white papers, ebooks, meta-analysis reviews, editing, consulting,  business, and market research-related activities in biomedicine, technology,  and health. In addition to its well-known role in the development of  medicines, I am a big believer in biotechnology’s ability to revolutionize  industries such as food-tech, agtech, textiles & fashion.