Nath, Uttam Kumar

Abstract Background: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by red blood cell overproduction. In the phase 2 REVIVE study (NCT04057040), rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for therapeutic phlebotomy (PHL) in patients (pts) with PV who were PHL dependent prior to study entry (Kremyanskaya M, et al. N Engl J Med. 2024;390(8):723-35). During the open-label extension portion of REVIVE (Part 3), combining rusfertide and PHL with or without cytoreductive therapy (CRT) controlled erythrocytosis, provided long-term control of Hct, and was associated with a greater than 8-fold reduction in the estimated annual PHL rate (Gerds AT, et al. Blood. 2024;144(Suppl. 1):4559). Pts who participated in REVIVE Part 3 were eligible to transition to the open-label phase 2 THRIVE extension study (NCT06033586) and receive up to 2 additional years of rusfertide treatment. Our objective is to present initial results describing the long-term durability of response and safety profile of rusfertide in pts with PV who participated in REVIVE and transitioned to THRIVE. Methods Pts with PV who participated in REVIVE, completed ≥12 months of rusfertide therapy, and had an end-of-treatment visit were eligible to transition to THRIVE. Pts who enrolled in THRIVE continued to receive subcutaneous rusfertide once weekly with or without CRT. Median Hct and the number of PHLs each pt received were assessed in all pts who received ≥1 dose of rusfertide and had ≥1 efficacy assessment on study. Safety data were also collected, including treatment-emergent adverse events (AEs), serious adverse events (SAEs), non-PV malignancies, and thromboembolic events (TEs). New-onset AEs (ie, AEs that were reported in THRIVE but not REVIVE) were also recorded. Results: Forty-six/58 pts (79%) who enrolled in Part 3 of REVIVE transitioned to THRIVE. At the data cutoff date (27 May 2025), 44 of the 46 pts (96%) who enrolled in THRIVE remained on study. Median (range) age was 58 (27-77), and the majority were male (74%). More than half (57%) had high-risk PV; 54% of pts were on concurrent CRT. Median (range) treatment duration in THRIVE was 48 (22-66) weeks; median (range) treatment duration in REVIVE and THRIVE combined was 198 (154-267) weeks, or 3.8 (3.0-5.1) years. At baseline, mean (standard deviation [SD]) Hct was 42.3% (3.7) in THRIVE. At Week 60, mean (SD) Hct was 43.0% (4.2). In addition, mean hemoglobin and erythrocyte levels remained stable throughout THRIVE. Prior to study entry in REVIVE, the mean (SD) annualized PHL rate (ie, PHL/year) for the 46 pts who eventually rolled over to THRIVE was 9.2 (5.2) PHL/year. The mean (SD) annualized PHL rate during REVIVE Part 3 and THRIVE was 0.6 (0.8) and 0.7 (1.1) PHL/year, respectively. Overall, the most common AEs in the pts who participated in REVIVE and THRIVE were Grade 1-2 injection site reactions (87%), fatigue (59%), COVID-19 (50%), pruritus (44%), arthralgia (39%), dizziness (35%), anemia (30%), paresthesia (28%), headache (26%), abdominal pain and nausea (24% each), and diarrhea, dyspnea, and upper respiratory tract infection (22% each). In THRIVE, the most common new-onset AEs were anemia (20%) and fatigue (15%). Twelve pts (26%) had a prior history of non-PV cancer. Six pts (13%) had a new-onset cancer event, including basal cell carcinoma (n=3; 7%), squamous cell carcinoma (n=2, 4%), non-invasive bladder cancer (n=1, 2%), and multiple myeloma (n=1; 2%). Of these 6 pts, 5 (83%) had a prior history of non-PV cancer. Nine pts (20%) had a history of TEs prior to enrolling in REVIVE. One patient with cardiovascular risk factors and a TE prior to enrollment in REVIVE had a new-onset TE of cerebrovascular accident in THRIVE. Overall, there were no TEs in pts with low-risk PV in either REVIVE or THRIVE. Conclusions: After transitioning to THRIVE, continued treatment with rusfertide with or without CRT demonstrated consistent, long-term Hct control with reduced therapeutic PHLs compared to baseline. With a median of 3.8 years of treatment, rusfertide's safety profile was consistent with prior observations. Support Protagonist Therapeutics, Inc.

Background: PV is a myeloproliferative neoplasm that leads to excessive production of erythrocytes and increased platelet and leukocyte counts. The current standard of care is to use therapeutic phlebotomy (TP) with or without cytoreductive therapy (CRT) to treat PV. Over time, the CRT dose often needs to be increased to treat PV progression. Preliminary results from the phase 2 REVIVE study (NCT04057040) demonstrated that rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for TP in patients who were phlebotomy-dependent prior to study entry (Kremyanskaya et al. EHA2023. [Abstract LB2710]; Kremyanskaya et al. New Engl J Med 2024;390:723-35).Final data from REVIVE will be presented. Methods: In Part 1 (Weeks 1-29), subcutaneous rusfertide (starting dose: 20 mg q1w) was initiated and titrated to control Hct to <45%. In Part 2 (Weeks 29-41; blinded randomized withdrawal phase), patients were randomized to receive rusfertide or placebo. Randomized patients were eligible to participate in the open-label extension (OLE) portion of the study (Part 3), in which all patients could receive rusfertide and investigators could make CRT dose adjustments. Results: In Part 1, 70 patients were enrolled; 59 were randomized in Part 2. Fifty-eight patients continued to Part 3. As of 9 July 2024, 50 (71.4%), 37 (52.9%), and 17 (24.3%) patients received rusfertide for ≥2, ≥2.5, or ≥3 years, respectively.Overall, median (range) patient age was 57.5 years (27-77); the majority were male (70%) and had high-risk disease (55.7%). Overall, 52.9% and 47.1% of patients were treated with TP alone or TP plus CRT, respectively. Prior to enrollment, the estimated average (mean) phlebotomy rate (EAPR) in patients who enrolled on study was 8.5/year, which was reduced to <1.0/year in Part 1. In Part 2, the EAPR was <1.0/year and 6.6/year in the rusfertide and placebo groups, respectively. For patients who continued onto Part 3 and received rusfertide, the EAPR remained at <1.0/year. In Parts 1, 2, and 3, the mean (SD) weekly average rusfertide dose was 30.7 mg (12.2), 38.5 mg (21.3), and 44.9 mg (20.3), respectively. Rusfertide consistently maintained Hct <45%, including in patients receiving therapy for ≥3 years. Platelets increased following initiation of rusfertide therapy and stabilized over time; mean leukocyte counts remained stable. Prior to enrollment, iron-related parameters were consistent with systemic iron deficiency. Throughout the study, rusfertide resulted in the normalization of mean serum ferritin levels, increased mean transferrin saturation, and increased mean serum iron levels. Overall, mean corpuscular volume increased slightly over the duration of the study. Throughout the study, there was no evidence of increased markers of inflammation (eg, C-reactive protein or interleukin 6). The most common (≥20%) treatment-emergent adverse events (TEAEs) were injection site reactions (85.7%), fatigue (38.6%), COVID-19 (32.9%), pruritus (34.3%), arthralgia (30.0%), dizziness (30.0%), nausea (24.3%), headache (24.3%), and anemia (21.4%). Grade 3 TEAEs occurred in 25.7% of patients.There were no Grade 4 or 5 TEAEs. One patient developed acute myeloid leukemia after treatment discontinuation. After more than 150 patient-years of rusfertide exposure, malignancies (most of which were skin cancers) were reported in 11 patients (all had risk factors that may have contributed to the development of these malignancies). There was no obvious correlation between increasing exposure to rusfertide and malignancies reported. Six thrombotic events (5 arterial and 1 venous) occurred in 5 patients with high-risk PV. Conclusions: In REVIVE, rusfertide added to TP with or without CRT provided long-term durable control of Hct and decreased the need for TP. Patients are eligible to roll over to the phase 2 THRIVE OLE study (NCT06033586), which will continue to assess the long-term safety and efficacy of rusfertide for a total period of up to 5.8 years. The randomized phase 3 VERIFY study (NCT05210790) is ongoing and will evaluate rusfertide vs placebo in PV patients.