EpiGene request for partnership
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Early cancer detection kits provide epigenetic PCR tests for screening and early detection of colon, lung, breast and stomach cancers. The developer, EpiGene LLC, is seeking a partnership to enter global markets. Their novel GLAD-PCR assay method allows for quick, sensitive and affordable epigenetic cancer diagnostics using DNA methylation markers. Clinical trials in Russia will evaluate their tests for lung, breast and stomach cancers, having already achieved 97% accuracy for colon cancer detection.
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EpiGene request for partnership
- 1. Early cancer detection kits
- 2. Product evgeny.dubinin@epigene.ru2 Epigenetic PCR tests for colon, lung, breast and stomach cancers screening and early detection EpiGene LLC, 2017
- 3. Targeting deadly cancers 5,8M of incidents and 3,5M of deaths annually 180k of incidents (26% of all) 119k of deaths in Russia 900k of patients registered Up to 50% - late diagnosed 3 evgeny.dubinin@epigene.ruEpiGene LLC, 2017
- 4. Market overview evgeny.dubinin@epigene.ru4 Global market of epigenetic diagnostics is still being formed Experts admit this segment to be one of the most prospective despite the lack of technology that can be widely used in clinical practice Currently used methods are complicated and expensive. Besides they have a number of limitations Today is a good time to enter into a forming market Market estimations [2014] [2019] Worldwide in vitro diagnostic market* M USD 51 100 70 300 Worldwide cancer molecular diagnostic market*** M USD 2 300 4 200 Worldwide cancer epigenetic diagnostic market** M USD 50 1500 Russia in vitro diagnostic market*** M USD 400 550 Russia cancer epigenetic diagnostic market M USD 0 - * Frost & Sullivan, 2013 Analysis of the Global In Vitro Diagnostics Market ** Next Generation Cancer Diagnostics 2014, BCC Research; *** Jain PharmaBiotech EpiGene LLC, 2017
- 5. Competitive environment evgeny.dubinin@epigene.ru5 Competitors Status Price Samples examined Assay duration Sensitivity/ specificity 1. ELISA tests on market 5-35 Eur Blood, biopsy, stool < 1 day 15-60% / 50-80% 2. Epi proColon, Epi proLung by Epigenomics AG on market, R&D 150 EUR (EU, USA, China) Blood 5-7 days (central lab) 68% / 80% 3. Confirm MDx for Prostate Cancer on market (US) 146 USD (США) biopsy 7-10 days (central lab) 68% / 64% 4. DecisionDx on market (US) No data Biopsy, tissue 2-3 weeks (central lab) Not for Dx, sensitivity from 80% 5. EpiGene tests R&D 30-40 Eur Blood Up to 6 hours At least 90% / 90% EpiGene LLC, 2017
- 6. evgeny.dubinin@epigene.ru66 GLAD-PCR-assay Vs Bisulfite conversion GLAD-PCR-assay Bisulfite conversion 4-6 hours > 12 hours > 20 pg of DNA > 500 pg of DNA 3 stages In 1 tube > 5 stages Blood sample RESULT DNA extraction Sensitivity Simplicity Duration Mistakes Less than 1% 15-20% Usage Exact RCGY site within genome, up to 4 in multiplex DNA region excessive EpiGene LLC, 2017
- 7. Innovation: DNA methylation markers, but new detection method evgeny.dubinin@epigene.ru7 Simple Quick Sensitive Usual qPCR Cheap IP GlaI GLAD -PCR IP Breast cancer test Stomach cancer test Lung cancer test Colon cancer test Unique enzymes DNA methylation detection method for Dx Proprietary technological platform for rapid diagnostics development EpiGene LLC, 2017 Epig. Seq IP Epigenetic sequencing tech for markers search IP
- 8. Current status: 2005-2008 2008-2013 2014-2016 New type of enzymes discovered, studied and their production started New DNA methylation detection method developed Pilot R&D for colon cancer diagnostics finished R&D for lung, breast and stomach cancers diagnostics started Own financing by SibEnzyme Grant of Ministry of Science; Equity by SYGMA.Novosibirsk Grant of Skolkovo Foundation; coinvestment by SYGMA.Novosibirsk 8 years of basic tech development $1M raised since 2014, no more required for R&D 97% CRC test diagnostic efficiency (AUC) EpiGene LLC, 2017 evgeny.dubinin@epigene.ru8
- 9. Next steps EpiGene LLC, 2017 evgeny.dubinin@epigene.ru9 2017 2018 2019 2020 Trials for lung, breast and stomach cancers diagnostics in Russia R&D for lung, breast and stomach cancers diagnostics Grant of Skolkovo Foundation; coinvestment by SYGMA.Novosibirsk Trials of colon cancers test in Russia Partnership is required for entering global market
- 10. Request for partnership evgeny.dubinin@epigene.ru10 Possible partners on IVD market «Full license» «Sales» «Joint venture» Diagnostic tests producer on local markets • certification • production • distribution Diagnostic tests distributor on local markets • foreign test certification • distribution VC • Joint venture company for production and marketing of tests on local market EpiGene LLC, 2017
- 11. evgeny.dubinin@epigene.ru11 Additional markets: Other applications Diagnostics Assessment of treatment Choice of therapy EpiGene LLC, 2017 Other diseases Cancers Cardiovascular diseases 2nd type diabetes Alzheimer's disease
- 12. Project team evgeny.dubinin@epigene.ru12 Evgeny Dubinin Project leader, PhD Experience in project management, new products marketing, project financing Sergey Kh Degtyarev Scientific leader PhD, professor Founder of SibEnzyme Ltd Experience on a global market Nina Netesova Main developer PhD Molecular biologist, experience in clinical trials Murat Abdurashitov Leading developer PhD One of developers of new enzymes and their application methods Our team also include molecular biologists, bioinformatists, members experienced in certificatin, clinical trials, quality management and others Alla Dmitrieva Head of diagnostic lab in Tomsk territory oncology center, PhD Andrey Karpov Honored doctor of the Russian Federation, PhD, professor, Seversk territory biophysic scientific center Lev Kudyakov Chief physician of Tomsk territory oncology center, PhD Involved oncologists: EpiGene LLC, 2017
- 13. Contacts evgeny.dubinin@epigene.ru EpiGene LLC, Evgeny Dubinin, PhD Cell +7(906)906-68-86 E-mail: evgeny.dubinin@epigene.ru Web: www.epigene.ru 13 EpiGene LLC, 2017
- 15. IP evgeny.dubinin@epigene.ru15 SibEnzyme Ltd is the developer and patent holder of enzymes and GLAD-PCR-assay. SibEnzyme is focused of products for research use only. EpiGene LLC is a spin-off company of SibEnzyme, a medical technologies application division. EpiGene has an exclusive license for usage of GLAD-PCR- assay in cancer diagnostics EpiGene has preemptive right for enzyme in case SibEnzyme will stop its production. EpiGene LLC, 2017
- 16. DNA methylation in cancer Aberrant DNA methylation of RCGY sites in regulatory region of tumor-suppressor genes is resulting in genes silencing and shown for the most types of cancer1 Such methylation occurs at the early stages1 when still there are no clinical indications of disease Upon cancer cells destruction aberrantly methylated DNA gets into the blood stream. Epigenetic analysis of cell-free DNA from the blood samples allows to detect aberrantly methylated RCGY sites. There are tumor-suppressor genes whose methylation is specific for different types of cancer2. Determination of their methylation status allows to distinguish cancer types and detect it at the most early stages. Thus epigenetic diagnostics seems to be the most perspective IVD for early cancer detection 16 evgeny.dubinin@epigene.ru 1 Jeronimo C., Henrique R. Epigenetic biomarkers in urological tumors: A systematic review // Cancer Lett. 2014; 342(2):264-274 2 Xueguang Sun, Jill E. Petrisko, Lam K. Nguyen, Marc Van Eden & Xi‐Yu Jia Epigenetic biomarker discovery, validation for diagnosis, and therapeutic intervention for Hepatocellular Carcinoma EpiGene LLC, 2017
- 17. Possible solution Diagnostics should be based on epigenetic approach, but new method for methylation detection should be used Novel methylation detection method – GLAD-PCR-assay Based on proprietary enzyme GlaI GLAD-PCR-assay – a universal tool for epigenetic diagnostics development Thus the aim of such development project is to find tumor-suppressor genes whose methylation is specific for examined type of cancer 17 evgeny.dubinin@epigene.ruEpiGene LLC, 2017
- 18. New type of enzymes Methyl-directed site-specific DNA endonucleases belong to a new type of enzymes discovered by SibEnzyme (Russia). These enzymes are very similar to restriction enzymes in biochemical properties and cleave DNA completely, but act in opposite way: they cleave only methylated DNA and do not cleave unmethylated DNA at all Now 9 different MD DNA-endonucleases are commercially available 18 evgeny.dubinin@epigene.ruEpiGene LLC, 2017
- 19. Method description GLAD-PCR Assay is the novel methylation detection method developed by SibEnzyme Simple. 3 easy steps in one tube Quick. 4-6 hours Sensitive. From 6 molecules of methylated DNA Requires only standard real time PCR machine Cheap. From 15€ in bulk and 40€ for patient Method works with any source of DNA like sputum, urine, smear, tissue samples, but most versatile and convenient is blood For details see http://md.sibenzyme.com/2GLAD-PCR%20assay.pdf Method demonstration: http://sibenzyme.com/info7820.php or our site http://www.epigene.ru/glad-pcr-assay/ 19 evgeny.dubinin@epigene.ruEpiGene LLC, 2017
- 20. Epigenetic typing of human cancer cell lines by GLAD PCR assay 20 GeneDNA Raji Jurkat U-937 Hela L-68 G Mouse RASSF1 100 55 - - - - - CEBPD 100 1,3 1,0 - - - - TWIST1 100 1,0 0,5 - - - - EGFR 100 1,0 1,2 - - - - LIN28 100 90 100 90 - - - RARB 100 60 90 100 1,0 1,0 - HS3ST2 100 12 13 55 0,5 0,5 - NANOG* 1,1 0,4 0,4 1,1 55 100 - * Gene regulator of cell differentiation Methylation, % 0 <1,5 1,5-50 50-100 EpiGene LLC, 2017 evgeny.dubinin@epigene.ru
- 21. RC YG GY CR CH3 CH3 RC YG GY CR GlaI GLAD-PCR assay Ligase PCR Universal adapter Regulation region Gene Regulation region GeneGenome primer TaqMan probe Hybryd primer Genome primer TaqMan probe Stage 1: GlaI digestionStage 2: Universal adapter ligationStage 3: Real-time PCRde novo DNA methylation DNMT3 silencing EpiGene LLC, 2017evgeny.dubinin@epigene.ru21
- 22. GLAD-PCR assay specifity GLAD-PCR assay of GCGG and ACGC sites in regulation regions of CEBPD and RARB genes respectively in DNA from Raji cell line. 22 Amplification chart of GLAD PCR assay of 15 ng DNA per reaction using Bio-Rad CFX96. EpiGene LLC, 2017 evgeny.dubinin@epigene.ru
- 23. GLAD-PCR assay sensitivity 23 CEBPD RARB DNA Raji, pg 15 000 5 000 1 666 555 185 62 21 7 Equivalent of normal DNA copies 4 412 1 471 490 163 54 18 6 2 Cq Mean 23 24,1 25,9 27,7 29,1 30,4 31,8 - DNA Raji, pg 15 000 5 000 1 666 555 185 62 21 7 Equivalent of normal DNA copies 4 412 1 471 490 163 54 18 6 2 Cq Mean 24,4 26 27,9 29 30,4 31,8 33,6 - EpiGene LLC, 2017 evgeny.dubinin@epigene.ru
- 24. Value proposition evgeny.dubinin@epigene.ru24 • For the patients: • Routine blood test – no biopsies or unpleasant procedures • Applicable at early stages • Reliable results • Affordable • For the physicians/practitionners: • Simple & Quick • Easy to explain • Do not require special equipment or skills • For government: • Reduction of costs for diagnostics & treatment, the increasing life expectancy of the population EpiGene LLC, 2017
- 25. Colon test efficiency EpiGene LLC, 2017 evgeny.dubinin@epigene.ru25 Preclinical results of test validation on colon cancer patents (n=200) and healthy donors (n=200): 88,5% sensitivity 93,5% specifity 97% AUC
- 26. Project parties SibEnzyme Basic activities are discovery, study and production of enzymes and kits for genetic engineering and medical applications. Big collection of bacterial strains-producers of enzymes, including more than 100 recombinant ones. There are three companies in the world producing more than 200 restriction enzymes: New England Biolabs (USA), Life Technologies (USA) and SibEnzyme (Russia). First in a world discovered site-specific methyl-directed DNA endonucleases. SYGMA.Novosibirsk Government owned multidisciplinary nanotechnology centre, part of the network of nanocentres created by RUSNANO EpiGene is especially founded LLC for development of early detection tests for colorectal, lung, breast and stomach cancers. The resident of Skolkovo biomedical cluster since 2015 evgeny.dubinin@epigene.ru26 EpiGene LLC, 2017
Editor's Notes
- We are the only Russian developers of epigenetic PCR tests with outstanding efficiency based on our proprietary technology
- Lung, breast, stomach and colorectal (CRC) cancers are one of the widest spread malignancies. 5,8M of incidents in 2012 and 3,5M of deaths. Nowadays about 50% of all patients are diagnosed with cancer at advanced stages third or even fourth. Of course, all of you understand, that it’s difficult to reach a positive result in the cancer treatment at these stages. At the same time early cancer detection significantly improves a treatment of disease and the patient cure: the 5 years survival rate increases from 5-20% for patients diagnosed on 3-4th stage to 20-50% for patients diagnosed on 2nd stage and 60-99% - on 1st stage That is why so much attention is paid to early cancer detection.
- Global cancer detection market is huge. But its epigenetic segment is still being formed. Experts admit this segment to be one of the most prospective despite the lack of technology that can be widely used in clinical practice. So it has very big growth potential. Today is a good time to enter into a forming market.
- Traditional ELISA tests of cancer biomarkers shows very poor effectiveness on early stages. There are only few epigenetic tests on the market, this diagnostic segment is still being formed. Currently used methods are complicated and expensive. Besides they have a number of limitations. The pioneer of the epigenetic diagnostics market is Epigenomics AG (Germany). They developed their colorectal cancer test Epi proColon and in 2016 received FDA approval. Besides they have got a strategic agreement with BioChain (China) for marketing of Epi proColon on Chinese market and received CFDA approval by the end of 2015. Never-the-less Epi proColon is based on bisulfite convertion technology and is complicated and performs poorly: its sensitivity is only about 70% and specifity is not much than 80%. Out test shows much more effective.
- GLAD-PCR assay is more effective than excel Bisulfite conversion in every point: in sensitivity, simplicity, it can detect methylation of single selected site within DNA, it requires much less time and it makes much less mistakes
- By present moment we have got the proprietary technological platform for rapid diagnostics delelopment. It is based on unique enzymes, which were discovered and produced by our team. We’ve got a technology for epigenetic sequencing which allows us methylation markers search. GLAD-PCR assay – a methylation detection technology is used for diagnostics. It is very simple and quick, extremely sensitive requires only usual real-time PCR and it is relatively cheap. Based on our technology we already finished a pilot project for colorectal cancer detection kit development. Lung, breast and stomach cancer kits will be ready by 2019.
- We are more than 12 years in project. First 8 years were devoted to basic tech of methylation detection development. Then we started pilot project for colorectal cancer test development. Now it is finished and lung, breast and stomach cancer tests are under development. We raised $1M since 2014, no more required for R&D. Achieved CRC test diagnostic efficiency (AUC) is 97%.
- I have to mention that as our methylation detection technology is universal is give additional prospects to our project. It can be applied not only for diagnostics but also for choice of therapy and assessment of treatment effectiveness. Besides it may be applied not only for cancers but also for most of diseases engaging epigenetic changes such as cardiovascular diseases, diabetes, Alzheimer's disease and others.
- Our team includes members with more than 30 years experience in the project field, including Dr. Degtyarev – founder of SibEnzyme – which is more than 25 years on global market in life science. Besides we attracted to our projects clinicians from Seversk biophysical scientific center and Tomsk oncological clinic. We’ve got also specialists in bioinformatics, certification, quality management, marketing and others.
- Please fill free to contact me any time. Thank you for your attention
- Moreover as in previous works we showed that RCGY sites are 100% methylated in CEBPD and RARB genes in Raji cell line we used this sites to test specifity and sensitivity of the method. We tested Raji cell line — Burkitt’s lymphoma And Controls: L-68 — fibroblast cell line, G — human peripheral blood DNA, Mouse — A/He mouse DNA, negative control As you can see GLAD-PCR showed very high specifity
- Then we estimated its sensitivity by doing consequent assays lowering amount of analyzed DNA at each step. We did 3 separate tests in each series. And we stopped the study at the step at which we’ve got only two points of three. As you can see, GLAD-PCR showed extremely high sensitivity, being able to detect even 6 molecules or 21 pg of methylated DNA