Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort.

BACKGROUND: Terminal complement pathway deficiencies often present with severe and recurrent infections. There is a lack of good-quality data on these rare conditions. This study investigated the clinical outcome and genetic variation in a large UK multi-center cohort with primary and secondary terminal complement deficiencies. METHODS: Clinicians from seven UK centers provided anonymised demographic, clinical, and laboratory data on patients with terminal complement deficiencies, which were collated and analysed. RESULTS: Forty patients, median age 19 (range 3-62) years, were identified with terminal complement deficiencies. Ten (62%) of 16 patients with low serum C5 concentrations had underlying pathogenic CFH or CFI gene variants. Two-thirds were from consanguineous Asian families, and 80% had an affected family member. The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections. Nine (22%) were treated in intensive care for meningococcal septicaemia. Two patients had died, one from intercurrent COVID-19. Twenty-one (52%) were asymptomatic and diagnosed based on family history. All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics. DISCUSSION: The genetic etiology and clinical course of patients with primary and secondary terminal complement deficiency are variable. Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important. Only half of the patients develop septicaemia, but all should have a clear management plan.

Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019.

INTRODUCTION: Terminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe coronavirus disease 2019 (COVID-19). Ravulizumab, a humanized monoclonal antibody that binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being evaluated as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase 3 randomized controlled trial (ALXN1210-COV-305). To address the overactivation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted. This analysis evaluates preliminary pharmacokinetic/pharmacodynamic data to confirm the modified dosing regimen. METHODS: Weight-based ravulizumab doses were administered on days 1, 5, 10, and 15. Serum levels of ravulizumab and free C5 were measured before and after administration of ravulizumab and any time on day 22. Free C5 levels < 0.5 µg/mL indicate complete C5 inhibition. The pharmacokinetic target was defined as ravulizumab concentrations at the end of the dosing interval > 175 µg/mL, the concentration above which C5 is completely inhibited. RESULTS: Twenty-two patients were included in this evaluation. At baseline, mean C5 concentration was 240 ± 67 µg/mL. In all patients and at all individual timepoints after the first dose was administered, ravulizumab concentrations remained > 175 µg/mL and free C5 concentrations remained < 0.5 µg/mL. CONCLUSION: High levels of baseline C5 observed in patients with severe COVID-19 contribute to the growing body of evidence that suggests this disease is marked by amplification of terminal complement activation. Data from this preliminary pharmacokinetic/pharmacodynamic evaluation of 22 patients with severe COVID-19 show that the modified ravulizumab dosing regimen achieved immediate and complete terminal complement inhibition, which can be sustained for up to 22 days. These data support the continued use of this dosage regimen in the ongoing phase 3 study. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04369469.

While many people have no or mild COVID-19 symptoms, a small number of people become very sick and require hospitalization in intensive care units. One part of their immune system, known as complement, overreacts and attacks the lungs and other organs. Researchers are looking for a way to keep the immune system from attacking the body instead of protecting it. Ravulizumab is a medication currently used to do this in other diseases. Ravulizumab is being studied to see if it can reduce the destructive and deadly effects of the coronavirus infection. In this evaluation, ravulizumab effectively reduced complement in patients with severe COVID-19.