New Data from SLN124 Study in Healthy Volunteers Strengthen Broad Therapeutic Potential in Hematologic Diseases
- Data presented at 2021 ASH annual Encounter showed dsustained reductions in serum iron and transferrin saturation, strong security profile and long duration of action
- Datassupport ongoing studies in patients with thalassemia and myelodysplastic syndrome and a new study planned in polycythemia vera
12 December 2021
LONDON, Silence Therapeutics plc, Nasdaq: SLN (“Silence” or “the Company”), a leader in the discovery, development and delivery of new therapeutic agents based on short interfering ribonucleic acid (siRNA) for the treatment of diseases with significant unmet medical need, presented additional positive data from the SLN124 healthy volunteer study today at the 2021 American Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia, USA. United). SLN124, an siRNA targeting the TMPRSS6 gene expressed by the liver, is currently under development for conditions of iron overload anemia, thalassemia and myelodysplastic syndrome (MDS).
The phase 1, randomized, double-blind, placebo-controlled, single-dose escalating study evaluated the safety and tolerability of SLN124 (doses of 1.0, 3.0 and 4.5 mg / kg) in 24 healthy volunteers. Pharmacokinetic parameters and pharmacodynamic biomarkers of iron metabolism were also measured to assess iron reduction.
Giles Campion, MD, EVP, Chief Medical Officer and Head of Research & Development at Silence, say: “we have developed our owner MRNA GOLDâ¢ Platform with the focus on delivery target, precision drugs for many diseases that lack effective treatment. The study on healthy volunteers represents the first clinical data from our platform and demonstrated our ability to translate strong preclinical results in humans. By modulating endogenous hepcidin in a very controlled manner, we to believe SLN124 to the potential at address the Needs sick people in a wide range of hematological diseases. We look forward to data from ongoing studies in patients with thalassemia and MDS scheduled for the third quarter of next year. “
Principal author, John Porter, MD., Professor and consultant Hematologist, Red Cell Disorders Unit, University College London and University of College London Hospitals, commented: “Silencing the TMPRSS6 gene represents a new and promising therapeutic approach to manipulate hepcidin, which in turn has the potential to control a number of hematologic conditions. I look forward to further development of SLN124 in people with iron anemia, who may positively benefit from the effects we have seen in healthy volunteers.
New data presented to ASH today showed that SLN124 was rapidly distributed (median tmax was 4.0 or 5.0 hours) and largely cleared from plasma within 24 hours of dosing in all dosing groups. Plasma concentrations of SLN124 increased above the linear dose between administration groups.
Dose-related increases in circulating hepcidin, a key endogenous regulator of iron balance and distribution, were evident at day 8; all doses resulted in sustained increases throughout the study period, consistent with robust target engagement and TMPRSS6 gene suppression. SLN124 induced lasting reductions in serum iron; the percent change from baseline was approximately 50% on day 29 with doses of 3.0 and 4.5 mg / kg.
All doses of SLN124 induced marked reductions in transferrin saturation (TSAT); absolute levels of TSAT achieved (10-16%) are below the level (
As previously stated, the results showed that all doses of SLN124 were well tolerated, with no serious or serious treatment-related adverse events (TREs) or EIETs leading to withdrawal. ADEs did not appear to be dose dependent and the majority were mild, including transient injection site reactions that resolved without intervention.
The poster titled “SLN124 a GalNAc Conjugated 19-mer Double Stranded siRNA Reduces Iron and Raises Hepcidin Levels in Healthy Volunteers in a Phase 1 Clinical Study” is available here.
SLN124 is being evaluated in two phase 1 single-dose escalating studies in patients with thalassemia and MDS. SLN124 has the orphan drug designation for both conditions and the rare pediatric disease designation for beta thalassemia. Silence plans to launch a phase 1 study of SLN124 in polycythemia vera in the second half of 2022.
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About thalassemia and myelodysplastic syndrome (MDS)
Thalassemia and MDS are two rare conditions that prevent a person from making enough healthy red blood cells. Low levels of healthy red blood cells, known as anemia, cause a decrease in the supply of oxygen to different parts of the body. This can cause symptoms such as excessive fatigue and weakness. It can also lead to other serious health problems, such as heart disease. People with thalassemia or MDS can also store too much iron in their bodies, which leads to a phenomenon called âiron overload,â which can damage organs such as the liver, heart, and endocrine system.
Both conditions are often treated with repeated blood transfusions, which makes the problem of iron overload worse. Iron chelation therapy removes excess iron from the body with the help of special drugs. While it helps reduce the amount of body iron in people with thalassemia or MDS, it does not treat the underlying cause of the anemia or prevent it from progressing. There is therefore a need for therapies which directly address the biological factors of anemia.
About true polycythemia (PV)
PV is a rare cancer of the blood and belongs to a related group known as “myeloproliferative neoplasms” (NMPs). Unlike thalassemia and MDS where the body does not make enough red blood cells, people with PV make too many red blood cells. This makes the blood thicker and less able to move around the body, causing a variety of problems ranging from headaches and dizziness to more serious complications, such as blood clots.
Current treatments focus on treating the symptoms of PV to reduce the number of red blood cells and reduce the risk of blood clots. They do not target the underlying genetic cause of the disease.
SLN124 is a gene “silence” therapy, designed to temporarily block the message of a specific gene that would otherwise trigger an adverse reaction. In this case, SLN124 aims to temporarily “silence” TMPRSS6, a gene that prevents the liver from producing a central regulator of iron balance and distribution in the body: hepcidin. Inactivation of TMPRSS6 by SLN124 increases endogenous hepcidin, with potential beneficial effects in several hematologic disorders. SLN124 has demonstrated the safety and proof of the mechanism in a study in healthy volunteers and is currently under investigation in patients with thalassemia and MDS. SLN124 has the orphan drug designation for both conditions and the rare pediatric disease designation for beta thalassemia. Silence plans to launch a phase 1 study of SLN124 in polycythemia vera in the second half of 2022.
About Silence Therapeutics
Silence Therapeutics is developing a new generation of drugs by harnessing the body’s natural mechanism of RNA interference, or RNAi, to inhibit the expression of specific target genes believed to play a role in the pathology of diseases with significant unmet needs. Silence’s proprietary mRNAi GOLD â¢ platform can be used to create siRNAs (short interfering RNAs) that precisely target and silence disease-associated genes in the liver, representing a substantial opportunity. Silence’s wholly owned product candidates include SLN360 designed to address the high and widespread unmet medical need for cardiovascular risk reduction in people born with high levels of lipoprotein (a) and SLN124 designed to treat rare hematologic diseases. Silence also maintains ongoing research and development collaborations with AstraZeneca, Mallinckrodt Pharmaceuticals and Hansoh Pharma, among others. For more information, please visit https://www.silence-therapeutics.com/.
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