REVIVE: Results from the randomized withdrawal phase

Polycythemia vera (PV) is characterized by an excessive production of red blood cells and an increased risk of thromboembolism and cardiovascular complications.¹ While phlebotomy and cytoreductive therapy is commonly used to maintain hematocrit control <45%, the hepcidin mimetic rusfertide is currently under investigation in the phase II REVIVE trial (NCT04057040) for patients diagnosed with PV and uncontrolled erythrocytosis.¹ Part 1 of the study was previously reported in an MPN Hub article.

During the European Hematology Association (EHA) 2023 Hybrid Congress, Kremyanskaya¹ presented results from the randomized withdrawal phase of the study, which represents the primary aim of the REVIVE trial. We summarize the key results from this EHA top abstract below.

Study design

• The study design of the REVIVE trial and baseline patient characteristics during part 1 have been reported in a previous MPN Hub article.
• During part 2 of the study, patients were randomized 1:1 to receive rusfertide or matching placebo.
• The aim of the study was to maintain hematocrit levels <45%.
• Patients were considered responders if they met three criterion:
  • Hematocrit control without phlebotomy
  • No therapeutic phlebotomy
  • Completed 12 weeks of treatment

Results

Efficacy

A total of 53 patients were included in part 2 of the study; 27 treated with placebo and 26 with rusfertide. Full baseline patient characteristics are shown in Table 1.

Table 1. Baseline patient characteristics*

HU, hydroxyurea; IFN, interferon; JAKi, Janus kinase inhibitor; PV, polycythemia vera. *Adapted from Kremyanskaya.1
Characteristic, % (unless otherwise stated)	Placebo (n = 27)	Rusfertide (n = 26)
Age, years	60.7	54.9
Sex
Male	63.0	80.8
Female	37.0	19.2
Disease characteristic, years
Age at diagnosis	55.9	50.3
PV duration	5.0	4.6
Risk
High	63.0	42.3
Low	37.0	57.7
Cytoreductive therapy
HU	33.3	15.4
IFN	18.5	7.7
JAKi	7.4	7.7

• Patients treated with rusfertide had a response rate of 69.2% vs 18.5% for patients on placebo (p = 0.0003).
• Treatment with rusfertide was superior to placebo in patients treated with phlebotomy only (p = 0.0209) and phlebotomy and cytoreductive therapy (p = 0.0215).
• Rusfertide significantly improved maintenance of response.
  • Patients no longer needed phlebotomy.
  • Hematocrit control was also consistent (p < 0.0001).
• The rate of patients treated with rusfertide who achieved a phlebotomy-free state was 92.3%.

Safety

• Rusfertide treatment was well tolerated.
• Treatment-emergent adverse events (TEAEs) of Grade 1 or Grade 2 severity were experienced by 83% of patients.
  • 17% of patients experienced Grade 3 events.
  • There were no Grade 4 or Grade 5 events.
• The most common TEAEs were localized injection site reactions of Grade 1 or Grade 2 severity.
• Only two TEAEs led to treatment discontinuation.
• Of all patients treated with rusfertide, 74.3% remained on treatment for ≥1 year.

Conclusion

The randomized withdrawal phase of the REVIVE study met its primary endpoint and showed rusfertide to be an effective treatment for sustained and durable hematocrit control, as well as reducing the need for phlebotomy. Treatment was well tolerated, with most TEAEs being of Grade 1 or Grade 2 severity and >70% of patients remaining on treatment for ≥1 year. The phase III VERIFY trial (NCT05210790), which continues to evaluate the use of rusfertide in patients with PV, is ongoing, and a follow-on 2-year extension of the REVIVE study is expected to begin shortly.