REVIVE

Incomplete

Kremyanskaya M, et al. "Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera". The New England of Medicine. 2024. 390(8):723-735.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with phlebotomy-dependent polycythemia vera (PV), what is the efficacy and safety of rusfertide for controlling haematocrit as compared to placebo?

Bottom Line

In patients with phlebotomy-dependent polycythemia vera, rusfertide was associated with a better hematocrit control than placebo.

Major Points

In polycythemia vera, maintaining a hematocrit control with phlebotomy and cytoreductive agents is often difficult. The international, phase 2 REVIVE trial showed that rusfertide, a hepcidin mimetic, was effective in maintaining a hematocrit of <45%. Grade 1 and 2 adverse events, including injection site reactions, were common; however, no grade 4 or 5 adverse events were reported.

Guidelines

As of January 2025, no guidelines have been published that reflect the results of this trial.

Design

• International, phase 2 trial with 3 parts:
  • Part 1: dose-finding study (28 weeks), N=70
    • Efficacy evaluation periof was weeks 17-29
  • Part 2: double-blind, randomized withdrawal period (12 weeks), N=53
    • Rusfertide (n=26)
    • Placebo (n=27)
  • Part 3: open-label extension period (week 41 up to year 3), N=58
• Setting: 16 centers in the United States and India
• Enrollment: October 2019 to March 2022
• Mean follow-up: not reported
• Analysis:
  • Part 1: Intention-to-treat
  • Part 2: Full analysis
• Primary outcome: response as indicated by hematocrit control, not requiring phlebotomy, and completed the 12-week part 2 trial regimen
  • Hematocrit control includes:
    • hematocrit ≥45% that was ≥3% higher than the hematocrit at week 29 (before randomization)
    • hematocrit >48%
    • hematocrit ≥5% higher than the hematocrit at week 29 (before randomization)

Population

Inclusion Criteria

• ≥18 years of age
• Eastern Cooperative Oncology Group performance status ≤2
• PV according to the revised 2016 WHO criteria
• Phlebotomy-dependence: ≥3 phlebotomies during the 28 weeks before the first dose of rusfertide in part 1 of the trial, with the most recent within 12 weeks before screening
• Patients receiving a stable or decreasing dose of interferon alfa, hydroxyurea, or ruxolitinib for ≥8 weeks prior to the first dose of rusfertide in part 1 are also eligible
• Hematocrit <45% at screening
• Records all phlebotomies performed for ≥28 weeks

Exclusion Criteria

• Absolute neutrophil count <1000/µL
• Platelet count <100,000/µL
• Estimated glomerular filtration rate <60 mL/min/1.73 m2
• Alanine aminotransferase or aspartate aminotransferase ≥2.5 × upper limit of normal (ULN) or direct bilirubin >1.5 × ULN
• Clinically significant thrombosis within 4 weeks of screening
• Active or chronic bleeding within 4 weeks of screening
• Infection requiring antimicrobial therapy within 4 weeks of dosing
• Infection requiring hospitalisation or intravenous antimicrobials, or opportunistic infection within 3 months of dosing
• Post-PV myelofibrosis
• Females who are pregnant or breastfeeding
• Primary or secondary immunodeficiency
• Known Hepatitis B, C or Human Immunodeficiency Virus (HIV) infection
• Invasive cancer within past 2 years
• Inability to provide consent
• Surgery requiring general anesthesia within 1 month pre-screening, or planned elective surgery during the trial
• History of alcohol dependence or illicit drug use within 1 year pre-screening
• Recipent of an investigational agent within 30 days of screening
• Usage of medications known to prolong QT interval and/or are associated with a risk of Toursade de Pointes 1 week before the first dose

Baseline Characteristics

Part 1:

• Mean age: 57.3±12.2 years
• Male: 70%
• Caucasian ethnicity: 81%
• Mean BMI: 29.6±5.4 kg/m2
• Age at diagnosis of PV: 52.3±13.5 years
• Duration of PV: 5.1±6.2 years
• Number of phlebotomies: 4.7±1.6
• High-risk disease: 57%
• Concurrent therapy with phlebotomy alone: 53%
• Concurrent cytoreductive therapy with supplemental phlebotomy: 47%

Part 2:

Comparisons are Rusfertide vs. placebo

• Mean age: 54.2±13.0 vs. 60.6±11.3 years
• Male: 80 vs 62%
• Caucasian ethnicity: 93 vs. 86%
• Mean BMI: 29.3±5.3 vs. 29.9±5.7 kg/m2
• Age at diagnosis of PV: 49.9±12.4 vs. 55.8±12.1 years
• Duration of PV: 4.2±5.4 vs. 4.9±4.6 years
• Number of phlebotomies: 4.7±1.6 vs. 4.8±1.6
• High-risk disease: 43 vs. 62%
• Concurrent therapy with phlebotomy alone: 67 vs. 41%
• Concurrent cytoreductive therapy with supplemental phlebotomy: 33 vs. 49%

Interventions

• Part 1: open-label, dose-finding period of 28 weeks
  • rusfertide administered subcutaneously weekly, dose between 10 to 120 mg to maintain a hematocrit of <45%
• Part 2: double-blind, randomized withdral period of 12 weeks
  • randomized to rusfertide or placebo in a 1:1 ratio
  • dose of rusfertide as per part 1
  • participants seen every 4 weeks to evaluate safety and efficacy
  • treatment assignment for participants who become eligible for phlebotomy, or who have a hematocrit increase >5% confirmed 2 to 14 days later was unblinded
  • sponsor was unblinded to the treatment assignment after the last visit for the last participant
• Part 3: open-label extension period

Outcomes

Comparisons are rusfertide vs placebo unless indicated otherwise.

Primary Outcomes

Response as indicated by hematocrit control, not requiring phlebotomy, and completed the 12-week part 2 trial regimen

60 vs. 17% (P=0.002)

Secondary Outcomes

In part 1:

Mean number of phlebotomies per year in the 28-week period before the first dose of rusfertide vs. during part 1

8.7±2.9 vs. 0.6±1.0 (estimated difference of 8.1 phlebotomies per year)

Mean number of phlebotomies per year in weeks 16-28 before the first dose of rusfertide vs. during part 1

6.7±4.2 vs. 0.5±1.3

Response, that is not requiring phlebotomy (hematocrit of >48%, or hematocrit of ≥45% that was ≥3 percentage points higher than baseline) during the efficacy evaluation period (weeks 17 to 29)

82.9%

In part 2:

Hematocrit change from baseline to week 41

0.3±3.1 vs. 2.0±2.6 percentage points

Patient-reported Outcomes

Change in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) from baseline to week 29

At baseline, the mean score was low (15.6±15.3). In part 1, lower severity of symptoms was observed with rusfertide treatment. In part 2, comparison of the trial groups was not possible.

Adverse Events

• All participants had at least one grade 1/2 adverse event, most commonly injection-site reactions: 86 vs 10%.
• 10 grade 3 adverse events occurred in nine patients (13%).
• No grade 4/5 adverse events were noted.

Criticisms

• Limited number of participants
• Limited follow-up duration precludes the assessment of the efficacy of rusfertide on complications of PV (e.g., thrombosis, disease progression)
• Participant's report of symptoms may be biased due to open-label treatment
• While PV treatments are known to increase the risk of skin cancers, there is limited current data to determine if this applies to rusfertide. Frequent skin examinations were incorporated into the trial
• Effects on rusfertide on patient-reported outcome (MPN-SAF) could not be evaluated in the randomized phase 2 part of the study

Funding

Protagonist Therapeutics

Further Reading

1. Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al. Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera. N Engl J Med. 2024;390(8):723-735. doi:10.1056/NEJMoa2308809