HUB Organoids: a Patient in the Lab A Paradigm-shifting Technology Drug Discovery & Development, Companion Diagnostics and (pre) Clinical Patient Stratification H U B R E C H T O R G A N O I D T E C H N O L O G Y
Summary 2
Drug Development – Inefficient, Unpredictable, Expensive Small Molecules Antibodies Pre-Clinical IO Drugs Development Very limited predictive biomarker development Highly Innovative Drugs Biomarkers & Predictive Tests Clinical Phase I-III Bridge the Gap Between Lab & Clinic Patient in the Lab Post Registration 3
Why HUB Organoids: Credible Models for Drug Development Pr Preclinical Mo Most t Pati tient R t Relevant t Identif ification on of of Pati tient Str t Strati tificati tion Mo Model. Cli linic ical R Respon onse Mim imic Pa Patie ient All Pa Al Patie ients. Biom Bi omarker. Resp sponse se. Comb mbina natio ion n Comp mpanio nion n Repre resent nt Tumo Tumor r Thera The rapy. Diagnos ostic. Het eter erogen enei eity. 4
Personalized Medicine – Current Practice Molecular & Patient Genomic Patient Diagno Sta tati tisti tics- Data Stratific sis & bas based d ation Treatm ent Pred rediction on of of Pati tient’ nt’s Clinical Respon onse Novel Data Biomarkers 5
Organoids – Key to Next Generation Predictive Diagnostics Molecular & Patient Genomic Patient Diagno Data Stratific sis & ation Treatm Org rganoi oid Func uncti tiona nal T Test t ent Dat ata of E Each P h Pati tient nt Clinical Novel Data Biomarkers 6
HUB Organoids – From Drug Discovery to Patient Application Organoid Characterization Post Registrations Pre-Clinical Population Development Preclinical Disc Dev Patient From in the Clinical Traditional to Lab Phase I-III Clinical Trial Patient Centric Biomarker Ident Post Pre-clinical Patient Registration Stratification 7
HUB Organoids – Central Role in Different Applications HUB Organoids Deeper understanding of tumour biology and drug response Pha harma maceuti utical Clin linic ical T l Tria ials ls Develop opment (Pre)Clinical More/better patient targeted drugs stratification Personalized Medicine Clin linic ical l Appl pplicat ation Predictive diagnostics 8
HUB – Global Reference Center for Organoid Technology Indu dustry C y Collabo aborat ation (Partnering/Licensing) - 7 Organoid-based Clin linic ical T l Tria ials ls ongoing E.g. J&J, GSK, Eli Lilly, Boehringer Ingelheim, - >10 new drugs developed on Organoids in Vertex, Roche, AstraZeneca, Pfizer, Merck, clinical trial (>3years developmental time) CrownBio and many biotech companies. - Inv nvento entor of Organoid Technology - Extended IP portfolio covering all aspects - HUB Bi B Bioban bank containing most cancers of Organoid Technology - Diverse range of disease models - Global coverage (CF, IBD, COPD, AAT, malaria, virology,….) - >50 granted Pate tents nts globally (EU as one) HUB D Dat atabas abase Containing: tive Dia iagn gnostic ics - First Organoid Pred edicti - Organoid characterization data used for reimbursement (NL, CF) - Patient clinical data - Implementation of predictive diagnostic - Genomics and proteomics data centers in EU, US and China - In process of EMA and FDA approval 9
HUB Organoids: Most Patient Relevant Models 10
HUB Organoids Patient in the Lab In-vitro Models Generated From Any Patient and Most Organs Capturing patient & tumor Mimic clinical patient Genetically & heterogeneity . response . phenotypically stable . 11 Sato to et a t al., ., Natu ture 2 2009; Gastoe oenterol olog ogy 20 2011 11
HUB Organoid Application Living Biobanks Grown in vitro from patient Heterogeneity of (cancer) patient population in the biopsies lab Unlimited expansion, stable Database genotype and phenotype Data-driven drug development and treatment Drug Discovery and Validation High-throughput in vitro drug Predict activity and toxicity of new compounds screening (combinations) Preclinical Clinical Trials Organoid-based clinical trial Organoid-based efficacy and toxicity data for patient stratification Organoid-based predictive Predictive Diagnostics Improve patient treatment and cost effectiveness diagnostics 12
HUB Organoid Drug Development Platform Technology HUB Ca Capabilit ilitie ies I s Inf nfra rast struc ructure ure Chang Cha nging ing P Para radig igm I In n Onc ncolog ology Bioban obank C Can ancer HUB B Exper erti tise & e & Dru rug Bey eyond nd Kno Known Mode odels Metho ethods Dev evel elopment ent Targ Ta rgets • Lung • IHC, IF • Expand and diversify • New assays bio-banks • Colon • Transfection • Pathway Identification • Platform for high • Ovarian • Gene editing throughput screening • Co-culture with immune • Pancreas • 384-w screens cells • Run ex-vivo clinical trials • Liver for combinations • • Imaging Discover new, actionable targets • Stomach • Pre-clinical clinical trials • Automation • Translation of drug • Small intestine • Target population • Genetic modification sensitivity to genomics identification • Head & Neck • High throughput • Predictive Diagnostics • Biomarker ident. Screening • Breast, and more… 13
HUB Organoids – Unique Platform to Develop Drugs for Patients on Patients Huma uman O n Organ Huma uman D n Disease Animal ( (Spec ecies es) PDX DX Pri rimary ry Cell Ce ll-Line Orga ganoi oids Breast Cystic Fibrosis Dog Tissue Colon Genetic Diseases (A1AT, Mouse Kidney etc) Mini pig Sc Scalability Lung IBD Rat Costs Liver COPD Monkey Pancreas Cancer Reprod oducibility Small intestine Infectious Diseases Stomach Thr hroughp hput ut (Virology (e.g. SARS- Head & Neck COVID), Malaria, HBV Clinical Ovary etc.) Rel elev evan ance … … Captu apture R e Rar are e Mutati tations Repla lacin ing g Red educ ucing ng Pati tient R ent Rel elev evant nt Time e & C Costs ts. Anim imals ls. Mode odel. 14
Clinical Validation of Organoids 15
Cancer Organoids – Independent Clinical Validation A living biobank of breast cancer organoids Pre-treatment Post-treatment capture disease heterogeneity oid rol ontrol rganoi • Sachs et al., Cell 2018; 172: 373-386. Con Org Patient-derived organoids model treatment response of metastatic gastrointestinal cancers Organ anoid de d deat ath • Vlachogiannis et al., Science 2018; 359: 920-926. oid tient nt rganoi Organoid Profiling identifies common Pati responders to chemotherapy in pancreatic Org cancer • Tuveson et al., Cancer Discov 2018; 8(9): 1112–29. Orga rganoid gro growth Pancreatic cancer organoids recapitulate disease and allow personalized drug screening t ent Scan CT Sca tien • Driehuis et al., PNAS 2019; 26, 116 (52) 26580-26590. Pati Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer Tumor gro r growth • Hua et al., Cell Stem Cell 2020; 26, 17-26. 16
Predictive Diagnostics in Practice - Cancer 17
Organoids Mimic Clinical Responses Organoid Generation and Characterization Organoid Characterization Breast Cancer Tissue Drug RNA-Seq. Histology Whole Personalize Testing Genome Diagnostics DNA Seq. Organoid Response in the Lab and Patient Response in the Clinic Match Organoid R d Respon onse Patie ient R Response Pati tient ent 1 1 Metastatic Breast Cancer Clinical Response Organoid d Responde der Pati tient ent 2 2 Pati tient ent 1 1 Tu Tumor R r Response Organ Or anoid N Non on- Responde der Pati tient ent 2 2 Progr gressiv ive D Dis isease 18 Sachs Sa hs et a al. l. C Cell 2 ll 2017, 172, 3 373-386 86
Predictive Diagnostics in Practice – Cystic Fibrosis Predictive Diagnostics Cystic Fibrosis, First Organoid Clinical Success • A CF assay on Cystic Fibrosis patient Healthy CFTR activation: Swelling of Organoids Organoids • Patients treated based on results of organoid tests Implemented in the Netherlands Organoids as reimbursement tool for insurance companies Mutated CFTR activation: Mutated CFTR activation after Drug No-Swelling of Organoids Treatment: Swelling of Organoids 19
Next Gen. Treatment – Focus Shift From Drug to Patient • This paradigm shift from a drug-centric view towards personalized diagnostic will improve treatment efficiency, cost effectiveness, drug development process, etc. • Revolution that started with NGS can be realized with Organoid Technology Focus o Fo s on Dru rugs gs Focus us o on n Patie ient nt 20
Human Organoid Models Examples: IBD, Toxicology and Immuno-Oncology 21
Intestinal Organoids: Disease Models VEO-IBD Tissue Patient (2 days old) Organoid Patient TTC7 Mutation, Rock Inhibitor Reverses Phenotype 22 Bigo gorgn rgne et. al. l., J J. Clinic linical I l Inv nvestig igatio ion, n, 2 2014
Animal-Derived Organoid Models • Organoids derived from different species recapitulate discrepancies in toxicity. Beagle • Species: • Rat (Wistar WU) • Dog (Beagle) • Mouse • Mini pig Wistar WU • Monkey • More in pipeline… 23 Minipig
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