Evaluation of the novel TMPRSS6 antisense inhibitor sapablursen for treatment of polycythemia vera: Results of the imprssion clinical trial
Bibliographic record
Abstract
Abstract Background: Polycythemia vera (PV) is characterized by excessive erythrocytosis and elevated hematocrit (Hct), which is associated with increased risk of thrombotic events. Controlling Hct levels (<45%) is a key therapeutic goal to reduce thrombotic events. Sapablursen (ISIS 702843) is a liver-directed, ligand-conjugated antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6) to enhance hepcidin production thereby restricting iron availability and reduced erythrocytosis. We are reporting the topline results of the IMPRSSION study (NCT05143957), an ongoing global, open-label phase 2 trial evaluating the safety and efficacy of sapablursen for Hct control and reducing phlebotomy rate in patients with PV. Methods: Eligible patients met 2016 WHO diagnostic criteria for PV, were required to have >3 phlebotomies within six months prior to screening, including >1 phlebotomy in the last 12 weeks. There were no exclusions for HCT prior to randomization. Patients received monthly subcutaneous doses of sapablursen in Cohort A (high dose) or Cohort B (low dose), during a 37-week treatment period. The primary efficacy endpoint was the reduction in the frequency of phlebotomy during the last 20 weeks of the treatment period (Week 17-37) compared to baseline (defined as the mean weekly phlebotomy rate during the six months prior to screening through the first dose of sapablursen). Phlebotomy was performed when Hct levels were ≥45% or at the investigator's discretion, confirmation of Hct was not required for phlebotomy. Serial assessments of serum hepcidin, TSAT and ferritin were conducted. The 10-item Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) assessed the change in symptoms from baseline to Week 37. Results: Forty-nine (49) patients received at least one dose of sapablursen (full analysis set) in either Cohort A (n=32) or Cohort B (n=17). The median age was 61 years, 40 (82%) were male, and 29 (59%) classified as high risk. The primary endpoint was met at both dose levels. The weekly phlebotomy rate (mean±SD) decreased from baseline of 0.15±0.07 (~7.8/yr) to 0.05±0.09 (~2.6/yr) during the primary endpoint window (Week 17-37) in Cohort A (n=32, p<0.0001; 95%CI, -0.13, -0.07), and from 0.17±0.07 (~8.9/yr) to 0.07±0.07 (~3.6/yr) in Cohort B (n=17, p=0.0001; 95%CI, -0.14, -0.06). The mean MPN-SAF-TSS was reduced at Week 37 by 32% in Cohort A (change from baseline LSM -6.2, p=0.005) and 11% in Cohort B (change from baseline LSM -2.7, p=0.344). The proportion of patients with Hct control (<45%) without phlebotomy from week 17 to 37 in Cohort A and B was 53% (17/32) and 35% (6/17), respectively. Serum hepcidin was increased from baseline values of 0.25±0.6 to 5.05±4.7 nM at Week 13 in Cohort A (p<0.0001) and from 0.68±1.7 to 2.06±3.6 nM in Cohort B (p=0.0142). A sustained low TSAT was observed between Weeks 17-37 (6.0±2.1% and 5.5±2.0% in Cohort A and 8.9±5.0% and 7.0±3.4% in Cohort B). Serum ferritin increased over time from 18±22 ng/mL and 28±58 ng/mL at baseline in Cohort A and B, respectively, to 44±47 ng/mL and 41±85 ng/mL at Week 37, respectively. Sapablursen was generally safe and well-tolerated. The incidence of injection site reactions was 12.2% (6/49). Injection site reactions did not recur following multiple injections, were not progressive and resolved spontaneously. There was one death on study due to transformation to AML which was deemed as not related to the study drug. Conclusions: Treatment of PV patients with sapablursen increased serum hepcidin, controlled Hct, reduced phlebotomy need and improved quality of life in a dose-dependent manner. These findings highlight the potential of sapablursen as a therapeutic approach in PV and support further development.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".