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Polycythemia Vera mRNA Therapy Receives FDA Fast Track Designation

SLN124 was well-tolerated in a previous clinical trial involving healthy volunteers.

Silence Therapeutics’ SLN124, an investigational siRNA therapy intended for the treatment of rare hematological diseases, has been granted fast track designation by the FDA for the treatment of polycythemia vera (PV).1

SLN124 functions by inhibiting expression of the TMPRSS6 gene in order to increase endogenous levels of hepcidin, a key regulator of iron balance and distribution. Data from aprevious clinical trial (NCT04559971) involving healthy volunteers completed last year were presented at the 2021 American Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia, and established a proof of mechanism and showed that SLN124 was well-tolerated, with no serious or severe treatment emergent adverse events (AEs) reported.1,2

"The granting of fast track designation represents an important recognition by the FDA of SLN124’s potential to address a significant unmet need in the treatment of PV," Craig Tooman, president and chief executive officer, Silence Therapeutics, said in a statement regarding the news.1 "We plan to leverage Fast Track to expedite our development path as we seek to provide an important new treatment option to those suffering from this very serious and chronic genetic disease.”

Silence Therapeutics intends to begin a new phase 1/2 clinical trial (NCT05499013) in patients with PV before the end of 2022. The open-label, multicenter study is expected to enroll up to 65 patients aged 18 years or older with confirmed diagnoses of PV. In order to be included, participants must either be on a stable dose of cytoreductive therapy for at least 12 weeks before treatment with no planned change in dose or have been off any prior cytoreductive therapy for at least 24 weeks before treatment and have recovered from any AEs related to cytoreductive therapy. Participants are additionally required to undergo a dermatological examination within the 6 months before screening and are required to have an Eastern Cooperative Oncology Group score of 0 to 2. Patients with a history of intolerance to oligonucleotides, GalNAc, any component of SLN124, or to subcutaneous injections will be excluded from the study, as will patients who have experienced clinically significant thrombosis within the 12 months before screening. Additional exclusion criteria relate to history of major bleeding events, requirements for blood transfusion therapy, meeting the criteria for post-PV myelofibrosis, prior reception of investigational or marketed drugs, biochemical and hematological parameters, and other clinically significant co-morbidities.

Participants in the phase 1 and phase 2 experimental arms will receive SLN124 via subcutaneous injection, while participants in the phase 2 blinded placebo comparator arm will receive a sodium chloride solution via subcutaneous injection. Primary end points will include the incidence of treatment-emergent AEs and a periodic assessment of the number of phlebotomies. Pharmacokinetic secondary end points include the area under the plasma concentration and peak plasma concentration, while pharmacodynamic secondary end points include changes in hematocrit, transferrin saturation, and hepcidin. The study’s estimated completion date is June 2025.

SLN124 is also currently being investigated in a separate phase 1 clinical trial (NCT04718844) for patients with α/β-thalassaemia and very low- and low-risk myelodysplastic syndrome. SLN124 previously received orphan disease designations from the FDA for PV, thalassemia, and myelodysplastic syndrome and rare pediatric disease designation for thalassemia.

“The healthy volunteer study represents the first clinical data from our platform and demonstrated our ability to translate strong preclinical results in humans,” Giles Campion, MD, EVP, chief medical officer and head of Research & Development, Silence Therapeutics, said in a previous statement regarding the healthy volunteer trial data in December 2021.2 “By modulating endogenous hepcidin in a highly controlled manner, we believe SLN124 has the potential to address the needs of patients in a broad range of hematological diseases. We look forward to data from the ongoing studies in patients with thalassemia and MDS anticipated in the third quarter of next year.”

REFERENCES
1. Silence Therapeutics announces FDA fast track designation for SLN124, a novel investigational siRNA therapy for the treatment of polycythemia vera. News release. Silence Therapeutics plc. September 8, 2022. https://silence-therapeutics.com/investors/press-releases/press-releases-details/2022/Silence-Therapeutics-Announces-FDA-Fast-Track-Designation-for-SLN124-a-Novel-Investigational-siRNA-Therapy-for-the-Treatment-of-Polycythemia-Vera/default.aspx 
2. New data from SLN124 healthy volunteer study reinforce broad therapeutic potential in hematological diseases. News release. Silence Therapeutics plc. December 12, 2021. https://silence-therapeutics.com/investors/press-releases/press-releases-details/2021/New-Data-from-SLN124-Healthy-Volunteer-Study-Reinforce-Broad-Therapeutic-Potential-in-Hematological-Diseases/default.aspx