Evaluating the efficacy and safety of pozelimab in patients with CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy disease: an open-label phase 2 and 3 study

Abstract

Background: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5.

Methods: This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting.

Findings: 11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab.

Interpretation: Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab.

Funding: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Figure 1:. Serum albumin, albumin transfusions, and hospitalizations over time

Panel A is a plot of serum albumin concentration as a function of time. Each colored line represents a patient. Horizontal line at 3·5 g/dL is the lower range of the normal per the local clinical laboratory. Panel B is a plot of albumin transfusions (“X” symbols) as a function of time. Pre-study albumin transfusions were collected from medical history and prior/concomitant medications, and on-study albumin transfusions were captured as adverse events. Panel C is a plot of the post hoc analysis of hospitalizations due to either ≥1 sign or symptom of CHAPLE disease or complications of CHAPLE disease (“X” symbols) as a function of time. Pre-study hospitalizations are based on historical medical records of hospitalizations regardless of reason or duration. On-study hospitalizations were defined as admission to a hospital or emergency room for longer than 24 hours. For panels B and C, each bar represents a patient, and the length of the bar represents the time to the last scheduled visit prior to the cut-off date. Data in all panels are plotted from 48 weeks prior to baseline through the data cut-off date of May 24, 2022. Treatment was initiated at study day 1. Full Analysis Set presented.

Figure 1:. Serum albumin, albumin transfusions, and hospitalizations over time

Panel A is a plot of serum albumin concentration as a function of time. Each colored line represents a patient. Horizontal line at 3·5 g/dL is the lower range of the normal per the local clinical laboratory. Panel B is a plot of albumin transfusions (“X” symbols) as a function of time. Pre-study albumin transfusions were collected from medical history and prior/concomitant medications, and on-study albumin transfusions were captured as adverse events. Panel C is a plot of the post hoc analysis of hospitalizations due to either ≥1 sign or symptom of CHAPLE disease or complications of CHAPLE disease (“X” symbols) as a function of time. Pre-study hospitalizations are based on historical medical records of hospitalizations regardless of reason or duration. On-study hospitalizations were defined as admission to a hospital or emergency room for longer than 24 hours. For panels B and C, each bar represents a patient, and the length of the bar represents the time to the last scheduled visit prior to the cut-off date. Data in all panels are plotted from 48 weeks prior to baseline through the data cut-off date of May 24, 2022. Treatment was initiated at study day 1. Full Analysis Set presented.

Figure 2:. Body weight-for-age and stature-for-age based on the CDC growth charts

Panels A and B are the weight-for-age plots for males (four patients) and females (six patients), respectively. Panels C and D are the stature-for-age plots for males (four patients) and females (six patients), respectively. Each line and corresponding colored symbol represents a patient. Arrows indicate the first administration of pozelimab. Percentiles are sourced from the CDC (https://www.cdc.gov/growthcharts/percentile_data_files.htm). Full Analysis Set presented.

Figure 2:. Body weight-for-age and stature-for-age based on the CDC growth charts

Panels A and B are the weight-for-age plots for males (four patients) and females (six patients), respectively. Panels C and D are the stature-for-age plots for males (four patients) and females (six patients), respectively. Each line and corresponding colored symbol represents a patient. Arrows indicate the first administration of pozelimab. Percentiles are sourced from the CDC (https://www.cdc.gov/growthcharts/percentile_data_files.htm). Full Analysis Set presented.

Figure 2:. Body weight-for-age and stature-for-age based on the CDC growth charts

Panels A and B are the weight-for-age plots for males (four patients) and females (six patients), respectively. Panels C and D are the stature-for-age plots for males (four patients) and females (six patients), respectively. Each line and corresponding colored symbol represents a patient. Arrows indicate the first administration of pozelimab. Percentiles are sourced from the CDC (https://www.cdc.gov/growthcharts/percentile_data_files.htm). Full Analysis Set presented.

Figure 2:. Body weight-for-age and stature-for-age based on the CDC growth charts

Panels A and B are the weight-for-age plots for males (four patients) and females (six patients), respectively. Panels C and D are the stature-for-age plots for males (four patients) and females (six patients), respectively. Each line and corresponding colored symbol represents a patient. Arrows indicate the first administration of pozelimab. Percentiles are sourced from the CDC (https://www.cdc.gov/growthcharts/percentile_data_files.htm). Full Analysis Set presented.

Figure 3:. Physician assessments of facial and peripheral edema over time

Panels A and B show data for facial and peripheral edema, respectively. Data are plotted from baseline through the data cut-off date of May 24, 2022. Each line represents a patient. Severity assessed with response levels of: 1 = no edema, 2 = mild edema, 3 = moderate edema, 4 = severe edema, 5 = very severe edema. Full Analysis Set presented. BL, baseline; WK, week.