Dr Bose on the Rationale for Evaluating Sapablursen in Polycythemia Vera

Minimizing or eliminating phlebotomy [and] controlling the hematocrit in a sustained manner [are] still unmet needs [in polycythemia vera].

Prithviraj Bose, MD, a professor of leukemia at The University of Texas MD Anderson Cancer Center, discussed the rationale for evaluating the novel TMPRSS6 antisense inhibitor sapablursen (formerly ISIS 702843) for treatment of polycythemia vera.

Bose began by outlining the evolving treatment landscape for polycythemia vera and highlighted the emerging role of hepcidin-modulating therapies in addressing persistent unmet needs in disease management. Although current treatment options, such as hydroxyurea, ropeginterferon alfa-2b-njft (Besremi), and ruxolitinib (Jakafi) provide effective cytoreduction and may offer disease-modifying potential, Bose emphasized that maintaining sustained hematocrit control remains a central therapeutic objective for patients with polycythemia vera. Keeping hematocrit level below 45% is critical for reducing thrombotic risk, he explained, yet therapeutic phlebotomy alone often fails to provide consistent control and can be associated with procedural burden, unpredictability, and tolerability concerns.

Bose explained that investigational hepcidin-modulating agents represent a novel strategy to address this gap. He noted that rusfertide, a once-weekly subcutaneous hepcidin mimetic with positive data from the phase 3 VERIFY trial (NCT05210790), has generated enthusiasm within the field and may soon become an approved treatment option. Sapablursen, by contrast, increases endogenous hepcidin production through TMPRSS6 inhibition. Despite differing mechanisms, both approaches ultimately restrict erythropoiesis by limiting iron availability to the bone marrow, thereby reducing excessive red blood cell production, Bose continued.

In the phase 2 IMPRSSION trial (NCT05143957), 2 dose levels of sapablursen led to a significant reduction in weekly phlebotomy rate between weeks 17 and 37 compared with baseline, meeting the primary end point for both cohorts. The agent is being further evaluated in the phase 3 INTREPID trial (NCT07429266).

According to Bose, hepcidin-modulating agents have the potential to minimize or eliminate the need for phlebotomy and simultaneously provide more durable hematocrit control. He also suggested that hepcidin modulators could complement existing cytoreductive therapies rather than replace them. In this treatment paradigm, agents such as interferon or ruxolitinib could continue to target the underlying disease biology, whereas hepcidin-directed therapies address hematocrit control, together offering a more comprehensive approach to the treatment of patients with polycythemia vera.