On October 17, 2021 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, metabolic, autoimmune and other major diseases, reported that the sintilimab ORIENT-31 study has met its prespecified primary endpoint of progression-free survival (PFS) at the first interim analysis (Press release, Innovent Biologics, OCT 17, 2021, View Source [SID1234591407]).

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Globally, ORIENT-31 is the first prospective, double-blind, multi-center, Phase 3 study that has demonstrated significant PFS improvement of anti-PD-1 and anti-VEGF antibody combination therapy (i.e., sintilimab plus BYVASDA [bevacizumab biosimilar injection] combined with chemotherapy [pemetrexed and cisplatin]) in patients with epidermal growth factor receptor (EGFR)-mutated nonsquamous non-small cell lung cancer (nsqNSCLC) that has progressed after treatment with an EGFR tyrosine kinase inhibitor (TKI).

In the first interim analysis reviewed by the Independent Data Monitoring Committee (IDMC), in the intent-to-treat (ITT) population, based on assessment by the Blinded Independent Radiographic Review Committee (BIRRC), sintilimab in combination with BYVASDA (bevacizumab biosimilar injection) and chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy. Sintilimab in combination with chemotherapy also showed a trend of PFS benefit compared to chemotherapy alone (data is not yet mature). Additionally, the prespecified PFS futility analysis that compares sintilimab in combination with BYVASDA (bevacizumab biosimilar injection) and chemotherapy to sintilimab in combination with chemotherapy did not cross futility stopping boundary. A numerical benefit of adding BYVASDA (bevacizumab biosimilar injection) to sintilimab and chemotherapy combination can be observed. The safety profile of this study was consistent with that observed in previously reported studies of sintilimab and BYVASDA (bevacizumab biosimilar injection), with no additional safety signals. The detailed results of ORIENT-31 will be presented at an upcoming medical meeting.

The principal investigator of the ORIENT-31, Prof. Shun Lu from the Oncology Department of Shanghai Chest Hospital, stated, "For patients with EGFR-mutated advanced nsqNSCLC who have progressed following EGFR-TKI treatment, platinum-based chemotherapy is the current standard of care, but with limited benefit. New treatments are clearly imperative. ORIENT-31 is the first prospective, double-blind Phase 3 study worldwide to demonstrate significant PFS benefit with an anti-PD-1 antibody combination therapy in this patient population. It has shown the clinical value of adding sintilimab plus BYVASDA (bevacizumab biosimilar injection) to platinum chemotherapy. This quadruple regimen has the potential to bring forth a new and more effective treatment option to patients with EGFR-mutated nsqNSCLC following treatment with an EGFR TKI."

Dr. Hui Zhou, Senior Vice President of Innovent, stated, "Lung cancer has the highest mortality rate among all tumor types both in China and worldwide. In China, EGFR-mutated NSCLC accounts for 40% to 50% of nonsquamous NSCLC, and the treatment options for these patients after treatment with first, second and third generation EGFR-TKIs are very limited, representing a large unmet medical need. Through the joint efforts of investigators, ORIENT-31 achieved these encouraging research results. We are grateful for all the contributions made by the investigators and patients in this study – together we accomplished this important milestone."

About Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death worldwide, and the second most commonly diagnosed tumor type. Non-small cell lung cancer (NSCLC) accounts for about 80% to 85% of all lung cancer, in which about 70% of NSCLC patients present with locally advanced or metastatic disease that is not suitable for surgical resection at diagnosis. In China, nsqNSCLC accounts for 70% of NSCLC, in which about 40% to 50% of nsqNSCLC patients have an EGFR mutation. The standard first-line treatment for patients with advanced EGFR-mutated NSCLC is a third generation EGFR TKI, or first or second generation EGFR TKI. For patients who have progressed following EGFR-TKI treatment, platinum-based chemotherapy is still the standard therapy with limited benefit, representing a large unmet medical need.

About the ORIENT-31 Study

ORIENT-31 is a randomized, double-blind, multicenter Phase 3 clinical study evaluating sintilimab, with or without BYVASDA (bevacizumab biosimilar injection), combined with chemotherapy (pemetrexed and cisplatin) in patients with EGFR-mutated locally advanced or metastatic non-squamous NSCLC who have progressed following EGFR TKI treatment (ClinicalTrials.gov, NCT003802240). The primary endpoint is PFS as assessed by BIRRC based on RECIST v1.1. The secondary endpoints include overall survival (OS), PFS as assessed by investigators, objective response rate (ORR) and safety.

Eligible patients included: patients with disease progression following first or second generation EGFR TKI and confirmed as T790M negative, or T790M positive but further progressed on third generation EGFR-TKI treatment, or patients with disease progression following third generation EGFR-TKI as first line treatment.

Patients were randomized in a 1:1:1 ratio to receive sintilimab plus BYVASDA (bevacizumab biosimilar injection) combined with pemetrexed and cisplatin, sintilimab plus placebo 2 combined with pemetrexed and cisplatin, or placebo 1 plus placebo 2 combined with pemetrexed and cisplatin. After 4 cycles of combination treatment, patients will receive maintenance treatment of sintilimab plus BYVASDA and pemetrexed, sintilimab plus placebo 2 and pemetrexed, placebo 1 plus placebo 2 and pemetrexed, until radiographic disease progression, unacceptable toxicity or any other conditions that required treatment discontinuation. Target accrual is 480 patients.

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Eli Lilly and Company. Sintilimab is an immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies of sintilimab worldwide, to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved for four indications, including:

The treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of nonsquamous non-small cell lung cancer
In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer
In combination with BYVASDA (bevacizumab biosimilar injection) for the first-line treatment of hepatocellular carcinoma
Additionally, Innovent currently has one regulatory submission under review in China for sintilimab, for the first line treatment of esophageal squamous cell carcinoma.

Additionally, four clinical studies of sintilimab have met their primary endpoints:

Phase 3 study in combination with oxaliplatin and capecitabine for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma.
Phase 2 study as second-line treatment of esophageal squamous cell carcinoma
Phase 3 study as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy
Phase 3 study in combination with BYVASDA (bevacizumab biosimilar injection) and chemotherapy (pemetrexed and cisplatin) for EGFR-mutated nonsquamous NSCLC following EGFR-TKI treatment.
In May 2021, the U.S. FDA accepted for review the Biologics License Application (BLA) for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous non-small cell lung cancer.

Sintilimab was included in China’s National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

About BYVASDA (bevacizumab biosimilar injection)

BYVASDA, also known as IBI305, is a bevacizumab biosimilar and a recombinant humanized anti-VEGF monoclonal antibody drug. Vascular endothelial growth factor (VEGF) is an important factor in angiogenesis that is highly expressed by the endothelial cells in most human tumors. An anti-VEGF antibody binds VEGF-A selectively with high affinity and blocks its binding to VEGF-2 receptors on the surface of vascular endothelial cells, thereby inhibiting signaling pathways such as PI3K-Akt/PKB and Ras-Raf-MEK-ERK. BYVASDA produces anti-tumor effects by inhibiting the growth, proliferation and migration of vascular endothelial cells, blocking angiogenesis, reducing vascular permeability, blocking blood supply to tumor tissues, inhibiting the proliferation and metastasis of tumor cells and inducing apoptosis in tumor cells. Since its launch, bevacizumab has been approved for the treatment of patients with multiple malignant tumors globally, including non-small cell lung cancer, metastatic colorectal cancer, glioblastoma, renal cell carcinoma, cervical cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer. The efficacy and safety of bevacizumab in these tumor types have been well recognized worldwide.

In China, BYVASDA (bevacizumab biosimilar injection) is approved for indications including advanced non-small cell lung cancer, metastatic colorectal cancer, adult recurrent glioblastoma, and advanced or unresectable hepatocellular carcinoma.

On October 16, 2021 Tyligand Bioscience, a clinical-stage biotechnology company developing innovative small-molecule therapeutics against drug resistant cancers, reported that the U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application for its novel drug TSN084 for treating solid tumors (Press release, Tyligand Bioscience, OCT 16, 2021, View Source [SID1234644990]). TSN084 is a first-in-class multi-kinase inhibitor targeting CDK8/19 and several other kinases implicated in tumorigenesis and immune evasions. The clinical study is about to start at M.D Anderson Cancer Center in the US soon.

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Dr. Tony Zhang, cofounder and CEO of Tyligand Bioscience, commented, "TSN084 is the front runner of the Tyligand pipeline of molecules designed to treat tumors that become resistant to targeted therapies. We hope the potent activities demonstrated by TSN084 against a unique combination of kinase targets responsible for several major cancer hallmarks in preclinical studies can be translated into clinical outcomes for patients suffering NSCLC and TNBC. FDA’s clearance has moved us one step closer towards achieving that goal！"

On October 15, 2021 Pepper Bio, the world’s first transomics drug discovery company, reported the company emerges from stealth to leverage its proprietary transomics — including phosphoproteomics — data translation technology to discover new drugs, rediscover new uses for existing therapeutics, and rescue drugs that may be on a course toward failing (Press release, Pepper Bio, OCT 15, 2021, View Source [SID1234638709]).

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Drug discovery is often a bad bet for pharma. Pepper Bio significantly reduces that risk.
Currently, the successful development of a new therapy is estimated to cost around $2.6 billion on average and last over a decade through a variety of failed and successful trials. Because of the high cost and risks involved, many diseases will go untreated because of their low expected return on investment in drugs that may work. With hundreds of thousands of therapeutics candidates being evaluated each year, 86 percent of clinical trials of drug candidates fail to earn FDA approval, according to a new study from the MIT Sloan School of Management. More than 30 percent of drugs entering Phase II clinical trials fail to progress, and 58 percent of drugs fail in Phase III. These end-stage studies commonly cost upward of hundreds of millions of dollars for manufacturing, clinical trial design, implementation, and data analysis.

"From my experience as a drug development strategist, many therapeutic programs were killed simply because they would have cost too much with an inadequate return on investment," said Jon Hu, co-founder and CEO, Pepper Bio. "These are very difficult decisions because they are made with the understanding that many people who may benefit from these potential new drugs would never have that opportunity. We founded Pepper Bio in order to significantly improve the volume, quality, and accuracy of the data analysis used to evaluate opportunities for novel new therapeutics. We empower our drug discovery partners with a much higher level of informed confidence. Ultimately, our work will result in many more drug development initiatives going forward to help people around the world struggling with diseases that are left untreated today."

A first in drug discovery, Pepper Bio and their partners make significantly more informed strategic decisions by relying on more accurately analyzed data. This allows them to develop therapeutics that treat diseases at their root cause, have less toxicity and higher response rates with patients exhibiting fewer symptoms. Already, Pepper Bio has demonstrated proof of concept of the company’s proprietary platform across three therapeutic areas: Neurodegenerative, Oncology, and Inflammatory.

Pepper Bio’s proprietary capability to translate multiple levels of complex transomic data unlocks a new level of sophistication in drug discovery, much like Waze leverages multiple layers of data to direct travelers on the optimal and safe road to their destination. Pepper Bio identifies how and why novel drug candidates may or may not be effective in specific patient populations and diseases, directing drug discovery initiatives toward the most promising disease targets and patients who will be helped most with reduced side effects.

The success of Pepper Bio is rooted in the company’s proprietary capacity to access and analyze transomic data leveraging three pillars of the field: Global (1), comprehensive data from the entire biological system are analyzed to determine functional (2) characteristics of intercellular biologic activity. Multiple omic layers, including phosphoproteomics, the layer at the top of the biotech stack, are analyzed. By analyzing all layers combined, Pepper Bio empowers drug developers to identify and reach accurate, much more informed causal (3) inferences.

"Pepper Bio is working to ensure that the right therapeutics and combinations of drugs are developed in a precise, effective, efficient, and safe manner. Our proprietary capacity to translate complex transomic data into meaningful, evidence-based guidance for drug discovery programs significantly improves the likelihood of success for clinical trials. This promises to conserve many millions of dollars that may otherwise be funneled into traditional methods of research and development," said Samantha Dale Strasser, Ph.D., Co-Founder and Chief Scientific Officer, Pepper Bio.

The industry moving towards transomics is inevitable and Pepper Bio is leading the way." said Omri Amirav Drory, General Partner at NFX, an investor in Pepper Bio. NFX was an early backer of biotech companies such as Mammoth Biosciences and c2i genomics.

CEO Jon Hu is experienced in pharmaceutical research and development (Shire Pharmaceuticals), corporate strategic consulting (Bain & Company), and venture capital (Guild Capital). Hu earned his Bachelor’s degrees in biomedical engineering and economics, and earned his MBA from Harvard Business School. CSO Samantha Dale Strasser, Ph.D., developed the foundation of Peppe Bio’s technology during her time as a National Science Foundation Graduate Research Fellow at the Massachusetts Institute of Technology, where she earned her Doctorate in Electrical Engineering and Computer Science. She earned her Master’s Degree in M.Phil in Physics at the University of Cambridge as a Churchill Scholar and her Bachelor’s degrees in Biomedical Engineering and Applied Mathematics from Northwestern University.

Mr. Hu and Dr. Strasser are joined by Christopher Nicholson, Ph.D., Head of Biology, and Caitlin Brown, Ph.D., Head of Business Development. Dr. Nicholson earned his doctorate from Newcastle University and was a Senior Research Fellow at Harvard Medical School and MGH. Dr. Brown earned her doctorate from Brown University.

Pepper Bio announced its scientific and strategic advisory board members today: Douglas Lauffenberger, Ph.D., Professor, MIT; Founder, Biological Engineering, MIT.; Dean Felsher, MD, Ph.D., Professor, Oncology, Stanford; Director, Translational Research, Stanford. Imran Nasrullah, JD, VP & Head, Open Innovation Center, North America – East, Bayer; Former Director, Strategic Partnering & Business Development & Licensing, Boehringer-Ingelheim. Tom Rush, Ph.D., Chief R&D Officer, Variant Bio; Former US Lead, Functional Genomics, GlaxoSmithKline. Jerome Windsor, PharmD, SVP, Corporate Development & Product Strategy, GNS Healthcare; Former VP, Strategy & Business Development, Median Technologies. Peter Hornbeck, Ph.D., Director, Cell Signaling Technology; Founder, PhosphoSitePlus.

On October 15, 2021 Hervolution Therapeutics reported that Hervolution is one of just 65 European companies to receive funding through the European Innovation Council Accelerator of 2.5M EUR (Press release, Hervolution Therapeutics, OCT 15, 2021, View Source [SID1234637208]).

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On October 15, 2021 Silence Therapeutics plc, AIM:SLN and Nasdaq:SLN ("Silence" or "the Company"), a leader in the discovery, development and delivery of novel short interfering ribonucleic acid (siRNA) therapeutics for the treatment of diseases with significant unmet medical need, reported the Company’s intention to cancel the admission of its ordinary shares of nominal value £0.05 each (the "Ordinary Shares") to trading on AIM (the "AIM Delisting"), subject to shareholder approval, with effect from 30 November 2021 (Press release, Silence Therapeutics, OCT 15, 2021, View Source [SID1234591430]). Subject to shareholder approval, the Company’s last day of trading on AIM will be 29 November 2021. Silence will retain the listing on the Nasdaq Global Market ("Nasdaq") of American Depositary Shares, each representing three Ordinary Shares (the "ADSs"), under ticker symbol "SLN". The Company expects Nasdaq to become the primary trading venue for its equity securities. Existing holders of ADSs not also holding Ordinary Shares do not need to take any action in relation to the AIM Delisting; and

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the posting of a circular to shareholders (the "Circular") which contains further information on the AIM Delisting and the process to deposit Ordinary Shares for delivery of ADSs and notice of a general meeting to be held on 1 November 2021 at 72 Hammersmith Road, London W14 8TH at 2.00 p.m. (London time) (the "General Meeting") at which shareholder approval will be sought, inter alia, for the AIM Delisting

The Proposed AIM Delisting and the General Meeting

Highlights

Following the AIM Delisting, the Company’s ADSs will remain listed on Nasdaq, which will become the primary trading venue for its equity securities, and securities in the Company will only be publicly tradeable in the form of Nasdaq-listed ADSs.

The board of directors of the Company (the "Board" and the "Directors") believes that the AIM Delisting should enhance the liquidity of trading in the Company’s ADSs as all such trading will be concentrated in a single venue.

The Company is providing an opportunity for shareholders to deposit their Ordinary Shares with the Company’s ADS depositary in exchange for delivery of ADSs, without cost, in connection with the AIM Delisting whether prior, on, or subsequent to 30 November 2021 (being the date on which the AIM Delisting takes effect), except that the Depositary has not agreed to waive that fee with respect to more than 81,831,467 Ordinary Shares, which is the number of Ordinary Shares that were in issue but not represented by ADSs on 15 October 2021 and has not agreed to waive fees on any deposit made by the Company.

Mark Rothera, President and Chief Executive Officer of Silence Therapeutics, said: "This marks a very important step in the evolution of our company and positions Silence as a global RNAi leader. With our mRNAi GOLD platform advancing in the clinic, we see substantial opportunity to build value over the next 12 months and longer term. We are grateful to have the continued support of our loyal shareholders and look forward to this exciting new chapter of growth."

Craig Tooman, Chief Financial Officer of Silence Therapeutics, said: "A key priority for us has been to create a more attractive and efficient trading mechanism for our shareholders and to support increasing interest from new investors. We believe the move to trade exclusively on the Nasdaq – a top global exchange – accomplishes that objective. This is an exciting time for Silence and we look forward to continuing to expand our global shareholder base."

The Company will today be posting the Circular to shareholders which will set out further information on the process to deposit Ordinary Shares for delivery of ADSs, including personalised forms for those holders of certificated Ordinary Shares who wish to deposit their Ordinary Shares for delivery of ADSs, as well as containing the notice of General Meeting. Copies will also be available on Silence’s website at www.silence-therapeutics.com.

Background to the AIM Delisting

The Company was incorporated in 1994 and its Ordinary Shares have been admitted to trading on AIM since 1995. In September 2020, the Company undertook a direct listing of ADSs representing its Ordinary Shares on the Nasdaq Capital Market. In February 2021, the Company announced an oversubscribed private placement of ADSs for gross proceeds of approximately $45 million. In June 2021, the Company moved its Nasdaq listing from the Nasdaq Capital Market tier to the Nasdaq Global Market tier.

As at 13 October 2021, being the last practicable date prior to the date of this announcement, approximately 8.9 per cent. of the Company’s Ordinary Shares are represented by ADSs tradeable on Nasdaq. All shareholders who have not already deposited their Ordinary Shares for delivery of ADSs are currently able to do so at any time. Affiliates of the Company who deposit their ordinary shares may be subject to limitations on resale of ADSs under U.S. securities law. The Company intends to convert an existing secondary resale shelf registration statement on Form F-1 to a short-form registration statement on Form F-3, which will, upon effectiveness, continue to grant such affiliates the ability to freely resell such restricted securities without restriction.

The AIM Rules for Companies published by London Stock Exchange plc (the "London Stock Exchange") (the "AIM Rules for Companies") require that, unless the London Stock Exchange otherwise agrees, the cancellation of a company’s shares from trading on AIM requires the consent of not less than 75 per cent. of votes cast by its shareholders given in a general meeting. Notwithstanding that the Company may be able to seek the agreement of the London Stock Exchange that shareholder consent in general meeting is not required due to the listing of ADSs on Nasdaq, the Board has determined to seek shareholder approval for the proposed AIM Delisting.

Reasons for the AIM Delisting

The Board has decided to implement the AIM Delisting for the following reasons:

The AIM Delisting is expected to further enhance the liquidity of trading in the Company’s securities by combining on Nasdaq the volume of transactions from both Nasdaq and AIM.

Having securities solely listed on Nasdaq, rather than dual-listed on Nasdaq and AIM as is the case at present, is expected to increase the willingness of US-based investors to invest in the Company’s securities.

A Nasdaq-only listing structure provides for a streamlined operation that showcases the global nature of the Company’s scope and places it more clearly within the ranks of international biotechnology companies that are its true peers.

The cost of complying with the AIM Rules for Companies is incremental to that for complying with the Nasdaq market rules and the Company sees advantages in reducing its cost base as it progresses its clinical programmes and commercial strategy.

Internal financial and legal staff time spent on compliance with the AIM Rules for Companies is incremental to that required for compliance with the Nasdaq market rules.

ADSs representing the Company’s Ordinary Shares will remain tradeable on Nasdaq.

Accordingly, the Directors believe that it is no longer in the best interests of the Company or its shareholders as a whole for the Company to retain admission of its Ordinary Shares to trading on AIM. However, the Company is providing an opportunity for shareholders to deposit their Ordinary Shares with the Company’s ADS depositary in exchange for delivery of ADSs, without cost, in connection with the AIM Delisting whether prior, on, or subsequent to 30 November 2021 (being the date on which the AIM Delisting takes effect), except that the Depositary has not agreed to waive that fee with respect to more than 81,831,467 Ordinary Shares, which is the number of Ordinary Shares that were in issue but not represented by ADSs on 15 October 2021 and has not agreed to waive fees on any deposit made by the Company.

Effect of the AIM Delisting

If the resolutions are passed at the General Meeting, Shareholders will no longer be able to buy and sell Ordinary Shares on AIM after 29 November 2021. Holders of Ordinary Shares should read "Information for holders of Ordinary Shares" below which explains in more detail the process of depositing Ordinary Shares for delivery of ADSs.

As a company incorporated in England and Wales, the Company will continue to be subject to the requirements of the Companies Act 2006.

Following the AIM Delisting taking effect, the Company will no longer be subject to the AIM Rules for Companies or be required to retain the services of an independent nominated adviser. The Company will also no longer be subject to the QCA Corporate Governance Code or be required to comply with the continuing obligations set out in the Disclosure Guidance and Transparency Rules (the "DTRs") of the Financial Conduct Authority (the "FCA") or, provided the Company’s securities remain outside the scope of the regulation, UK MAR. In addition, the Company and its shareholders will no longer be subject to the provisions of the DTRs relating to the disclosure of changes in significant shareholdings in the Company. The Company intends to continue to comply with all regulatory requirements for the Nasdaq listing of ADSs, including all applicable rules and regulations of the SEC.

Shareholders who continue to hold Ordinary Shares following the AIM Delisting will continue to be notified of the availability of key documents on the Company’s website, including publication of annual reports and annual general meeting documentation. Holders of ADSs will be able to continue to access all such information via the Silence website. Holders of Ordinary Shares and ADSs will remain entitled to receive any future dividends that may be declared thereon, which dividends will also accrue to ADS holders in accordance with the terms of the Deposit Agreement.

Application of the City Code following the AIM Delisting

Following the AIM Delisting, as the Company will remain a public limited company incorporated in England and Wales but its securities will not be admitted to trading on a regulated market or multilateral trading facility in the United Kingdom (or a stock exchange in the Channel Islands or the Isle of Man), the City Code on Takeovers and Mergers (the "City Code") will only apply to the Company if it is considered by the Panel on Takeovers and Mergers (the "Panel") to have its place of central management and control in the United Kingdom (or the Channel Islands or the Isle of Man). This is known as the "residency test". The way in which the test for central management and control is applied for the purposes of the City Code may be different from the way in which it is applied by the United Kingdom tax authorities, Her Majesty’s Revenue & Customs ("HMRC"). Under the City Code, the Panel looks to where the majority of the directors of the Company are resident, amongst other factors, for the purposes of determining where the Company has its place of central management and control.

The Panel has confirmed to the Company that following the AIM Delisting, based on the current composition of the Board, the City Code will continue to apply to the Company. However, the City Code could cease to apply to the Company in the future if any changes to the Board composition result in the majority of the Directors not being resident in the United Kingdom, Channel Islands and Isle of Man.

Further details of the Panel, the City Code and the protections given by the City Code are set out in the Circular. Shareholders are encouraged to read this information carefully as it outlines certain important protections which they will be giving up if they agree to the AIM Delisting and the Company subsequently ceases to be subject to the City Code.

The Board is seeking shareholder approval to an amendment to the Company’s articles of association (the "Articles") which would apply in the event that the City Code ceased to apply to the Company. This amendment would insert a new article 159 into the Articles which would apply in the event that the City Code were no longer to apply to the Company. Article 159 includes certain takeover protections so that the Company is able to defend itself and its shareholders from hostile takeovers. An ordinary resolution will be put to shareholders at each annual general meeting, starting with the annual general meeting in 2022, as to whether article 159 should continue to apply for the period until the next following annual general meeting. The full text of article 159 is set out in Appendix B to the Circular.

Information for holders of Ordinary Shares

If the resolutions are passed at the General Meeting, the Company’s Ordinary Shares will continue to be traded on AIM until market close (4.30 p.m. London time) on 29 November 2021. Thereafter, holders of Ordinary Shares can still hold the Ordinary Shares, but there will be no public market in the United Kingdom on which the Ordinary Shares can be traded, and the Ordinary Shares will not be tradeable on Nasdaq in this form.

To sell Ordinary Shares on a public market following the AIM Delisting, shareholders will need to deposit their Ordinary Shares for delivery of ADSs. Each ADS represents three Ordinary Shares. This deposit can be made at any time, including before the AIM Delisting, subject in all cases to the provisions of, and the limitations set forth in, the New York law governed deposit agreement dated 4 September 2020 between the Company, the Bank of New York Mellon (the "Depositary") and all holders and beneficial owners of ADSs issued thereunder (the "Deposit Agreement").

The Board considers that shareholders should consider depositing their Ordinary Shares for delivery of ADSs prior to the AIM Delisting on 30 November 2021 for the following reasons:

For those shareholders who hold their Ordinary Shares in certificated form and wish to deposit their Ordinary Shares for delivery of ADSs, the Company’s Receiving Agent, Link Group, will facilitate, on the Company’s behalf, a block transfer process. Shareholders who hold their Ordinary Shares in certificated form will find enclosed with the Circular a personalised block transfer participation request form for use if they wish to deposit their Ordinary Shares for delivery of ADSs. Subject to the requisite documents being returned to Link Group by the required deadline (being 1.00 p.m. on 3 November 2021), Link Group will arrange for the relevant Ordinary Shares to be transferred to and through Link Group’s CREST account to the CREST account of the Custodian, which has been appointed by the Depositary, The Bank of New York Mellon, to safe keep the Ordinary Shares upon deposit, so that the Depositary can arrange to deliver the corresponding number of ADSs. The Custodian, on behalf of the Depositary, will hold all deposited Ordinary Shares in a custody account for the benefit of the holders and beneficial owners of ADSs.

Shareholders who elect to deposit their Ordinary Shares for delivery of ADSs prior to the AIM Delisting will not incur a UK stamp duty, or SDRT, charge. However, it is expected that shareholders who elect to deposit their Ordinary Shares for delivery of ADSs following the AIM Delisting will incur a stamp duty, or SDRT, charge, at a rate of 1.5 per cent. of the market value of the Ordinary Shares being deposited, to the UK taxation authority, HMRC.

Ordinarily, shareholders who deposit their Ordinary Shares for delivery of ADSs are charged an ADS issuance fee, by the Depositary, of up to $5.00 per 100 ADSs or portion thereof. However, no ADS issuance fees will be charged to shareholders who elect to deposit their Ordinary Shares in connection with the AIM Delisting whether prior, on, or subsequent to 30 November 2021 (being the date on which the AIM Delisting takes effect), except that the Depositary has not agreed to waive that fee with respect to more than 81,831,467 Ordinary Shares, which is the number of Ordinary Shares that were in issue but not represented by ADSs on 15 October 2021 and has not agreed to waive fees on any deposit made by the Company.

Otherwise than in connection with the AIM Delisting, ADS issuance fees of up to $5.00 per 100 ADSs or portion thereof will be charged by the Depositary in connection with any future deposits of Ordinary Shares.

Ordinary Shares may be deposited for delivery of ADSs only in multiples of three Ordinary Shares. It is not possible to receive a fraction of an ADS, so in the event that the deposit is completed after the AIM Delisting, there is a risk that shareholders will be left with a small number of Ordinary Shares (up to a maximum of two shares) which cannot be deposited for delivery of ADSs. If the deposit is made before the AIM Delisting has taken effect, any residual Ordinary Shares can be sold by shareholders on AIM prior to, and including, 29 November 2021 so long as those Ordinary Shares are in uncertificated form. Shareholders who hold their Ordinary Shares in certificated form may elect to donate their residual shares to the charity Share Gift by making that election on their personalised block transfer participation request form.

Shareholders who do not elect to participate in the block transfer process can utilise the services of a broker who is able to facilitate deposits of Ordinary Shares at the shareholder’s convenience.

Shareholders whose Ordinary Shares are held in uncertificated form in CREST and who wish to deposit their Ordinary Shares for delivery of ADSs, should contact their broker without delay to request that their Ordinary Shares are deposited.

Silence advises holders of Ordinary Shares to seek independent financial advice regarding the AIM Delisting and the deposit of their Ordinary Shares for delivery ADSs.

Information on the process to deposit Ordinary Shares for delivery of ADSs and the forms to be completed accompany the Circular. The information and forms, and contacts at the Company’s Receiving Agent, Link Group, in respect of completion of the block transfer participation request form for certificated holders, and the Depositary, The Bank of New York Mellon, are included on Silence’s website at www.silence-therapeutics.com.

If the Resolutions are not passed at the General Meeting, all documents provided to Link Group and/or The Bank of New York Mellon in relation to the deposit of Ordinary Shares for delivery of ADSs shall be of no effect and all original share certificates will be returned to shareholders by Link Group.

UK tax treatment

Many investors purchase AIM-quoted shares because they are classed as unlisted/unquoted securities which may qualify individuals who are UK tax resident and UK domiciled for relief from inheritance taxation and certain other preferential tax benefits. Silence cannot and does not provide any form of taxation advice to shareholders and therefore shareholders are strongly advised to seek their own taxation advice to confirm the consequences of continuing to hold unlisted Ordinary Shares or depositing Ordinary Shares for delivery of ADSs.

The following summary does not constitute legal or tax advice and is not exhaustive. The Company’s understanding of the current position for UK individuals who are UK domiciled for relevant tax purposes is as follows but it should be noted that the position on certain points is not free from uncertainty and that the Company has not taken steps to confirm the current position with HMRC. Therefore, the following should not be relied upon by shareholders without taking further advice (and the Company accepts no liability in respect of any such reliance on any information provided herein on taxation matters):

The AIM Delisting should not prevent the Ordinary Shares from qualifying as unlisted/unquoted securities for the purposes of certain specific UK tax rules (notably, the UK inheritance tax business property relief rules). Accordingly, it is expected that HMRC should accept that those shareholders who elect to continue to hold unlisted Ordinary Shares should continue to be regarded as holding unlisted/unquoted securities under those same rules.

Under HMRC’s stated practice those shareholders who elect to deposit their holdings of Ordinary Shares for delivery of Nasdaq-listed ADSs should not be considered as disposing of the Ordinary Shares for UK capital gains tax purposes when transferring the shares to the Depositary, The Bank of New York Mellon, in exchange for issue of ADSs on the basis that the shareholder retains beneficial ownership of the Ordinary Shares.

Shareholders who elect to deposit their holdings of Ordinary Shares for delivery of Nasdaq-listed ADSs prior to the AIM Delisting should not incur a stamp duty, or SDRT, charge. It is expected that shareholders who elect to deposit their holdings of Ordinary Shares for delivery of Nasdaq-listed ADSs following the AIM Delisting may incur a stamp duty, or SDRT, charge at the rate of 1.5 per cent. of the market value of the Ordinary Shares being deposited.

It is strongly recommended that shareholders obtain appropriate professional advice in respect of these and other taxes.

Further information in relation to the AIM Delisting

The Board believes that the proposed AIM Delisting is an appropriate next step for the Company and is in the best interests of shareholders as a whole. Further information about the process required to deposit Ordinary Shares for delivery of ADSs tradeable on Nasdaq, together with a set of Frequently Asked Questions, accompany the Circular.

Details of the General Meeting and action to be taken in respect of the General Meeting

A notice convening the General Meeting, which is to be held at 72 Hammersmith Road, London W14 8TH at 2.00 p.m. (London time) on 1 November 2021 is set out in the Circular.

At the time of publication of the notice of General Meeting, it is anticipated that the General Meeting will proceed as an open meeting. However, given ongoing uncertainty, and bearing in mind the broader public health considerations and for the safety of others, the Board will continue to monitor government guidance in relation to the COVID-19 pandemic, and if any changes to the arrangements set out in the notice of General Meeting are required, this will be communicated via a regulatory information service and the Company’s website.

Expected timetable for the AIM Delisting

Dispatch of the Circular and the enclosed documents 15 October 2021

Latest date for receipt of proxy voting instructions and (if applicable) hard copy forms of proxy 2.00 p.m. on 28 October 2021

General Meeting 2.00 p.m. on 1 November 2021

Last date for receipt by Link Group from certificated shareholders of duly completed block transfer participation request forms and original share certificates 3 November 2021 at 1.00 p.m.

Last date for receipt by The Bank of New York Mellon from CREST holders of duly completed issuance forms 17 November 2021 at 3.00 p.m.

Expected date of issuance of ADSs to block transfer participants 24 November 2021

Expected date of posting of ADS confirmations to shareholders by The Bank of New York Mellon 24 November 2021

Last day of dealings in the Ordinary Shares on AIM 29 November 2021

Cancellation of admission to trading on AIM of the Ordinary Shares 30 November 2021 at 7.00 a.m.
Notes

(1) References to time in this announcement are to London time unless otherwise stated.

(2) Each of the times and dates in the above timetable are subject to change. If any of the above times and/or dates change, the revised times and/or dates will be notified to shareholders by announcement through a Regulatory Information Service.

(3) All steps after the General Meeting are dependent on the resolutions being passed at the General Meeting. If the resolutions are not passed at the General Meeting, all documents provided to Link Group and/or The Bank of New York Mellon in relation to the deposit of Ordinary Shares for delivery of ADSs shall be of no effect and all original share certificates will be returned to shareholders by Link Group.