Silence Therapeutics Profile
Silence Therapeutics plc (Silence) operates as a biotechnology company.
The company focuses 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 RNA interference, or 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 its mRNAi GOLD platform, the company has generated siRNA product candidates both for its 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.
SLN360, an siRNA targeting the LPA gene, is the company’s wholly owned product candidate in phase 2 clinical development (ALPACAR-360 trial), to reduce high levels of lipoprotein(a), or Lp(a), a genetically determined cardiovascular risk factor affecting up to 20% of the world’s population. In February 2022, the company reported positive results from the single-ascending dose portion of the APOLLO phase 1 program evaluating SLN360 in 32 healthy adults with high Lp(a) greater than or equal to 150 nmol/L. In the APOLLO trial, participants in the top two SLN360 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. In January 2023, the company started dosing in the ALPACAR-360 phase 2 trial evaluating subjects with high Lp(a) greater than or equal to125 nmol/L at high risk of atherosclerotic cardiovascular disease, or ASCVD, events and it expects to complete enrollment by the end of 2023.
The APOLLO phase 1 clinical program is a global randomized, double-blind, placebo controlled, single-ascending dose and multiple-ascending dose study to investigate the safety, tolerability, pharmacodynamic and pharmacokinetic response of SLN360 administered subcutaneously in up to 88 people total with high Lp(a) levels of approximately greater than or equal to 60mg/dL or greater than or equal to 150 nmol/L.
In February 2022, the company reported positive results from the single-ascending dose portion of the APOLLO phase 1 program evaluating SLN360 in 32 healthy adults with high Lp(a) greater than or equal to150 nmol/L.
SLN124, an siRNA targeting the TMPRSS6 gene, is the company’s wholly owned product candidate that has shown the potential to address a range of hematological conditions by modulating endogenous hepcidin, a peptide hormone that is the master regulator of systemic iron balance. SLN124 is being evaluated in the SANRECO phase 1/2 trial in patients with polycythemia vera, or PV, and the GEMINI II phase 1 trial in patients with non-transfusion dependent, or NTD, thalassemia. SLN124 demonstrated proof of mechanism in the GEMINI phase 1 trial in healthy volunteers completed in May 2021, or the GEMINI trial, representing the first clinical data from the company’s mRNAi GOLD platform. SLN124 has FDA Fast Track and orphan drug designations for PV, as well as orphan drug and rare pediatric disease designations for beta-thalassemia. The European Medical Agency has also granted SLN124 orphan drug designation and rare pediatric disease designation for beta-thalassemia.
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 16 pipeline programs and approximately $7.5 billion in potential milestones plus royalties.
The potential for the company’s mRNAi GOLD platform to address disease-associated genes in the liver is substantial. The company’s mRNAi GOLD platform comprises elements of its GalNAc-siRNA toolbox, its liver cell targeting technology and its 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 its double-stranded siRNA structure, known as blunt-ended 19-mers, either singly or in different combinations depending on individual siRNA sequences.
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 the biology underlying an indication, disease epidemiology and addressable population, the 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.
The company’s pipeline is centered around its liver-targeting mRNAi GOLD platform and consists of a diversified set of therapeutic areas, including cardiovascular disease, hematology and rare diseases.
SLN360 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. SLN360 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). SLN360’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.
SLN360 is administered by subcutaneous injection and was observed to have a long duration of action in the APOLLO trial, potentially allowing for infrequent dosing, such as every three months or less frequently. In April 2022, results from the single-ascending dose portion of the APOLLO program in 32 healthy adults with high Lp(a) greater than or equal to150 nmol/L were simultaneously presented in a late-breaking presentation at the American College of Cardiology Annual Meeting and published in The Journal of the American Medical Association, or JAMA. In January 2023, the company started dosing in the ALPACAR-360 phase 2 clinical trial evaluating subjects with high Lp(a) greater than or equal to125 nmol/L at high risk of ASCVD events and it expects to complete enrollment in the fourth quarter of 2023.
SLN360 has undergone an extensive nonclinical safety and pharmacokinetic evaluation, including rat biodistribution, repeat dose toxicity in two animal species (rat and the pharmacologically relevant cynomolgus monkey), including safety pharmacology investigations, and in vitro and in vivo genetic toxicity studies. SLN360 has displayed a typically short pharmacokinetic profile, where the compound is almost completely cleared from circulation in the blood after 24 hours. SLN360 distribution was largely restricted to the liver and kidney, with levels in other organs (including reproductive organs) at less than 1% of peak liver levels. SLN360 was shown to be non-genotoxic in the standard battery of genotoxic tests. In good laboratory practice (GLP) toxicology studies, SLN360 was well tolerated up to the maximum dose administered. All findings in both species were considered to be non-adverse. In the cynomolgus monkey, the most relevant species, the No Observed Adverse Effect Level, or NOAEL, was 60 times the pharmacologically active dose, and no dose-related changes in clinical chemistry, hematology, circulatory and electrocardiography, or ECG, parameters, respiratory rate, neurobehavior, plasma cytokines, complement activation or c-reactive protein levels were noted.
In February 2022, the company reported positive results from the single-ascending dose portion of the APOLLO phase 1 program evaluating SLN360 in 32 healthy adults with high Lp(a) greater than or equal to150 nmol/L.
SLN124 is an siRNA molecule designed to treat ineffective erythropoiesis, or the production of red blood cells, associated with iron overload disorders and with primary or secondary dysregulation of hepcidin synthesis. These constitute diseases associated with pathologically low hepcidin and diseases in which there is inadequate hepcidin response for the degree of iron loading, such as beta-thalassemia and PV. Left untreated, iron overload disorders cause damage to the heart, liver, pituitary gland, adrenal gland, testes, pancreas, ovaries and kidney and endocrine organs.
SLN124 is administered by subcutaneous injection and has been observed to have a long duration of action in the GEMINI healthy volunteer trial completed in May 2021. Data from the trial showed that SLN124 was effective in reducing plasma iron levels and had a long duration of action. In September 2022, the company reported preliminary safety data from the single dose component of the GEMINI II phase 1 trial of SLN124 in patients with NTD thalassemia. Data showed SLN124 was well tolerated with no serious safety issues identified. The multiple dose component of the GEMINI II trial is ongoing and expected to readout in the fourth quarter of 2023. SLN124 is also being evaluated in the SANRECO phase 1/2 trial in PV patients.
In 2019, the EMA granted SLN124 orphan drug designation for the treatment of beta-thalassemia. In 2020, the FDA granted rare pediatric disease designation for the treatment of beta-thalassemia and orphan drug designations for the treatment of MDS and adult beta-thalassemia. In 2022, the FDA granted Fast Track and orphan drug designations for SLN124 in PV.
A majority of PV patients have a JAK2 gene gain of function mutation, JAK2V617F. Importantly, the company’s model animals displayed hepcidin levels in line with control animals, again corresponding to what has been previously reported in PV patients.
In its preclinical studies of beta-thalassemic mice, the company also observed that administration of SLN124 improved anemia, which led to reduced extramedullary erythropoiesis, evident by the reduction in spleen weight shown in the left panel of the figure below. In these studies, mice were dosed twice over two weeks, following which their spleen weight and hemoglobin levels were measured over five weeks. As shown in the right panel of the figure below, the company observed a median increase of 2.5 g/dL in hemoglobin levels, or 30% more than the control group, in the mice receiving SLN124 in this study. Increases of at least 1.5 g/dL are generally considered to be clinically relevant responses, based on 2018 International Working Group standardized response criteria for showing hematologic improvement in patients with MDS.
The GEMINI trial, was a randomized, double-blind, placebo controlled, single-ascending dose study to investigate the safety, tolerability, PK and PD response of SLN124 (1.0, 3.0 and 4.5 mg/kg doses) administered subcutaneously in 24 healthy volunteers. In May 2021, the company reported positive data from the GEMINI trial, which was the first clinical data from its mRNAi GOLD platform. In December 2021, the company presented further clinical data from the study at the American Society of Hematology (ASH) Annual Meeting. Key outcomes included:
The GEMINI II phase 1 trial is a global, randomized, single-blind, placebo controlled, single-ascending and multiple-ascending dose studies to investigate the safety, tolerability, PK and PD response of SLN124 in approximately 24 adults with NTD thalassemia. In September 2022, the company reported preliminary safety results from the single-ascending dose portion of the trial showing SLN124 was well tolerated with no serious adverse events, or AEs, no severe treatment emergent AEs that were SLN124 related and no TEAEs leading to withdrawal identified. Effects on hepcidin, serum iron, transferrin saturation and hemoglobin are being evaluated in the ongoing multiple-dose arm expected to readout in the fourth quarter of 2023.
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 SLN124 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. In January 2023, the company announced that sites are open for enrollment.
SLN501 is the company’s siRNA partnered with Mallinckrodt that targets C3 and is in development for complement-mediated diseases. In June 2022, the company initiated a phase 1 trial in healthy volunteers.
Collaborations
In July 2019, the company announced a strategic collaboration with Mallinckrodt plc (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 its C3 targeting program, SLN501, with options to license additional complement-mediated disease targets from it, with Mallinckrodt exercising the option for two additional targets in July 2020. The company is responsible for preclinical activities, and for conducting each development program until the end of phase 1 clinical trials, after which Mallinckrodt will assume clinical development and responsibility for global commercialization.
In March 2020, the company announced a strategic collaboration with AstraZeneca PLC (AstraZeneca) to discover, develop and commercialize siRNA therapeutics for the treatment of cardiovascular, renal, metabolic and respiratory diseases.
On October 15, 2021, the company announced a collaboration agreement with Hansoh Pharmaceutical Group Company Limited (Hansoh), one of the leading biopharmaceutical companies in China, to develop siRNAs for three undisclosed targets leveraging Silence's proprietary mRNAi GOLD platform. Under the terms of the agreement, the company retains exclusive rights to the first two targets in all territories except the China Region (Greater China, Hong Kong, Macau and Taiwan). Hansoh has the exclusive option to license rights to those two targets in the China Region following the completion of phase 1 studies. Silence will be responsible for all activities up to option exercise and will retain responsibility for development outside the China region post phase 1 studies. Hansoh will also have the exclusive option to license global rights to a third target at the point of IND filing. In December 2022, the company initiated work on the second target which it retains global rights to outside the China Region.
Intellectual Property
Patents
As of December 31, 2022, the company solely owned 44 granted patents, of which 21 are U.S.-issued patents. The company also owned 178 pending patent applications, of which 11 are co-owned and 22 are U.S. pending patent applications. Commercially or strategically important non-U.S. jurisdictions in which it holds issued or pending patent applications include (in addition to Europe): Australia, Brazil, Canada, China, Egypt, Hong Kong, India, Indonesia, Israel, Japan, Mexico, New Zealand, the Philippines, Russia, Singapore, South Africa, South Korea, Taiwan and Vietnam. The company also solely owned seven priority applications (priority year pending), of which four 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 its SLN360, SLN124 and SLN501 product candidates, if and when granted, would not be expected to expire until at least 2038.
Research and Development
The company’s research and development expenses for the year ended December 31, 2022, were £35.6 million.
Government Regulation and Product Approval
The company’s operations are subject to non-U.S. anti-corruption laws such as the Bribery Act. As with the Foreign Corrupt Practices Act (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.
History
Silence Therapeutics plc was incorporated in 1994.
