Will the FDA approve rusfertide for the treatment of adult patients with polycythemia vera?
The FDA has accepted and granted priority review to a new drug application (NDA) seeking the approval of rusfertide (PTG-300) for the treatment of adult patients with polycythemia vera.1
The NDA is supported by data from the phase 3 VERIFY trial (NCT05210790), including findings from the study’s
In the 32-week analysis of part 1a of VERIFY, data showed that from weeks 20 to 32, 76.9% of patients treated with rusfertide plus current standard-of-care (SOC) therapy (n = 147) achieved a clinical response compared with 32.9% of those treated with placebo plus SOC (n = 146; P < .0001).2 Patients treated with rusfertide experienced a mean of 0.5 phlebotomies (SD, 1.2) from weeks 0 to 32 compared with 1.8 phlebotomies (SD, 1.5) for those in the placebo arm (P < .0001). Additionally, 62.6% of patients in the rusfertide arm maintained a hematocrit level below 45% from baseline to week 32 compared with 14.4% of patients in the placebo arm (P < .0001), and the least-squares (LS) mean difference in PROMIS Fatigue Short Form (SF)–8a total T-score from baseline to week 32 was –1.78 and 0.17, respectively (difference, 1.95; SE, 0.88; P = .0268). The LS mean difference in Myelofibrosis Symptom Assessment Form Total Symptom Score 7 (MFSAF TSS7) at week 32 was –2.40 for rusfertide vs –0.54 for placebo (difference, 1.87; SE, 0.822; P = .0239).
Findings from the 52-week analysis showed that 84.1% of responders in the rusfertide arm (n = 113) saw their responses continue through week 52.3 Among patients from the placebo arm who crossed over to receive rusfertide in part 1b from weeks 40 to 52 (n = 140), responses were experienced by 77.9%. The longer-term findings also showed sustained hematocrit control below 45% and phlebotomy ineligibility through week 52 with the use of rusfertide.
The FDA has assigned a target action date for the third quarter of 2026.1
“There is an urgent need for innovative treatment options in polycythemia vera, where patients currently face limited therapeutic choices to control their hematocrit and significant symptom burden,” Andy Plump, MD, PhD, president of Research and Development at Takeda, stated in a news release.1 “The FDA's acceptance of our NDA brings us closer to potentially offering a first-in-class therapy that could meaningfully improve clinical outcomes and quality of life. This milestone is a reflection of our successful partnership with Protagonist and Takeda’s unwavering commitment to advancing innovative treatments in hematologic cancers where significant unmet needs persist.”
VERIFY was a 2-part, randomized trial designed to evaluate rusfertide, a first-in-class subcutaneous peptide mimetic of the endogenous hormone hepcidin, in patients with polycythemia vera who underwent at least 3 phlebotomies in 28 weeks prior to enrollment or at least 5 phlebotomies in 1 year prior to enrollment.2
During part 1a of the study, patients were randomly assigned 1:1 to receive rusfertide at 20 mg once per week or placebo, both in combination with SOC therapy (phlebotomy with or without cytoreductive therapy). In this portion of the study, patients were stratified by current SOC therapy, and this treatment period lasted from week 0 to 32. Part 1b served as an open-label period, with all patients receiving rusfertide plus current SOC from weeks 32 to 52. Part 2 was a long-term, open-label safety period that ran through week 156.
In parts 1a and 1b, permitted rusfertide dosing levels ranged from 10 mg to 90 mg; in part 2, the range was 10 mg to 120 mg.
Clinical response rate from weeks 20 to 32 served as the trial’s primary end point. Key secondary end points from weeks 0 to 32 included mean number of phlebotomies, proportion of patients with a hematocrit level below 45%, mean change in PROMIS Fatigue SF-8a score, and mean change in MFSAF TSS7 score.
Safety data from the 32-week analysis (n = 291) showed that the median treatment exposure was 32 weeks in both arms, and patients in the experimental group received a median rusfertide dose of 30 mg (range, 10-90 mg). Treatment-emergent adverse effects (TEAEs) led to treatment discontinuation in 5.5% of patients in the rusfertide arm (n = 145) vs 2.7% of patients in the placebo arm (n = 146). TEAEs of any grade occurred at rates of 89% and 86.3%, respectively.
The most common any-grade TEAEs reported in at least 6.5% of patients in either arm included injection-site reactions (rusfertide, 55.9%; placebo, 32.9%), anemia (15.9%; 4.1%), fatigue (15.2%; 15.8%), headache (10.3%; 11.6%), COVID-19 (9.7%; 11.0%), pruritus (9.7%; 9.6%), diarrhea (8.3%; 5.5%), dizziness (8.3%; 6.2%), arthralgia (7.6%; 8.2%), constipation (7.6%; 7.5%), abdominal distension (6.9%; 5.5%), and thrombocytosis (6.9%; 0%).
“Rusfertide exemplifies Protagonist’s end-to-end expertise, from exploring a novel hepcidin mimetic mechanism to address unmet needs in polycythemia vera to discovering the peptide and driving its clinical development through NDA filing. We are very pleased with the FDA granting rusfertide priority review and look forward to its potential approval in 2026,” Dinesh V. Patel, PhD, president and chief executive officer of Protagonist, said in the news release.1 “We have identified a great partner in Takeda as rusfertide progresses toward this milestone, thereby bringing a successful closure to our more than decade-long journey from concept to commercialization.”
