Prithviraj Bose, MD, overviews the ongoing investigation of sapablursen in polycythemia vera.
Although agents such as ruxolitinib (Jakafi) and ropeginterferon alfa-2b-njft (Besremi) carry disease-modifying potential for patients with polycythemia vera, hepcidin modulators, such as sapablursen (formerly ISIS 702843), could represent a strategy for improved hematocrit control and reduced phlebotomy dependence, according to Prithviraj Bose, MD.
After meeting the primary end point of the phase 2 IMPRSSION trial (NCT05143957) by generating a significant reduction in the frequency of phlebotomies, sapablursen in under further investigation in the phase 3 INTREPID trial (NCT07429266), which is evaluating the agent vs placebo in patients with phlebotomy-dependent polycythemia vera.1,2
“Any [patient who is undergoing] phlebotomies, with or without cytoreduction, could be considered for [INTREPID], as long as they meet the definition of phlebotomy dependence in the trial,” Bose said. “This is going to be an important [study that] will hopefully lead to registration for sapablursen.”
In an interview with OncLive®, Bose explained why hepcidin modulators could represent important treatment options for patients with polycythemia vera, broke down phase 2 data for the agent, and looked ahead to the enrolling INTREPID trial.
Bose is a professor and co-leader of the Section of Myeloproliferative Neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.
Bose: [Sapablursen] is an antisense oligonucleotide [ASO] that targets TMPRSS6, [which] is a negative regulator of hepcidin. If you target it, you ultimately end up upregulating hepcidin, [meaning] you can induce hepcidin [production]. A number of agents are now looking to target TMPRSS6, and there are different classes of drugs, but this particular one [with] sapablursen in an ASO. The ultimate idea is to induce hepcidin [production] to increase levels of endogenous hepcidin.
Polycythemia vera has, in recent times, seen a lot of interest from a drug development standpoint. Currently, we use hydroxyurea, ropeginterferon alfa-2b, and ruxolitinib. This class of hepcidin modulators is a relatively new kid on the block. Rusfertide is probably the most advanced, and
The Ongoing Investigation of Sapablursen in Polycythemia Vera
Rusfertide is a hepcidin mimetic, and it’s given subcutaneously once per week. The success of rusfertide has spurred a lot of interest in hepcidin modulation. If you increase endogenous hepcidin, as sapablursen would do, or you mimic the action of hepcidin, like rusfertide would do, you ultimately end up restricting erythropoiesis because the iron gets sequestered in the reticuloendothelial system. Frankly, the bone marrow is starved of iron for making red blood cells. It’s a clever mechanism, whether as a hepcidin mimetic like rusfertide or induction with sapablursen.
Regarding unmet needs, we have drugs that we believe are disease-modifying and can have other benefits in polycythemia vera, such as ropeginterferon alfa-2b or ruxolitinib. However, there is also an unmet need for controlling the hematocrit [level] and keeping it controlled, because that is the primary goal in polycythemia vera management: to prevent clots. We want to keep that hematocrit [level] consistently under 45%, which is something that phlebotomy is not able to do well. Also, phlebotomy can have its share of problems: it’s unpredictable and [is associated with] some adverse effects in some people. We need to keep the hematocrit [level] under 45% at all times, and this is where this class of agents can be useful. They could be used in combination with a cytoreductive drug that is able to lower the JAK2 variant allele frequency and perhaps bring about disease modification, but this area of minimizing or eliminating phlebotomy and controlling the hematocrit [level] in a sustained manner is still an unmet need.
Sapablursen was studied in the IMPRSSION study, and that was presented in an oral session at ASH 2025. This was a relatively small study, but it was phase 2. Forty-nine patients received the drug, and there were initially 2 doses evaluated [in cohort A]. It became apparent early on that the higher dose [of 120 mg] was perhaps a bit too potent in what it did and caused anemia, so that dose was not pursued further. The 80-mg dose is the dose going forward, and it’s given subcutaneously every 4 weeks. [This is] an important distinction that I would like to make from rusfertide, which is a weakly subcutaneous drug.
In terms of responses [for sapablursen] in both dose cohorts, they were better with the 80-mg [dose]. There was a different dose cohort at 40 mg. This was a bit of an exploratory study with looking at different doses, [and] 80 mg had the best balance of efficacy and safety. As you would expect this class of agents to do, phlebotomy was reduced in both arms, more so in the 80-mg arm.
[Regarding] toxicity, there were some injection site reactions, but primarily [we saw] anemia, which is something you would expect from the mechanism of action. You’re trying to control that hematocrit [level], and sometimes you’re going to overshoot and cause anemia. However, overall, it was well tolerated, and that is what led to the phase 3 [study].
Hepcidin modulators have been quite safe overall. We have data on rusfertide, we have data now on sapablursen, and we also have some data on divesiran, which is a small-interfering RNA [therapy directed] against TMPRSS6. They [have all shown that] they’re safe. They are primarily distinguished by their frequency of administration. Rusfertide is weekly, sapablursen is every 4 weeks, and divesiran could be [every] 6 to 12 weeks. They’re different in regard [to dosing frequency], but in terms of toxicity, anemia is what want to watch for because if you have an increase in endogenous hepcidin [levels], or, in the case of rusfertide, the different doses can mimic the action of hepcidin to different extents, and with that, you can see some anemia. You’ve got to dose adjust, but other than that, there’s no particular class of toxicity that jumps out with this group of agents.
We had one successful phase 3 trial, the VERIFY trial of rusfertide, and the INTREPID trial is generally designed similarly. It’s a placebo-controlled trial of sapablursen in patients with phlebotomy-dependent polycythemia vera. This is a risk-agnostic trial, and as long as patients need phlebotomies, [they can enroll]. Usually what the field has done, pretty uniformly in this space, is define [phlebotomy dependency] as 3 or more phlebotomies in the preceding 6 months, or 5 or more [phlebotomies] in the preceding year. Any patient needing phlebotomies, with or without cytoreductive therapy, [can enroll in INTREPID]. It is important to appreciate that this [trial] is not just for low-risk patients who are not underogoing cytoreduction. It is for any patient who is still needing phlebotomy as defined in the protocol. [For eligible patients], the cytoreductive therapy dose has to be stable. [Patients] can’t be having a lot of dose changes within a certain period, but as long as they are still needing phlebotomies on a stable dose of cytoreduction, they’re eligible.
Hepcidin modulators could serve as good adjuncts to therapy, and they also could serve as monotherapy, perhaps in low-risk patients where we may be less inclined to use cytoreductive therapy. [For example], let’s say you’re using hydroxyurea or ropeginterferon alfa-2b, and you are not getting that degree of hematocrit [level] control, [maybe] because the doses you need to achieve are too toxic. That is where these agents could easily fit. Another [scenario] is the low-risk patient where you may be less inclined to use cytoreduction. There are some data for ropeginterferon alfa-2b in low-risk [patients], but again, most low-risk patients tend to not be offered cytoreduction. [In this setting, hepcidin modulators] could eliminate [the need for] phlebotomy or at least greatly reduce phlebotomy rates for them.
[Regarding] the symptom benefit, [hepcidin modulators] have an unexpected but significant symptom benefit. We saw this with rusfertide in its phase 2 and phase 3 trials, and then we saw this with sapablursen in the [IMPRSSION] trial. [In INTREPID], we hope to see the same. Symptoms are a key feature of polycythemia vera, and they are probably, at this time, best addressed by ruxolitinib. They are not addressed that well by hydroxyurea or even ropeginterferon alfa-2b. However, hepcidin modulators, perhaps through iron redistribution, although that mechanism is not well understood, lead to improved symptom scores and quality of life.
