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IPIG 2025 | A Phase IV trial assessing the switch from high-dose eculizumab to weight-based ravulizumab in PNH
Austin Kulasekararaj, MBBS, MD, MRCP, FRCPath, King’s College Hospital NHS Foundation Trust, London, UK, comments on the safety and efficacy of switching from high-dose intravenous eculizumab to weight-based intravenous ravulizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH). A Phase IV trial conducted in the United Kingdom (NCT04320602) found that patients could tolerate the switch without significant complications, highlighting the potential benefits of this treatment approach. This interview took place at the 2nd International PNH Interest Group (IPIG) Conference in Paris, France.
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Transcript
Historically, when we had eculizumab as the only treatment available for treating patients with PNH, the dose of eculizumab was not done in a systematic way when this drug was first indicated in the treatment of PNH. So we gave 900 milligram as a maintenance dose every two weeks, while compared to atypical HUS where it’s indicated the dose was 1200 milligram every two weeks, same drug, similar condition of complement activation...
Historically, when we had eculizumab as the only treatment available for treating patients with PNH, the dose of eculizumab was not done in a systematic way when this drug was first indicated in the treatment of PNH. So we gave 900 milligram as a maintenance dose every two weeks, while compared to atypical HUS where it’s indicated the dose was 1200 milligram every two weeks, same drug, similar condition of complement activation.
So additionally we found right from the pilot data of 11 patients there was 20 percent of patients who would have needed a higher dose of eculizumab to keep the complement activation at control in a steady state over this two-week period. So we conventionally up-dosed these group of patients to 1200 milligram of eculizumab, even higher doses of 1500 and occasionally 1800 as well in rare scenarios.
Unfortunately, these group of patients above the 900 milligram standard dose were unable to go into the pivotal ravulizumab clinical trials because the trial only included patients with the baseline dose, i.e. approved dose of 900 milligram. So this prompted a very UK-specific trial because we had two centers treating patients with PNH. We knew we had a good proportion of patients who were on a higher than standard dose of eculizumab who were not eligible to other clinical trials. And this is where the concept of doing a Phase IV trial, i.e. switching all these patients from 1200 milligram with the run-in period of three months to see what their stability is during that three months of eculizumab 1200 and then switch them over for a year’s worth of ravulizumab and again we were very pleased to note that these patients did not have any significant complications, they were able to tolerate the higher dose of ravulizumab without any significant evidence of breakthrough hemolysis either clinically or biochemically or based on PKPD which was one of the main primary drivers of the study.
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Disclosures
Research support (to institution): Celgene/BMS, Novartis; Consultant: Samsung, Novo Nordisk, Alexion/AstraZeneca, Arrowhead Pharmaceuticals, Silence Therapeutics, AdaRx, Ono Pharma; Speaker’s fees: Alexion/AstraZeneca, Amgen, Celgene/BMS, Pfizer, Novartis, Ra Pharmaceuticals/UCB, Roche, Sobi, Janssen; Scientific advisory board/data monitoring committee: Alexion/Astra Zeneca, Apellis, Amgen, Agios, BioCryst, Celgene/BMS, Geron, Novartis, Pfizer, Regeneron, Roche, Sobi, Janssen, Samsung.
