RARE DISEASE
Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome
Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome
Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome
Synonyms: CD55 deficiency, CHAPLE syndrome
Synonyms: CD55 deficiency, CHAPLE syndrome
Synonyms: CD55 deficiency, CHAPLE syndrome
Drug discovery
1
drug
With orphan designation
Overview
Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy (CHAPLE) syndrome is an ultra-rare autosomal recessive disorder caused by biallelic CD55 mutations, resulting in impaired complement regulation. This leads to systemic complement hyperactivation, lymphatic intestinal damage, and protein-losing enteropathy. Clinical features include abdominal pain, vomiting, diarrhea, hypoproteinemic edema, malnutrition, recurrent infections (due to hypogammaglobulinemia), and life-threatening thromboembolic events [1][3][8]. Diagnosis is confirmed via genetic testing and low serum CD55 expression [6][8].
Burden
Mortality: 20% risk of fatal thromboembolism without treatment [6][8]
Morbidity: Growth failure (100%), chronic anemia (91%), and recurrent hospitalizations for hypoalbuminemia/infections [1][6]
Quality of life: Severe GI dysfunction limits oral intake and daily activities, with 70% requiring transfusions pre-treatment [6][8]
Therapies
Targeted therapy: Pozelimab (C5 inhibitor) – FDA-approved first-line treatment showing serum albumin normalization and symptom resolution [7][8]
Supportive care: Albumin infusions, immunoglobulin replacement, anticoagulants, and nutritional support (less effective without complement inhibition) [3][6]
Investigational: Eculizumab (anti-C5 monoclonal antibody) demonstrated efficacy in early trials [3][6]
Categories: rare gastroenterological diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
108 drug discovery papers about Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
108 drug discovery papers about Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-17 | Targeted complement inhibition with pozelimab in children with CD55 deficiency.
CHAPLE syndrome is an ultra-rare genetic cause of protein-losing enteropathy (PLE) resulting from uncontrolled complement activation due to CD55 deficiency. We report two paediatric patients presenting with recurrent diarrhoea, hypoalbuminaemia, hypogammaglobulinaemia and growth failure, both initially evaluated as intestinal lymphangiectasia. Persistent symptoms and poor response to conventional therapy prompted genetic evaluation, which revealed pathogenic variants in the CD55 gene in both children, confirming the diagnosis of CHAPLE syndrome. Both patients required repeated albumin and intravenous immunoglobulin replacement prior to diagnosis. Targeted therapy with pozelimab was initiated. Rapid clinical and biochemical improvement was observed within 2 weeks, with sustained normalisation of albumin, total protein and immunoglobulin levels. At 3-month follow-up, both children remained in clinical remission without further need for albumin or immunoglobulin infusions. These cases highlight the importance of considering genetic causes in children with refractory PLE and demonstrate the effectiveness of early targeted complement inhibition in CHAPLE syndrome.
2026-05-28 | C5 inhibition restores B cell homeostasis and humoral immunity in CHAPLE disease patients.
CHAPLE disease is a monogenic disorder in which CD55 deficiency drives gastrointestinal pathology. How CD55 deficiency affects adaptive immunity is unknown. Herein, molecularly, we characterize eight patients with genetically novel CD55 deficiency. Clinically, all patients developed early-onset protein-losing enteropathy, frequently complicated by thrombotic events, inflammatory bowel disease-like lesions, and recurrent respiratory infections. Ex vivo, immunophenotyping revealed disruption of the B cell compartment, marked by depletion of transitional B cells, expansion of CD21lo B cells, and accumulation of class-switched memory B cells and plasmablasts, while T cell subsets were largely preserved. In vivo, eculizumab rapidly resolved intestinal pathology, normalized serum albumin and immunoglobulin levels, and re-established a normal B cell profile. Furthermore, C5 inhibition enabled effective humoral protection and optimal pneumococcal vaccine responses. Together, these findings establish complement inhibition as central to B cell homeostasis in CHAPLE disease.
2026-04-01 | P15 When N <100: compassionate use of a novel therapy in CHAPLE syndrome
C H A P L E syndrome (CD55 deficiency) is an ultra-rare primary immunodeficiency, with fewer than 100 cases reported globally. 1 A paediatric patient at a tertiary paediatric centre in the United Kingdom was granted compassionate access to pozelimab, a novel monoclonal antibody imported from the United States. Delivering this treatment required close multidisciplinary collaboration between the consultant immunologist, specialist nurse, and pharmacy teams, including clinical, quality assurance, and procurement.The pharmacy team ensured the clinical appropriateness of the treatment through independent evaluation of the patient’s condition and the available evidence. In the absence of established protocols or reference sources, they implemented clinical governance measures to support safe prescribing and administration, including documentation, dosing guidance, and risk mitigation strategies. Pharmacists played an active role in patient and family engagement, providing education and counselling to support informed decision-making. In parallel, the pharmacy team also managed regulatory liaison, importation, and arrangements for continued supply.An online meeting was held with the patient and parent to explore their perspectives on the compassionate use process. The patient, who had previously received immunosuppressants including biologics, expressed relief at finally having a confirmed diagnosis and a treatment specifically targeting her condition. Although initially concerned about side effects, she understood the associated risks from prior experience and felt reassured. She preferred receiving verbal information from the consultant, nurse, and pharmacist but felt written material would be helpful for future reference. She was surprised that the medication came in a vial rather than a prefilled pen or syringe but ultimately preferred the vial and appreciated the team’s efforts to explore pain-minimising techniques that worked for her.The parent also expressed relief at the diagnosis, but noted difficulty accessing peer support or patient experiences due to the rarity of the condition. Despite receiving written materials and links to the manufacturer’s website, she felt reading about others’ experiences would have offered greater reassurance when deciding to start treatment. She highly praised the multidisciplinary approach and the effectiveness of communication across the team. The pharmacist’s presence during the first administration was particularly valued, though she suggested earlier pharmacy involvement—ideally when the drug was first proposed in clinic—would have been beneficial. She also identified a need for more lifestyle and dietary guidance to support ongoing care. Overall, both parent and patient felt supported in their decision to begin treatment and expressed high satisfaction with the pharmacy team’s contribution and the collaborative approach.Conclusion Delivering compassionate use treatment for ultra-rare diseases requires coordinated, multidisciplinary care. The input of the consultant, nurse, and pharmacy teams was central to supporting the family and ensuring treatment was initiated safely. This case highlights the importance of early pharmacy involvement, structured governance processes, and person-centred communication. Patient and parent feedback reinforced the value of accessible information and the reassurance provided by collaborative, transparent care in the context of rare disease management.Reference Litcher-Kelly L, Ozen A, Ollis S, et al. The patient experience of CHAPLE disease: results from interviews conducted as part of a clinical trial for an ultra-rare condition. Orphanet Journal of Rare Diseases 2025;20:68.
2026-03-24 | Evaluating pozelimab in the treatment of CHAPLE disease.
CHAPLE disease (Complement Hyperactivation, Angiopathic Thrombosis, and Protein-Losing Enteropathy [PLE]) is a rare, life-threatening disorder caused by biallelic mutations in the CD55 gene, which encodes decay-accelerating factor, a key regulator of the complement system. The disease typically manifests in early childhood with hypoalbuminemic edema, gastrointestinal symptoms, recurrent infections, and failure to thrive, alongside an elevated thrombotic risk due to complement-mediated endothelial injury and coagulation activation. Given these pathogenetic mechanisms, complement-targeted therapies have emerged as a rational approach to disease management. Eculizumab, a monoclonal antibody against complement component C5, initially demonstrated clinical benefit when administered on a compassionate-use basis. Building upon this success, pozelimab, a next-generation subcutaneous anti-C5 monoclonal antibody, was evaluated in CHAPLE patients and subsequently received U.S. FDA approval for this indication. Pozelimab effectively inhibits terminal complement activation, leading to sustained remission of PLE, obviating the need for albumin replacement, reducing hospitalization rates, improving symptom control and nutritional status, and ultimately enhancing overall quality of life. This review highlights the evolving role of pozelimab in CHAPLE disease by discussing its mechanistic basis, emerging clinical evidence, and implications for patient-centered care.
2025-11-22 | The Critical Role of Biochemical and Genetic Diagnosis in Differentiating CHAPLE Syndrome from Treatment-Resistant IBD: A Case Study
Background: CHAPLE syndrome (Complement Hyperactivation, Angiopathic Thrombosis, and Protein-Losing Enteropathy) is an extremely rare and life-threatening monogenic disease caused by loss-of-function mutations of CD55 leading to dysregulation of the alternative complement pathway. The clinical pattern characterized by PLE and chronic inflammatory disease is frequently misattributed to idiopathic bowel disease (IBD) with consequent inappropriate and prolonged treatment with immunosuppressive drugs. Methods: We report on a 6-year-old boy with early-onset chronic diarrhea, failure to thrive and steroid-dependent PLE that was initially identified as IBD. To resolve the diagnostic confusion, a fulminant biochemical and genetic lookups were performed. Results: This patient's sustained biochemical abnormalities severe hypoalbuminemia (15-22 g/L), profound thrombocytosis (platelets> 800 x 10⁹/l) and dimorphic anaemia were unrelated to traditional IBD. Genetic central sequencing demonstrated a homozygous deleterious CD55 variant, confirming the diagnosis of CHAPLE syndrome. This diagnosis provided the pathophysiological explanation for complement activation. Discussion: Treatment was consequently changed from corticosteroids to pozelimab, a complement C5 inhibitor monoclonal antibody. This therapy resulted in a prompt normalization of serum albumin and relief from gastrointestinal symptoms with subsequent prolonged clinical remission. Conclusions: We report a case, which highlights that a particular combination of biochemical aberrations in a previously well individual with refractory IBD should bring to mind monogenic causes including CHAPLE syndrome. Genetic testing is the best and most accurate way to diagnose a disorder. It is a revolution in the treatment of disease: away from nonspecific suppression of the immune system and toward targeted biologic therapy aimed at its precise cause — with dramatically better outcomes. Identification of these patterns and advising on confirmatory testing is a responsibility of clinical biochemists.
2026-08-17 | Targeted complement inhibition with pozelimab in children with CD55 deficiency.
CHAPLE syndrome is an ultra-rare genetic cause of protein-losing enteropathy (PLE) resulting from uncontrolled complement activation due to CD55 deficiency. We report two paediatric patients presenting with recurrent diarrhoea, hypoalbuminaemia, hypogammaglobulinaemia and growth failure, both initially evaluated as intestinal lymphangiectasia. Persistent symptoms and poor response to conventional therapy prompted genetic evaluation, which revealed pathogenic variants in the CD55 gene in both children, confirming the diagnosis of CHAPLE syndrome. Both patients required repeated albumin and intravenous immunoglobulin replacement prior to diagnosis. Targeted therapy with pozelimab was initiated. Rapid clinical and biochemical improvement was observed within 2 weeks, with sustained normalisation of albumin, total protein and immunoglobulin levels. At 3-month follow-up, both children remained in clinical remission without further need for albumin or immunoglobulin infusions. These cases highlight the importance of considering genetic causes in children with refractory PLE and demonstrate the effectiveness of early targeted complement inhibition in CHAPLE syndrome.
2026-05-28 | C5 inhibition restores B cell homeostasis and humoral immunity in CHAPLE disease patients.
CHAPLE disease is a monogenic disorder in which CD55 deficiency drives gastrointestinal pathology. How CD55 deficiency affects adaptive immunity is unknown. Herein, molecularly, we characterize eight patients with genetically novel CD55 deficiency. Clinically, all patients developed early-onset protein-losing enteropathy, frequently complicated by thrombotic events, inflammatory bowel disease-like lesions, and recurrent respiratory infections. Ex vivo, immunophenotyping revealed disruption of the B cell compartment, marked by depletion of transitional B cells, expansion of CD21lo B cells, and accumulation of class-switched memory B cells and plasmablasts, while T cell subsets were largely preserved. In vivo, eculizumab rapidly resolved intestinal pathology, normalized serum albumin and immunoglobulin levels, and re-established a normal B cell profile. Furthermore, C5 inhibition enabled effective humoral protection and optimal pneumococcal vaccine responses. Together, these findings establish complement inhibition as central to B cell homeostasis in CHAPLE disease.
2026-04-01 | P15 When N <100: compassionate use of a novel therapy in CHAPLE syndrome
C H A P L E syndrome (CD55 deficiency) is an ultra-rare primary immunodeficiency, with fewer than 100 cases reported globally. 1 A paediatric patient at a tertiary paediatric centre in the United Kingdom was granted compassionate access to pozelimab, a novel monoclonal antibody imported from the United States. Delivering this treatment required close multidisciplinary collaboration between the consultant immunologist, specialist nurse, and pharmacy teams, including clinical, quality assurance, and procurement.The pharmacy team ensured the clinical appropriateness of the treatment through independent evaluation of the patient’s condition and the available evidence. In the absence of established protocols or reference sources, they implemented clinical governance measures to support safe prescribing and administration, including documentation, dosing guidance, and risk mitigation strategies. Pharmacists played an active role in patient and family engagement, providing education and counselling to support informed decision-making. In parallel, the pharmacy team also managed regulatory liaison, importation, and arrangements for continued supply.An online meeting was held with the patient and parent to explore their perspectives on the compassionate use process. The patient, who had previously received immunosuppressants including biologics, expressed relief at finally having a confirmed diagnosis and a treatment specifically targeting her condition. Although initially concerned about side effects, she understood the associated risks from prior experience and felt reassured. She preferred receiving verbal information from the consultant, nurse, and pharmacist but felt written material would be helpful for future reference. She was surprised that the medication came in a vial rather than a prefilled pen or syringe but ultimately preferred the vial and appreciated the team’s efforts to explore pain-minimising techniques that worked for her.The parent also expressed relief at the diagnosis, but noted difficulty accessing peer support or patient experiences due to the rarity of the condition. Despite receiving written materials and links to the manufacturer’s website, she felt reading about others’ experiences would have offered greater reassurance when deciding to start treatment. She highly praised the multidisciplinary approach and the effectiveness of communication across the team. The pharmacist’s presence during the first administration was particularly valued, though she suggested earlier pharmacy involvement—ideally when the drug was first proposed in clinic—would have been beneficial. She also identified a need for more lifestyle and dietary guidance to support ongoing care. Overall, both parent and patient felt supported in their decision to begin treatment and expressed high satisfaction with the pharmacy team’s contribution and the collaborative approach.Conclusion Delivering compassionate use treatment for ultra-rare diseases requires coordinated, multidisciplinary care. The input of the consultant, nurse, and pharmacy teams was central to supporting the family and ensuring treatment was initiated safely. This case highlights the importance of early pharmacy involvement, structured governance processes, and person-centred communication. Patient and parent feedback reinforced the value of accessible information and the reassurance provided by collaborative, transparent care in the context of rare disease management.Reference Litcher-Kelly L, Ozen A, Ollis S, et al. The patient experience of CHAPLE disease: results from interviews conducted as part of a clinical trial for an ultra-rare condition. Orphanet Journal of Rare Diseases 2025;20:68.
2026-03-24 | Evaluating pozelimab in the treatment of CHAPLE disease.
CHAPLE disease (Complement Hyperactivation, Angiopathic Thrombosis, and Protein-Losing Enteropathy [PLE]) is a rare, life-threatening disorder caused by biallelic mutations in the CD55 gene, which encodes decay-accelerating factor, a key regulator of the complement system. The disease typically manifests in early childhood with hypoalbuminemic edema, gastrointestinal symptoms, recurrent infections, and failure to thrive, alongside an elevated thrombotic risk due to complement-mediated endothelial injury and coagulation activation. Given these pathogenetic mechanisms, complement-targeted therapies have emerged as a rational approach to disease management. Eculizumab, a monoclonal antibody against complement component C5, initially demonstrated clinical benefit when administered on a compassionate-use basis. Building upon this success, pozelimab, a next-generation subcutaneous anti-C5 monoclonal antibody, was evaluated in CHAPLE patients and subsequently received U.S. FDA approval for this indication. Pozelimab effectively inhibits terminal complement activation, leading to sustained remission of PLE, obviating the need for albumin replacement, reducing hospitalization rates, improving symptom control and nutritional status, and ultimately enhancing overall quality of life. This review highlights the evolving role of pozelimab in CHAPLE disease by discussing its mechanistic basis, emerging clinical evidence, and implications for patient-centered care.
2025-11-22 | The Critical Role of Biochemical and Genetic Diagnosis in Differentiating CHAPLE Syndrome from Treatment-Resistant IBD: A Case Study
Background: CHAPLE syndrome (Complement Hyperactivation, Angiopathic Thrombosis, and Protein-Losing Enteropathy) is an extremely rare and life-threatening monogenic disease caused by loss-of-function mutations of CD55 leading to dysregulation of the alternative complement pathway. The clinical pattern characterized by PLE and chronic inflammatory disease is frequently misattributed to idiopathic bowel disease (IBD) with consequent inappropriate and prolonged treatment with immunosuppressive drugs. Methods: We report on a 6-year-old boy with early-onset chronic diarrhea, failure to thrive and steroid-dependent PLE that was initially identified as IBD. To resolve the diagnostic confusion, a fulminant biochemical and genetic lookups were performed. Results: This patient's sustained biochemical abnormalities severe hypoalbuminemia (15-22 g/L), profound thrombocytosis (platelets> 800 x 10⁹/l) and dimorphic anaemia were unrelated to traditional IBD. Genetic central sequencing demonstrated a homozygous deleterious CD55 variant, confirming the diagnosis of CHAPLE syndrome. This diagnosis provided the pathophysiological explanation for complement activation. Discussion: Treatment was consequently changed from corticosteroids to pozelimab, a complement C5 inhibitor monoclonal antibody. This therapy resulted in a prompt normalization of serum albumin and relief from gastrointestinal symptoms with subsequent prolonged clinical remission. Conclusions: We report a case, which highlights that a particular combination of biochemical aberrations in a previously well individual with refractory IBD should bring to mind monogenic causes including CHAPLE syndrome. Genetic testing is the best and most accurate way to diagnose a disorder. It is a revolution in the treatment of disease: away from nonspecific suppression of the immune system and toward targeted biologic therapy aimed at its precise cause — with dramatically better outcomes. Identification of these patterns and advising on confirmatory testing is a responsibility of clinical biochemists.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome, including 1 approved therapy.
1 orphan drug designation for Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
pozelimab-bbfg [Veopoz] | antibodies | FDA | 2020-04-13 | 2023-08-18 | Regeneron Pharmaceuticals, Inc. |
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