Terminal Complement Inhibition and Control of Hemolysis in Paroxysmal Nocturnal Hemoglobinuria Following Switching from High-Dose Eculizumab to Ravulizumab: An Interim Analysis

Background: Intravenous (IV) complement component 5 (C5) inhibitors, eculizumab and ravulizumab, are the current standards of care in patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare chronic blood disorder characterized by terminal complement activation, intravascular hemolysis (IVH), thrombotic events and organ damage. Ravulizumab is a second-generation analog of eculizumab with substitutions of four amino acids in the chemical backbone. This design enables ravulizumab to provide the same clinical benefit as eculizumab in patients with PNH at a longer dosing interval (every 8 weeks [q8w] vs every 2 weeks [q2w]). Approximately 10-15% of patients with PNH who receive the approved, fixed eculizumab dose (900 mg q2w) experience insufficient inhibition of IVH, as characterized by breakthrough hemolysis (BTH) towards the end of the dosing interval. In such patients, increasing the eculizumab dose (to > 900 mg q2w) can be effective. However, currently there are no recommendations or clinical trial data regarding the impact of switching these patients to ravulizumab.

Aim: To assess the safety of switching from high-dose eculizumab to approved, weight-based ravulizumab dosing in patients with PNH.

Methods: Study 401 (NCT04320602) is an ongoing, phase 4, single-arm, multicenter trial designed to investigate the impact of switching treatment from fixed, high-dose IV eculizumab (1200 mg q2w) to weight-based IV ravulizumab q8w in adult (≥ 18 years of age; N = 18) patients with PNH. Prior to (≥ 3 months) screening, patients receive high-dose IV eculizumab (1200 mg q2w); patients continue to receive this throughout the 3-month screening period before switching to weight-based IV ravulizumab. Patients receive loading and maintenance ravulizumab doses, as per the approved prescribing information (Alexion, AstraZeneca Rare Disease. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761108s000lbl.pdf). The primary endpoint is the proportion of patients who experience serum free C5-associated BTH (defined as ≥ 1 new or worsening symptom or sign of IVH [fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia, major adverse vascular events, dysphagia or erectile dysfunction] with lactate dehydrogenase [LDH] levels ≥ 2 × upper limit of normal [ULN] and free C5 concentrations ≥ 0.5 μg/mL). Other endpoints include change in free C5 concentrations and LDH levels over time, and the proportion of patients with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs). This interim analysis describes data up to day 183 of follow-up.

Results: Data for 10/18 enrolled patients (55.6%) were available. Baseline demographics and clinical characteristics are described in Table 1. From baseline to day 183, no instances of free C5-associated BTH were reported and free C5 concentrations remained below 0.5 μg/mL for all patients at all study timepoints (Figure 1). Similarly, from baseline to day 183, LDH levels remained ≤ 1.5 × ULN in all patients. Up to day 183, 7/10 patients (70.0%) reported TEAEs that were mild (n = 3, 30.0%) or moderate (n = 4, 40.0%) in severity. There were no instances of meningococcal infection, TESAEs and none of the documented TEAEs led to death or study withdrawal. BTH was reported in one patient (local laboratory-reported LDH level = 492.0 U/L; local normal range: 120.0-246.0 U/L), this was deemed to be vaccine-related as both coronavirus disease 2019 and influenza vaccinations were administered the day prior to the event. However, no elevated free C5 level was detected in the earliest available sample (0.11 μg/mL, collected four days after the event) and the patient continued ravulizumab treatment.

Conclusions: Results of this interim analysis showed that, based on a small sample of patients with PNH (N = 10), switching treatment from high-dose IV eculizumab (1200 mg q2w) to standard, weight-based IV ravulizumab q8w was well tolerated, with minimal changes in laboratory measures associated with PNH symptoms. Up to day 183, no free C5-associated BTH was reported and the safety profile of ravulizumab was considered comparable to previously published studies, with no instances of meningococcal infection or TESAEs reported.

Griffin:Alexion: Honoraria, Other: Conference support; BioCryst Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: educational work sponsored by Apellis with unrestricted grant paid to Medscape. Gandhi:Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hicks:Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in private company. Jain:Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in private company. Kelly:Biocryst: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: educational work sponsored by Apellis with unrestricted grant paid to Medscape; Swedish Orphan Biovitrum AB: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: conference support; Sobi: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Biologix: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Amgen: Consultancy. Munir:Janssen, AstraZeneca, Alexion, Sobi, Novartis, Roche, Abbvie, Gilead: Honoraria; Janssen, AstraZeneca, Alexion, Abbvie, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Muus:Sobi: Other: travel support , Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Ogawa:Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in private company. Trikha:Sobi: Consultancy. Yu:Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in private company. Kulasekararaj:F. Hoffmann-La Roche: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau; Samsung: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau.