Silence Therapeutics plc is a biotechnology company focused on discovering and developing novel molecules incorporating short interfering ribonucleic acid, or siRNA, to inhibit the expression of specific target genes thought to play a role in the pathology of diseases with significant unmet medical need.
The company’s siRNA molecules are designed to harness the body’s natural mechanism of RNAi by specifically binding to and degrading messenger RNA, or mRNA, molecules that encode specific target...
Silence Therapeutics plc is a biotechnology company focused on discovering and developing novel molecules incorporating short interfering ribonucleic acid, or siRNA, to inhibit the expression of specific target genes thought to play a role in the pathology of diseases with significant unmet medical need.
The company’s siRNA molecules are designed to harness the body’s natural mechanism of RNAi by specifically binding to and degrading messenger RNA, or mRNA, molecules that encode specific targeted disease-associated proteins in a cell. By degrading the message that encodes the disease-associated protein, the production of that protein is reduced and its level of activity is lowered. In the field of RNAi therapeutics, this reduction of disease-associated protein production and activity is referred to as ‘gene silencing’. The company’s proprietary mRNAi GOLD (GalNAc Oligonucleotide Discovery) platform consists of precision engineered product candidates designed to accurately target and ‘silence’ specific disease-associated genes in the liver. Using the company’s mRNAi GOLD platform, the company has generated siRNA product candidates both for the company’s internal development pipeline, as well as for out-licensed programs with third-party collaborators. The company’s wholly owned pipeline is focused in three therapeutic areas of high unmet need: cardiovascular disease, hematology and rare diseases.
Zerlasiran (SLN360) is the company’s wholly owned siRNA designed to lower the body's production of apolipoprotein(a), a key component of lipoprotein(a), or Lp(a), that has been associated with an increased risk of cardiovascular events. High Lp(a) is a genetically determined cardiovascular risk factor affecting up to 20% of the world’s population and is associated with a high risk of heart attack, stroke and aortic stenosis. There are no approved medicines that selectively lower Lp(a). In February 2022, the company reported positive results from the single-ascending dose portion of the APOLLO phase 1 program evaluating zerlasiran in 32 healthy adults with high Lp(a) =150 nmol/L. In the single dose trial, participants in the top two zerlasiran single dose groups (300 mg and 600 mg) were observed to have experienced up to a 96% and 98% median reduction in Lp(a) levels, respectively, and median reductions of up to 71% and 81% from baseline persisted at 150 days. Further analysis showed median time-averaged Lp(a) reductions over 150 days exceeded 80% in the zerlasiran 300 mg and 600 mg dose groups. At day 365, some participants still exhibited substantial knockdown of Lp(a) to approximately 50% of baseline. Zerlasiran was well tolerated with no serious safety concerns reported. In November 2023, the company reported positive topline results from the multiple dose portion of the APOLLO program in 36 adults with baseline Lp(a) levels =150 nmol/L and stable atherosclerotic cardiovascular disease (ASCVD). In the multiple dose trial, zerlasiran (200 mg, 300 mg and 450 mg) was administered twice subcutaneously at two different dosing intervals. Data demonstrated a significant reduction from baseline in Lp(a) of up to 99% at 90 days following injection of repeated doses. Lp(a) levels remained approximately 90% lower than baseline at 201 days (end of treatment period) at the two highest doses. A dose dependent reduction in low-density lipoprotein cholesterol (LDL cholesterol) and apolipoprotein B (ApoB) was also observed. Zerlasiran was well tolerated; no clinically important safety concerns were identified. Zerlasiran is being evaluated in the fully enrolled ALPACAR-360 phase 2 study in patients with Lp(a) levels 125 nmol/L at high risk of ASCVD events. The company expects to report topline 36-week data in the first quarter of 2024 (primary endpoint) and topline 48-week data in the second quarter of 2024. The company is finalizing the design of its phase 3 Clinical Outcomes Trial. The company continues to engage in global partnership discussions for future zerlasiran development and for potential future commercialization.
Divesiran (SLN124) is the company’s wholly owned siRNA designed to inhibit TMPRSS6 expression in the liver to raise hepcidin, a peptide hormone that is the master regulator of systemic iron balance. Divesiran has shown preclinical potential in several hematological disorders. Furthermore, divesiran has demonstrated proof of mechanism in the GEMINI phase 1 trial in healthy volunteers completed in May 2021. In the GEMINI study, divesiran was observed to increase average hepcidin approximately four-fold and reduce serum iron by approximately 50% after a single dose with effects persisting for at least two months. Data were presented at the American Society of Hematology (ASH) 2021 Annual Meeting and published in the American Journal of Hematology in July 2023. Divesiran is being studied in the SANRECO phase 1/2 trial in patients with polycythemia vera (PV). Divesiran has FDA Fast Track and orphan disease designations for PV. The company plans to report data from the phase 1 portion of the study in the first half of 2024.
The potential of the company’s mRNAi GOLD platform has been validated through ongoing research and development collaborations with leading pharmaceutical companies, such as AstraZeneca, Mallinckrodt and Hansoh. These collaborations collectively represent up to 14 pipeline programs.
The company aims to maximize its mRNAi GOLD platform by advancing both the company’s proprietary and partnered pipelines.
mRNAi GOLD Platform
The company’s mRNAi GOLD platform comprises elements of the company’s GalNAc-siRNA toolbox, the company’s liver cell targeting technology and the company’s target selection and screening process.
GalNAc-siRNA Toolbox. The company’s mRNAi GOLD platform is a toolbox comprising several different elements that can be incorporated into the company’s double-stranded siRNA structure, known as blunt-ended 19-mers, either singly or in different combinations depending on individual siRNA sequences. The toolbox elements include sugar modifications of one or more select individual nucleotides; stabilizing modifications of one or more internucleoside linkages in the sense and antisense strands; stabilizing modifications at one or more of the ends of the siRNA molecules; and a versatile linker chemistry for GalNAc ligand conjugation in various numbers and configurations.
When applying these elements of the company’s toolbox, the company also aims to reduce the overall content of the sugar modifications and the number of undefined stereogenic centers in the siRNA molecule.
Liver Cell Targeting Technology. Blood flow and fenestra, or small openings in the endothelium, result in a large amount of the injected dose of a conjugated siRNA passing through the liver and reaching the main cell type of the liver known as a hepatocyte. Hepatocytes are cuboidal epithelial cells that line the liver sinusoids. Individual hepatocytes have approximately 0.5 to 1.0 million cell surface ASGPRs. GalNAc binds to ASGPRs with high affinity so that when GalNAc-conjugated siRNA reaches the hepatocytes, they are internalized into the cells where siRNA can bind and, as a result, can degrade the target mRNA, which in turn reduces production of the encoded protein and that protein’s activity, thereby silencing the respective gene. Only a small fraction of the initial dose reaches the hepatocyte and the right compartment of the cell, but once the siRNA is there, it can stay active and intact for several months, allowing a small number of internalized siRNA molecules to exert a potent effect on the target mRNA. The company applies the toolbox elements in the lead optimization phase to identify candidates that will be potent with a long duration of action and have a favorable safety profile.
Target Selection and Screening Process. The company is able to source potential product candidates through a proprietary target selection process. The selection of new targets involves a careful analysis of human genetics evidence, the biology underlying an indication, disease epidemiology and addressable population, the current standard of care and resulting medical need, the commercial landscape and the envisaged clinical path.
The company’s screening process relies on a proprietary in silico algorithm that seeks to predict the most efficacious and specific siRNAs for any given target. This bioinformatics function is designed to continuously improve in silico predictions for finding potentially potent and safe siRNA sequences. The highest scoring drug candidates subsequently undergo a multi-step evaluation process involving several rounds of in vitro screening in cell lines and primary hepatocytes to identify the most potent molecules. Top candidates identified in vitro are then tested for safety and potential efficacy in animal models. At this point in the process, additional modification patterns and new chemistries are introduced for improvement of activity and duration of action while maintaining the desired safety profile. To be selected as a drug candidate for clinical trials, it further needs to be shown that a molecule is well tolerated, elicits no serious adverse effects, and achieves strong and long-lasting knockdown of the targeted gene in a study with non-human primates.
siRNA Product Candidates
Zerlasiran (SLN360)
Zerlasiran is an siRNA molecule designed for the treatment of cardiovascular disease associated with elevated Lp(a), a lipoprotein in the blood. Available human data validate Lp(a) as an independent risk factor increasing the chances of developing premature cardiovascular diseases, including coronary heart disease and unstable angina, as well as myocardial infarction and ischemic stroke. Zerlasiran is administered by subcutaneous injection and has the potential to reduce these diseases by specifically binding to and inducing RNAi-mediated degradation of the mRNAs made from LPA, the gene that encodes apolipoprotein(a), a protein specifically found in Lp(a). Zerlasiran’s mode of action creates an opportunity to develop this product candidate for several indications for which Lp(a) has been shown to be a causal, independent risk factor.
APOLLO Phase 1 Clinical Program
The APOLLO phase 1 clinical program was a global randomized, double-blind, placebo controlled, single-ascending dose and multiple-ascending dose study investigating the safety, tolerability, pharmacodynamic and pharmacokinetic response of zerlasiran administered subcutaneously in healthy adults and ASCVD patients with high Lp(a) levels of approximately = 60mg/dL or = 150 nmol/L.
In February 2022, the company reported positive results from the single-ascending dose portion of the APOLLO phase 1 program in 32 healthy adults with high Lp(a) = 150 nmol/L. In April 2022, results were simultaneously presented in a late-breaking presentation at the ACC Annual Meeting and published in JAMA. In the single dose trial, participants in the top two dose groups (300 mg and 600 mg) were observed to have experienced up to a 96% and 98% median reduction in Lp(a) levels, respectively, and median reductions of up to 71% and 81% from baseline persisted at 150 days. Those receiving a placebo saw no change in Lp(a) levels. Other efficacy measures included the effects of zerlasiran on low-density lipoprotein cholesterol (LDL cholesterol) and ApoB, both of which are associated with an increased risk of cardiovascular events. The highest doses of zerlasiran reduced LDL cholesterol and ApoB by about 25%. Zerlasiran was well tolerated with no serious safety concerns reported. In November 2022, the company presented a further analysis from the APOLLO trial up to 365 days at the American Heart Association 2022 Annual Meeting. The analysis showed median time-averaged Lp(a) reductions over 150 days exceeded 80% in the zerlasiran 300 mg and 600 mg dose groups. At day 365, some participants still exhibited substantially reduced levels of Lp(a) of approximately 50% compared to baseline. Additionally, extension data to day 365 showed no new drug related safety findings.
In November 2023, the company reported positive topline results from the multiple-ascending dose portion of the APOLLO program in 36 adults with stable ASCVD and high Lp(a) =150 nmol/L. In the multiple dose trial, zerlasiran (200 mg, 300 mg and 450 mg) was administered twice subcutaneously at two different dosing intervals. Data demonstrated a significant reduction from baseline in Lp(a) of up to 99% at 90 days following injection of repeated doses. Lp(a) levels remained approximately 90% lower than baseline at 201 days (end of treatment period) at the two highest doses. A dose dependent reduction in low-density lipoprotein cholesterol (LDL cholesterol) and apolipoprotein B (ApoB) was also observed. Zerlasiran was well tolerated; no clinically important safety concerns were identified.
ALPACAR-360 Phase 2 Clinical Program
The ALPACAR-360 phase 2 clinical trial is a randomized, double-blind, placebo-controlled trial enrolling approximately 160 patients with high Lp(a) = 125nmol/L at high risk of ASCVD events. The primary endpoint is time averaged change in Lp(a) from baseline. The study is fully enrolled and the company expects to report topline 36-week data (primary endpoint) in the first quarter of 2024 and topline 48-week data in the second quarter of 2024.
Divesiran (SLN124)
Divesiran is an siRNA molecule designed for the treatment of genetic hematological conditions, including polycythemia vera (PV). PV is a myeloproliferative neoplasm characterized by the overproduction of blood cells and platelets. Elevated hematocrit is a hallmark of the disease, indicating the overproduction of red blood cells. Patients with hematocrit between 45-50% are four-times more likely to die from cardiovascular causes or major thrombotic events than those with hematocrit less than 45%.
Divesiran is administered subcutaneously and works by specifically binding to and inducing RNAi-mediated degradation of mRNAs made from the TMPRSS6 gene. TMPRSS6 is a negative regulator of hepcidin, which is the main hormone controlling iron homeostasis in the body. In PV, red blood cells are over-produced as a form of cancer, causing an increase in total red blood cell mass and overall blood thickness/stickiness, as well as iron deficiency that adversely affects other cell types. Lowering levels of the TMPRSS6 protein could increase hepcidin production, restricting iron availability to reduce red cell mass, hemoglobin levels, and hematocrit, as well as reallocate iron to normal functions.
Divesiran demonstrated proof of mechanism in the GEMINI phase 1 trial in healthy volunteers completed in May 2021. In the GEMINI study, divesiran was observed to increase average hepcidin approximately four-fold and reduce serum iron by approximately 50% after a single dose with effects persisting for at least two months. Data were presented at the American Society of Hematology (ASH) 2021 Annual Meeting and published in the American Journal of Hematology in July 2023. Divesiran has FDA Fast Track and orphan disease designations for PV, and is being evaluated in the SANRECO phase 1/2 trial in PV patients.
GEMINI Trial
The GEMINI trial was a randomized, double-blind, placebo controlled, single-ascending dose study to investigate the safety, tolerability, PK and PD response of divesiran (1.0, 3.0 and 4.5 mg/kg doses) administered subcutaneously in 24 healthy volunteers.
Divesiran was rapidly distributed (median tmax was 4.0 or 5.0 hours) and largely eliminated from plasma within 24 hours post-dose in all dosing groups. Divesiran plasma concentrations increased in a greater than dose-linear fashion between dosing groups.
All divesiran doses induced marked reductions in transferrin saturation, or TSAT; absolute levels of TSAT achieved (10–16%) are below the level (< 20%) where iron availability to tissue is restricted and at or below that (< 16%) required to support normal erythropoiesis in health.
GEMINI II Phase 1 Program
The GEMINI II phase 1 trial evaluated divesiran in non-transfusion dependent thalassemia patients. In the study, divesiran was well tolerated with no safety issues identified. While proof of mechanism has been established in healthy volunteers, the effects on indicators of iron metabolism were variable in this study population of heterogeneous thalassemia subjects. The company is prioritizing R&D efforts on the ongoing PV program and do not have plans to advance development in thalassemia at this time.
SANRECO Phase 1/2 Program
The SANRECO phase 1/2 trial is a two-part clinical trial which includes a phase 1 open-label, dose finding trial followed by a phase 2 randomized, double-blind, placebo-controlled parallel arm study of divesiran in PV patients. The trial is expected to enroll approximately 65 participants total. The primary endpoint for the phase 1 portion of the trial is safety/tolerability and the assessment of the number of phlebotomies at different intervals. The phase 2 portion of the trial will evaluate the number of patients who are phlebotomy free after treatment. The company plans to report data from the phase 1 portion of the study in the first half of 2024.
Collaborations
AstraZeneca
In March 2020, the company entered into a collaboration agreement with AstraZeneca to discover, develop and commercialize siRNA therapeutics for the treatment of cardiovascular, renal, metabolic and respiratory diseases.
Mallinckrodt
In July 2019, the company entered into a collaboration agreement with Mallinckrodt to develop and commercialize RNAi drug targets designed to silence the complement cascade in complement-mediated disorders. Under the agreement, the company granted Mallinckrodt an exclusive worldwide license to the company’s C3 targeting program, SLN501, with options to license two additional undisclosed complement-mediated disease targets from the company. In July 2020, Mallinckrodt exercised options on the two additional complement targets.
In March 2023, the company reacquired exclusive worldwide rights from Mallinckrodt to the two undisclosed preclinical complement targets. SLN501, the C3 targeting program, remained under the original collaboration agreement. In March 2024, Mallinckrodt notified the company that they will not pursue further development of SLN501 following the completion of the phase 1 clinical trial. This will conclude all activities and commitments under the collaboration agreement.
Hansoh
In October 2021, the company announced a collaboration agreement with Hansoh, one of the leading biopharmaceutical companies in China, to develop siRNAs for three undisclosed targets leveraging the company’s proprietary mRNAi GOLD platform. Under the terms of the agreement, Hansoh will have the exclusive option to license rights to the first two targets in Greater China, Hong Kong, Macau and Taiwan following the completion of phase 1 trials. The company will retain exclusive rights for those two targets in all other territories. The company will be responsible for all activities up to option exercise and will retain responsibility for development outside the China region post phase 1 trials. Hansoh will also have the exclusive option to license global rights to a third target at the point of IND filing. Hansoh will be responsible for all development activities post option exercise for the third target.
Intellectual Property
Patents
As of December 31, 2023, the company solely owned 40 granted patents, of which 10 are U.S.-issued patents, and the company owned 151 pending patent applications, of which 15 are U.S. pending patent applications and 10 are co-owned. Commercially or strategically important non-U.S. jurisdictions in which the company holds issued or pending patent applications include (in addition to Europe): Australia, Brazil, Canada, Chile, China, Colombia, Hong Kong, India, Indonesia, Israel, Japan, Malasia, Mexico, New Zealand, the Philippines, Russia, Singapore, South Africa, South Korea, Taiwan, Ukraine and Vietnam. As of December 31, 2023, the company solely owned two and jointly owned one priority application (priority year pending), each of which are first priority applications.
The company’s granted patents and pending patent applications include compositions of matter claims directed to siRNA molecules and compositions. They also include claims directed to siRNA molecules having specific nucleic acid modifications and linkers, as well as specific nucleic acid sequences. In addition, the company’s pending patent applications with an effective filing date after 2003 also include claims directed to methods of use and processes relating to such siRNA molecules and compositions.
The company’s earliest filed patent applications directed to 19-mer blunt-ended siRNAs with particular siRNA modification patterns expire in August 2023, subject to potential extension. The company’s patent application families directed to toolbox elements, if and when granted, would not be expected to expire until at least 2036. The company’s patent families covering siRNA sequences directed to specific target genes and associated uses for the company’s SLN360, SLN124 and SLN501 product candidates, if and when granted, would not be expected to expire until at least 2038.
Government Regulation and Product Approval
The Foreign Corrupt Practices Act (FCPA) obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the company, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.
The company’s operations are also subject to non-U.S. anti-corruption laws, such as the Bribery Act. As with the FCPA, these laws generally prohibit the company and its employees and intermediaries from authorizing, promising, offering, or providing, directly or indirectly, improper or prohibited payments, or anything else of value, to government officials or other persons to obtain or retain business or gain some other business advantage.
The company is also subject to other laws and regulations governing the company’s international operations, including regulations administered by the governments of the United Kingdom and the United States and authorities in the European Union, including applicable export control regulations, economic sanctions and embargoes on certain countries and persons, anti-money laundering laws, import and customs requirements and currency exchange regulations, collectively referred to as trade control laws.
Research and Development
The company’s research and development costs were £44.0 million for the year ended December 31, 2023.
History
Silence Therapeutics plc was incorporated in 1994.
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