1. Pistoia Alliance HELM Project Setting the Standard for Biomolecular Data Exchange 13th Annual Pharmaceutical IT Congress London, UK September 24, 2015 Sergio H. Rotstein, Ph.D.

2. © Pistoia Alliance Background Pfizer Goal –“Top-tier biotherapeutics company” But supporting informatics infrastructure had many gaps Biomolecules Team Goal –Make biomolecules “first-class citizens” of the informatics tool portfolio Working on therapeutic oligonucleotides since 2008 Build on this work to support additional entities for –Registration –Visualization –Analysis and design –Workflows HELM is a result of this initiative

3. © Pistoia Alliance What is a “Biomolecule” Peptides Biomolecule: Anything that is not a small molecule

4. © Pistoia Alliance Stuck in the middle… Small Molecules Sequences Biomolecules Small Molecule Tools Sequence-Based Tools

5. © Pistoia Alliance “Fit-for-Purpose” Structure Representation Ab MTTSASSHLNKGIKQVYMSLPQGEKVQAMYIWIDGTGEGLRCKTRTLDSEPKCVEELPEWNFDGSSTLQSEGSNSDM YLVPAAMFRDPFRKDPNKLVLCEVFKYNRRPAETNLRHTCKRIMDMVSNQHPWFGMEQEYTLMGTDGHPFGWPSN GFPGPQGPYYCGVGADRAYGRDIVEAHYRACLYAGVKIAGTNAEVMPAQWEFQIGPCEGISMGDHLWVARFILHRVC EDFGVIATFDPKPIPGNWNGAGCHTNFSTKAMREENGLKYIEEAIEKLSKRHQYHIRAYDPKGGLDNARRLTGFHETSNI NDFSAGVANRSASIRIPRTVGQEKKGYFEDRRPSANCDPFSVTEALIRTCLLNETGDEPFQYKN

6. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical Extensible Able to handle “entity complexity”

7. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Biomolecules are “multi-level polymers” Complex PolymerSimple PolymerMonomerAtom

8. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Biomolecules are “multi-level polymers” Complex PolymerSimple PolymerMonomerAtom

9. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Biomolecules are “multi-level polymers” Complex PolymerSimple PolymerMonomerAtom

10. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Biomolecules are “multi-level polymers” Complex PolymerSimple PolymerMonomerAtom

11. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Biomolecules are “multi-level polymers” Complex PolymerSimple PolymerMonomerAtom

12. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Supports multi-level structures Complex Polymer ⇒ Simple Polymer ⇒ Monomer ⇒ Atom

13. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Supports multi-level structures Complex Polymer ⇒ Simple Polymer ⇒ Monomer ⇒ Atom Extensible –Allows addition of new polymer types E.g. Polysaccharides

14. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Supports multi-level structures Complex Polymer ⇒ Simple Polymer ⇒ Monomer ⇒ Atom Extensible –Allows addition of new polymer types E.g. Polysaccharides Able to handle entity complexity Oligonucleotide hybridization Chemically modified Biologics –Unnatural amino acids –Bioconjugates

15. © Pistoia Alliance Examples HELM notation RNA1{R(G)P.R(G)P.R(C)P.R(A)P.R(C)P.R(U)P.R(U)P.R(C)P.R(G)P.R(G)P.R(U)P.R(G)P.R(C)P.R(C) }$$RNA1,RNA1,11:pair-32:pair|RNA1,RNA1,5:pair-38:pair|RNA1,RNA1,14:pair- 29:pair|RNA1,RNA1,8:pair-35:pair|RNA1,RNA1,2:pair-41:pair$$ HELM notation PEPTIDE1{A.R.G.[dF].C.K.[meA].E.D.A}$$$$

16. © Pistoia Alliance HELM at Pfizer: Drawing Editor Centralized Monomer DB (smiles, InChI, mol)

17. © Pistoia Alliance HELM at Pfizer: Registration Compound Registration

18. © Pistoia Alliance HELM at Pfizer: Analysis & Design PFRED PFRED: A computational tool for siRNA and antisense design. Simon Xi, Qing Cao, Christine Lawrence, Tianhong Zhang, Simone Sciabola, Sergio Rotstein, Jason Hughes, Daniel Caffrey, and Robert Stanton, PLOS ONE, Submitted

19. © Pistoia Alliance HELM at Pfizer: Workflow 19 AntibodyLinker PayloadADCWorkflow

20. © Pistoia Alliance The Pistoia Alliance 20 The Pistoia Alliance is a global, non- profit alliance of life science companies, vendors, publishers, and academic groups that work together to solve common problems and lower barriers to innovation in R&D

21. © Pistoia Alliance

22. Pistoia HELM Project Goal Transition HELM technology from Pfizer proprietary to Open Source Provide an industry-wide standard for data exchange within and between organizations Reduce software development costs by minimizing the need for companies to develop similar functionality

23. © Pistoia Alliance Open Source HELM API HELM Notation Toolkit HELM Editor https://github.com/PistoiaHELM Code for HELM Toolkit HELM Editor HELM Antibody Editor Permissive MIT license

24. © Pistoia Alliance HELM Editor API HELM Editor Import structural information in a number of formats Draw from scratch Create and manage monomers Export in a variety of formats

25. © Pistoia Alliance HELM Antibody Editor by Roche API HELM Editor Import sequence (e.g. FASTA) Annotated antibody displayed and can be manipulated Automatic domain recognition Drug conjugates can be added and fully represented Stefan Klostermann

26. © Pistoia Alliance OpenHelm.org Introduction to HELM and the project News Links to resources http://www.openhelm.org 26

27. © Pistoia Alliance Online resources 27 Specifications User guides Presentations Links to code

28. © Pistoia Alliance HELM Evolution 28 2012 201320142015 Paper published Pistoia project started OpenHELM Released Exchangeable HELM HAbE Released ChEMBL20 with HELM Inline HELM Search Prototype Andreas Bender Group UNIVERSITY OF CAMBRIDGE

29. © Pistoia Alliance How do you take the HELM? 29 Biomolecule Data Exchange Mechanism Foundation for your biomolecule informatics infrastructure Registration Visualization Analysis and design Workflows Level of Adoption

30. © Pistoia Alliance The HELM Ecosystem Pharma / Biotech / Institutes –BMS, GSK, Lundbeck, Merck, Novartis, Pfizer, Roche Software vendors –ACD/Labs, Arxspan, Biochemfusion, BioMax, Biovia, ChemAxon, NextMove, Scilligence Content / Service Providers –EBI (ChEMBL), eMolecules, quattro Active discussions on-going with others

31. © Pistoia Alliance HELM Phase 2 - Ambiguity Systems need to handle molecules that are not always fully defined A design for the representation of ambiguity has been drafted RFP Issued and bid selected Development work starting soon 31

32. © Pistoia Alliance IDMP The implementation guide for ISO 11238: Health Informatics - Identification of medicinal products will include HELM as an acceptable format. Working with the FDA to include HELM as a format within GInAS. GInAS will provide a common global identifier for all substances used in medicinal products or active substances under clinical investigation 32

33. © Pistoia Alliance HELM Team Members Pfizer Team Peter Henstock David Klatte Christine Lawrence Frank Loganzo Hongli Li Sergio Rotstein Simone Sciabola Rob Stanton Nathan Tumey Simon Xi Tianhong Zhang The Pistoia Alliance HELM Project Team, especially: Sergio Rotstein (Pfizer) – Domain Lead Claire Bellamy (Pistoia Alliance) – Project Manager Active Team Members: Roland Knispel (ChemAxon) Matthias Nolte (BMS) Jan Holst Jensen (Chembiofusion) Thomas Gan (Merck) Stefan Klostermann (Roche) Sven Neumeyer (Novartis) Yohann Potier (Novartis) Tianhong Zhang (Pfizer) Steering Committee Members: John Wise (Pistoia Alliance) Margret Assfalg (Roche) Leah O'Brien (GSK) Ramesh Durvasula (BMS) Sergio Rotstein (Pfizer) Alex Drijver (ChemAxon) Chris Waller (Merck) Quan Yang (Novartis)

34. © Pistoia Alliance 34 www.OpenHelm.org info@openhelm.org