Pistoia Alliance HELM ProjectSetting the Standard for Biomolecular Data Exchange

13th Annual Pharmaceutical IT Congress

London, UK

September 24, 2015

Sergio H. Rotstein, Ph.D.

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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

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What is a “Biomolecule”

PeptidesTherapeutic

Proteins

ADCsAntibodies Vaccines

ASOs siRNAs

Biomolecule: Anything that is not a small molecule

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GAP

Stuck in the middle…

N

NH

O

O

O

N

NH

O

O

O

Small Molecules

Sequences

Biomolecules

Small Molecule Tools Sequence-Based Tools

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“Fit-for-Purpose” Structure Representation

N

NH

O

O

O

F

O

OO

O N

N

Ab

MTTSASSHLNKGIKQVYMSLPQGEKVQAMYIWIDGTGEGLRCKTRTLDSEPKCVEELPEWNFDGSSTLQSEGSNSDMYLVPAAMFRDPFRKDPNKLVLCEVFKYNRRPAETNLRHTCKRIMDMVSNQHPWFGMEQEYTLMGTDGHPFGWPSNGFPGPQGPYYCGVGADRAYGRDIVEAHYRACLYAGVKIAGTNAEVMPAQWEFQIGPCEGISMGDHLWVARFILHRVCEDFGVIATFDPKPIPGNWNGAGCHTNFSTKAMREENGLKYIEEAIEKLSKRHQYHIRAYDPKGGLDNARRLTGFHETSNINDFSAGVANRSASIRIPRTVGQEKKGYFEDRRPSANCDPFSVTEALIRTCLLNETGDEPFQYKN

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Hierarchical Editing Language for Macromolecules

• Hierarchical• Extensible• Able to handle “entity complexity”

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Hierarchical Editing Language for Macromolecules

• Hierarchical– Biomolecules are “multi-level polymers”

Complex Polymer Simple Polymer Monomer Atom

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Hierarchical Editing Language for Macromolecules

• Hierarchical– Biomolecules are “multi-level polymers”

Complex Polymer Simple Polymer Monomer Atom

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Hierarchical Editing Language for Macromolecules

• Hierarchical– Biomolecules are “multi-level polymers”

Complex Polymer Simple Polymer Monomer Atom

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Hierarchical Editing Language for Macromolecules

• Hierarchical– Biomolecules are “multi-level polymers”

Complex Polymer Simple Polymer Monomer Atom

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Hierarchical Editing Language for Macromolecules

• Hierarchical– Biomolecules are “multi-level polymers”

Complex Polymer Simple Polymer Monomer Atom

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Hierarchical Editing Language for Macromolecules

• Hierarchical– Supports multi-level structures

• Complex Polymer Simple Polymer Monomer Atom⇒ ⇒ ⇒

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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

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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

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Examples

HELM notationRNA1{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 notationPEPTIDE1{A.R.G.[dF].C.K.[meA].E.D.A}$$$$

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HELM at Pfizer: Drawing

Editor

Centralized Monomer DB (smiles, InChI, mol)

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HELM at Pfizer: Registration

Compound Registration

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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

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HELM at Pfizer: Workflow

Antibody Linker Payload ADC Workflow

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The Pistoia Alliance

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

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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

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Open Source HELM

API

HELM Notation Toolkit

HELM Editorhttps://github.com/PistoiaHELM

Code for• HELM Toolkit• HELM Editor• HELM Antibody Editor

Permissive MIT license

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HELM Editor

APIHELM Editor

• Import structural information in a number of formats• Draw from scratch• Create and manage monomers• Export in a variety of formats

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HELM Antibody Editor by Roche

APIHELM Editor

Import sequence (e.g. FASTA)

Annotated antibody displayed and can be manipulated

Automatic domain recognition

Drug conjugates can be added and fully representedStefan Klostermann

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OpenHelm.org

• Introduction to HELM and the project

• News• Links to

resources

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Online resources

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• Specifications• User guides• Presentations• Links to code

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HELM Evolution

2012 2013 2014 2015

Paper published

Pistoiaproject started

OpenHELMReleased

Exchangeable HELM

HAbEReleased

ChEMBL20 with HELM

InlineHELM

SearchPrototype

Andreas Bender Group

UNIVERSITY OFCAMBRIDGE

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How do you take the HELM?

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Biomolecule DataExchange Mechanism

Foundation for your biomolecule informatics infrastructure•Registration•Visualization•Analysis and design•Workflows

Level of Adoption

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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

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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

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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

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HELM Team MembersPfizer 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)

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www.OpenHelm.orginfo@openhelm.org