Rusfertide acetate

Incyte’s Jakafi and PharmaEssentia’s Besremi are already approved in polycythemia vera. Silence Therapeutics has spoken up about its phase 1 polycythemia vera (PV) clinical trial, providing an early look at how its siRNA prospect may match up to rivals from Incyte and Takeda.  PV patients undergo regular blood draws, a procedure known as a phlebotomy, to reduce the number of blood cells and decrease blood volume. At baseline, all subjects in Silence’s trial had undergone at least three phlebotomies in the past six months or five phlebotomies in the past year. In total, the participants underwent 59 blood draws in the six months before starting the study.  The data set features 16 patients split across three doses of divesiran. Silence enrolled participants with levels of hematocrit above and below the threshold it has identified as increasing the risk of thrombotic and cardiovascular events.  None of the participants with well-controlled hematocrit at baseline underwent a phlebotomy during the follow-up period, which ranged from four to 34 weeks in the data set. Two patients on the middle dose had one blood draw each. The patients who needed phlebotomies had the highest hematocrit at baseline.  Silence also showed how levels of hematocrit changed over time in the first two dose cohorts. Levels trended down in the cohorts and fell below the risk threshold identified by Silence. However, the cohorts are small, featuring 12 patients in total, and the error bars are wide. Silence saw a bigger change at the higher of the two doses, leading it to say the data suggest a potential dose response.  No patients had drug-related serious adverse events or withdrew because of divesiran side effects. The results position Silence to continue toward the conclusion of the study, enrollment in which is scheduled to wrap up this month, but leave questions about the competitiveness of divesiran unanswered.  Incyte’s Jakafi and PharmaEssentia’s Besremi are already approved in the indication, although both leave room for improvement. Takeda is leading the charge to deliver a better PV drug. Having paid Protagonist Therapeutics $300 million upfront early this year, the Japanese drugmaker has rights to the phase 3 PV prospect rusfertide.  Protagonist’s molecule is an injectable peptide mimetic of the master iron regulatory hormone hepcidin. Divesiran is designed to inhibit expression of a target involved in hepcidin expression. The two molecules represent different ways of achieving the same goal, namely raising hepcidin to lower the production of red blood cells.

Silence Therapeutics announced encouraging results from its ongoing Phase I study of divesiran (SLN124), a potential first-in-class siRNA therapy for patients with polycythaemia vera (PV). The drug, which targets TMPRSS6, aims to increase hepcidin production, thereby restricting iron availability to the bone marrow and reducing the excessive red blood cell production that is characteristic of the disease."What we see today is a very clear picture," said CEO Craig Tooman on a call with investors. "We are excited about the potential for divesiran to be the first siRNA therapy for PV." He added that a Phase II study start is planned by year-end.The treatment goal for PV is to lower haematocrit (HCT) levels to less than 45% in order to reduce cardiovascular and major thrombotic events. Current standard of care includes repeated phlebotomies to lower HCT and/or cytoreductive agents to reduce red blood cell production.Near elimination of phlebotomiesThursday's readout centres on data from 16 patients enrolled in the ongoing SANRECO study. It included three dose cohorts who received divesiran administered subcutaneously every six weeks over the course of the 34-week study. The trial included both well-controlled patients – meaning they had HCT of ≤45% at baseline – as well as those with HCT levels over 45% despite being on current standard therapies.According to Silence, none of the eight well-controlled patients required phlebotomy during the treatment period, and only two out of the other eight patients with baseline HCTs over 45% required one phlebotomy. As a comparison, there were a total of 59 phlebotomies across the 16 patients reported during the six months prior to study entry.Less frequent dosing?While the company tested a six-week dosing schedule, R&D head Steven Romano noted that "based on the data we're collecting and continue to collect, we do see an opportunity potentially for a less frequent dosing strategy, but that will not be determined until we complete Phase I and move into Phase II."The company also reported favourable effects on iron metabolism indices across all dose groups, while hepcidin levels increased and remained within physiological ranges, demonstrating effective target engagement. No major safety issues were reported. More detailed results will be shared at a scientific meeting later this year.The SANRECO readout follows Silence's recent report of encouraging longer-term Phase II data for zerlasiran, another experimental siRNA therapy it is working on, but for cardiovascular disease. Zerlasiran demonstrated sustained reductions in lipoprotein(a) levels through 48 weeks in patients at high risk of atherosclerotic cardiovascular disease events.Takeda-partnered rivalMeanwhile, the progress of divesiran comes amid increasing interest in novel therapies for PV. Earlier this year, Takeda agreed to pay $300 million upfront as part of a licensing deal with Protagonist Therapeutics for rusfertide, an injectable hepcidin mimetic peptide currently in Phase III testing for PV. The company anticipates 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 showed durable HCT control and decreased phlebotomy for up to three years.