Executive Summary / Key Takeaways

• Strategic Pipeline Prioritization: Silence Therapeutics is executing a focused strategy, prioritizing its wholly-owned RNAi programs in rare diseases, particularly Divesiran for Polycythemia Vera (PV), which shows compelling Phase 1 data and is on track for full Phase 2 enrollment by year-end 2025.
• Zerlasiran's Partner-Dependent Path: The company's high-value cardiovascular asset, Zerlasiran for high Lp(a), has completed Phase 3 readiness but will only advance into its outcomes study once a strategic partner is secured, a move designed to extend the cash runway and optimize resource allocation.
• Robust Technology Platform: The proprietary mRNAi GOLD platform, utilizing GalNAc siRNA, offers a differentiated approach with a historically higher success rate in clinical development and the potential for durable, infrequent dosing, providing a strong competitive moat.
• Extended Financial Runway: Recent strategic decisions, including the Zerlasiran partnering contingency, have extended the company's projected cash runway into 2028, supported by existing cash and anticipated collaboration milestones.
• Evolving Competitive Landscape: Operating in a dynamic RNAi market, Silence Therapeutics leverages its technological precision and strategic collaborations to compete against larger, more established players, while navigating regulatory complexities and the need for continuous innovation.

The RNAi Revolution and Silence's Strategic Pivot

Silence Therapeutics plc (SLN) stands at the forefront of the RNA interference (RNAi) revolution, a transformative field in biotechnology that promises to redefine the treatment of genetic diseases. Leveraging its proprietary mRNAi GOLD GalNAc Oligonucleotide Discovery platform, Silence develops short interfering ribonucleic acid (siRNA) molecules designed to precisely target and silence specific disease-associated genes, primarily in the liver. This innovative approach aims to reduce the production of disease-causing proteins, offering a fundamental shift from symptom management to addressing the root cause of illness.

The company's overarching strategy is a hybrid model, balancing the advancement of its wholly-owned pipeline with strategic collaborations that provide non-dilutive capital and expand its global reach. This approach is particularly critical in the highly competitive RNAi space, where established players like Alnylam Pharmaceuticals (ALNY), Ionis Pharmaceuticals (IONS), and Arrowhead Pharmaceuticals (ARWR) command significant market presence. Silence positions itself as an innovator, focusing on areas of high unmet medical need, particularly rare diseases, where its precision technology can deliver first-in-class or best-in-class therapies.

The mRNAi GOLD platform is a core competitive advantage. Its GalNAc siRNA approach has demonstrated a "much higher success rate in moving from Phase 1 to Phase 3 compared to the pharma industry average," as highlighted by management. This de-risks development and suggests a potentially more efficient path to market. The technology's ability to achieve robust gene knockdown with strong durability after a single dose, facilitating infrequent dosing, offers a significant convenience advantage for patients and a commercial differentiator. For instance, Zerlasiran has shown Lp(a) reductions exceeding 90% and up to 98% after a single dose, with effects persisting over five months, and up to 99% after multiple doses, persisting for 201 days. This long-acting profile is a hallmark of the platform. Furthermore, Silence is actively investing in extra-hepatic programs, aiming to expand its platform's reach beyond liver-targeted therapies, which could unlock new therapeutic areas and diversify its pipeline.

Compared to Alnylam, a leader with multiple approved products and robust revenue streams, Silence's strength lies in its specialized, precise liver-targeted therapies and its innovation speed in specific applications. While Ionis, with its broader antisense RNA portfolio and established alliances, offers greater operational scale, Silence's siRNA technology may provide more precise gene silencing for certain indications. Against Arrowhead, another RNAi player focused on liver diseases, Silence's mRNAi GOLD platform could offer qualitative advantages in specificity for rare diseases. These technological differentiators are crucial for Silence to carve out its niche and compete effectively against larger, more financially mature rivals.

A History of Innovation and Strategic Evolution

Silence Therapeutics, initially incorporated as SR Pharma plc in 1994, has undergone a significant evolution, culminating in its current focus on RNAi therapeutics. Key collaborations have punctuated its journey, starting with Mallinckrodt in 2019, followed by a major partnership with AstraZeneca (AZN) in March 2020, which brought in $20 million upfront and an additional $40 million in May 2021. These partnerships validated the platform's potential and provided crucial non-dilutive capital. The company's first successful clinical data from its mRNAi GOLD platform emerged in May 2021 with the SLN124 healthy volunteer study, demonstrating its ability to translate preclinical promise into clinical reality.

Further solidifying its financial foundation and global presence, Silence secured a new collaboration with Hansoh Pharma in October 2021, including a $16 million upfront payment. A strategic delisting from AIM in November 2021 to exclusively list on NASDAQ attracted new U.S. healthcare investors, enhancing its capital base, notably with a $45 million private placement in February 2021 and a $120 million PIPE financing in February 2024. This period also saw important strategic shifts in its pipeline. In March 2023, Silence reacquired exclusive worldwide rights to two preclinical complement targets from Mallinckrodt, believing these assets offered a more competitive opportunity for its portfolio. However, both the Mallinckrodt (SLN501 program) and Hansoh Pharma collaborations concluded in March and December 2024, respectively, as partners opted not to pursue further development. Crucially, Silence retained global rights to these targets, providing new opportunities for internal development or future partnerships. Effective January 1, 2025, Silence transitioned to a U.S. domestic issuer, aligning with U.S. GAAP and incurring additional compliance expenses, a reflection of its growing presence in the U.S. market.

Deep Dive into the Pipeline: Prioritizing Precision

Silence Therapeutics is now strategically prioritizing its pipeline to focus on rare conditions where its mRNAi GOLD platform can deliver significant impact. This pivot is evident in the advancement of Divesiran and the strategic decision regarding Zerlasiran.

Divesiran (SLN124): A First-in-Class Opportunity in PV

Divesiran (SLN124) is a wholly-owned siRNA product candidate designed to temporarily silence TMPRSS6 expression in the liver. TMPRSS6 is a negative regulator of hepcidin, the body's master regulator of iron metabolism. By silencing TMPRSS6, Divesiran aims to increase hepcidin levels, thereby redirecting iron delivery away from the bone marrow and reducing excessive red blood cell production. This mechanism positions Divesiran as a potentially first-in-class siRNA for polycythemia vera (PV).

PV is a rare myeloproliferative neoplasm characterized by the overproduction of red blood cells, leading to elevated hematocrit (HCT) levels. HCT levels of 45% or higher are associated with a four-times higher rate of death from cardiovascular or thrombotic events. PV affects approximately 150,000 individuals in the U.S. and 3.5 million worldwide, representing a significant unmet medical need. Current treatments, primarily repeated phlebotomies and cytoreductive agents, are often burdensome, can cause iron deficiency, and may not consistently maintain safe HCT levels.

Phase 1 data from the SANRECO study for Divesiran in PV patients were highly encouraging. The study "essentially eliminated the need for phlebotomies in phlebotomy-dependent PV patients" and lowered and maintained mean HCT levels at or below 45% for all cohorts, regardless of baseline levels. Divesiran was also well tolerated, with the majority of adverse events being mild. Management aims for Divesiran to be the first siRNA in the PV market, with a key differentiator being infrequent dosing. While the exact dosing frequency for Phase 3 is still being optimized, the long-acting profile of the GOLD platform suggests a significant convenience advantage over existing therapies. The Phase 2 SANRECO study is progressing well, exceeding 50% enrollment by June 2025, with full enrollment anticipated by year-end 2025. Beyond PV, the mechanistic understanding of Divesiran suggests broader therapeutic potential in other conditions where hepcidin manipulation is beneficial, such as hereditary hemochromatosis.

Zerlasiran (SLN360): A Strategic Path to Market for High Lp(a)

Zerlasiran (SLN360) is Silence's wholly-owned siRNA candidate targeting apolipoprotein(a) (Lp(a)), a genetically determined cardiovascular risk factor affecting at least 20% of the global population (approximately 1.4 billion people). High Lp(a) is associated with a significant risk of heart attack, stroke, and aortic stenosis, and unlike LDL, its levels are largely unaffected by diet or lifestyle. There are currently no approved therapies that selectively lower Lp(a), highlighting a major unmet need.

The ALPACAR-360 Phase 2 study of Zerlasiran in ASCVD patients with high Lp(a) delivered positive results, showing median Lp(a) reductions of 90% or greater for both tested doses at week 36. These results were consistent with Phase 1 data, which demonstrated Lp(a) reductions up to 98% after a single dose and up to 99% after multiple doses, with durable effects. Zerlasiran has consistently shown a well-tolerated safety profile. Silence has completed core Phase 3 readiness activities, including manufacturing and supply scale-up, and has received positive regulatory feedback on its Phase 3 study design.

However, in a strategic pivot, Silence has decided to initiate the Phase 3 outcomes study for Zerlasiran only once a partner is secured. This decision, influenced by shareholder feedback, aims to strengthen the company's cash position and provide flexibility for investing in its innovative pipeline. While Zerlasiran faces competition from other Lp(a)-lowering therapies in development, Silence believes its differentiated Phase 3 design and the sheer size of the Lp(a) market opportunity make it a highly attractive asset for potential partners.

Emerging Pipeline and Extra-hepatic Expansion

Beyond its lead clinical programs, Silence is actively advancing its broader pipeline. Following the conclusion of the Hansoh Pharma collaboration, Silence retained global rights to three undisclosed preclinical liver targets, which have generated encouraging preclinical data. The company is evaluating these programs for internal development or new partnerships, aligning with its focus on rare conditions.

A third siRNA product candidate, SLN312, from the mRNAi GOLD platform is also in Phase 1 development under the AstraZeneca collaboration for an undisclosed indication, demonstrating the continued productivity of the partnership. Furthermore, Silence is making selective investments in extra-hepatic programs, where it is observing promising initial preclinical activity in mice models. This expansion beyond liver-targeted therapies represents a strategic move to broaden the platform's applicability, though the company has decided to pause the initiation of a Phase 1 study for SLN548 (targeting complement factor B) to prioritize these extra-hepatic activities.

Financial Performance: A Strategic Rebalancing

Silence Therapeutics has consistently incurred operating losses since its inception, a common characteristic of clinical-stage biotechnology companies. The company's financial performance in recent periods reflects its intensive R&D efforts and strategic rebalancing.

For the six months ended June 30, 2025, total revenue was $0.37 million, a significant decrease from $16.46 million in the prior year period. This decline was primarily due to the conclusion of the Hansoh Collaboration in December 2024 and the absence of comparable milestone payments from the AstraZeneca Collaboration in 2025. In 2024, annual revenue reached $43.26 million, up from $25.38 million in 2023, largely driven by a $24.6 million cumulative catch-up from the Hansoh collaboration upon completion of its obligations. Royalty income from Alnylam also ceased after December 2023.

Operating expenses remain substantial, with Research and Development (R&D) costs being the largest component. R&D expenses increased to $38.46 million for the six months ended June 30, 2025, up from $25.65 million in the prior year, primarily due to the advancement of the Divesiran Phase 2 clinical trial and increased contract manufacturing activities for Zerlasiran's Phase 3 readiness.

General and Administrative (G&A) expenses, however, decreased to $12.82 million for the same period, down from $13.64 million, reflecting efforts to reduce administrative costs, including a non-recurring workforce reduction that resulted in $1.32 million in restructuring charges in Q2 2025. This reduction was also aided by the company no longer expecting to be a large accelerated filer in 2026, reducing reporting and compliance requirements.

The company reported a net loss of $55.88 million for the six months ended June 30, 2025, compared to $22.07 million in the prior year period. For the full year 2024, the net loss was -$45.31 million.

Operating cash outflow increased to -$34.09 million for the six months ended June 30, 2025, from -$14.55 million in the prior year, mainly due to reduced collaboration milestones and higher contracted development costs.

Despite these losses, Silence maintains a strong liquidity position. As of June 30, 2025, cash, cash equivalents, and short-term investments totaled $114.2 million. This robust position was bolstered by a $120 million PIPE financing and $27.7 million from ATM sales in 2024. Critically, the company believes its current capital resources, combined with anticipated collaboration milestones of $20 million over the next three years, are "sufficient to fund its anticipated operating and capital expenditure requirements into 2028." This extended cash runway, a direct result of the strategic decision to partner Zerlasiran's Phase 3, provides significant flexibility for pipeline investment.

Risks and Regulatory Headwinds

Investing in Silence Therapeutics carries inherent risks typical of a clinical-stage biotechnology company. A primary concern is the ongoing need for additional funding, particularly for large-scale clinical programs like Zerlasiran's Phase 3. While the company has extended its cash runway, future funding remains dependent on the achievement of collaboration milestones, which are not guaranteed, or successful equity/debt financings.

The regulatory landscape presents significant challenges. Silence is subject to stringent and evolving data privacy and security laws, including GDPR and CCPA, with non-compliance potentially leading to substantial fines and operational disruptions. The complexities of cross-border data transfers, especially from Europe to the U.S., pose ongoing legal and logistical hurdles. Furthermore, the increasing use of generative AI by employees introduces new compliance costs and potential legal risks.

Healthcare legislative and regulatory reforms in both the U.S. and Europe could negatively impact Silence's business. In the U.S., proposals to control drug costs and changes to healthcare access (e.g., the OBBBA) could affect future pricing and reimbursement. In Europe, the EU Clinical Trials Regulation (CTR) has increased administrative burdens, and the new HTA Regulation, effective January 2025, could influence pricing and reimbursement decisions. Proposed revisions to EU laws governing medicinal product authorization could also decrease data and market exclusivity opportunities, leading to earlier generic competition. The uncertainty surrounding UK-EU regulatory alignment post-Brexit further complicates clinical trial and marketing authorization strategies. Finally, Silence's ability to claim cash rebates from the U.K. R&D tax credit regime is contingent on maintaining "RD-intensive SME" status, and any changes to this regime could materially impact its cash flow.

Conclusion

Silence Therapeutics is at a pivotal juncture, strategically refining its focus to maximize the potential of its mRNAi GOLD platform. The company's disciplined approach to pipeline development, prioritizing high-impact rare disease programs like Divesiran for PV, while seeking a strategic partner for the large-market Zerlasiran, underscores a commitment to capital efficiency and shareholder value. The proven efficacy and durability of its siRNA technology, coupled with a significantly extended cash runway into 2028, provide a solid foundation for future growth.

While the path forward involves navigating a complex competitive landscape and evolving regulatory environment, Silence's technological leadership in precision gene silencing and its strategic flexibility position it to unlock substantial value. Investors should closely monitor the progress of Divesiran's Phase 2 enrollment, the outcome of Zerlasiran partnering discussions, and the advancement of its extra-hepatic pipeline as key indicators of the company's ability to translate its innovative science into commercial success and sustained financial performance.