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Switching between complement inhibitors in paroxysmal nocturnal hemoglobinuria: Analysis of strategy, efficacy, and
Morag Griffin1, Bruno Fattizzo2,3, Jong Wook Lee4
1Haematology Department St James University Hospital Leeds United Kingdom.
Insights
Patients with paroxysmal nocturnal hemoglobinuria (PNH) switching complement inhibitors (CIs) may not need overlapping treatment. Close monitoring for hemolysis is crucial, particularly when shifting from proximal to terminal inhibition.
Area of Science:
- Hematology
- Rare Diseases
- Pharmacology
Background:
- Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-orphan hematologic disorder.
- Multiple complement inhibitors (CIs), including C5 inhibitors and proximal inhibitors (PIs), are approved for PNH treatment.
- Clinical guidelines exist for switching from terminal to proximal CIs, but not for switching from PIs to other CIs.
Purpose of the Study:
- To analyze the safety and outcomes of treatment changes between different classes of complement inhibitors in patients with PNH.
- To provide real-world data on managing treatment transitions in PNH patients with multiple CI changes.
- To assess the occurrence of hemolytic events following different types of CI switches.
Main Methods:
- International cohort study including 65 PNH patients who switched from a proximal inhibitor (PI) to a different CI.
- Analysis of 149 CI treatment changes, categorized as terminal-to-proximal, proximal-to-proximal, and proximal-to-terminal.
- Monitoring for hemolytic events within 14 days of CI switch.
Main Results:
- Hemolytic events occurred in 6/75 terminal-to-proximal switches, 2/45 proximal-to-proximal switches, and 13/29 proximal-to-terminal switches.
- Overlapping treatment for PI-to-other CI switches was not required.
- Tapering treatment did not appear effective in preventing hemolysis.
Conclusions:
- Treatment interruption or overlapping is not necessary when switching PIs to other CIs in PNH.
- Patients switching from proximal to terminal CIs require close monitoring for hemolysis.
- Further prospective studies are recommended to optimize management strategies for PNH patients undergoing multiple CI changes.
Abstract:
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-orphan disease. In 2026, approved complement inhibitors (CIs) for PNH include three C5 inhibitors (C5i) and three proximal inhibitors (PIs). Clinical trials for the approved PI pegcetacoplan, iptacopan, and C5i + danicopan had clear protocols for changing from terminal to PI, extrapolated into real-world practice. There is no guidance for patients changing from a PI to a different CI. We present the largest international cohort to date. The inclusion criteria were as follows: patients established on a PI, who have changed treatment to a different CI. Sixty-five patients with a median age at PNH diagnosis of 40 years were included. Indications for CI switch were as follows: hemolysis (extravascular/recurrent breakthrough/not specified), side effects, trial termination, patient choice, and other. CI changes (149) were classified as (1) terminal-to-proximal (75/149), 6 hemolytic events reported within 14 days of CI change; (2) proximal-to-proximal (45/149), 2 hemolytic events reported within 14 days of CI change; and (3) proximal-to-terminal (29/149), 13 hemolytic events within 14 days of CI change. This is the largest cohort of PNH patients facing multiple CI changes. With the increasing availability of different CI classes, patients may experience several treatment changes over their disease course. CI should not be interrupted. The cohort would suggest that overlapping treatment for patients changing from PI to another CI is not required. Tapering of treatment does not seem to be effective at preventing hemolysis complications. Patients should be monitored closely for hemolysis, especially when changing from proximal-to-terminal inhibition. Prospective clinical/laboratory analysis is recommended for further clarification management for this patient group.
