Silence's siRNA enters Phase II for polycythemia vera, challenging Takeda rival

Silence Therapeutics has announced promising results from its ongoing Phase I study of divesiran (SLN124), a novel siRNA therapy aimed at treating polycythaemia vera (PV). This pioneering drug targets the TMPRSS6 gene to elevate hepcidin production, thereby limiting iron availability to the bone marrow and curbing the excessive production of red blood cells, a hallmark of PV. CEO Craig Tooman expressed optimism about divesiran's potential during a recent investor call, noting plans to commence a Phase II study by the end of the year.

The primary treatment objective for PV is to lower haematocrit (HCT) levels below 45% to minimize the risk of cardiovascular and major thrombotic events. Current treatments typically involve repeated phlebotomies to reduce HCT or the use of cytoreductive agents to decrease red blood cell production.

The latest data release focused on 16 patients participating in the ongoing SANRECO study, which involves three dosage cohorts receiving subcutaneous divesiran every six weeks over a 34-week period. The study included both patients with well-controlled HCT levels (≤45%) at baseline and those with elevated HCT levels despite existing treatments.

Notably, none of the eight patients with well-controlled HCT levels required phlebotomy during the treatment period. Among the eight patients with baseline HCT levels above 45%, only two needed a single phlebotomy. This is a significant reduction compared to the 59 phlebotomies reported across the 16 patients in the six months prior to the study.

Silence Therapeutics is exploring the possibility of less frequent dosing based on the data collected thus far. Head of R&D, Steven Romano, indicated that while a six-week dosing schedule is currently used, further data might support a less frequent administration in the future. However, this determination will only be made after the completion of the ongoing Phase I study and subsequent Phase II.

Additionally, the company reported positive effects on iron metabolism across all dosage groups, with increased hepcidin levels staying within physiological norms, demonstrating effective target engagement. No significant safety concerns were noted. More comprehensive results will be shared at an upcoming scientific meeting later this year.

This announcement follows Silence Therapeutics' recent encouraging Phase II data for another experimental siRNA therapy, zerlasiran, aimed at cardiovascular disease. Zerlasiran has shown sustained reductions in lipoprotein(a) levels over 48 weeks in patients at high risk for atherosclerotic cardiovascular events.

The progress of divesiran comes amid heightened interest in innovative therapies for PV. Earlier this year, Takeda entered into a licensing agreement with Protagonist Therapeutics, paying $300 million upfront for rusfertide, an injectable hepcidin mimetic peptide currently in Phase III trials for PV. Takeda expects to release topline data from the VERIFY study by the end of the first quarter of 2025.

Recent long-term follow-up data from rusfertide's Phase II REVIVE trial have shown durable control of HCT levels and reduced need for phlebotomy for up to three years, underscoring the potential for novel treatments in managing PV.

In summary, Silence Therapeutics' Phase I study of divesiran has yielded promising results, showing potential in reducing the need for phlebotomies and effectively managing iron metabolism in PV patients. With plans for a Phase II study and further data anticipated, divesiran could represent a significant advancement in the treatment landscape for this condition.

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