Divesiran hits 88% versus 19% in Phase 2 polycythemia vera — Silence takes quarterly dosing into a 1H 2027 Phase 3

Eighty-eight percent of divesiran-treated patients were clinical responders against 19% on placebo — a placebo-adjusted 69 percentage points, p<0.0001 — in the randomized Phase 2 portion of SANRECO, in 48 polycythemia vera patients who were still phlebotomy-dependent despite standard of care ^[1]. Silence Therapeutics disclosed the topline on 10 August 2026 in a release filed as an exhibit to an 8-K ^[1]. The hepcidin pathway is an established therapeutic axis in PV and myelofibrosis ^[5]; the readout is a placebo-controlled Phase 2 on phlebotomy avoidance and hematocrit for a TMPRSS6-directed siRNA ^[1][2].

What happened

SANRECO's Phase 2 is a three-part, global, randomized, double-blind, placebo-controlled study of divesiran 6 mg/kg subcutaneously, dosed either every six weeks or every twelve, in patients with uncontrolled hematocrit who remain phlebotomy-dependent on standard care that could include hydroxyurea, interferon and/or ruxolitinib ^[1]. The randomized portion ran 36 weeks ^[1]. The primary endpoint was the proportion of patients with absence of phlebotomy and maintenance of hematocrit below 45% during weeks 18 to 36 ^[1].

Both dose groups cleared it: 93.8% at every-six-weeks dosing and 81.3% at every-twelve-weeks ^[1]. The key secondary endpoint — phlebotomy rate across weeks 0 to 36 — was also met, at a mean 0.2 phlebotomies per patient on divesiran versus 2.1 on placebo, p<0.0001 ^[1]. Silence also reports improvements in hematocrit control, iron markers including ferritin, and patient-reported symptom burden on the MPN-SAF Total Symptom Score, but disclosed no numbers for any of the three ^[1].

Safety was described as in line with prior trials, with no new findings, infrequent and self-limiting injection site reactions, and two investigator-reported grade 1 anemia cases ^[1]. Anemia is the on-target risk of the mechanism — divesiran silences TMPRSS6, a negative regulator of hepcidin, so hepcidin rises and iron is redirected away from the marrow, which is exactly how red cell production falls ^[2]. Two grade 1 events reported without a denominator or arm attribution is not enough to characterise that risk; the full dataset is.

The readout landed inside the guided window. Silence completed enrollment on 23 October 2025 and guided topline to the third quarter of 2026 ^[2]; the March 2026 corporate deck still carried that guidance ^[4]. Execution to the calendar, on a company that has had to ration its own pipeline, is itself a data point.

Why it matters

The interesting decision is not the headline number — it is which arm Silence is taking forward. The Phase 3 will test divesiran every twelve weeks against placebo, with initiation anticipated in the first half of 2027 ^[1]. That is the 81.3% arm, not the 93.8% arm. The release gives no p-value for the difference between doses and no per-arm patient counts, so whether the twelve-point gap is real or noise cannot be resolved from the topline; Prognyx reads the choice as a deliberate trade of nominal response rate for quarterly dosing rather than every six weeks, in a disease where the placebo arm still averaged 2.1 phlebotomies over 36 weeks ^[1]. Therapeutic phlebotomy is still recommended in international guidelines for erythrocytosis, and its role in a pharmacologic era is under active re-examination in the literature ^[6].

Note what the Phase 3 does not do: it does not drop the placebo control ^[1]. What it will have to clear is unknown — Silence has not disclosed the Phase 3 endpoint, size, geography or how background cytoreduction will be handled.

The pathway question deserves a calendar, not an acronym. Divesiran holds FDA Fast Track and Orphan Drug designations in PV ^[2]. Neither sets a review clock, and no marketing application exists in the record Prognyx reviewed, so no PDUFA date range can be derived. The datable path runs through the trial. Applying the Phase 2's own cadence — enrollment completion announced 23 October 2025 ^[2], topline 10 August 2026 ^[1], roughly nine and a half months from that announcement to topline, and an upper-bound proxy at that, since the last-patient-in date is not disclosed — to a Phase 3 starting in the first half of 2027 puts the earliest conceivable randomized topline in mid-2028 only if enrollment were instantaneous, and in 2029 on anything resembling a real Phase 3 accrual for a larger study. That is Prognyx's arithmetic, and it rests on Phase 3 size and accrual assumptions the company has not published. A US approval decision sits later still.

The financing question sits inside that window. Silence's last sourced balance sheet showed $147.3M in cash, cash equivalents and short-term investments at 31 December 2024, against a FY2024 net loss of $45.3M and R&D expense of $67.9M ^[3]. In February 2025 the company said it would only start the zerlasiran Phase 3 cardiovascular outcomes study once a partner was secured, extending projected runway into 2027 and prioritising divesiran and rare disease ^[3]. A Phase 3 start guided to the first half of 2027, against a runway last guided "into 2027" on numbers now eighteen months stale, is a partnering or financing event waiting to be scheduled.

Who is exposed, by name

The registry entries below state what each company is testing, not how well it works.

Same disease, same placebo question. Ono Pharmaceutical is running INTREPID, a Phase 3 of sapablursen versus placebo in polycythemia vera, currently recruiting (NCT07429266) ^[7]. That is the closest structural analogue to what Silence just described and to what it plans for 2027: a PV trial with a placebo comparator. Disc Medicine has an open-label Phase 2 of DISC-3405 in PV, active but no longer recruiting (NCT06985147), plus DISC-0974 in myelofibrosis and MDS-associated anemia (NCT05320198) ^[8][15]. Mabwell has 9MW3011 in a recruiting Phase 1 in PV (NCT06752746) ^[13].

Same patient, different mechanism. Italfarmaco is recruiting a Phase 3 of givinostat versus hydroxyurea in PV (NCT06093672) ^[10] — the only active Phase 3 in this set with an active cytoreductive comparator rather than placebo. PharmaEssentia has a Phase 3 of ropeginterferon alfa-2b in adult PV, active but no longer recruiting (NCT05481151) ^[11]. Kartos ran KRT-232 against ruxolitinib specifically in phlebotomy-dependent PV, now active but no longer recruiting (NCT03669965) ^[9] — the same population label divesiran used.

Adjacent and watching. Merck is recruiting a Phase 3 of bomedemstat (NCT06351631) ^[12]; the registry entry does not name the indication. Novartis (pelabresib plus ruxolitinib in myelofibrosis, NCT04603495) ^[14] and GSK (momelotinib plus luspatercept in transfusion-dependent myelofibrosis, NCT06517875) ^[16] are in the neighbouring MPN indication where the hepcidin axis has also been evaluated ^[5].

One framing Prognyx will not adopt: a comparison to rusfertide. No rusfertide efficacy figure, phase or regulatory status was retrieved, and no Protagonist or Takeda primary source. No comparison is drawn here, and none should be inferred.

What we could not verify

No ClinicalTrials.gov record for SANRECO was retrieved, so the NCT number, registry status, arm structure and primary completion date are unconfirmed; the company's own statement is that all patients have completed the placebo-controlled portion and are now in three-year double-blind and open-label extensions, with the study ongoing ^[1]. Per-arm patient counts, confidence intervals and the between-dose comparison are absent from the topline. The ferritin, hematocrit-control and MPN-SAF TSS results are qualitative only. The congress that will host the full dataset is not named ^[1]. Silence's October 2025 line that no approved therapy specifically targets red blood cells and hematocrit ^[2] is a dated company statement and is reproduced here as such, not as a current claim. Zerlasiran's partnering status as of August 2026, and the share reaction to the readout, are outside what Prognyx could source.

What to watch

The congress presentation — full Phase 2 SANRECO data, including per-arm n, the dose comparison, iron-marker and symptom-score effect sizes, and the anemia cases with denominators. Silence says it is coming; it has not named the meeting or the date ^[1].

A Phase 3 protocol posting, which Prognyx would expect ahead of the first-half-2027 initiation Silence has guided to ^[1]: size, endpoint, geography and how background cytoreduction is handled will determine whether this replicates the Phase 2 or raises the bar.

The next financial disclosure, which is where the runway-versus-Phase-3 arithmetic and any divesiran partnership get resolved ^[3].

Verdict: high threat to any PV asset whose value rests on phlebotomy avoidance in the phlebotomy-dependent segment; the window to reposition runs until the Phase 3 protocol posts ahead of a first-half-2027 start.