E therapeutics : Annual Report for the year ended 31 January 2024

Computing the future of medicineTM

e-therapeutics plc

Annual report and accounts 2024

We integrate computational power and biology to discover life- transforming RNAi medicines.

Vision

Solve human disease through computation

Mission

Integrate computational power and biological data to discover life-transforming RNAi medicines

Purpose

Build an in-house pipeline of more effective medicines at a greater speed and significantly reduced costs compared to industry standards

To view our site visit:

www.etherapeutics.co.uk

Contents

Strategic report

1. Highlights
2. At a glance
3. Investment case
4. Chairman's statement

1. Chief Executive Officer's statement

1. Financial review

1. Our approach

1. Therapeutic pipeline

1. Business model

1. Our strategy

1. Section 172(1) statement
2. Stakeholder engagement

1. Environmental, social and governance
2. Risk management

Corporate governance

1. Chairman's introduction to governance
2. Board of Directors
3. Executive Team
4. Corporate governance statement

1. Governance structure

1. Audit Committee report
2. Remuneration Committee report

1. Remuneration policy

1. Statement of remuneration

1. Directors' report

1. Directors' responsibilities statement

Financial statements

1. Independent Auditor's report

1. Income statement

1. Statement of comprehensive income
2. Statement of changes in equity
3. Statement of financial position
4. Statement of cash flow
5. Notes to the financial statements

Annual General Meeting

1. Notice of Annual General Meeting

1. Explanatory notes to the resolutions

1. Advisors

HIGHLIGHTS

Operational highlights

Pipeline

• Unveiled a therapeutic pipeline of five GalOmic™ RNA interference (RNAi) programs spanning a variety of therapeutic areas with high unmet need.
• Completed positive preclinical proof-of-concept data packages for four GalOmic™ assets.
• Selected two assets for progression towards the clinic, with IND-enabling studies to commence in due course: ETX-312 for the treatment of metabolic dysfunction- associated steatohepatitis (MASH) and ETX-407 for dry age-related macular degeneration.

Data

• Expansion of data on metabolic dysfunction and associated fatty liver disease through strategic collaboration with Arcturis Data (Arcturis) to integrate Arcturis' high quality, clinically rich real-world evidence
  (RWE) patient data within HepNet™.
• Generation of a wealth of in-house experimental data significantly expanding the proprietary datasets that feed into HepNet™.

Computation

• Advanced projects developing and implementing large language models (LLMs) across e-therapeutics' processes and systems, further enhancing computational capabilities.
• Continued to leverage our HepNet™ computational platform, including network analytics, a hepatocyte- specific knowledge graph, and predictive short interfering RNA (siRNA) construct design capabilities to rapidly develop life-transforming RNAi therapies.
• Last near-term milestone successfully achieved in collaboration with iTeos Therapeutics in immuno-oncology, resulting in an additional payment to the Company and further validating its computational approach to identifying novel targets.

Intellectual property (IP)

• Sustained IP activity with priority patent applications filed on nine further inventions, and international patent applications filed for eight inventions arising from the
  Company's proprietary GalNAc-siRNA technology,
  GalOmic™.

People

• Continued investment in leading industry talent, including new hires on the East Coast of the USA, a major biotech hub.
• Effective 20 September 2023, Timothy Bretherton assumed the role of Chief Financial Officer (CFO, non-Board).

Post period highlights

• Successful fundraise of £28.9 million announced in April 2024 by way of a subscription by funds managed by M&G Investment Management Limited and Richard
  Griffiths, both existing shareholders of the Company.
• Completed cancellation of admission of our Ordinary Shares to trading on AIM as of 9 May 2024.
• Strengthened the Board of Directors with the appointment of Lord David Prior as Chair, as of 23 May 2024.

Financial highlights

Revenue								Average headcount
£0.3m	35
2024								2024
		£0.3m				35
2023			£0.5m	2023		38
2022								2022
		£0.5m		32
Year-end cash*	R&D spend
£20.7m	£10.2m
2024							2024
	£20.7m								£10.2m
2023			£31.7m	2023		£7.2m
2022						2022
	£26.4m				£6.1m
Operating loss	R&D tax credit receivable
£13.8m	£1.9m
2024						2024
		£13.8m				£1.9m
2023		£10.2m		2023		£1.5m
2022			2022
	£9.6m			£1.5m

* Year-end cash and short-term investment bank deposits.

e-therapeuticsplcAnnual Report 2024

01

Strategic report

AT A GLANCE

Better medicines faster

To materially increase the likelihood of successfully developing effective medicines it is essential to overcome some fundamental obstacles in drug development:

Biology		Druggability		Efficiency		Novelty
Limited understanding		Conventional modalities		The R&D process is slow		New target discovery
of human biology across		are often challenged by		and expensive with poor		remains rare, with
the biopharma industry		an inability to design		methods of de-risking		crowded competitive
		and develop a drug		therapeutic hypotheses		landscapes around the
		despite having		early		same established
		identified a potential				targets
		target

e-therapeutics has developed a powerful validated platform approach to help overcome these obstacles. By uniquely connecting the worlds of computation and RNA interference (RNAi) we can rapidly generate and prosecute previously undiscovered potential drug candidates in a reproducible and translatable way.

The medicines we create are focused on silencing genes expressed in hepatocytes (liver cells) which perform key functions in biological processes vital for human health and represent important targets for a broad range of diseases.

HepNetTM

Our hepatocyte-focused computational platform that enables identification of novel gene targets, improves drug design, and increases automation.

		GalOmicTM
Computational	RNAi platform	Our proprietary RNAi platform that
generates potent and safe GalNAc-
platform
	siRNA therapeutics to selectively
		silence novel disease-associated genes
		in hepatocytes.

Our GalOmic™ RNAi platform is underpinned by proprietary siRNA chemistry knowledge and intellectual property, enabling creation of potent and durable GalNAc-siRNA therapies. Our HepNet™ computational platform is formed of a vast hepatocyte-specific knowledgebase and advanced computational approaches that are implemented across the entire drug development process, from the identification of novel gene targets to the in silico design of GalOmic™ constructs. Together, GalOmic™ and HepNet™ allow us to rapidly discover and develop life-transforming medicines for patients.

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INVESTMENT CASE

Our investment case

Strategic report

1

Unique market position

Our highly differentiated market position combining computation and AI with the RNAi therapeutic modality enables us to consistently develop therapies at the fastest pace and lowest development cost currently available in the industry.

2

Well-established computational platform

We have extensive experience using computation to model complex biology. This specialist expertise and proprietary computational technology underpin HepNet™, our world- class hepatocyte-focused computational platform that drives every stage of our drug development process.

3

Expanding therapeutic pipeline

We have a growing in-house pipeline of compelling "first-on- target" GalOmic™ candidates across a wide range of disease areas with high unmet need. These assets are being rapidly progressed towards the clinic, with our most advanced assets currently progressing to IND-enabling studies.

4

Demonstrable speed of execution

Through the unique combination of computation and RNAi, we progress assets from target identification to beginning of preclinical proof-of-concept experiments in less than six months. This enables us to identify clinical candidates in under a year. We continually leverage cutting-edge developments in computation to further reduce

R&D timelines.

5

Single-cell focus advantage

Hepatocyte-targeted interventions offer the opportunity to address a large variety of diseases through access to thousands of gene targets, while avoiding side effects caused by systemic knockdown. This also allows us to focus on highly specific datasets and tools that promote superior computational depth and accuracy.

6

High barrier to entry

In addition to the need for proprietary computational methods, operating in the field of RNAi requires a high degree of technical, platform and IP know-how. We have deep expertise in the space across biology, chemistry, and IP.

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03

CHAIRMAN'S STATEMENT

A year of tangible advancement

This year was marked by significant scientific advancements and financial resilience, all of which underscore the Company's commitment to redefining the landscape of RNAi therapeutics through computational and AI-driven innovations.

Lord David Prior

Independent Non-Executive Chairman

I am delighted to present this statement on behalf of the Board of e-therapeutics (ETX). However, as I joined the Board very recently, I cannot take any credit for what follows.

This year was marked by significant scientific advancements and financial resilience, all of which underscore the Company's commitment to redefining the landscape of RNAi therapeutics through computational and AI-driven innovations.

Realising the potential of AI and RNAi

This year ETX announced its GalOmic™ therapeutic pipeline, the tangible product of its innovative approach to drug development. The Company is successfully prosecuting multiple GalOmic™ assets targeting novel

genes, distinguishing it from other RNAi therapeutics companies with vastly overlapping pipelines. Notably, ETX-407 and ETX-312 are now progressing to IND-enabling studies after demonstrating significant potential in addressing unmet needs in dry age-related macular degeneration (dry AMD) and metabolic dysfunction- associated steatohepatitis (MASH) respectively. This highlights ETX's commitment to strategic investment in the progression of specific assets towards the clinic, enabling higher value partnering opportunities. These achievements, alongside the successful completion of preclinical proof-of- concept studies in representative disease models for ETX-148 (for the treatment of haemophilia and bleeding disorders) and ETX-291 (for the treatment of cardiometabolic disease), mark critical milestones in the Company's quest to deliver transformative RNAi treatments to patients.

This impressive and rapid progression of assets is a direct result of ETX's unique combination of RNAi as a genetic medicine modality and the HepNet™ computational platform. Together, this creates a reproducible drug development engine that has thus far yielded an outstanding success rate. The Company continues to apply AI approaches at all stages of discovery and development, from novel target gene identification to siRNA sequence design, improving efficiency at every step.

The integration of large language models (LLMs) into HepNet™ will further accelerate the development of life-transforming RNAi medicines. The Company has spent the last year identifying the most impactful use cases for LLM agents whilst developing the necessary infrastructure and models. This period of development will enable a smooth transition into the implementation phase of the projects during the next year. Unlike other companies leveraging the recent developments in AI, ETX has a robust starting position in applying computation to biology and a huge breadth of proprietary hepatocyte-specific data. LLM technology may be widely available, but ETX has the expertise and data to enable effective, tailored, and meaningful application.

People and culture

During the past year ETX has strengthened the team with additional hires in the East Coast of the United States, creating a hub in the thriving biotech community in Boston. Across the Company, ETX continues to drive a dynamic environment that allows the team to pursue innovative ideas and take advantage of cutting-edge technology, as demonstrated by the ability to leverage the latest advancements in LLMs quickly once the technology had sufficiently matured. This has been further enhanced by the decision to return to the London office four days a week with US colleagues visiting regularly, allowing the team to collaborate and communicate with ease.

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Financial position

Financially, the Company has demonstrated remarkable resilience. Closing the year with a cash position of £20.7m is a testament to its prudent financial and operational management. In Q4, the Company achieved its final near-term success milestone from its collaboration with iTeos, further strengthening its financial position. This strong financial footing enables the Company to continue its ambitious research and development efforts, even in the face of challenging macroeconomic and sector conditions.

Post period

Following the conclusion of the 2023/24 financial year, ETX has continued to make significant strides. In April 2024, the Company announced a proposed raise of £28.9 million through a subscription by M&G Investment Management Limited and Richard Griffiths. The net proceeds will advance multiple GalOmic™ pipeline assets towards the clinic, initiate clinical trials for one program, and pursue further candidate compounds. This funding will also accelerate the integration of AI systems into HepNet™.

Additionally, the Company announced its decision to delist from the London Stock Exchange's Alternative Investment Market (AIM). This move was influenced by the lack of institutional UK interest during a recent raise roadshow and feedback indicating a preference for private or NASDAQ- listed companies. Transitioning away from AIM is expected to attract a broader and more receptive investor base, aligning with ETX's strategic goals.

Looking ahead

As we move into 2024, we do so with great confidence and a clear plan. The progress the Company has made positions us strongly to advance our assets towards the clinic, with the ultimate goal of delivering life-transforming therapies to patients. The Company's success is a collective achievement, made possible by the hard work and talent of its team, the trust of its partners, and the strong, long-term support of its shareholders. I would also like to take this opportunity to particularly thank Professor Trevor Jones for his enormous contribution. I look forward to continuing to work with him and the rest of the Board to help e-therapeutics achieve its strategic goals.

On behalf of the Board, I extend our deepest gratitude for your continued support. Together, we are entering a new phase in medicine, driven by the powerful combination of computation and RNAi. We look forward to sharing our journey with you in the year ahead and beyond.

Lord David Prior

Independent Non-Executive Chairman

5 June 2024

Strategic report

Q&A with David

1. What differentiates e-therapeutics from other
   AI-led biotech companies?

1. e-therapeuticsis the only company combining a dedicated in-house effort in advanced computation with siRNA, a well-tolerated and highly specific modality. This unique combination has enabled the Company to create something extremely rare - a reproducible drug development engine that leads to fast clinical candidate generation. In addition, e-therapeutics' extensive experience in computational biology means the Company is well positioned to leverage new developments in the space quickly, as exemplified by the ongoing integration of specialist LLM agents into the HepNet™ platform.

1. What do you think is limiting RNAi's potential to become the next big modality?

1. RNAi is a very attractive modality. siRNA-based medicines are safe, clinically validated and dosed infrequently by subcutaneous injection. However, many RNAi biotech companies have difficulty identifying novel targets with disease-modifying potential, resulting in a high degree of overlap between pipelines. This on-target competition and limited innovation, particularly in the GalNAc-siRNA space, give the appearance of limited potential. Through use of its HepNet™ computational platform, e-therapeutics proves that the modality enables access to a wide variety of opportunities, even when focused on a single cell type, hepatocytes.

1. How has e-therapeutics'in-house therapeutic pipeline developed over the last year?

1. After a period of focus, e-therapeutics has now publicly announced its therapeutic pipeline of five preclinical GalOmic™ assets. The pipeline spans a variety of therapeutic areas, from prevalent cardiometabolic disease to rare haematology, owing to the wide influence the liver has throughout the body. During the year e-therapeutics progressed four assets to the end of preclinical proof-of-concept and are advancing two of these programs to IND- enabling studies. ETX-258 has progressed from target nomination to drug design and will soon be entering disease models relevant to its undisclosed indication. In addition, the Company has a pool of further targets undergoing target- indication assessment that will keep its early pipeline populated. Together, this progress, which has been achieved by a lean team, demonstrates the Company's ability to develop GalOmic™ RNAi assets at pace, driven and supported by insights from HepNet™.

e-therapeuticsplcAnnual Report 2024

05

CHIEF EXECUTIVE OFFICER'S STATEMENT

A positive year

The potential of e-therapeutics as a biotech company that fully integrates the latest advances in computation and artificial intelligence is clear, ultimately leading to the development of life-transforming RNAi medicines for patients.

Ali Mortazavi

Chief Executive Officer

2023/24 has been an important year for e-therapeutics, marking the beginning of a period of effective execution in advancing our therapeutic pipeline. Over the past 12 months we have delivered solid pipeline progress, generating positive preclinical proof-of-concept data for four GalOmic™ RNAi assets. Data generated on our GalOmic™ assets have also further validated HepNet™'s ability to identify novel gene targets with disease-modifying potential and design potent, long-acting siRNA constructs in silico. Taken together, this demonstrates, with multiple case studies, the validity of our business model and confirms the robustness of our strategy since the pivot to the RNAi drug modality. The potential of e-therapeutics as a biotech company that fully integrates the latest advances in computation and artificial intelligence is clear, ultimately leading to the development of life-transforming RNAi medicines for patients.

Therapeutic pipeline

We have made exciting progress in advancing our pipeline of novel and highly differentiated RNAi therapies. The positive proof-of-concept data generated in the past year has confirmed our ability to develop RNAi therapies with disease-modifying potential across a broad range of therapeutic areas. We progressed our most recent programs from target nomination to completion of preclinical proof- of-concept within 12 months, an impressive improvement on the industry standard. Our current pipeline spans indications within cardiometabolic disease, haematology, and ophthalmology, showcasing the breadth of diseases that can be treated with hepatocyte-targeted therapies.

ETX-407 for the treatment of dry age-related macular degeneration (dry AMD) exemplifies our ability to impact diseases affecting organs beyond the liver. Dry AMD is a highly prevalent disease, affecting approximately 176 million people globally with 16% progressing to legal blindness within two years. Current treatments are highly invasive, administered weekly by intravitreal injection (directly into the eye). Preclinical data suggests that ETX-407 could be dosed quarterly by subcutaneous injection, providing a much lower burden option for the millions that suffer from dry AMD.

We also remain focused on the cardiometabolic space, through the development of ETX-312 for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) and ETX-291 for the treatment of cardiometabolic disease. MASH is an area that has seen significant activity over recent months in terms of clinical readouts and large business development transactions. There is now one treatment approved for the indication, but many patients that take it do not achieve clinically meaningful outcomes. In addition, current data suggests that there are still a significant number of patients that do not meet primary endpoints in clinical trials of emerging therapies. Preclinical data from an industry-leadingdiet-induced obesity (DIO) model of MASH showed that ETX-312 administration leads to an impressive reduction in hepatic steatosis and inflammation, the key drivers of MASH pathophysiology. To account for the role that combination treatments will likely play in the future

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treatment of MASH, ETX-312 was also assessed in combination with emerging treatments. This included a combination with GLP-1 receptor agonists which resulted in increased efficacy compared to either therapy alone. We consider these results to be extremely significant in the context of the approved and emerging MASH treatment landscape and we look forward to presenting further data in the near future. Should the preclinical data from ETX-312 translate to humans, this asset could become part of the future standard of care for patients with MASH.

During the year we also completed preclinical proof-of- concept packages for ETX-291 for the treatment of cardiometabolic disease and ETX-148 for the treatment of haemophilia. ETX-291 targets a gene with human genetic evidence of disease-modifying benefit. Cardiometabolic disease is driven by a multitude of different factors, meaning considerable cardiovascular risk remains when patients are treated with therapies affecting a single risk factor. The residual risk is often attributed to a complicated network of overlapping factors, highlighting the need for therapies with a pleiotropic effect. In preclinical studies in a representative disease model, ETX-291 impacted multiple cardiometabolic disease drivers, meaning it has the potential to treat a broad range of cardiometabolic indications.

ETX-148 is being developed as a safe and effective treatment for haemophilia A and B, and potentially other bleeding disorders. Despite there being several approved therapies in the space, recent studies have shown that significant unmet need remains, including high treatment burden and impact on quality of life. Histological data from a preclinical haemophilia joint bleed (haemarthrosis) model suggests ETX-148 can effectively protect against joint damage due to bleeding. Joint bleeds make up 70-80% of all bleeds in haemophilia. In addition, ETX-148 could be dosed quarterly by subcutaneous injection, offering a low burden treatment option. Extensive safety experiments have shown that prophylactic ETX-148 treatment is also compatible with emergency haemophilia treatments such as factor VIII, factor IX, and bypassing agents, without increasing thrombotic risk. The proof-of-concept data generated indicates that ETX-148 has the potential to be an effective pan-haemophilia therapy with low treatment burden and the option to safely take emergency treatments if needed, in line with our target product profile for this asset.

In our January business update we announced a crucial step forward as a company: our plan to progress two of our GalOmic™ assets into IND-enabling studies. We will be conducting these studies in a staggered fashion. ETX-312IND-enabling studies have now commenced and ETX-407 will follow in due course. This demonstrates our ongoing commitment to creating a balanced pipeline across several therapeutic areas, comprised of preclinical assets to partner early and assets that we will progress to early clinical trials to reach a more significant value inflection point, retaining more value. Non-dilutive funding opportunities via partnerships remain a key component of our strategy and data generated on our first few GalOmic™ RNAi programs is validating our platforms.

Strategic report

Q&A with Ali

1. Are you limited by only targeting genes in the liver?

1. No - we have 16,000 hepatocyte-expressed genes in our knowledgebase which could be targeted by our GalOmic™ RNAi therapies. Many genetic medicine competitors continue to target the same, obvious genes, but we can identify novel targets with disease-modifying potential, something that cannot be easily achieved with traditional drug discovery approaches. In addition, hepatocytes interact with a wide variety of cells and tissues across the body, allowing us to impact a wide variety of diseases beyond the liver, as exemplified by our haemophilia (ETX-148) and dry age-related macular degeneration (ETX-407) programs.

1. What is e-therapeutics' indication strategy?

1. We develop therapies for any disease that has high unmet medical need. Our pipeline includes therapies for both rare and prevalent indications across a wide variety of disease areas, demonstrating the versatility of our liver- targeting RNAi therapies. Before target-indication pairs enter our pipeline, we assess the current and emerging treatment landscape to ensure that there is sufficient unmet need that could be addressed with a GalOmic™ RNAi asset. This means we always aim for our medicines to be life transforming, whilst also de-risking our investment in the development process.

1. How do your computational approaches improve the drug development process?

1. Our HepNet™ computational platform enables us to make better medicines faster through generation of novel insights and increased automation across all stages of drug development, from the identification of novel targets to in silico design of preclinical siRNA constructs. This has resulted in tangible improvements on the traditional drug discovery process. For example, we have been able to significantly reduce costs associated with development by minimising the number of sequences requiring in vitro screening through use of our AI siRNA design and efficacy prediction model.

e-therapeuticsplcAnnual Report 2024

07

CHIEF EXECUTIVE OFFICER'S STATEMENT CONTINUED

Therapeutic pipeline continued

Our earlier pipeline opportunities include ETX-258, which is progressing in an undisclosed indication and we hope to reveal further details about this program within the next year. In addition, we have multiple novel gene targets currently under evaluation, providing a constant supply of pipeline program opportunities that can be pursued.

HepNet™: expanding our knowledgebase and integration of LLMs

Our therapeutic pipeline is underpinned by our HepNet™ computational platform, which we continually innovate on, iterate, and improve. HepNet™ can be divided into four core layered capabilities which access the extensive proprietary and public data foundation within the platform: network analytics, a hepatocyte-specific knowledge graph, AI-driven siRNA design, and a recently developed hepatocyte-specific LLM agent ecosystem.

Through application of our network analytics to our world- class hepatocyte knowledgebase and leveraging our knowledge graph, we have been able to identify novel, disease-modifying gene targets with an impressive success rate. All nominated pipeline targets investigated to date have yielded positive results in preclinical studies, which we attribute to the successful combination of artificial intelligence and our proprietary RNAi drug platform.

Our network approach to target identification allows us to account for the true complexity of disease biology, meaning we can nominate target-indication pairs with confidence.

We also continually expand HepNet™'s foundational data, as exemplified by our collaboration with Arcturis Data to integrate Arcturis' Real-World Evidence (RWE) within HepNet™. Arcturis' RWE utilises a platform comprised of high quality, clinically rich real-world data and analytical expertise derived from its unique access to anonymised patient data. This data will give us further unique insights into the biological mechanisms driving metabolic dysfunction and associated fatty liver disease that we can target to deliver effective RNAi medicines to patients.

In last year's Annual Report, I announced our intention to leverage the recent advances in LLMs and integrate them within HepNet™. A key focus of the past year has been identifying use cases for which we can develop LLM agents to significantly improve laborious processes or materially enhance our pre-existing computational approaches. This has led to the initiation of a variety of projects, including the enhancement of our AI siRNA design and efficacy prediction model. This model is already capable of designing and predicting the most potent and long-acting GalOmic™ siRNA sequences in silico, significantly reducing the number of siRNA sequences screened in vitro and reducing cost of development.

KPIs

PipelineTechnology

5	14m
GalOmic™ RNAi programs currently in	hepatocyte-specific data points
preclinical development
4	20,000
GalOmic™ assets with preclinical	coding and non-coding genes
proof-of-concept data	in knowledgebase
2	3,000
programs progressing to	hepatocyte-associated diseases
in knowledgebase
IND-enabling studies in house
Multiple	Outperformance
target-indication pairs in viable target pool	of proprietary network algorithms against
	industry standards
1000s	Millions
of accessible target genes in multiple disease areas	of hypotheses identified and tested in silico

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