Long‐term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2‐year results from two pivotal phase 3 studies

Abstract

Objectives: The complement component 5 (C5) inhibitor ravulizumab demonstrated non-inferiority to eculizumab following 26 weeks of treatment in complement inhibitor-naïve and complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH; studies 301 and 302, respectively). This study aims to describe the results of both studies from 27 weeks to 2 years.Methods: Patients (N = 441) continued to receive ravulizumab throughout the extension period. Efficacy endpoints included lactate dehydrogenase (LDH) normalization, transfusion avoidance and fatigue score (FACIT-F). Safety analyses were also performed.Results: From 27 weeks to 2 years, improvements in LDH levels were maintained in both study populations. Transfusion avoidance was maintained in 81.9% (study 301) and 85.6% (study 302) of patients, and FACIT-F scores remained stable. Ravulizumab was well tolerated, and the incidence of adverse events (AEs) were similar between patients of both studies. Incidence of serious AEs deemed related to ravulizumab treatment was low (<3%).Conclusions: This study reports, to date, the longest period of follow-up in over 400 patients with PNH treated with ravulizumab (662 patient-years). Long-term, ravulizumab demonstrated durable efficacy and was well tolerated, highlighting the importance of C5 inhibitors as the mainstay of PNH treatment.

Low‐molecular weight inhibitors of the alternative complement pathway

“…As the key component of the alternative pathway, the C3 convertase (C3bBb), is predominantly activated locally on cell surfaces, alternative pathway-driven diseases often manifest locally. However, several of these diseases also display signs of systemic pathway activation, for example, through the production of soluble complement activation and inactivation Genetic: Mutations in the X-linked phosphatidylinositol glycan class A (PIG-A) gene on some hematopoietic stem cell clones reduces membrane expression the C3bBb regulator CD55 and the C9 regulator CD59 135 Functional: Erythrocytes from conditional PIG-A −/− mice show sensitivity to complement attack, 136,137 PNH patient erythrocytes are susceptible to complement lysis 138 Pharmacological: Clinical efficacy of eculizumab 139 and ravulizumab 140 116 and humanized C3 mice lacking C3 regulation by (murine factors 152 ) show C3G-like disease Pharmacological: Case report for efficacy of eculizumab in C3G 153,154 Danicopan BCX9930 Iptacopan 2. Autoantibody-mediated diseases with secondary involvement of the AP…”

The importance of terminal complement inhibition in paroxysmal nocturnal hemoglobinuria

“… 28 , 57 , 58 However, there was one fatal case of meningococcal sepsis 2.2 years after a patient received their first dose of ravulizumab. 88 …”

“…According to the results from pivotal phase 3 clinical trials of eculizumab and ravulizumab in PNH, 17 , 28 , 29 , 43 , 57 , 58 , 88 and the findings of a 10-year eculizumab pharmacovigilance analysis (in patients with PNH and atypical hemolytic uremic syndrome), 44 both drugs are well tolerated. The most frequently reported adverse events were headache, nasopharyngitis, fatigue, and upper respiratory tract infection, and no new safety risks apart from meningococcal infection were reported.…”

Thrombosis in Pregnant Women with Hemolytic Anemia

“…Phase 3 clinical trials demonstrated comparable safety and tolerability of eculizumab and ravulizumab. 37,38 Long-term experience of using eculizumab provided evidence that mitigates initial concerns about infectious events. To minimize the risk of meningococcal infections, associated with complement inhibitors, vaccination and monitoring are recommended.…”