Silence Therapeutics plc (SLN) is a global clinical-stage biotechnology company at the forefront of transforming people's lives by silencing diseases through its innovative siRNA (short interfering RNA) technology. Founded in 1994 and headquartered in London, Silence has established itself as a leader in the rapidly advancing field of RNA interference (RNAi), developing a robust pipeline of proprietary and partnered programs targeting a wide range of diseases.
Business Overview and History
Silence Therapeutics was originally incorporated as Stanford Rook Holdings plc in 1994 in the United Kingdom. In 2005, the company acquired Atugen AG, a German company specializing in siRNA technology, marking a pivotal milestone in its evolution. Following this acquisition, the company changed its name to Silence Therapeutics plc in 2007, reflecting its strategic focus on developing RNAi-based therapeutics.
Throughout its history, Silence has faced various challenges in developing its siRNA technology platform. In 2017, the company initiated patent infringement litigation against Alnylam Pharmaceuticals concerning Alnylam's RNAi product ONPATTRO. This legal dispute was resolved in December 2018 when Silence and Alnylam entered into a settlement and license agreement.
Silence has established several strategic collaborations to advance its siRNA pipeline. In 2019, the company partnered with Mallinckrodt to develop and commercialize RNAi drug targets designed to silence the complement cascade in complement-mediated disorders. The following year, Silence entered into a collaboration agreement with AstraZeneca to discover, develop, and commercialize siRNA therapeutics for the treatment of cardiovascular, renal, metabolic, and respiratory diseases.
Despite the challenges faced, Silence has made significant progress in advancing its proprietary siRNA programs. The company's lead candidates include divesiran, an siRNA targeting TMPRSS6 for the treatment of polycythemia vera, and zerlasiran, an siRNA designed to lower lipoprotein(a) levels. Both of these product candidates have undergone early-stage clinical trials. Additionally, Silence has advanced a third siRNA candidate from its GOLD platform into clinical development through its collaboration with AstraZeneca.
Over the years, Silence has built a strong intellectual property portfolio, with 62 granted patents and 150 pending patent applications as of December 31, 2024. The company's proprietary mRNAi GOLD platform serves as the foundation for its siRNA product candidates, enabling the precise targeting and silencing of disease-associated genes.
Silence's pipeline is currently focused on three key therapeutic areas: cardiovascular disease, hematology, and rare diseases. The company's lead programs include zerlasiran, an siRNA targeting lipoprotein(a) (Lp(a)) for the treatment of atherosclerotic cardiovascular disease (ASCVD), and divesiran, an siRNA targeting TMPRSS6 for the treatment of polycythemia vera (PV), a rare blood cancer.
In 2024, Silence reported positive results from the Phase 2 ALPACAR-360 study of zerlasiran, which demonstrated significant time-averaged Lp(a) reductions exceeding 80% in ASCVD patients with high Lp(a) levels. The company is now preparing to initiate a Phase 3 cardiovascular outcomes study, subject to securing a partner.
Divesiran, Silence's first-in-class siRNA for PV, also made significant strides in 2024. The Phase 1 portion of the SANRECO study showed that divesiran eliminated the need for phlebotomy in all well-controlled PV patients and lowered hematocrit levels across the study population, with a favorable safety and tolerability profile. Silence is currently enrolling patients in the Phase 2 portion of the SANRECO study, anticipating full enrollment by the end of 2025.
In addition to its proprietary pipeline, Silence has established several strategic collaborations to leverage its expertise in RNAi therapeutics. In 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. Silence has also collaborated with Mallinckrodt and Hansoh Pharmaceutical Group to advance additional RNAi programs.
Financial Performance
As of December 31, 2024, Silence reported cash, cash equivalents, and short-term investments of $147.3 million, providing the company with a strong financial position to support its ongoing operations and pipeline development. The company's net loss for the full year of 2024 was $45.3 million, compared to a net loss of $54.2 million in 2023.
Silence's revenue for the year ended December 31, 2024, was $43.3 million, up from $31.6 million in the previous year. This increase was primarily driven by revenue associated with the company's collaboration agreements, including a $24.6 million contribution from the Hansoh Pharma collaboration, which concluded in 2024.
Research and development expenses increased to $67.9 million in 2024, compared to $56.9 million in 2023, reflecting Silence's continued investment in advancing its proprietary programs, such as zerlasiran and divesiran, as well as platform development. General and administrative expenses remained relatively stable, rising to $26.9 million in 2024 from $26.2 million in the prior year.
For the most recent quarter, Silence reported revenue of $1.1 million and a net loss of $27 million. The decrease in revenue from the prior year was primarily due to the completion of the Hansoh Pharma collaboration in 2024, partially offset by increased revenue from the AstraZeneca collaboration. The increase in net loss was primarily due to higher research and development expenses associated with the advancement of the company's proprietary programs.
Silence operates primarily in the United States and United Kingdom, with some revenue from its collaboration agreements coming from the China region. The majority of the company's revenue and assets are concentrated in the United States and United Kingdom.
Liquidity
Notably, in 2024, Silence made the strategic decision to only initiate the Phase 3 outcomes study for zerlasiran once a partner is secured. This decision extends the company's projected cash runway into 2027, providing additional flexibility to invest in its innovative pipeline, including the prioritization of divesiran and other rare disease programs.
Silence maintains a strong financial position with no outstanding debt and a robust cash position to fund its ongoing operations and clinical development activities. As of December 31, 2024, the company reported a debt-to-equity ratio of 0.0015, a current ratio of 9.31, and a quick ratio of 9.31.
Product Pipeline
Silence Therapeutics' product pipeline is focused on three main therapeutic areas: cardiovascular disease, hematology, and rare diseases. The company's lead product candidates are divesiran (SLN124) and zerlasiran (SLN360).
Divesiran (SLN124) is Silence Therapeutics' wholly owned siRNA product candidate designed to inhibit TMPRSS6 expression in the liver. TMPRSS6 is a negative regulator of hepcidin, the body's master regulator of iron metabolism. By silencing TMPRSS6 in polycythemia vera (PV) patients, divesiran aims to increase hepcidin production and release by liver hepatocytes, leading to the restriction of iron to the bone marrow and reducing the excessive production of red blood cells, a process dependent on iron availability.
In December 2024, Silence Therapeutics presented positive interim results from the Phase 1 portion of the SANRECO clinical trial of divesiran in PV patients. The data showed that divesiran substantially reduced phlebotomy requirements and lowered hematocrit levels following infrequent dosing, with the product candidate being well-tolerated to date. The company also announced the initiation of the Phase 2 portion of the SANRECO trial, with full enrollment anticipated by year-end 2025. Divesiran has received Fast Track and orphan drug designations from the FDA for the treatment of PV, and the European Commission has also granted it orphan drug designation in Europe.
Zerlasiran (SLN360) is Silence Therapeutics' wholly owned siRNA product candidate designed to lower the body's production of apolipoprotein(a), a key component of lipoprotein(a) (Lp(a)). Elevated Lp(a) levels, defined as 125 nmol/L or higher, are a genetically determined cardiovascular risk factor affecting at least 20% of the global population and are associated with an increased risk of heart attack, stroke, and aortic stenosis.
In Phase 1 and Phase 2 clinical trials, zerlasiran has shown the potential to substantially reduce Lp(a) levels in patients with atherosclerotic cardiovascular disease (ASCVD), with effects persisting following infrequent dosing and the product candidate being well-tolerated. During the fourth quarter of 2024, Silence Therapeutics received positive regulatory feedback from the FDA and EMA on the Phase 3 cardiovascular outcomes study design for zerlasiran in patients with high Lp(a) and at high risk of a cardiovascular event. The company is engaged in global partnership discussions for the potential Phase 3 development and future commercialization of zerlasiran.
In addition to its two lead wholly owned clinical-stage programs, Silence Therapeutics has a third siRNA product candidate from its mRNAi GOLD platform in Phase 1 development in an undisclosed indication through its collaboration with AstraZeneca. The company is also progressing several undisclosed preclinical programs that have shown promising results, as it continues to maximize the potential of its mRNAi GOLD platform.
Future Outlook
Silence Therapeutics has provided several key updates and guidance for its future plans:
1. The company will only initiate the Phase 3 outcomes study for zerlasiran once a partner is secured, which strengthens their cash position and extends their projected runway into 2027.
2. For divesiran, Silence completed follow-up in the Phase 1 SANRECO study and plans to present additional data at medical meetings this year. They also anticipate full enrollment in the Phase 2 SANRECO study by the end of 2025.
3. Silence plans to start a Phase 1 study of their wholly-owned siRNA SLN548 targeting complement factor B in the second half of 2025.
Risks and Challenges
As a clinical-stage biotechnology company, Silence Therapeutics faces various risks and challenges inherent to the industry. The successful development and commercialization of the company's product candidates are subject to the inherent uncertainties of the drug development process, including the potential for delays or failures in clinical trials, regulatory approvals, and manufacturing.
Additionally, Silence operates in a highly competitive environment, with other biotechnology and pharmaceutical companies developing their own RNAi-based therapies and alternative treatment approaches. The company's ability to maintain its competitive edge will depend on its continued innovation, successful execution of its clinical programs, and effective partnering and commercialization strategies.
Furthermore, as a global company, Silence is exposed to foreign exchange risks and regulatory changes in the various jurisdictions in which it operates. The company's financial performance and liquidity position could be impacted by fluctuations in currency exchange rates and evolving regulatory landscapes.
Conclusion
Silence Therapeutics is well-positioned to capitalize on the growing momentum in the RNAi therapeutics field. With a robust pipeline, a strong financial position, and a talented team, the company is poised to continue its transformation of people's lives by silencing diseases through its innovative siRNA therapies.
The upcoming data readouts and potential partnership announcements for zerlasiran and the ongoing progress of divesiran and other pipeline programs will be key catalysts for Silence in the near future. As the company navigates the challenges of the biotechnology industry, its unwavering commitment to advancing its technology and delivering life-changing treatments to patients worldwide will be instrumental in driving long-term shareholder value.