PNH is a clonal disorder of hematopoietic progenitor cells caused by an acquired mutation of the X-linked phosphatidylinositol glycans class A (PIG-A) gene . The absence of glycosylphosphatidylinositol (GPI) anchored complement regulatory proteins CD55 and CD59 from the membrane of circulatory cells is responsible for activation of the complement system on the surface of the red cell membrane. This leads to complement mediated intravascular hemolysis, activation of platelets, and the coagulation cascade resulting in a hypercoagulable state . PNH, although rare, can be fatal and includes an increased risk of thromboembolism and severe end-organ damage. Approximately, 35% of patients die within five years if untreated due to thrombosis and related complications .
Ravulizumab (ALXN1210; Alexion Pharmaceuticals, Inc) is a second generation humanized monoclonal antibody that prevents complement protein 5 (C5) cleavage and activation, ultimately blocking membrane attack complex (MAC) formation in the complement pathway . Ravulizumab is now approved by the FDA to treat PNH. It has an extended 8 weeks maintenance dosing interval and reduces the need for frequent drug administration with subsequent improvement in symptom control and better quality of life.
The complement system activation is a critical component in the sequalae of COVID19 infection. Evidence suggests that severe outcomes in COVID19 infection are attributed to the excessive activation of the complement cascade leading to acute lung injury and associated is with an increased prothrombotic state [2, 4, 11, 12]. Notably, C5a concentration was noted to be higher in patients with COVID19 infection [2, 12]. Based on these observations, complement component blockers can be used as potential therapeutic targets in COVID-19 patients.
Several clinical trials have been ongoing to target the complement mediated inflammatory response in the emerging COVID19 outbreak. An anti C3 agent, compstatin analog Cp40/AMY-101 has shown efficacy in complement mediated severe ARDS in COVID19 patients, and a phase II clinical trial is ongoing . In addition, a multicenter phase II/III trial using monoclonal neutralizing anti-C5a antibody (IFX-1) is recruiting patients with severe COVID19 pneumonia . Following these studies, a phase III trial is underway investigating the effect of ravulizumab (Ultomiris®, Alexion Pharmaceuticals, Boston, MA, USA) in COVID-19 patients on survival, duration of mechanical ventilation, and hospital stay with severe pneumonia/ARDS (NCT04369469, first posted 4/30/2020). Alexion also initiated a clinical trial in critical COVID19 patients on a related drug, eculizumab (Soliris®, Alexion Pharmaceuticals, Boston, MA, USA). However, thus far, therapeutic use of complement inhibitors has not been approved in immunocompromised patients.
Immunocompromised patients are at higher risk for severe COVID19 infections and may experience prolonged hospitalization due to COVID19-related morbidity, and mortality. Additionally, administration of most scheduled anti-cancer treatments may be delayed or interrupted. In our case, the continuation of Raviluzumab during COVID19 infection may have assisted a prompt recovery by attenuating complement activation.
The CDC recommends adopting strategies to minimize the risk of COVID19 exposure, such as limiting contacts between patients and health-care providers. Ravulizumab has a longer therapeutic window and therefore less frequent dosing schedule than eculizumab. We recommend against interrupting or holding the dose of ravulizumab even during systemic inflammation to combat complement mediated tissue damage and multiorgan failure. We also recommend switching the PNH patients who are on eculizumab to every 8 weeks schedule with ravulizumab to minimize exposure to COVID19 and other infections and reduce economic burden on hospital systems due to less frequent dosing.
Given the worldwide COVID19 pandemic, specific clinical and economic cost effective therapeutic options should be explored and prioritized. Treatment with ravulizumab during COVID19 pneumonia was safe, cost-effective, and found to have a favorable clinical course in a patient with PNH. A systemic prospective trial is warranted to demonstrate the utility and usefulness of ravulizumab in patients with PNH in the COVID-19 outbreak.