The novel small interfering RNA (siRNA) therapy divesiran (SLN124) has demonstrated encouraging safety and efficacy signals in treating polycythemia vera patients, according to new data from the phase 1/2 SANRECO trial presented at the 2024 ASH Annual Meeting.
The study enrolled 21 patients across three dosing cohorts, showing a marked reduction in the need for phlebotomies - a key treatment goal for polycythemia vera patients. Prior to treatment, participants required 79 phlebotomies collectively, which decreased dramatically to just 5 procedures during the treatment period and 2 during follow-up.
Mechanism of Action and Drug Design
Divesiran represents a first-in-class GalNAc-conjugated siRNA targeting TMPRSS6, a negative regulator of hepcidin expression. The drug's unique design aims to increase hepcidin levels and reduce iron delivery to the bone marrow, thereby decreasing erythropoiesis. Its target sequence was specifically selected to maximize TMPRSS6 knockdown while maintaining specificity.
Safety Profile and Tolerability
The safety data has been particularly promising, with no dose-limiting toxicities observed across all dosing cohorts (3 mg/kg, 6 mg/kg, and 9 mg/kg). The majority of treatment-emergent adverse effects (84%) were mild, classified as grade 1, with none exceeding grade 2. Notable adverse events included:
- Injection site reactions (61.9% of patients)
- Anemia (33.3%)
- Fatigue (23.8%)
- Headache (19.0%)
Importantly, no treatment-related serious adverse events or discontinuations were reported.
Clinical Efficacy Markers
Dr. Marina Kremyanskaya, Medical Director at The Mount Sinai Hospital, and her colleagues reported significant clinical benefits across multiple parameters:
- Consistent hematocrit reduction across all patient cohorts
- Increased ferritin levels in all treatment groups
- Stable white blood cell counts
- Increased platelet counts by day 29, showing no dose dependency
Patient Population and Trial Design
The SANRECO trial enrolled adult patients meeting the 2016 WHO criteria for polycythemia vera. Key eligibility criteria included:
- Minimum of 3 phlebotomies in previous 6 months or 5 in prior 12 months
- ECOG performance status ≤2
- Platelet count up to 1 million/µL
- White blood cell count up to 25,000/µL
The study population had a mean age of 55 years, with predominantly male (76%) and White (52%) participants. Most patients (62%) were receiving hydroxyurea as cytoreductive therapy, while one patient was on ruxolitinib.
Clinical Implications
"Divesiran is safe and well-tolerated at doses up to 9 mg/kg," stated Dr. Kremyanskaya. The drug's ability to decrease phlebotomy requirements while maintaining stable blood counts represents a significant advancement in polycythemia vera treatment.
The positive early results from SANRECO, particularly the dramatic reduction in phlebotomy needs and consistent hematocrit control, support further development of divesiran as a potential new treatment option for polycythemia vera patients. The therapy's novel mechanism of action and favorable safety profile make it a promising candidate for addressing the unmet needs in polycythemia vera management.
