INTREPID Trial Aims to Advance Sapablursen for Phlebotomy-Dependent Polycythemia Vera

Sapablursen, an investigational antisense oligonucleotide (ASO) directed at TMPRSS6, represents one of the key research avenues aimed at sustaining hematocrit control and reducing or eliminating the need for phlebotomies in patients with polycythemia vera, according to Pankit Vachhani, MD, and Prithviraj Bose, MD.

Building on the phase 2 IMPRSSION trial (NCT05143957), the ongoing phase 3 INTREPID trial (NCT07429266) is evaluating sapablursen vs placebo in patients with polycythemia vera who remain phlebotomy-dependent, regardless of concurrent cytoreductive therapy.^1,2

“[Hepcidin modulation is] a very clever mechanism, whether it’s hepcidin mimesis like with rusfertide [PTG-300] or induction like with sapablursen,” Bose said in an interview with OncLive^®. “If you increase endogenous hepcidin, as sapablursen would do, you ultimately end up restricting erythropoiesis because the iron gets sequestered in the reticuloendothelial system, so the bone marrow is [essentially] starved of iron in terms of being able to make red blood cells.”

Bose is a professor and co-leader of the Section of Myeloproliferative Neoplasms (MPNs) in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. Vachhani is an assistant professor of medicine and an associate scientist of experimental therapeutics at the University of Alabama at Birmingham.

What is the rationale for targeting hepcidin in polycythemia vera?

Polycythemia vera is an MPN driven by an acquired JAK2 mutation that produces a hyperactive JAK-STAT pathway and panmyelosis, with erythrocytosis and elevated hematocrit its defining features.¹ Maintaining a hematocrit below 45% is the central therapeutic goal in polycythemia vera, Vachhani noted. Hydroxyurea, ropeginterferon alfa-2b-njft (Besremi), and ruxolitinib (Jakafi) remain the available cytoreductive agents; although ropeginterferon alfa-2b and ruxolitinib are viewed as potentially disease-modifying, consistent hematocrit control remains a gap.

The class of hepcidin modulators has advanced rapidly, led by the hepcidin mimetic rusfertide, which produced positive data in the phase 3 VERIFY trial (NCT05210790) to support priority review of a new drug application seeking approval of the agent for the treatment of adult patients with polycythemia vera.³ Furthermore the short interfering RNA therapy divesiran (SLN124), which targets TMPRSS6 like sapablursen, more recently met its primary response end point vs placebo in patients with polycythemia vera in the phase 2 portion of the SANRECO trial (NCT05499013).⁴

Sapablursen and divesiran are distinguished from rusfertide primarily by dosing interval; rusfertide is administered weekly, sapablursen every 4 weeks, and divesiran every 6 to 12 weeks, Bose said.

Unmet needs for patients with polycythemia vera extend beyond hematocrit control to the burden of phlebotomy itself, which is unpredictable, incompletely effective, and a driver of iron deficiency and its associated fatigue and cognitive symptoms, Bose and Vachhani contended.

“Real-world analysis shows that the majority of our patients are not kept below 45%, and therein lies the unmet need, to have drugs which consistently maintain a hematocrit below 45% and negate the need for phlebotomies,” Vachhani said.

What did the phase 2 IMPRSSION trial show for sapablursen?

IMPRSSION was a phase 2a, multicenter, randomized, open-label trial that evaluated sapablursen in patients with phlebotomy-dependent polycythemia vera, with or without background cytoreductive therapy, and results were presented at the 2025 ASH Annual Meeting and Exposition.¹ In IMPRSSION, patients in cohort A (n = 32) received sapablursen at 120 mg every 4 weeks, which was later reduced to 80 mg because of reductions in hemoglobin; those in cohort B (n = 17) received sapablursen at 40 mg every 4 weeks. The primary end point was a reduction in the weekly rate of phlebotomies.

The trial met its primary end point in both cohorts, with the mean weekly phlebotomy rate declining from 0.15 (standard deviation [SD], 0.07) at baseline to 0.05 (SD, 0.09) between weeks 17 and 37 in cohort A (mean change, −0.10; P < .0001) and from 0.17 (SD, 0.07) to 0.07 (SD, 0.07) in cohort B (mean change, −0.10; P = .0001). The median number of phlebotomies during the 20-week primary end point window fell to 0.0 (range, 0-1.0) in cohort A and 1.5 (range, 0-2.5) in cohort B, each from a baseline median of 5.0.

The mean change from baseline in the 10-item MPN Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) was −6.2 in cohort A (P = .0052) and −2.7 in cohort B (P = .3442). Sapablursen also produced dose- and time-dependent increases in serum hepcidin with corresponding, sustained reductions in hematocrit, alongside a modest increase in platelet count with no clinical sequelae and no effect on leukocyte count.

“We want to do something more than just a reduction of phlebotomies, and it was very good to see that there was symptom improvement happening as well,” Vachhani said. “It is very nice to see that the drug works in a way that we were hoping for it to work.”

Sapablursen was generally well tolerated, with treatment-emergent adverse effects (TEAEs) occurring in 92% the pooled safety population from cohorts A and B (n = 49), with anemia the most common (37%). Serious TEAEs occurred in 18% of patients, and 8% discontinued treatment because of TEAEs. TEAEs led to death in 1 patient treated in cohort A, which was attributed to transformation to acute myeloid leukemia and not deemed treatment-related. Injection-site reactions were local, mild, and did not recur with repeated dosing.

How is the phase 3 INTREPID trial being conducted?

INTREPID is a global, randomized, double-blind, placebo-controlled study that plans to enroll approximately 250 patients.² Eligible patients need to have polycythemia vera diagnosed by 2022 WHO/International Consensus Classification criteria, be phlebotomy-dependent, and have a hematocrit level of less than 45% at the start of study treatment. Patients receiving cytoreductive therapy must be on a stable dose at study initiation, but concurrent cytoreductive therapy is not required.

“This [trial] is not just for low-risk patients who are not on cytoreduction; it is for anybody who is still needing phlebotomy as defined in the protocol, which could be low risk or high risk, and on cytoreduction or not,” Bose said.

The study is structured in three parts. Part 1a is a 32-week double-blind period in which patients are being randomly assigned 1:1 to receive sapablursen at 80 mg subcutaneously every 4 weeks or placebo; during this portion of the study, investigators will evaluate the primary end point: the absence of phlebotomy eligibility between weeks 20 and 32.

Part 1b is a 20-week open-label period evaluating the durability of sapablursen, where placebo-assigned patients cross over to receive the investigational therapy, followed by a 104-week part 2 safety extension.

Key secondary end points include the number of phlebotomies from weeks 0 to 32, hematocrit control over the same window, and patient-reported symptom outcomes captured by the PROMIS Fatigue Short Form and the MPN-SAF-TSS.

What could the approval of sapablursen mean for the polycythemia vera treatment paradigm?

Bose and Vachhani positioned sapablursen as a potential monotherapy for lower-risk patients managed with phlebotomy alone and as an adjunct for patients whose hematocrit is inadequately controlled on cytoreductive therapy.

“A drug like sapablursen, if and when it meets the [INTREPID] end points and gets approved, could be used either as monotherapy to avoid the need for phlebotomies and therefore have a better iron profile in the body, or in an adjunct fashion to our other cytoreductive therapies,” Vachhani said, adding that once-every-4-week dosing sits in a practical “sweet spot.”

Bose emphasized the symptom dimension, noting that hepcidin modulators have shown a symptom benefit that is not fully explained but is reproducible across the class.

“These agents have somewhat unexpected but very significant symptom benefit,” he said. “Perhaps through iron redistribution, the mechanism is not well understood, but they definitely lead to improved symptom scores and quality of life. I think these are the two main benefits: symptoms and hematocrit control.”

References

1. Palmer JM, How J, Bose P, et al. Evaluation of the novel TMPRSS6 antisense inhibitor sapablursen for treatment of polycythemia vera: results of the IMPRSSION clinical trial. Presented at: 2025 ASH Annual Meeting; December 6-9, 2025; Orlando, FL.
2. INTREPID: a study of sapablursen evaluating the safety and efficacy in participants with polycythemia vera (PV). ClinicalTrials.gov. Updated 2026. Accessed August 25, 2026. https://clinicaltrials.gov/study/NCT07429266
3. 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 25, 2026. https://www.takeda.com/newsroom/newsreleases/2026/nda-rusfertide/
4. 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 25, 2026. https://www.businesswire.com/news/home/20260810915756/en/Silence-Therapeutics-Announces-Positive-Topline-Results-from-Phase-2-SANRECO-Trial-of-Divesiran-in-Polycythemia-Vera-Supporting-its-Potential-Best-in-Class-Profile