Big picture - Why invest in e-Therapeutics plc
e-Therapeutics plc Snapshot
e-Therapeutics’ aims are to discover and out-license effective new medicines. We have a strong balance sheet which enables us to plan for the optimal point at which to out-license our drug assets to maximise returns for our shareholders whilst we recognise that there are, at present, opportunities for much earlier stage out-licensing of candidates for certain indications.
Our primary focus is on cancer, with an emphasis on immune action and therapeutic resistance, along with antivirals. The primary focus on cancer reflects the fact that these diseases are biologically complex, are increasingly prevalent with age, often incurable and in many cases severe. These characteristics mean that the drugs addressing such diseases represent high-value licensing opportunities. Our preclinical stage projects include:
- ETS2300, telomerase inhibition in anti-cancer
- ETS3100, small molecule anti-TNFα
- ETS2400, Hedgehog pathway inhibition
- ETS5200, broad spectrum antivirals
We also have other programmes with a particular focus on immunotherapy in cancer and on treating therapeutic resistance to modern ‘targeted’ therapies in cancer.
Cells contain many different proteins. These proteins interact to form complex networks. These networks carry out all the varied aspects of normal function. Alterations to them are often a defining feature of disease.
e-Therapeutics’ discovery processes begin by identifying the specific physiology that we wish to affect in a target disease. The proteins that participate in the networks that mediate this specific physiology are then identified, and the networks in which they function are mapped. This complex network of proteins is then analysed to identify multiple intervention points that, if impacted simultaneously, will disrupt the disease-related network.
We then seek drug molecules with the best overall impact in the disease-related network. This search process takes account of the chemical biology profile of the molecules. This approach, sometimes called Network Pharmacology, differs from ‘conventional’ drug discovery, which is typically based on high-affinity inhibition of a single protein ‘target’. We believe that, by accounting more realistically for both the complexity of disease at the outset and for the many effects of the presence of a drug molecule in the body, our approach has the potential to discover more effective drug treatments.
We maintain active research collaborations with a number of academic groups including
- the Systems Approaches to Biomedical Sciences (SABS) Centre for Doctoral Training at Oxford University
- the Industrially Focused Mathematical Modelling (InFoMM) Centre for Doctoral Training at Oxford University
- the School of Electrical and Electronic Engineering at Newcastle University.
Examples of recent projects are:
- “Structural robustness of protein interaction networks” with Alice Schwarze and Mason Porter as part of the SABS program at Oxford. 2015-present.
- “Multilayer-Network analysis of protein interaction networks” with Florian Klimm, Charlotte Dean and Mason Porter as part of the SABS program at Oxford. 2015-present.
- “High-performance computing systems for analysis of massive networks” with Newcastle University School of Electrical and Electronic Engineering. 2012-present.
- “Development and in vitro testing of a working Parkinson’s Disease network model” with the SABS program at Oxford. 2011-2014.
- “Exploring new community-node-roles typology in protein-protein interaction networks with a focus on an In vitro model of Parkinson’s disease” with the SABS program at Oxford. 2011-2014.
- “Acceleration of drug discovery via graph streaming” with Newcastle University School of Electrical Engineering. 2014-2015.
TNFα is a master regulator of inflammation. Excessive production of TNFα drives the damaging inflammation characteristic of many inflammatory diseases.
Small molecule anti-TNFα
Inhibition of the effects of TNFα is efficacious in the treatment of rheumatoid arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ulcerative colitis. There is the potential for the use of TNFα-directed therapy in many other inflammatory disorders where TNFα is a key factor.
Our programme focuses on small molecule TNFα suppressors which could potentially avoid the inconvenience, unwanted effects and the development of drug-resistance associated with anti-TNFα biologic therapies. Our molecules are designed to regulate TNFα transcription and post-transcriptional TNFα expression.
Our lead compounds are small molecules with:
- good variability in chemotypes
- synthetic tractability
- good drug-like characteristics
- no significant toxicity in initial screens
- reduce TNFα titres to zero in LPS-induced PBMCs
The Hedgehog pathway plays a critical role during development, regulating patterning and proliferation. It is reactivated in many cancers.
Hedgehog Pathway inhibition: mitigating therapeutic resistance
Loss-of-function Patched mutations are associated with Gorlin and Li-Fraumeni syndromes and predispose individuals to basal cell carcinomas, medulloblastomas, and rhabdomyosarcomas. Activating mutations of SMO are also found in basal cell carcinomas and rare SUFU mutations in medulloblastomas, underscoring the involvement of the pathway in cancer.
The targeting of the pathway has been validated in cancer by the first generation of inhibitory molecules, which have targeted “SMO”. The most advanced of these agents, vismodegib and sonidegib, have been approved for use in the treatment of basal-cell carcinoma. Initial tumour responses are often impressive, but resistance is frequently observed. This has limited the clinical impact of these otherwise potentially important agents in cancer.
Our programme focuses on potent, selective Hedgehog pathway inhibitors with a reduced tendency to induce resistance, together with activity against tumours that are resistant to SMO inhibition. Mutation, amplification and deletion data indicate that the pathway as a whole is critical, and hence targeting a single component, such as SMO, will be a strong driver for mutation and clonal selection and the emergence of resistance. Targeting across several proteins that participate in the Hedgehog pathway reduces opportunity for the cancer cells to evolve around the drug’s action and so reduces the risk of target and pathway resistance.
A molecule showing potency in cellular assays in the nanomolar range, as potent as the leading SMO inhibitors, while not binding SMO, is shown below. Molecules in this family are well placed either to rescue SMO inhibitors from therapeutic resistance or displace them.
Our lead compounds are small molecules:
- with potency in cellular assays in the nanomolar range, and as potent as the leading SMO inhibitors
- while not binding SMO
- well placed to rescue existing SMO inhibitors from therapeutic resistance, or displace them
- have good variability in chemotypes
- with synthetic tractability
- have good drug-like characteristics.
Telomerase was identified as the enzyme responsible for maintaining telomeres (specialised complexes that 'protect' the ends of chromosomes). Telomerase is expressed in 90% of cancers, being required for replicative immortality, but is absent in most normal cells making it of interest as a target for anti-cancer drug discovery. Our approach has been to target multiple networks mediating the regulation of telomerase, its expression, activity, localisation and functional effects.
Telomerase: potent small molecule anti-proliferatives
Telomerase is expressed in 90% of cancers, being required for replicative immortality, but is absent in most normal cells making it of interest as a target for anti-cancer drug discovery. It exists as part of a highly regulated protein complex in the nucleus, but more recently has been revealed to have additional functions elsewhere in the cell. Our approach has been to target multiple networks mediating the regulation of telomerase, its expression, activity, localisation and functional effects.
Our lead compounds are small molecules with:
- cellular potency about 10 times greater than Imetelstat, and 100 times greater than the most potent small molecule previously known (e.g. BRACO19)
- good variability in chemotypes
- synthetic tractability
- good drug-like characteristics
- good selectivity for TERT+ cancer cells over TERT- fibroblasts
Dr. Raymond Barlow
Chief Executive Officer
Having completed a BSc in Chemistry from Leeds University in 1990, Dr. Barlow moved to the University of Manchester, from where he gained a PhD in Chemistry in 1994. He then spent a year at McGill University, Montreal as a post doctoral Fellow before entering the pharmaceutical industry as a senior scientist with Zeneca in Pharmaceutical R&D's Technology Access and Strategic Alliances team, of which he later became Team Leader in 1998.
Following the merger with Astra, he became a Global Manager in the Discovery and Development function, in-licensing technologies and working on the development of a range of molecules, including those in oncology, cardiovascular, respiratory and inflammatory disease areas.
Upon completion of a year as a Senior Business Analyst he was appointed Director of Corporate Development, reporting into AstraZeneca's London HQ. In this role he was involved in a number of transactions and was part of the team responsible for shaping AstraZeneca's strategy with the Board, including its move into biologics. During this period he graduated from Manchester Business School with an MBA and in 2004 he stepped out of the BD function into a Regional commercial leadership role in Brussels covering 14 countries in CEE and Russia.
After 10 years with AstraZeneca, Ray moved into the biotech sector working in senior business development roles for Microscience Limited and Emergent Solutions Inc (EBS: NASDAQ). During this period Ray out-licensed a portfolio of Meningitis B assets (invented at Imperial College) to Sanofi and was involved with the team that successfully listed EBS on NASDAQ.
Ray then spent 5 years running his own business (BD solutions Limited) focused upon aiding clients on corporate development and commercialisation projects. During this period he was CEO of Asterion Ltd, delivering research deals with Genzyme and Ipsen. In 2010 he joined Crucell NV and was instrumental in the sale of the business to Johnson & Johnson for whom he worked on a wide range of infectious disease and vaccine deals, before joining Amgen in 2012. At Amgen he has also completed numerous deals including immuno-oncology deals with Boehringer Ingelheim and Genenta, international commercial deals with GSK and Mitsubishi Tanabe as well as playing a key part in the acquisition of Onyx Pharmaceuticals and Dezima Pharma BV.
Interim Executive Chairman
Iain Ross has over 35 years’ experience in the international life sciences and technology sectors where he has completed multiple financing transactions, and >25 years in cross-border management as a Chairman and CEO. He has led and participated in 5 Initial Public Offerings, and has direct experience of M&A transactions in Europe, USA and Pacific Rim.
Currently he is a Non-Executive Director of Premier Veterinary Group plc (LSE) and Chairman of Biomer Technology Ltd; and also a Non-Executive Director of Anatara LifeSciences Ltd, Benitec Biopharma Ltd. and Novogen Ltd each of which is listed on the ASX. He is a qualified Chartered Director, and Vice Chairman of the Council of Royal Holloway, London University.
Previously, he has held significant roles in multi-national companies including Sandoz, Hoffman La Roche, Reed Business Publishing and Celltech Group plc where as Chief Executive Officer of Celltech Biologics plc, he moved the company from a loss-making position to reporting a net profit before the sale to Lonza. He has advised banks and private equity groups on numerous company turnarounds. These include as CEO of Quadrant Healthcare taking the Company public, signing numerous collaborations before selling the business to Elan in 2001. As Chairman and Chief Executive Officer, at Allergy Therapeutics, he re-structured the Company Balance Sheet to position Allergy Therapeutics as a virtually debt free cash generative company prior to its subsequent IPO. As Executive Chairman at Silence Therapeutics Plc (formerly SR Pharma plc), he turned the business around through M&A and established collaborations with Pfizer, Astra Zeneca and Dainippon Sumitomo before completing a merger with Intradigm Inc. Iain was appointed to the Board of e-Therapeutics in January 2016. He continues to consult for private equity groups on biotech & technology company turnarounds.
Finance Director and Interim Chief Operating Officer
Steve joined e-Therapeutics’ management team in April 2014, having previously advised the Company in its £40 million fundraising in 2013. He is a Chartered Accountant. Prior to joining e-Therapeutics, Steve worked in the UK equity market for over 20 years. During this time he was involved primarily in research and advised on numerous flotations, acquisitions and corporate transactions. He has held various research and executive roles within UK capital market companies including Altium Capital, N+1 Singer and Peel Hunt. He co-founded Blueprint Advisors in 2012.
Brad has over 20 years’ commercial experience in the pharmaceutical and biotechnology industries gained through financial and general management roles in the UK and US.
Brad is Director and co-founder of Seven Hills Venture Partners Limited, a life sciences advisory firm based in Edinburgh. Previously Brad was Chief Financial Officer of Plethora Solutions Holdings plc, an AIM-listed speciality pharmaceutical company; Chief Executive Officer of Xcellsyz Limited, a UK venture capital-backed life science company; and Senior Director of Geron Corporation’s stem cell-focused UK subsidiary. Prior to co-founding Seven Hills, Brad was Chief Financial Officer at Cyclacel Limited, a UK oncology company, and he held senior financial management positions at ChiRex Inc., a US-based pharmaceutical CMO. Brad is a Chartered Management Accountant. He was appointed as a Non-Executive Director of e-Therapeutics in September 2008, and chairs the audit committee and the remuneration committee.
Professor Trevor Jones CBE
Trevor has over 40 years’ distinguished experience in the pharmaceutical and biotech industry as well as in academia. He is currently Chairman of the international CRO, Simbec-Orion Group Limited, and a Non-Executive Director of the Welsh investment company, Arthurian Life Sciences Limited and the global health and life sciences investment company, Perceptive Bioscience Investments Ltd. He is also Visiting Professor at King’s College, London and holds honorary degrees and Gold Medals from seven universities.
Previously, Trevor held significant roles in industry including Director of Allergan Inc from 2005 to 2015 and R&D Director of The Wellcome Foundation from 1987-1994, where he was responsible for the development of AZT, Zovirax, Lamictal, Malarone and other medicines.
Trevor has also held a number of advisory and regulatory roles including Director General of the Association of the British Pharmaceutical Industry (ABPI), board member of the European Federation of Pharmaceutical Industry Associations (EFPIA) and the International Federation of Pharmaceutical Manufacturers Associations (IFPMA), a member of the UK Government regulatory agency, The Medicines Commission, a member of the UK Government Pharmaceutical Industry Ministerial Strategy Working Group on Pharmaceuticals, an adviser to the Cabinet Office on the Human Genome Project, a member of the Prime Minister’s Task Force on the Competitiveness of the Pharmaceutical Industry (PICTF) and Chair of the Government Advisory Group on Genetics Research. He joined the e-Therapeutics board in October 2015.
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