Although cytoreductive therapies can affect hematocrit levels in patients with polycythemia vera, treatments intended to specifically help maintain levels below 45% could improve outcomes and reduce the need for phlebotomies in this patient population, according to Pankit Vachhani, MD.
“A drug that [controls hematocrit could help patients] avoid the need for phlebotomies and therefore have a better iron profile in the body, [either as monotherapy] or in an adjunct fashion to our other cytoreductive therapies,” Vachhani said in an interview with OncLive®.
Several agents intended to control hematocrit in patients with polycythemia vera are currently being explored, with one approaching potential FDA approval. Rusfertide (PTG-300), a hepcidin mimetic peptide, is currently under FDA priority review for the treatment of adult patients with polycythemia vera, backed by positive data from the phase 3 VERIFY trial (NCT05210790).1
Additionally, the antisense oligonucleotide, sapablursen (formerly ISIS 702843) is designed to block the mRNA TMPRSS6 protein to increase the body’s natural production of hepcidin; this agent is under evaluation in the phase 3 INTREPID trial (NCT07429266) following positive data from the phase 2 IMPRSSION trial (NCT05143957) in patients with phlebotomy-dependent polycythemia vera.2 In August 2026, it was also announced that divesiran (SLN124), a first-in-class short interfering RNA therapy intended to silence TMPRSS6, produced a significantly higher proportion of clinical responders vs placebo in patients with phlebotomy-dependent polycythemia vera in the phase 2 portion of the SANRECO trial (NCT05499013).3
In the interview, Vachhani explained the rationale for targeting TMPRSS6 in polycythemia vera, underscored the importance of hematocrit control for this patient population, and explained how these therapies could affect the polycythemia treatment paradigm.
Vachhani is an assistant professor of medicine and an associate scientist of experimental therapeutics at the University of Alabama at Birmingham.
OncLive: What role does the TMPRSS6 protein play in polycythemia vera?
Why Hematocrit Control Matters in Polycythemia Vera
- Keeping hematocrit below 45% is a key target in polycythemia vera management, since strict control reduces thrombotic events and cardiovascular mortality.
- Therapies that raise hepcidin could curb red blood cell production, cut reliance on phlebotomies, and spare patients the iron deficiency and symptom burden.
- Several hepcidin-targeting agents are advancing, led by the hepcidin mimetic rusfertide now under FDA priority review, alongside the TMPRSS6-directed antisense oligonucleotide sapablursen and the siRNA therapy divesiran, both showing positive early-phase results in phlebotomy-dependent patients.
Vachhani: We know that polycythemia vera is driven by the JAK2 mutation; that leads to a hyperactive JAK-STAT pathway, and with that comes pain, myelosis in the bone marrow, and an increased lineage across the three lines. Red blood cell [counts] are increased, and so are the platelet and white blood cell counts. One of the defining features that we see in patients with polycythemia vera is the increase in red blood cell lineage, hematocrit, or hemoglobin. The one item that we absolutely must follow is keeping hematocrit below 45%
Why is that? We know that a strict control of hematocrit below 45%, as opposed to a more lenient control, leads to improvement in thrombotic events and overall mortality related to cardiovascular events.
Why is hematocrit control important in the management of polycythemia vera?
[Hematocrit control] is very important to note that yes, of course, polycythemia vera is driven by the JAK2 mutation, but at the heart of it, with regard to the hematocrit elevation [and other blood counts] is the point that there is a dysregulation in iron homeostasis. We know that in polycythemia vera, hepcidin levels are low, and that leads to excessive iron being circulated toward the bone marrow, which then leads to more erythrocytes being formed. Therein lies the problem: more erythrocytes being formed leads us to doing more phlebotomies, which leads to more iron deficiency, in turn leading to more symptoms for our patients.
The rationale over here behind sapablursen, which is an antisense oligonucleotide against TMPRSS6, is that by decreasing TMPRSS6 levels, we lead to an increase of hepcidin levels. Now remember, hepcidin is the master regulator of iron homeostasis in the body. When we lead to an increase of hepcidin levels in the body, that means that there is more iron storage overall, and at the same time, there is reduced amount of iron being diverted toward the bone marrow. [This means] you will see less erythrocytosis, and therefore a lesser need for phlebotomies. Patients will not be losing iron through phlebotomies, and you would see symptom benefits, as well. [This is on top of] the major benefit of not needing phlebotomies as much.
What could the development of hematocrit-controlling therapies address for patients with polycythemia vera?
For patients with polycythemia vera, [we want to keep] hematocrit below 45% at all times. [This threshold] has been shown to decrease the thrombotic event rates, including critical cardiovascular end points, which also lead to mortality. Therefore, we must make sure that we keep hematocrit below 45%. We do use cytoreductive therapies to do this. However, not all patients either tolerate cytoreductive therapies or have a great responses on them, and for that matter, patients with low spleen volume don't need cytoreductive therapies from the get-go. If we consider this scenario, many of our patients require ongoing assessments of their complete blood counts [CBCs] and then they [may] require phlebotomies to keep hematocrit below 45%. That leads to excessive time commitments.
There are patients who do not get their CBCs checked or their hematocrits continuously controlled below 45%. In fact, real-world analysis shows that the majority of our patients are not kept below 45%, and therein lies the unmet need, which is to have agents that consistently maintain a hematocrit below 45% and negate the need for phlebotomies. In addition to that, phlebotomies lead to iron deficiency, and that in itself leads to some symptom burden for our patients with polycythemia vera who already have symptoms from the very beginning. For example, we all know that patients with polycythemia vera have cognitive issues related to the [elevated] cytokine profile and add to it the iron deficiency that occurs from phlebotomies, that leads to more fatigue, more brain fog, more cognitive issues, not to mention the other long-term issues with iron deficiency.
References
- Takeda and Protagonist announce US Food and Drug Administration accepts new drug application and grants priority review for rusfertide as a potential first-in-class therapy for polycythemia vera. News release. Takeda. March 2, 2026. Accessed August 14, 2026. https://www.takeda.com/newsroom/newsreleases/2026/nda-rusfertide/
- Dr Vachhani on phase 2 efficacy/safety data for sapablursen in polycythemia vera. OncLive. June 30, 2026. Accessed August 14, 2026. https://www.onclive.com/view/dr-vachhani-on-phase-2-efficacy-safety-data-for-sapablursen-in-polycythemia-vera
- Silence Therapeutics announces positive topline results from phase 2 SANRECO trial of divesiran in polycythemia vera, supporting its potential best-in-class profile. News release. Silence Therapeutics. August 10, 2026. Accessed August 14, 2026. https://silence-therapeutics.com/investors/press-releases/press-releases-details/2026/Silence-Therapeutics-Announces-Positive-Topline-Results-from-Phase-2-SANRECO-Trial-of-Divesiran-in-Polycythemia-Vera-Supporting-its-Potential-Best-in-Class-Profile/default.aspx
