Comprehensive analyses of patient-reported outcomes from the phase 3 VERIFY study of rusfertide or placebo plus current standard of care for polycythemia vera

Abstract Background: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by erythrocytosis that is often accompanied by fatigue, pruritus, problems with concentration, and other symptoms. At times, these symptoms can be debilitating. Rusfertide is a first-in-class hepcidin mimetic peptide that controls erythrocytosis. In the ongoing randomized phase 3 VERIFY study (NCT05210790), compared to placebo (PBO) plus current standard of care (SOC), rusfertide added to SOC for PV met its primary endpoint, 2 key secondary patient-reported outcome (PRO) endpoints, and 2 additional key secondary endpoints at Week 32. Here, we present additional data from the 2 key secondary endpoints in VERIFY Part 1a that relied on the PROMIS Fatigue Short Form (SF)-8a and MFSAF Total Symptom Score 7 (TSS7) PROs and PRO-focused exploratory endpoints. Methods: In the VERIFY Part 1a double-blind period (Weeks 0-32), patients (pts) requiring frequent phlebotomy with or without cytoreductive therapy (CRT) to achieve and maintain hematocrit <45% received once-weekly rusfertide or PBO added to pts' current SOC. Two key alpha-controlled secondary endpoints evaluated mean change from baseline (BL) to end of VERIFY Part 1a (Week 32) in the PROMIS Fatigue SF-8a T-score and the MFSAF TSS7 (includes fatigue, night sweats, itch, abdominal discomfort, pain under left ribs, early satiety, and bone pain). Exploratory endpoints included mean change from BL at Week 32 in pts who were symptomatic at BL (ie, pts with moderate or severe symptoms at BL; severity determined using Patient Global Impression of Severity [PGI-S] groupings) in the PROMIS Fatigue SF-8a T-score, the MFSAF TSS4 (ie, PV-relevant symptoms, eg, fatigue, night sweats, itch, and abdominal discomfort), and the single item measuring problems with concentration from the MPN Symptom Assessment Form (MPN-SAF). Negative numbers indicate improvement in all these measures. Results: Pts (N=293; 73.0% male; median age, 57 yrs) received rusfertide (n=147) or PBO (n=146) with or without CRT. At BL, mean (standard deviation [SD]) PROMIS Fatigue SF-8a T-Score was similar in the rusfertide and PBO groups (52.5 [11.7] and 51.2 [10.1], respectively). Mean (SD) change from BL to Week 32 in the PROMIS Fatigue SF-8a T-Score was -3.9 (8.2) and -1.1 (8.1) in the rusfertide and PBO groups, respectively (least-squares means [LSM] difference (standard error [SE]), -1.98 [0.88]; p=0.025). At BL, mean (SD) MFSAF TSS7 was 10.7 (11.4) and 9.5 (10.2) in the rusfertide and PBO groups, respectively. Mean (SD) change from BL to Week 32 in the MFSAF TSS7 was -2.96 (8.0) and -0.06 (5.7) in the rusfertide and PBO groups, respectively (LSM difference [SE], -1.87 [0.82]; p=0.024). In pts who were symptomatic at BL, mean (SD) change from BL to Week 32 was a) -9.8 (8.8) and -5.2 (8.3) for the PROMIS Fatigue SF-8a T-score in the rusfertide and PBO groups, respectively (LSM difference [SE], -3.83 [1.92]; nominal p=0.0496), and b) was -6.4 (5.8) and -1.8 (5.7) for MFSAF TSS4 in the rusfertide and PBO groups, respectively (LSM difference [SE], -4.54 [1.33]; nominal p=0.001). In the rusfertide group, a greater number of pts improved by ≥1 severity category (eg, improvement from “severe” to “moderate”; improvement from “moderate” to “mild”) in the PROMIS Fatigue SF-8a and MFSAF TSS7 vs PBO. In pts who were symptomatic at BL, mean (SD) change from BL to Week 32 in the MPN-SAF problems with concentration item was -2.5 (1.9) and -1.9 (2.2) in the rusfertide and PBO groups, respectively (LSM difference [SE], -1.08 [0.48]; nominal p=0.027). Conclusions: In VERIFY, the first phase 3 study in PV to prospectively investigate PROs as key secondary endpoints, rusfertide led to statistically significant improvements vs PBO in patient-reported symptoms. Rusfertide significantly reduced fatigue and overall symptom burden (PROMIS Fatigue SF-8a and MFSAF TSS7 scores) and resulted in significant improvements from BL (p<0.05) in pts with moderate-to-severe symptoms at BL in core PV symptoms (MFSAF TSS4) and problems with concentration (MPN-SAF) vs PBO. In the rusfertide group, more pts improved by ≥1 severity category in the PROMIS Fatigue SF-8a and MFSAF TSS7 vs PBO. Overall, these results confirm the robustness of rusfertide's clinical benefit in PV, particularly in pts with moderate or severe symptoms at BL. Support: Protagonist Therapeutics, Inc.