#2261 2-y crovalimab paroxysmal nocturnal haemoglobinuria (PNH) data for fatigue, a relevant symptom in atypical haemolytic uraemic syndrome (aHUS) and PNH

Abstract Background and Aims aHUS is a rare, life-threatening, complement-mediated disease characterised by thrombotic microangiopathies. Established C5 inhibitors (C5is), such as eculizumab and ravulizumab, are effective for aHUS management but can be burdensome, typically requiring regular intravenous infusions every 2 weeks (eculizumab) or every 8 weeks (ravulizumab). Crovalimab is a novel C5i with low-volume, subcutaneous dosing every 4 weeks, with the possibility for self-administration. Crovalimab is currently being evaluated in two ongoing global, Phase III, single-arm trials in aHUS: COMMUTE-a (NCT04861259) and COMMUTE-p (NCT04958265). Crovalimab has also been evaluated in patients (pts) with PNH, another complement-mediated rare blood disorder, in the global, randomised, Phase III COMMODORE 2 (NCT04434092) and COMMODORE 1 (NCT04432584) trials (Röth AJH 2024; Scheinberg AJH 2024). Fatigue is a debilitating symptom that occurs in both aHUS and PNH. It is among the three most reported symptoms in aHUS (Greenbaum Kidney Int Rep 2020) and is the most common symptom in PNH (Cella J Patient Rep Outcomes 2023). Here, we report Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (Smith PM R 2010) data, a widely used pt-reported outcome (PRO) measure in aHUS and PNH, with a median 2-y follow-up from COMMODORE 2 and 1. Method COMMODORE 2 enrolled C5i-naive pts and COMMODORE 1 enrolled C5i-experienced pts with PNH, respectively. Pts in COMMODORE 2 and 1 were randomised 2:1 and 1:1, respectively, to receive crovalimab (Arm A) or eculizumab (Arm B) during the primary treatment period (baseline to Week 25). After the primary treatment period, pts assigned to the crovalimab arm continued crovalimab (Arm A) and pts assigned to the eculizumab arm (Arm B) switched to crovalimab (Arm B switch) if continuing in the extension period (>Week 25). Fatigue was assessed at scheduled visits from baseline throughout the extension period to Week 97 using FACIT-Fatigue, a 13-item PRO instrument designed to assess fatigue-related symptoms and impacts on daily functioning, with a total score ranging from 0 to 52 (higher scores indicate less fatigue). A ≥5-point increase in FACIT-Fatigue score is considered a clinically meaningful improvement (Cella J Patient Rep Outcomes 2023), and the normative population mean score is 43.5–46.6 (Cella J Pain Symptom Manag 2002; Butt J Pain Symptom Manag 2010; Montan Value Health 2018). Mean FACIT-Fatigue scores are reported. The clinical cutoff date (CCOD) was 12 March 2024. Results In COMMODORE 2, 129 of the 135 pts randomised to crovalimab in Arm A continued crovalimab, and 68 of the 69 pts randomised to eculizumab in Arm B switched to crovalimab (Arm B switch), in the extension period. At the CCOD, 116 pts in Arm A and 59 pts in Arm B switch were receiving ongoing crovalimab treatment. At Week 25, Arm A pts had achieved fatigue levels similar to healthy people without PNH. Mean absolute FACIT-Fatigue scores were maintained from >Week 25 to Week 97 and ranged from 41.9–44.3 in Arm A and 40.3–42.2 in Arm B switch (Fig. 1). In COMMODORE 1, all 44 pts randomised to crovalimab in Arm A continued crovalimab and 40 of the 42 pts randomised to eculizumab in Arm B switched to crovalimab (Arm B switch), in the extension period. At the CCOD, 42 pts in Arm A and 32 pts in Arm B switch were receiving ongoing crovalimab treatment. Mean absolute FACIT-Fatigue scores remained stable from >Week 25 to Week 97 and ranged from 40.8–42.9 in Arm A and 38.2–40.8 in Arm B switch (Fig. 2). Conclusion In COMMODORE 2, the improvements in pt-reported fatigue levels observed with crovalimab in the primary treatment period were maintained over a 2-y median follow-up. Accordingly, in COMMODORE 1, fatigue levels remained stable over this same time frame. Overall, these results indicate the long-term benefit that can be achieved with crovalimab. The COMMUTE-a and COMMUTE-p trials evaluating crovalimab in aHUS are ongoing, including assessment of fatigue using the FACIT-Fatigue PRO measure, given its importance in this population.