Group 1 - Silence Therapeutics PLC Sponsored ADR (SLN) shares have increased by 52% in the past four weeks, closing at $5.41, with a mean price target of $35.50 indicating a potential upside of 556.2% [1] - The mean estimate consists of six short-term price targets with a standard deviation of $23.86, where the lowest estimate is $3 (44.6% decline) and the highest is $75 (1286.3% increase) [2] - Analysts show strong agreement in revising earnings estimates higher, which correlates with potential stock price movements [11] Group 2 - The Zacks Consensus Estimate for SLN has increased by 4.4% due to one upward revision in the last 30 days, with no negative revisions [12] - SLN holds a Zacks Rank 2 (Buy), placing it in the top 20% of over 4,000 ranked stocks based on earnings estimates [13] - While the consensus price target may not be a reliable indicator of the stock's potential gain, it suggests a positive direction for price movement [13]

Core Viewpoint - Silence Therapeutics PLC (SLN) has shown a significant price increase of 68.5% over the past four weeks, with a mean price target of $35.50 indicating a potential upside of 590.7% from the current price of $5.14 [1] Price Targets and Analyst Consensus - The average price target for SLN includes six estimates ranging from a low of $3 to a high of $75, with a standard deviation of $23.86, indicating variability in analyst predictions [2] - The lowest estimate suggests a decline of 41.6%, while the highest points to an upside of 1359.1% [2] - A low standard deviation indicates a strong agreement among analysts regarding the stock's price direction, which can serve as a starting point for further research [9] Earnings Estimates and Analyst Optimism - Analysts have shown growing optimism regarding SLN's earnings prospects, as evidenced by a positive trend in earnings estimate revisions [11] - Over the last 30 days, one estimate has increased, leading to a 4.4% rise in the Zacks Consensus Estimate for the current year [12] - SLN holds a Zacks Rank 2 (Buy), placing it in the top 20% of over 4,000 ranked stocks based on earnings estimates, suggesting strong potential for upside [13]

[PART I – FINANCIAL INFORMATION](index=5&type=section&id=PART%20I%20%E2%80%93%20FINANCIAL%20INFORMATION) [Financial Statements](index=5&type=section&id=Item%201.%20Financial%20Statements) Silence Therapeutics reported Q1 2025 revenue of $0.1 million, a net loss of $28.5 million, and cash and equivalents of $64.9 million Condensed Consolidated Statements of Operations (in thousands) | | Three months ended March 31, 2025 | Three months ended March 31, 2024 | | :--- | :--- | :--- | | **Revenue** | **$142** | **$15,699** | | Gross profit | $88 | $12,899 | | Research and development costs | $(20,813) | $(11,845) | | General and administrative expenses | $(7,684) | $(6,635) | | **Operating loss** | **$(28,409)** | **$(5,581)** | | **Net Loss** | **$(28,530)** | **$(2,312)** | | Loss per share (basic and diluted) | $(0.20) | $(0.02) | Condensed Consolidated Balance Sheet Highlights (in thousands) | | March 31, 2025 | December 31, 2024 | | :--- | :--- | :--- | | Cash and cash equivalents | $64,886 | $121,330 | | Short-term investments | $71,648 | $26,004 | | **Total current assets** | **$169,790** | **$187,366** | | **Total assets** | **$185,298** | **$202,635** | | Total liabilities | $(72,555) | $(68,612) | | **Total shareholders' equity** | **$112,743** | **$134,023** | Condensed Consolidated Statements of Cash Flows Highlights (in thousands) | | Three months ended March 31, 2025 | Three months ended March 31, 2024 | | :--- | :--- | :--- | | Net cash used in operating activities | $(12,309) | $(9,143) | | Net cash used in investing activities | $(44,381) | $(49,908) | | Net cash provided by financing activities | $14 | $133,020 | - The company believes its current cash, cash equivalents, and short-term investments of **$136.5 million** are sufficient to fund operating expenses for at least the next twelve months from the financial statement issuance date[34](index=34&type=chunk)[35](index=35&type=chunk) [Management's Discussion and Analysis of Financial Condition and Results of Operations](index=19&type=section&id=Item%202.%20Management%27s%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) Management discusses the company's siRNA therapeutic pipeline, Q1 2025 financial performance, and liquidity, including a $120 million private placement [Overview and Business Developments](index=19&type=section&id=MD%26A_Overview) Silence Therapeutics develops siRNA therapeutics via its mRNAi GOLD™ platform, advancing Divesiran (PV) and Zerlasiran (Lp(a)) in clinical trials - **Divesiran (SLN124)** for polycythemia vera (PV) is currently in the Phase 2 portion of the SANRECO clinical trial, with enrollment expected to complete by year-end 2025[68](index=68&type=chunk)[75](index=75&type=chunk) - **Zerlasiran (SLN360)** for high Lp(a) has received positive regulatory feedback on its Phase 3 study design, and the company is actively engaged in global partnership discussions for its development and commercialization[69](index=69&type=chunk)[70](index=70&type=chunk) - A Phase 1 study of **SLN312**, licensed to AstraZeneca, is ongoing[75](index=75&type=chunk) [Collaborations](index=20&type=section&id=MD%26A_Collaborations) AstraZeneca collaboration continues with a $10 million milestone, while Mallinckrodt and Hansoh collaborations concluded, returning rights to Silence - AstraZeneca collaboration: A Phase 1 trial for an undisclosed program triggered a **$10 million milestone payment** in February 2024, with the collaboration allowing for up to 10 targets in total[74](index=74&type=chunk) - Mallinckrodt collaboration: Concluded in March 2024 as Mallinckrodt will not pursue further development of SLN501, with Silence having previously reacquired rights to two other preclinical complement targets[78](index=78&type=chunk)[81](index=81&type=chunk) - Hansoh collaboration: Concluded in December 2024 after Hansoh decided not to pursue further development, with Silence retaining exclusive global rights for all three targets from the collaboration[79](index=79&type=chunk)[84](index=84&type=chunk) [Results of Operations](index=21&type=section&id=MD%26A_Results_of_Operations) Q1 2025 revenue decreased to $0.1 million due to fewer milestones, while R&D costs increased by $9.0 million, leading to a $28.4 million operating loss Comparison of Operations (in thousands) | | Three months ended March 31, 2025 | Three months ended March 31, 2024 | Change | | :--- | :--- | :--- | :--- | | **Revenue** | **$142** | **$15,699** | **$(15,557)** | | Research and development costs | $(20,813) | $(11,845) | $(8,968) | | General and administrative expenses | $(7,684) | $(6,635) | $(1,049) | | **Operating loss** | **$(28,409)** | **$(5,581)** | **$(22,828)** | - The **$15.6 million decrease in revenue** was mainly due to a **$14.5 million reduction** in revenue from the AstraZeneca collaboration, as no similar milestones were achieved in Q1 2025 compared to Q1 2024[105](index=105&type=chunk) - R&D costs increased by **$9.0 million**, largely due to the advancement of clinical trials and an increase in contract manufacturing activities for proprietary programs[108](index=108&type=chunk) [Liquidity and Capital Resources](index=27&type=section&id=MD%26A_Liquidity_and_Capital_Resources) As of March 31, 2025, the company held $136.5 million in cash and investments, projected to fund operations into 2028, bolstered by a $120 million private placement - The company had cash, cash equivalents, and short-term investments of **$136.5 million** as of March 31, 2025[115](index=115&type=chunk) - In February 2024, the company raised gross proceeds of approximately **$120.0 million** from a private placement of ADSs[118](index=118&type=chunk)[124](index=124&type=chunk) - Management believes existing capital resources will fund operations into **2028**, which includes receipt of anticipated milestones from collaboration agreements of **$20 million** in the next three years[115](index=115&type=chunk) [Quantitative and Qualitative Disclosures about Market Risk](index=31&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20about%20Market%20Risk) The company manages market risks including credit, liquidity, currency, and interest rate fluctuations through conservative financial practices - The company's primary market risks are credit, liquidity, currency (USD, GBP, EUR), and interest rate risk[143](index=143&type=chunk) - Currency risk is managed by maintaining cash balances in different currencies to meet foreseeable expenses and considering forward exchange contracts for significant receipts[145](index=145&type=chunk) - Interest rate risk is not expected to significantly affect operating results or cash flows due to the conservative nature of the investment portfolio[146](index=146&type=chunk) [Controls and Procedures](index=31&type=section&id=Item%204.%20Controls%20and%20Procedures) Management concluded that disclosure controls and procedures were effective as of March 31, 2025, with no material changes to internal controls - The Chief Executive Officer and Chief Financial Officer concluded that the company's disclosure controls and procedures were **effective** as of March 31, 2025[149](index=149&type=chunk) - No material changes to internal control over financial reporting occurred during the three months ended March 31, 2025[150](index=150&type=chunk) [PART II – OTHER INFORMATION](index=33&type=section&id=PART%20II%20%E2%80%93%20OTHER%20INFORMATION) [Legal Proceedings](index=33&type=section&id=Item%201.%20Legal%20Proceedings) The company is not currently a party to any material legal proceedings - As of the report date, the company is **not party to any material legal proceedings**[153](index=153&type=chunk) [Risk Factors](index=33&type=section&id=Item%201A.%20Risk%20Factors) The company faces evolving risks from stringent U.S. and foreign data privacy laws, including GDPR, cross-border data transfers, and regulations on generative AI - The company is subject to stringent data privacy laws like the EU/U.K. GDPR, which carry potential fines of up to **4% of annual global revenue** for non-compliance[155](index=155&type=chunk)[158](index=158&type=chunk) - Transferring personal data from Europe to the U.S. is significantly restricted and subject to legal challenges, which could interrupt operations or require relocating data processing activities at significant expense[159](index=159&type=chunk)[160](index=160&type=chunk) - The use of generative AI by employees is subject to evolving privacy laws and regulations, which could result in additional compliance costs or competitive disadvantages if its use is restricted[163](index=163&type=chunk) - A new U.S. Department of Justice rule restricts certain data transactions involving countries of concern (e.g., China, Russia), which may impact vendor engagements, data sharing, and investor agreements[161](index=161&type=chunk) [Unregistered Sales of Equity Securities and Use of Proceeds](index=35&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities%20and%20Use%20of%20Proceeds) There were no unregistered sales of equity securities during the period - None[169](index=169&type=chunk) [Other Information](index=35&type=section&id=Item%205.%20Other%20Information) There is no other information to report for the period - None[172](index=172&type=chunk) [Exhibits](index=36&type=section&id=Item%206.%20Exhibits) This section lists exhibits filed with the Form 10-Q, including CEO and CFO certifications and Inline XBRL documents - Exhibits filed include CEO and CFO certifications pursuant to Sarbanes-Oxley Act Sections 302 and 906[174](index=174&type=chunk)

Report Overview [Management Commentary](index=1&type=section&id=Management%20Commentary) In the first quarter of 2025, Silence Therapeutics' management highlighted strong clinical and operational execution, emphasizing advancement of the SANRECO Phase 2 study for divesiran and cost-saving initiatives extending cash guidance into 2028 - The company is focused on advancing enrollment in the SANRECO Phase 2 study of divesiran and expects to complete it by the end of **2025**[2](index=2&type=chunk) - Additional results from the Phase 1 portion of the SANRECO study will be presented at the European Hematology Association (EHA) meeting in **June 2025**[2](index=2&type=chunk) - Cost-saving measures have been implemented to extend the company's cash runway into **2028**, with a cash, cash equivalents, and short-term investments balance of over **$136 million** at the end of Q1 2025[2](index=2&type=chunk) [First Quarter 2025 & Recent Business Highlights](index=1&type=section&id=First%20Quarter%202025%20%26%20Recent%20Business%20Highlights) The company reported significant progress in its key clinical programs, with divesiran Phase 2 enrollment on track, zerlasiran Phase 3 readiness progressing, and a partnered Phase 1 study with AstraZeneca ongoing [Divesiran for Polycythemia Vera (PV)](index=1&type=section&id=Divesiran%20for%20Polycythemia%20Vera%20%28PV%29) Progress continues on the divesiran program for Polycythemia Vera (PV), with Phase 2 SANRECO study enrollment advancing and new Phase 1 data accepted for presentation at EHA 2025 - Patient enrollment into the Phase 2 portion of the SANRECO study is on track to be completed by **year-end 2025**[7](index=7&type=chunk) - Additional Phase 1 results from the SANRECO study will be presented orally at the EHA 2025 Annual Congress in **June**[7](index=7&type=chunk) [Zerlasiran for Cardiovascular Disease](index=1&type=section&id=Zerlasiran%20for%20Cardiovascular%20Disease) The company is advancing its zerlasiran program for cardiovascular disease with core Phase 3 readiness activities on track for mid-2025 completion and ongoing partnering discussions - Core Phase 3 readiness activities, including manufacturing and supply scale-up, are on track to be completed by **mid-2025**[3](index=3&type=chunk) - Partnering discussions for potential Phase 3 development are ongoing[3](index=3&type=chunk) [Collaborations](index=1&type=section&id=Collaborations) The company's collaboration with AstraZeneca is active, with a Phase 1 study of the licensed product, SLN312, currently ongoing - A Phase 1 study of SLN312, which is licensed to AstraZeneca, is currently ongoing[4](index=4&type=chunk) [Corporate Updates](index=1&type=section&id=Corporate%20Updates) Silence Therapeutics strengthened its leadership by appointing Tim McInerney to its Board of Directors, effective May 5, 2025, leveraging his extensive experience - Tim McInerney, an executive with over **30 years** of experience in investment and pharmaceuticals, was appointed to the Board of Directors[5](index=5&type=chunk) Financial Results and Guidance [First Quarter 2025 Financial Highlights](index=1&type=section&id=First%20Quarter%202025%20Financial%20Highlights) For the first quarter of 2025, Silence Therapeutics reported a cash position of $136.5 million, increased R&D and G&A expenses, and a significantly wider net loss of $28.5 million Q1 2025 Key Financial Metrics | Metric | Q1 2025 | Q1 2024 | Change | | :--- | :--- | :--- | :--- | | Cash, Cash Equivalents, & Short-term Investments | $136.5 million | N/A | Down from $147.3M at YE 2024 | | R&D Expenses | $20.8 million | $11.8 million | +$9.0 million | | G&A Expenses | $7.7 million | $6.6 million | +$1.0 million | | Net Loss | $28.5 million | $2.3 million | +$26.2 million | | Net Loss Per Share (basic and diluted) | $0.20 | $0.02 | +$0.18 | [Updates to 2025 Financial Guidance](index=2&type=section&id=Updates%20to%202025%20Financial%20Guidance) The company has implemented strategic cost-saving initiatives, including reductions in general and administrative costs and prioritization of early-stage research, to extend its cash runway into 2028 - Cost savings initiatives have been implemented to extend the cash runway into **2028**[8](index=8&type=chunk) - These measures involve general and administrative reductions and prioritizing early-stage research projects[8](index=8&type=chunk) [Condensed Consolidated Statements of Operations](index=5&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations) For the three months ended March 31, 2025, revenue plummeted to $0.14 million from $15.7 million, while operating expenses increased, resulting in a significantly wider operating loss of $28.4 million and a net loss of $28.5 million Condensed Consolidated Statements of Operations (in thousands, except per share data) | | Three months ended March 31, | | | :--- | :--- | :--- | | | **2025** | **2024** | | Revenue | $ 142 | $ 15,699 | | Gross profit | 88 | 12,899 | | Research and development costs | (20,813) | (11,845) | | General and administrative expenses | (7,684) | (6,635) | | **Operating loss** | **(28,409)** | **(5,581)** | | **Net Loss** | **$ (28,530)** | **$ (2,312)** | | **Loss per share (basic and diluted)** | **$ (0.20)** | **$ (0.02)** | [Condensed Consolidated Balance Sheets](index=4&type=section&id=Condensed%20Consolidated%20Balance%20Sheets) As of March 31, 2025, total assets decreased to $185.3 million from $202.6 million at year-end 2024, primarily due to reduced cash, while total liabilities slightly increased to $72.6 million, resulting in a total shareholders' equity deficit of $112.7 million Condensed Consolidated Balance Sheet Highlights (in thousands) | | March 31, 2025 | December 31, 2024 | | :--- | :--- | :--- | | Cash and cash equivalents | $ 64,886 | $ 121,330 | | Short-term investments | 71,648 | 26,004 | | **Total current assets** | **169,790** | **187,366** | | **Total assets** | **$ 185,298** | **$ 202,635** | | Total current liabilities | (19,264) | (16,822) | | **Total liabilities** | **$ (72,555)** | **$ (68,612)** | | **Total shareholders' equity** | **(112,743)** | **(134,023)** |

Core Viewpoint - Silence Therapeutics PLC has been upgraded to a Zacks Rank 2 (Buy) due to an upward trend in earnings estimates, which is a significant factor influencing stock prices [1][3]. Earnings Estimates and Stock Price Movement - The Zacks rating system is based on changes in earnings estimates, which are closely correlated with near-term stock price movements [4][6]. - Institutional investors often rely on earnings estimates to determine the fair value of a company's shares, leading to stock price fluctuations based on their buying or selling actions [4]. Company Performance and Outlook - The upgrade for Silence Therapeutics indicates an improvement in the company's underlying business, which is expected to positively influence its stock price [5][10]. - For the fiscal year ending December 2025, Silence Therapeutics is projected to earn -$1.61 per share, reflecting a 62.6% decrease from the previous year's reported figure, although analysts have raised their estimates by 0.5% over the past three months [8]. Zacks Rank System - The Zacks Rank system classifies stocks into five groups based on earnings estimates, with a strong historical performance, particularly for Zacks Rank 1 stocks, which have averaged a +25% annual return since 1988 [7][9]. - Silence Therapeutics' upgrade to Zacks Rank 2 places it in the top 20% of Zacks-covered stocks, indicating a strong potential for market-beating returns in the near term [10].

Financial Data and Key Metrics Changes - For the year ended December 31, 2024, the company recorded revenues of $43.3 million, an increase from $31.6 million in 2023, representing a growth of $11.7 million largely due to collaboration arrangements for siRNA platform development [20][21] - The company's net operating loss for 2024 was approximately $63.3 million, a slight decrease from $64.4 million in 2023, attributed to increased revenue offset by rising R&D costs [26] - The net loss for 2024 was approximately $45.3 million compared to $54.2 million in 2023, reflecting improved financial performance [27] Business Line Data and Key Metrics Changes - The Phase 2 study of zerlasiran showed positive results with Lp(a) reductions exceeding 90%, supporting its competitive profile for further development [5][6] - Divesiran's Phase 1 study eliminated the need for phlebotomy in all well-controlled patients, indicating strong efficacy and safety [8][44] - The company plans to prioritize investment in programs targeting rare conditions, with divesiran for polycythemia vera (PV) remaining a top priority [10][29] Market Data and Key Metrics Changes - The company anticipates full enrollment in the SANRECO Phase 2 study for divesiran by the end of 2024, indicating strong market interest and potential for future growth [15][30] - The collaboration with AstraZeneca continues to advance, with expectations for additional milestones [20][21] Company Strategy and Development Direction - The company will only initiate the Phase 3 outcomes study for zerlasiran once a partner is secured, extending its cash runway into 2027 [12][28] - The focus remains on developing innovative siRNA therapies for rare conditions, leveraging the company's proprietary pipeline [10][29] - The company is evaluating multiple undisclosed programs from its GOLD platform for potential development or partnership [17] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the potential of zerlasiran and divesiran, highlighting the unique market opportunities for both products [12][60] - The company is actively engaged in partnership discussions for zerlasiran, with a focus on securing the right partner for development and commercialization [61] Other Important Information - Silence has transitioned to a U.S. domestic issuer effective January 1, 2025, requiring compliance with U.S. GAAP and SEC reporting [19] - The company recorded approximately $4.5 million in other income, primarily from U.S. treasury bill accretion, compared to $1.8 million in 2023 [27] Q&A Session Summary Question: Can you provide some color on partnership discussions for zerlasiran? - Management refrained from commenting specifically on ongoing partnership discussions but noted increased funding for Lp(a) studies from companies like Novartis [59][61] Question: How ready is the company for the Phase 3 trial of zerlasiran? - The company is wrapping up Phase 3 readiness activities and is prepared to make adjustments with a partner if needed [67] Question: What are the goals for divesiran regarding differentiation? - The company aims to be the first siRNA to market for PV, focusing on infrequent dosing and symptomatic improvement as key differentiators [75][76] Question: What are the biggest hurdles for partnering zerlasiran? - Hurdles vary by party, often revolving around business strategy and recognition of the large market opportunity [79][80] Question: What is the status of the candidates developed for Hansoh? - The company is interested in the programs developed in partnership with Hansoh and plans to evaluate them for potential internal development or partnership [84][86]

Financial Data and Key Metrics Changes - For the year ended December 31, 2024, the company recorded revenues of $43.3 million, an increase from $31.6 million in 2023, representing a growth of $11.7 million largely due to collaboration arrangements for siRNA platform development [20][21] - The company's net operating loss for 2024 was approximately $63.3 million, a slight decrease from $64.4 million in 2023, attributed to increased revenue offset by rising R&D costs [26] - The net loss for 2024 was approximately $45.3 million compared to $54.2 million in 2023, with cash, cash equivalents, and short-term investments totaling $147.3 million at the end of December 2024 [27] Business Line Data and Key Metrics Changes - The Phase 2 study of zerlasiran showed positive results with Lp(a) reductions exceeding 90%, supporting a competitive profile for further development in Phase 3 [5][6] - Divesiran's Phase 1 study results indicated it completely eliminated the need for phlebotomy in well-controlled patients, with a favorable safety profile [8][14] - The company plans to prioritize investment in programs targeting rare conditions, with divesiran for polycythemia vera (PV) remaining a top priority [10][29] Market Data and Key Metrics Changes - The company has received Orphan Drug Designation for divesiran from the European Commission, and it also holds FDA Fast Track and Orphan Drug Designations for PV [8] - The market opportunity for treating high Lp(a) is significant, with few cardiovascular assets targeting this unmet medical condition [12] Company Strategy and Development Direction - The company will only initiate the Phase 3 outcomes study for zerlasiran once a partner is secured, extending its cash runway into 2027 [28][53] - The focus will be on advancing innovative siRNA therapies for rare conditions, with a commitment to delivering life-changing treatments [29][56] - The company is evaluating multiple undisclosed programs from its GOLD platform for potential development or partnership [17] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the potential of zerlasiran and divesiran, highlighting the positive feedback received from global regulatory agencies regarding the Phase 3 program design for zerlasiran [6][12] - The company is actively engaged in partnership discussions for zerlasiran, with a focus on securing the right partner for development and commercialization [61] Other Important Information - Silence has transitioned to a U.S. domestic issuer effective January 1, 2025, requiring compliance with U.S. GAAP and SEC reporting [19] - The company plans to start a Phase 1 study of SLN548, targeting complement factor B, in the second half of the year [50] Q&A Session Summary Question: Can you provide some color on partnership discussions for zerlasiran? - Management did not comment specifically on ongoing partnership discussions but noted increased funding for Lp(a) studies from companies like Novartis [59][61] Question: How ready is the company for the Phase 3 trial of zerlasiran? - The company is wrapping up Phase 3 readiness activities and is on track to complete them by mid-year, allowing for some adjustments with a partner [67] Question: What is the goal for divesiran regarding differentiation? - The goal is to be the first siRNA to market for PV, with a focus on infrequent dosing and symptomatic improvement as key differentiators [75][78] Question: What are the biggest hurdles for partnering zerlasiran? - Hurdles vary by party, but discussions often revolve around business strategy and the recognition of the large market opportunity [79][80] Question: What is the status of the candidates developed for Hansoh? - The company is interested in the programs developed under the partnership and will evaluate the opportunity to develop them independently or through partnerships [84]

Clinical Trial Updates - ALPACAR-360 Phase 2 study of Zerlasiran delivered positive results in high Lp(a)[9, 10] - SANRECO Phase 1 study of Divesiran delivered positive results in PV and was granted orphan drug designation for PV in EU[9, 10] - SANRECO Phase 2 study of Divesiran dosed first PV patient, with full enrollment anticipated by year-end 2025[10, 12, 48] - SLN548 (complement factor B) Phase 1 study start anticipated in 2H 2025[12, 48] Divesiran in Polycythemia Vera (PV) - Divesiran is a first-in-class siRNA for PV with FDA Fast Track and Orphan Drug Designations[26, 27] - Phase 1 study showed Divesiran reduced phlebotomy frequency in PV patients who had 79 phlebotomies prior to dosing, but only 5 in the treatment period and 2 in follow-up[29, 31] - Divesiran decreased hematocrit in all cohorts in Phase 1 study[32, 34] - Divesiran treatment produced sustained increases in Hepcidin[36, 38] - Divesiran demonstrated a favorable safety and tolerability profile, with 84% of treatment emergent adverse events (TEAEs) being grade 1[40, 41] Financial Performance and Guidance - Revenue for FY 2024 was $43258 thousand, compared to $31634 thousand in FY 2023[16] - Net loss for FY 2024 was $45309 thousand, compared to $54228 thousand in FY 2023[16] - Cash position at the end of December 2024 was $147334 thousand, including $121300 thousand in cash and cash equivalents and $26000 thousand in short-term investments[16, 17] - Projected cash runway extended into 2027[18]

Part I [Business](index=7&type=section&id=Item%201.%20Business) Silence Therapeutics develops siRNA therapeutics using its mRNAi GOLD™ platform, focusing on cardiovascular, hematology, and rare diseases through its pipeline and collaborations - The company focuses on discovering and developing siRNA molecules to inhibit specific target genes using its proprietary **mRNAi GOLD™ platform**[23](index=23&type=chunk) - The wholly-owned pipeline is concentrated in three therapeutic areas: **cardiovascular disease, hematology, and rare diseases**[23](index=23&type=chunk) [Our Pipeline](index=8&type=section&id=Our%20Pipeline) The company advances siRNA programs from its mRNAi GOLD™ platform, including clinical-stage Divesiran for PV and Zerlasiran for cardiovascular disease, and a Phase 1 candidate with AstraZeneca - **Divesiran (SLN124)**, a wholly-owned siRNA candidate for polycythemia vera (PV), is in a Phase 2 clinical trial (SANRECO) and has received Fast Track and orphan drug designations from the FDA and Europe[24](index=24&type=chunk) - **Zerlasiran (SLN360)**, a wholly-owned siRNA candidate to lower lipoprotein(a) (Lp(a)), completed Phase 1 and 2 trials showing substantial Lp(a) reduction, and the company is seeking a partner for Phase 3 development[25](index=25&type=chunk)[26](index=26&type=chunk) - A third product candidate, developed with AstraZeneca, is in Phase 1 development for an undisclosed indication[27](index=27&type=chunk) [Collaborations](index=16&type=section&id=Collaborations) The company maintains strategic collaborations, including a Phase 1 program with AstraZeneca, while partnerships with Mallinckrodt and Hansoh have concluded, with Silence retaining rights for Hansoh targets - The AstraZeneca collaboration covers up to 10 targets, with **$60 million in upfront and unconditional payments**, a **$20 million equity investment**, and a **$10 million milestone payment** triggered by Phase 1 trial initiation, with potential for up to **$390 million per target** in milestones plus royalties[65](index=65&type=chunk)[66](index=66&type=chunk) - The Mallinckrodt collaboration concluded in March 2024 after Mallinckrodt decided not to pursue further development of SLN501, with Silence having reacquired rights to two other preclinical complement targets in March 2023[67](index=67&type=chunk)[68](index=68&type=chunk) - The Hansoh collaboration concluded in December 2024, with Silence retaining exclusive global rights for all three original targets[70](index=70&type=chunk) [Intellectual Property](index=17&type=section&id=Intellectual%20Property) The company protects its siRNA platform and product candidates through patents and trade secrets, holding 62 solely owned granted patents and 150 pending applications as of December 31, 2024 Patent Portfolio as of December 31, 2024 | Category | Count | | :--- | :--- | | **Solely Owned Granted Patents** | 62 (221 including EU validations) | | - U.S. Issued Patents | 14 | | **Pending Patent Applications** | 150 (138 solely owned) | | - U.S. Pending Applications | 11 (10 solely owned) | - Patent families covering the siRNA chemistry toolbox elements, if granted, are expected to expire no earlier than **2036**[84](index=84&type=chunk) - Patent families covering the siRNA sequences for product candidates **SLN360** and **SLN124**, if granted, are expected to expire no earlier than **2038**[84](index=84&type=chunk) [Government Regulation and Product Approval](index=19&type=section&id=Government%20Regulation%20and%20Product%20Approval) The company navigates extensive government regulations for drug approval in the US (FDA), EU (EMA), and UK (MHRA), covering preclinical, clinical, manufacturing, and post-market requirements, with an evolving regulatory landscape - The U.S. drug approval process involves preclinical studies, an effective IND, IRB-approved clinical trials (Phase 1, 2, 3), and NDA submission to the FDA[86](index=86&type=chunk) - In the EU, clinical trials are governed by the Clinical Trials Regulation (CTR), streamlining application and assessment through a centralized EU portal[132](index=132&type=chunk) - The UK has its own post-Brexit regulatory framework managed by the MHRA, including national authorization procedures and the International Recognition Procedure (IRP) leveraging other trusted regulators' approvals[157](index=157&type=chunk)[158](index=158&type=chunk) [Risk Factors](index=35&type=section&id=Item%201A.%20Risk%20Factors) The company faces significant risks including historical net losses, capital needs, inherent drug development uncertainties, reliance on third parties, intense competition, intellectual property challenges, and increased compliance costs from its U.S. domestic issuer transition - The company has a history of net losses, with a **net loss of $45.3 million in 2024** and an accumulated loss of **$474.0 million** as of December 31, 2024, anticipating continued significant losses[173](index=173&type=chunk) - The company's novel siRNA technology may not lead to marketable products, and its focus on a single technology platform increases inherent development risk[190](index=190&type=chunk)[192](index=192&type=chunk) - Reliance on third parties for manufacturing (CMOs) and clinical research (CROs) introduces risks related to performance, quality, and supply chain disruptions[210](index=210&type=chunk)[213](index=213&type=chunk) - Effective January 1, 2025, the company transitioned to a 'U.S. domestic issuer', resulting in increased compliance costs and reporting requirements under SEC rules[304](index=304&type=chunk) [Cybersecurity](index=74&type=section&id=Item%201C.%20Cybersecurity) The company manages cybersecurity risks through an information security program overseen by its audit and risk committee, employing threat identification, mitigation measures, and third-party vendor risk management - The company's cybersecurity risk management is overseen by the board's audit and risk committee and managed by the Head of IT[368](index=368&type=chunk)[369](index=369&type=chunk) - The security strategy includes incident detection and response, vulnerability management, disaster recovery, risk assessments, encryption, and employee training[363](index=363&type=chunk) - The company relies on third-party service providers for various functions and manages associated cybersecurity risks through vendor assessments and contractual requirements[366](index=366&type=chunk) [Properties](index=75&type=section&id=Item%202.%20Properties) The company leases all its facilities, including corporate headquarters in London, UK, and office/laboratory spaces in Berlin, Germany, and Hoboken, New Jersey, which are deemed adequate for near-term needs - The company leases office and lab space in London (UK), Berlin (Germany), and Hoboken (NJ, USA)[373](index=373&type=chunk) Part II [Market for Registrant's Common Equity, Related Stockholder Matters, and Issuer Purchases of Equity Securities](index=76&type=section&id=Item%205.%20Market%20for%20Registrant%27s%20Common%20Equity%2C%20Related%20Stockholder%20Matters%2C%20and%20Issuer%20Purchases%20of%20Equity%20Securities) The company's ADSs trade on Nasdaq under 'SLN' since September 2020, with no dividends paid or intended, as earnings are retained for business development - The company's ADSs (ticker: **SLN**) began trading on Nasdaq in **September 2020**, with each ADS representing three ordinary shares[378](index=378&type=chunk) - The company has never declared or paid dividends and does not intend to in the foreseeable future, retaining earnings for business growth[380](index=380&type=chunk) [Management's Discussion and Analysis of Financial Condition and Results of Operations](index=78&type=section&id=Item%207.%20Management%27s%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) For 2024, the company reported **$43.3 million in revenue** and a **net loss of $45.3 million**, with R&D expenses increasing to **$67.9 million**, and ended the year with **$147.3 million in cash** after significant capital raises [Results of Operations](index=86&type=section&id=Results%20of%20Operations) For 2024, revenue increased to **$43.3 million** due to the Hansoh collaboration, while R&D expenses rose to **$67.9 million**, resulting in an improved net loss of **$45.3 million** Consolidated Results of Operations (in thousands) | | 2024 | 2023 | 2022 | | :--- | :--- | :--- | :--- | | **Revenue** | **$43,258** | **$31,643** | **$21,655** | | Gross profit | 31,448 | 18,776 | 8,192 | | Research and development costs | (67,883) | (56,937) | (43,550) | | General and administrative expenses | (26,884) | (26,222) | (25,682) | | Operating loss | (63,319) | (64,383) | (61,040) | | **Net Loss** | **$(45,309)** | **$(54,228)** | **$(50,334)** | | Loss per share (basic and diluted) | $(0.33) | $(0.49) | $(0.52) | - Revenue increased to **$43.3 million** in 2024 from **$31.6 million** in 2023, primarily due to recognizing **$24.6 million** from the Hansoh Collaboration upon its conclusion[430](index=430&type=chunk) - Research and development expenses increased by **$11.0 million** year-over-year to **$67.9 million** in 2024, driven by additional clinical trials and increased contract manufacturing for proprietary programs[436](index=436&type=chunk) [Liquidity and Capital Resources](index=88&type=section&id=Liquidity%20and%20Capital%20Resources) As of December 31, 2024, the company held **$147.3 million** in cash and investments, bolstered by **$120.0 million** from a private placement and **$27.7 million** from ATM sales, with net cash outflow from operations at **$67.6 million** - As of December 31, 2024, the company had cash, cash equivalents, and short-term investments of **$147.3 million**[443](index=443&type=chunk) - In February 2024, the company raised approximately **$120.0 million** in gross proceeds through a private placement of ADSs[445](index=445&type=chunk) - In 2024, the company raised **$27.7 million** in proceeds (before fees) from sales of ADSs under its Open Market Sale Agreement (ATM facility)[444](index=444&type=chunk) Summary of Cash Flows (in thousands) | | 2024 | 2023 | 2022 | | :--- | :--- | :--- | :--- | | Net cash outflow from operating activities | $(67,640) | $(49,462) | $(57,044) | | Net cash (outflow)/inflow from investing activities | $(21,966) | $19,294 | $(20,498) | | Net cash inflow from financing activities | $142,087 | $31,937 | $52,581 | [Controls and Procedures](index=96&type=section&id=Item%209A.%20Controls%20and%20Procedures) Management concluded that disclosure controls and internal control over financial reporting were effective as of December 31, 2024, with PricewaterhouseCoopers LLP issuing an unqualified opinion on internal controls - Management concluded that the company's disclosure controls and procedures were effective as of **December 31, 2024**[489](index=489&type=chunk) - Management assessed internal control over financial reporting as effective as of **December 31, 2024**, based on the COSO framework[492](index=492&type=chunk) - The independent registered public accounting firm, PricewaterhouseCoopers LLP, issued an unqualified opinion on the effectiveness of the company's internal control over financial reporting as of **December 31, 2024**[494](index=494&type=chunk) Part III Information for Items 10 through 14, covering Directors, Executive Officers, Corporate Governance, Executive Compensation, Security Ownership, and Related Transactions, is incorporated by reference from the company's 2025 Proxy Statement [Directors, Executive Officers and Corporate Governance](index=98&type=section&id=Item%2010.%20Directors%2C%20Executive%20Officers%20and%20Corporate%20Governance) Information for this item is incorporated by reference from the company's 2025 Proxy Statement, which also details the adopted Code of Business Conduct and Ethics and Insider Trading Policy - Information for this item is incorporated by reference from the Proxy Statement for the **2025 Annual General Meeting of Shareholders**[500](index=500&type=chunk) [Executive Compensation](index=98&type=section&id=Item%2011.%20Executive%20Compensation) Information regarding executive compensation is incorporated by reference from the company's 2025 Proxy Statement - Information for this item is incorporated by reference from the Proxy Statement for the **2025 Annual General Meeting of Shareholders**[503](index=503&type=chunk) Part IV [Exhibits and Financial Statement Schedules](index=99&type=section&id=Item%2015.%20Exhibits%20and%20Financial%20Statement%20Schedules) This section lists the financial statements and exhibits filed as part of the Annual Report on Form 10-K, including auditor reports, consolidated financial statements, and various corporate governance documents Financial Statements [Report of Independent Registered Public Accounting Firm](index=103&type=section&id=Report%20of%20Independent%20Registered%20Public%20Accounting%20Firm) PricewaterhouseCoopers LLP issued an unqualified opinion on the consolidated financial statements and internal control over financial reporting, identifying R&D accruals as a Critical Audit Matter - The auditor, PricewaterhouseCoopers LLP, issued an unqualified (clean) opinion on both the consolidated financial statements and the effectiveness of internal control over financial reporting[525](index=525&type=chunk) - A Critical Audit Matter (CAM) was identified concerning the accuracy of management's assessment of accruals and prepayments for third-party research and development contracts, due to the significant judgment required to estimate the stage of completion[533](index=533&type=chunk)[534](index=534&type=chunk) [Consolidated Financial Statements](index=105&type=section&id=Consolidated%20Financial%20Statements) The consolidated financial statements show total assets of **$202.6 million** and total liabilities of **$68.6 million** as of December 31, 2024, with a **net loss of $45.3 million** on **$43.3 million in revenue** for the year Consolidated Balance Sheet Data (in thousands) | | Dec 31, 2024 | Dec 31, 2023 | | :--- | :--- | :--- | | Cash and cash equivalents | $121,330 | $68,789 | | Total current assets | $187,366 | $103,151 | | **Total assets** | **$202,635** | **$119,448** | | Total current liabilities | $(16,822) | $(22,336) | | **Total liabilities** | **$(68,612)** | **$(97,455)** | | **Total shareholders' equity** | **$(134,023)** | **$(21,993)** | Consolidated Income Statement Data (in thousands) | | Year ended Dec 31, 2024 | Year ended Dec 31, 2023 | Year ended Dec 31, 2022 | | :--- | :--- | :--- | :--- | | Revenue | $43,258 | $31,643 | $21,655 | | Operating loss | $(63,319) | $(64,383) | $(61,040) | | **Net Loss** | **$(45,309)** | **$(54,228)** | **$(50,334)** | [Notes to the Consolidated Financial Statements](index=110&type=section&id=Notes%20to%20the%20Consolidated%20Financial%20Statements) The notes detail accounting policies, including U.S. GAAP transition and revenue recognition, with significant 2024 contributions from AstraZeneca and Hansoh collaborations, and provide insights into equity changes and share-based compensation expenses - The company transitioned from IFRS to U.S. GAAP, applied retrospectively, due to the loss of its 'foreign private issuer' status[551](index=551&type=chunk) - Revenue from collaboration agreements is recognized over time using a cost-to-cost input method, as the license and R&D services are considered a single performance obligation per target[568](index=568&type=chunk) - In 2024, the company raised gross proceeds of **$120.0 million** from a private placement and **$27.7 million** from its ATM sales agreement[657](index=657&type=chunk)[658](index=658&type=chunk) - Share-based compensation expense for 2024 was **$16.3 million**, with **$29.1 million** of total unrecognized compensation cost related to unvested stock options as of year-end[665](index=665&type=chunk)[667](index=667&type=chunk)

[Full Year 2024 Financial Results and Business Update](index=1&type=section&id=Full%20Year%202024%20Financial%20Results%20and%20Business%20Update) [Business Highlights](index=1&type=section&id=Business%20Highlights) The company advanced its mRNAi GOLD™ platform with strong clinical execution, prioritizing rare disease programs and extending its cash runway into 2027 by partnering zerlasiran - The company is strategically prioritizing investments in programs for rare conditions, such as **divesiran for Polycythemia Vera (PV)**[2](index=2&type=chunk) - The Phase 3 cardiovascular outcomes study for zerlasiran will only be initiated after securing a partner, a decision that **extends the company's cash runway into 2027**[2](index=2&type=chunk)[6](index=6&type=chunk) [Zerlasiran for Cardiovascular Disease](index=1&type=section&id=Zerlasiran%20for%20Cardiovascular%20Disease) The zerlasiran program received positive regulatory feedback for its Phase 3 design and is prepared for H1 2025, with initiation contingent on securing a partnership - Received **positive feedback on the Phase 3 study design** from major global regulatory bodies including the U.S. FDA, European EMA, and Japanese PMDA[4](index=4&type=chunk) - The program is on track to be **Phase 3 ready in H1 2025**, but the study's start is dependent on securing a partner[4](index=4&type=chunk) [Divesiran for Polycythemia Vera (PV)](index=1&type=section&id=Divesiran%20for%20Polycythemia%20Vera%20(PV)) The divesiran program is advancing with Phase 1 follow-up concluded and Phase 2 enrollment expected to complete by year-end 2025 - Follow-up has concluded in the SANRECO Phase 1 study, with **data presentations anticipated in 2025**[4](index=4&type=chunk) - **Full enrollment in the SANRECO Phase 2 study** is expected by the end of 2025[2](index=2&type=chunk)[4](index=4&type=chunk) [Other mRNAi GOLD™ Pipeline Updates](index=1&type=section&id=Other%20mRNAi%20GOLD%E2%84%A2%20Pipeline%20Updates) The company plans a Phase 1 study for SLN548, continues the SLN312 study, and has regained rights to three preclinical programs from Hansoh Pharma - A Phase 1 study of **SLN548**, a wholly-owned siRNA candidate for complement-mediated diseases, is planned for **H2 2025**[3](index=3&type=chunk) - The collaboration with Hansoh Pharma has ended, and **Silence has regained global rights** to all three associated preclinical programs[9](index=9&type=chunk) - A Phase 1 study of **SLN312**, which is licensed to AstraZeneca, is currently ongoing[9](index=9&type=chunk) [Financial Highlights and Guidance](index=2&type=section&id=Financial%20Highlights%20and%20Guidance) The company reported a strong cash position of $147.3 million, increased collaboration revenue, a narrowed net loss, and an extended cash runway into 2027 Key Financial Metrics for Year End 2024 | Metric | 2024 | 2023 | | :--- | :--- | :--- | | Cash, Cash Equivalents, and Short-term Investments | $147.3 million | $68.8 million | | Collaboration Revenue | $43.1 million | $30.9 million | | R&D Expenses | $67.9 million | $56.9 million | | G&A Expenses | $26.9 million | $26.2 million | | Net Loss | $45.3 million | $54.2 million | | Net Loss Per Share | $0.33 | $0.49 | - The company's projected **cash runway is now extended into 2027**[2](index=2&type=chunk)[6](index=6&type=chunk) [Financial Statements](index=5&type=section&id=Financial%20Statements) The 2024 consolidated financial statements show increased revenue, a reduced net loss, and a significantly strengthened balance sheet with higher cash and lower liabilities [Consolidated Statements of Income (Loss)](index=5&type=section&id=Consolidated%20Statements%20of%20Income%20(Loss)) For fiscal year 2024, revenue increased to $43.3 million while the net loss improved to $45.3 million, or $0.33 per share Consolidated Statements of Income (Loss) (in thousands, except for loss per share) | | 2024 | 2023 | | :--- | :--- | :--- | | **Revenue** | **$ 43,258** | **$ 31,643** | | Gross profit | $ 31,448 | $ 18,776 | | Research and development costs | $ (67,883) | $ (56,937) | | General and administrative expenses | $ (26,884) | $ (26,222) | | Operating loss | $ (63,319) | $ (64,383) | | **Net Loss** | **$ (45,309)** | **$ (54,228)** | | **Loss per share (basic and diluted)** | **$ (0.33)** | **$ (0.49)** | [Consolidated Balance Sheets](index=6&type=section&id=Consolidated%20Balance%20Sheets) As of December 31, 2024, the balance sheet reflects strong liquidity with total assets of $202.6 million and significantly reduced total liabilities Consolidated Balance Sheets (in thousands) | | Dec 31, 2024 | Dec 31, 2023 | | :--- | :--- | :--- | | **Current assets** | | | | Cash and cash equivalents | $ 121,330 | $ 68,789 | | Short-term investments | $ 26,004 | $ — | | **Total current assets** | **$ 187,366** | **$ 103,151** | | **Total assets** | **$ 202,635** | **$ 119,448** | | **Current liabilities** | | | | Total current liabilities | $ (16,822) | $ (22,336) | | **Total liabilities** | **$ (68,612)** | **$ (97,455)** | | **Total shareholders' equity** | **$ (134,023)** | **$ (21,993)** |