Rusfertide or placebo plus current standard-of-care therapy for polycythemia vera: Durability of response and safety results through week 52 from the randomized controlled phase 3 VERIFY study

Abstract Background: Rusfertide is a weekly, self-administered, subcutaneously injected first-in-class hepcidin mimetic. Previously, we presented data from Part 1a (Weeks [Wks] 0-32) of the phase 3 VERIFY study (NCT05210790) showing that rusfertide added to current standard-of-care (SOC) therapy for polycythemia vera (PV) significantly reduced the mean number of phlebotomies (PHLs), improved hematocrit (Hct) control, and improved patient-reported outcomes addressing fatigue and disease-related symptoms (Kuykendall AT, et al. J Clin Oncol. 2025;43(17_suppl.):LBA3). Herein, we present results from Part 1b (Wks 32-52) to assess the durability of response in patients (pts) who continued rusfertide and the efficacy of rusfertide in pts who crossed over from PBO. Methods: In VERIFY Part 1a (double-blind period), pts requiring frequent PHL (≥3 PHLs in 28 wks or ≥5 in 52 wks prior to randomization) were randomized 1:1 to receive PBO or rusfertide once weekly in addition to current SOC therapy, including cytoreductive therapy (CRT). After completing Part 1a, all pts (including those on PBO) were eligible to receive rusfertide in Part 1b; pts completing Part 1b were eligible to receive rusfertide in Part 2 (long-term extension period; Wks 52-156). Pts randomized to rusfertide in Part 1a continued to receive the same dose at the beginning of Part 1b unless dose adjustment was needed. Pts randomized to PBO received a starting dose of 20 mg of rusfertide. Part 1b evaluated the proportion of rusfertide-treated pts who achieved absence of PHL eligibility (ie, durable response from Wks 0-52), median time to first Hct ≥45%, and median time to first PHL. Results: Of 293 pts randomized to receive rusfertide (n=147) or PBO (n=146), 274 (94%) began Part 1b, and 254 (87%) remain on study and are receiving open-label rusfertide in Part 2. Safety data are reported for the safety analysis set (n=291; 145 and 146 in the rusfertide and PBO groups, respectively). Median (range) rusfertide exposure was 61 (2, 133) wks. The proportion of pts who continued to have an absence of PHL eligibility between Wks 0-52 (ie, pts initially randomized to rusfertide with durable response through the end of Part 1b) was 61.9% (n=91/147). In pts originally randomized to PBO who crossed over to rusfertide at Wk 32, the proportion of pts who achieved absence of PHL eligibility was 32.9% (n=48/146) and 78.0% (n=110/141) in Parts 1a (Wks 20-32) and 1b (Wks 40-52), respectively. During Part 1a (Wks 0-32), median (95% confidence interval [CI]) time to first PHL was not reached (NR) and 16.1 wks (12.7, 20.1) in the rusfertide and PBO groups, respectively. During Part 1b (Wks 32-52), median time to first PHL was NR in the rusfertide group and those who crossed over from PBO to rusfertide at Wk 32. In the rusfertide group, median time to first Hct ≥45% was NR during Part 1b. Median (95% CI) time to first Hct ≥45% was 21.1 wks (20.1, NR) in pts who crossed over from PBO to rusfertide at Wk 32. Mean Hct remained <43% throughout Part 1b in pts who continued rusfertide and those who switched from PBO to rusfertide. During Part 1b, numerical improvements (ie, change from baseline) in the PROMIS Fatigue SF-8a and MFSAF TSS7 were durable in the rusfertide group. Overall, the most common treatment-emergent adverse events (AEs) in rusfertide-treated pts (n=285) were injection site reactions (47.4%), anemia (25.6%), and fatigue (19.6%); most were grade 1 or 2. In Part 1a, fatigue occurred in 15.8% and 15.9% of pts in the PBO and rusfertide groups, respectively, and in Part 1b, the incidence was similar between pts originally randomized to both PBO and rusfertide (9.3% vs 9%, respectively). Serious AEs occurred in 8.1% of rusfertide-treated pts. In Part 1a of this ongoing study, 3 (2.1%) and 8 (5.5%) pts in the rusfertide and PBO groups had a non-PV malignancy; during Part 1b, non-PV malignancies were reported in 6 (2.2%) pts. Two pts (rusfertide group) had TEs (1 pt each in Parts 1a and 1b). Conclusions: Rusfertide met the primary and all 4 key secondary endpoints in VERIFY and continued to provide durable, sustained control of Hct <45% and a relative absence of PHL up to Wk 52. This benefit was maintained across all subgroups, including age, PV risk category, and ongoing CRT. Similar findings were also observed after pts crossed over from PBO to rusfertide. Rusfertide's safety profile was consistent with prior observations.Supported by: Protagonist Therapeutics, Inc.