Executive Summary / Key Takeaways

• Silence Therapeutics (SLNCF) is strategically sharpening its focus on rare conditions and high-unmet-need cardiovascular diseases, leveraging its proprietary mRNAi GOLD platform for first-in-class and best-in-class siRNA therapies.
• The company's decision to pursue a partnership for the Phase 3 development of zerlasiran (SLN360) for high Lp(a) has extended its cash runway into 2027, providing financial flexibility to advance its innovative pipeline, including the high-priority divesiran program.
• Divesiran (SLN124) has demonstrated compelling Phase 1 results in polycythemia vera (PV), effectively eliminating the need for phlebotomy in well-controlled patients and showing a favorable safety profile, with Phase 2 enrollment anticipated to complete by year-end 2025.
• Silence's mRNAi GOLD platform offers a significant technological edge through precise, liver-targeted gene silencing, exhibiting strong durability and a historically higher success rate in clinical development compared to industry averages.
• While recent collaboration revenue has decreased due to milestone timing and the conclusion of certain partnerships, the company retains global rights to promising preclinical assets, offering future internal development or partnering opportunities.

The RNAi Revolution: Silence Therapeutics' Strategic Focus

Silence Therapeutics plc, a biotechnology company with over two decades of expertise in the RNA interference (RNAi) arena, is carving out a distinct niche in the discovery and development of novel short interfering ribonucleic acid (siRNA) therapeutics. The company's core mission is to inhibit the expression of specific target genes implicated in diseases with significant unmet medical needs, primarily focusing on cardiovascular, hematological, and rare conditions. This strategy is underpinned by its proprietary mRNAi GOLD™ (GalNAc Oligonucleotide Discovery) platform, which is designed for precise, liver-targeted gene silencing.

The biotechnology landscape, particularly in RNA therapeutics, is highly competitive, featuring established players like Alnylam Pharmaceuticals (ALNY), Ionis Pharmaceuticals (IONS), and Arrowhead Pharmaceuticals (ARWR). Silence Therapeutics positions itself as a challenger, emphasizing targeted innovation and strategic collaborations. While larger competitors like Alnylam and Ionis benefit from more established product portfolios and robust revenue streams, Silence's specialized liver-targeting technology and focused R&D approach offer a potential edge in developing highly effective therapies for specific indications. The company's strategic decision-making, including the reacquisition of promising preclinical assets and the prioritization of programs with clear unmet needs, reflects an agile response to market dynamics.

Technological Edge: The mRNAi GOLD Platform

At the heart of Silence Therapeutics' strategy is its mRNAi GOLD platform, a differentiated technology that harnesses the body's natural RNA interference mechanism. This platform designs siRNA molecules to specifically bind to and degrade messenger RNA (mRNA) molecules, thereby reducing the production of disease-associated proteins. The GalNAc (N-acetylgalactosamine) conjugation in the platform enables highly precise and efficient delivery of siRNAs directly to liver cells.

This targeted delivery offers several tangible benefits. Clinical data from programs like zerlasiran have demonstrated Lp(a) reductions exceeding 90% with durable effects following infrequent dosing, showcasing the potency and longevity of the platform. For divesiran, the mechanism of silencing TMPRSS6 to increase hepcidin has shown robust target engagement and sustained hepcidin elevation within physiological ranges, leading to significant clinical outcomes. The company highlights that GalNAc siRNA programs have historically exhibited a much higher success rate in progressing from Phase 1 to Phase 3 compared to the broader pharmaceutical industry average, underscoring the platform's reliability.

Beyond its current liver-focused applications, Silence is actively investing in extra-hepatic programs. These initiatives aim to expand the platform's reach to target multiple cell types beyond the liver, with promising initial preclinical activity observed in mice models. The strategic intent behind these R&D efforts is to unlock new therapeutic avenues and further broaden the company's pipeline, potentially enhancing its competitive moat and long-term growth prospects by addressing a wider array of diseases.

Proprietary Pipeline: Driving Internal Value

Silence Therapeutics is advancing a focused proprietary pipeline, with two lead candidates, zerlasiran and divesiran, demonstrating significant potential.

Zerlasiran (SLN360) for High Lp(a)

Zerlasiran is a wholly-owned siRNA candidate designed to temporarily silence LPA expression in the liver, thereby lowering the body's production of apolipoprotein(a), a key component of lipoprotein(a) (Lp(a)). High Lp(a) is a genetically determined cardiovascular risk factor affecting at least 20% of the world's population and is strongly associated with heart attack, stroke, and aortic stenosis. There are currently no approved medicines that selectively lower Lp(a), highlighting a major unmet medical need.

In Phase 1 and Phase 2 clinical trials, zerlasiran has substantially lowered Lp(a) levels, with reductions exceeding 90% and persisting effects from infrequent dosing. The drug has also been well tolerated with no major safety concerns. The company has received positive regulatory feedback from the FDA and EMA on its Phase 3 cardiovascular outcomes study design and has completed core Phase 3 readiness activities, including manufacturing and supply scale-up. However, in a strategic move to conserve cash and extend its runway, Silence has decided to initiate the Phase 3 outcomes study only once a partner is secured, a decision that extends its projected cash runway into 2027. This approach allows the company to manage its resources prudently while seeking the right partner to maximize the program's substantial market potential.

Divesiran (SLN124) for Polycythemia Vera

Divesiran is a first-in-class siRNA product candidate in Phase 2 development for polycythemia vera (PV), a rare myeloproliferative neoplasm characterized by excessive red blood cell production. Elevated hematocrit (HCT) levels (45% or higher) in PV patients are associated with a four-times higher rate of death from cardiovascular or thrombotic events. Current treatments often involve repeated phlebotomies and cytoreductive agents, which can be burdensome and may not consistently maintain safe HCT levels.

Divesiran works by temporarily silencing TMPRSS6 expression in the liver, a negative regulator of hepcidin, the body's master regulator of iron metabolism. By increasing hepcidin levels, divesiran aims to redirect iron away from the bone marrow, thereby lowering red blood cell production. The SANRECO Phase 1 study in PV patients demonstrated that divesiran lowered and maintained durable control of HCT, essentially eliminating the need for phlebotomies in phlebotomy-dependent patients. The drug was well tolerated with no dose-limiting toxicities. The SANRECO Phase 2 clinical trial is ongoing and remains on track to complete enrollment by year-end 2025. Divesiran has also received FDA Fast Track and orphan drug designations for PV, and the European Commission granted orphan drug designation for PV in December 2024. The company views divesiran as a top priority, given its potential to address a clear unmet need with a first-in-class siRNA.

SLN548 and Extra-hepatic Programs

Silence Therapeutics is also advancing SLN548, a wholly-owned siRNA targeting complement factor B, which could play a therapeutic role in complement-mediated renal diseases. The long-acting profile of the GOLD platform compounds suggests the potential for an infrequently-dosed therapeutic option. However, the company has decided to pause the initiation of a Phase 1 study for SLN548 to prioritize its extra-hepatic programs, where promising initial preclinical activity has been observed in mice models. This strategic shift underscores Silence's commitment to focusing resources on areas with the most compelling early data and highest potential impact.

Strategic Collaborations: External Validation and Funding

Silence Therapeutics operates with a hybrid business model that combines internal pipeline development with strategic collaborations, which have historically provided significant non-dilutive capital and external validation of its platform.

The collaboration with AstraZeneca (AZN), initiated in March 2020, covers the discovery, development, and commercialization of siRNA therapeutics for cardiovascular, renal, metabolic, and respiratory diseases. This partnership has yielded substantial milestone payments, including $10 million in 2023 for the nomination of the first product candidate and another $10 million in February 2024 for the initiation of a Phase 1 clinical trial for an undisclosed program. This collaboration continues to be a vital source of revenue and pipeline advancement for Silence.

The Hansoh Pharma collaboration, established in October 2021 for three undisclosed targets, concluded in December 2024 as Hansoh opted not to pursue further development. However, Silence Therapeutics retained exclusive global rights for all three targets. This outcome presents a new opportunity for Silence to either develop these programs internally or seek new partnerships, leveraging the encouraging preclinical data generated during the collaboration.

Similarly, the Mallinckrodt collaboration, initially focused on complement-mediated disorders, saw Silence reacquire exclusive worldwide rights to two preclinical complement targets in March 2023. While Mallinckrodt later decided not to pursue further development of SLN501 in March 2024, the reacquired assets remain part of Silence's internal pipeline, reflecting a strategic decision to focus on programs deemed a better fit for its portfolio.

Financial Performance and Liquidity

Silence Therapeutics has consistently incurred operating losses since its inception, reporting a net loss of $55.9 million for the six months ended June 30, 2025, and an accumulated deficit of $529.8 million as of the same date. The company anticipates continued operating losses as it invests heavily in research and development.

Revenue from collaboration agreements has fluctuated based on milestone achievements. For the six months ended June 30, 2025, revenue from contracts with customers was $0.366 million, a significant decrease from $16.312 million in the prior year period. This decline was primarily due to a $14.7 million reduction in AstraZeneca collaboration revenue, as no similar milestones were achieved in 2025, and the conclusion of the Hansoh collaboration. For the full year 2024, revenue was $43.3 million, largely boosted by a $24.6 million cumulative catch-up from the Hansoh collaboration's conclusion.

Research and development costs are the largest component of operating expenses, increasing by $12.8 million for the six months ended June 30, 2025, compared to the same period in 2024. This rise is attributed to the advancement of proprietary programs, particularly the Phase 2 clinical trial for divesiran, and increased contract manufacturing activities for zerlasiran's Phase 3 readiness. General and administrative expenses, however, decreased by $0.8 million in the first half of 2025, reflecting efforts to reduce administrative costs and a reduction in reporting and compliance requirements. The company also incurred $1.3 million in non-recurring restructuring charges in Q2 2025 due to a workforce reduction.

As of June 30, 2025, Silence Therapeutics held $114.2 million in cash, cash equivalents, and short-term investments. The company believes these resources, combined with anticipated milestone payments of $20 million from existing collaborations over the next three years, will fund operations into 2028. The strategic decision to partner zerlasiran's Phase 3 development further extends this projected cash runway into 2027, providing crucial financial flexibility.

However, net cash outflow from operating activities increased by $19.5 million in the first half of 2025, primarily due to reduced collaboration milestones and increased clinical expenditures. The company acknowledges the need for additional future funding, which may be sought through various financing or collaboration agreements.

Risks and Challenges

Investing in Silence Therapeutics carries inherent risks common to the biotechnology sector. The company faces significant regulatory hurdles, including stringent and evolving data privacy and security laws in the U.S. and abroad. Cross-border data transfer restrictions, particularly from the EEA and UK to the U.S., pose a substantial threat, potentially leading to operational disruptions, fines, and an inability to collaborate with partners. New U.S. Department of Justice rules regarding sensitive personal data and the increasing use of generative AI technologies by employees could further complicate compliance and increase costs.

Healthcare legislative and regulatory reforms also present challenges. The "One Big Beautiful Bill Act" (OBBBA) in the U.S. and proposed revisions to EU laws governing medicinal products could negatively impact market access, pricing, and data/market exclusivity for future products. The EU Clinical Trials Regulation (CTR) has introduced increased regulatory complexity and administrative burden, while the new Health Technology Assessment (HTA) Regulation could lead to delays in patient access if joint scientific advice slots are insufficient. These evolving regulatory landscapes could affect the cost and feasibility of conducting clinical trials and obtaining marketing authorizations. Furthermore, the company's ability to secure additional funding and achieve clinical and commercial success for its product candidates remains subject to significant uncertainties.

Conclusion

Silence Therapeutics stands at a pivotal juncture, strategically refining its focus to maximize the potential of its mRNAi GOLD platform. By prioritizing rare conditions and high-unmet-need cardiovascular opportunities like polycythemia vera and high Lp(a), the company aims to deliver first-in-class and best-in-class siRNA therapies. The compelling Phase 1 data for divesiran and the advanced Phase 3 readiness for zerlasiran underscore the platform's robust capabilities and the potential for significant clinical impact.

The decision to seek a partner for zerlasiran's Phase 3 development, while extending the cash runway, highlights a disciplined approach to capital allocation and a commitment to shareholder value. This strategic flexibility allows Silence to continue investing in its innovative pipeline, including promising extra-hepatic programs and reacquired assets from past collaborations. While facing inherent risks associated with clinical development, regulatory complexities, and the need for future funding, Silence Therapeutics' technological differentiation and focused pipeline position it as a compelling player in the evolving RNA therapeutics space. Investors should closely monitor the progress of divesiran's Phase 2 enrollment, the outcome of zerlasiran partnering discussions, and the advancement of its preclinical programs as key indicators of its long-term growth trajectory.