For BioIT 2016 Boston, Thursday 7th ´April Track 5, Bioinformatics 11:40

1. www.guidetopharmacology.org
Capturing BIA-10-2474 and related FAAH
inhibitor data in the IUPHAR/BPS Guide to
PHARMACOLOGY (GtoPdb)
Dr Christopher Southan, Senior Database Curator, IUPHAR/BPS Guide to
PHARMACOLGY, University of Edinburgh
BioIT Boston, 2016, Thu 7th ´April, Track 5, Bioinformatics 11:40
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http://www.slideshare.net/cdsouthan/capturing-bia102474-and-related-faah-inhibitor-data-in

2. Abstract (will skip for presentation)
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The clinical trial disaster in France where a fatality was associated with the Phase 1 FAAH inhibitor
BIA-10-2474 has been widely reported on since January 15th 2016. Commentaries in Science,
Nature News, Forbes and Chemical and Engineering News have included interviews with two of us
(SPHA and CS). While the unfortunate events will have wide repercussions, the immediate
consequence was a deficit of pharmacologically-relevant information. Because the IUPHAR/BPS
Guide to PHARMACOLOGY database (GtoPdb) has a primary focus on the annotation of drugs
and clinical candidates (PMID 26464438) we endeavoured to fill the gap. We already had entries
for the primary target FAAH and the possible secondary target FAAH2, so we extended these with
such provenanced data we could find. This is particularly important to support the in silico modelling
community as soon as possible (e.g. for off-target prediction, cross-docking and ADMET
computation). Since there were neither journal articles, nor name-to-structure declarations nor an
open clinical trials entry, BIA-10-2474 was completely blinded until the release of a clinical protocol
by Le Figaro newspaper on Jan 21st. This enabled us to curate N-cyclohexyl-N-methyl-4-(1-
oxidopyridin-1-ium-3-yl) imidazole-1-carboxamide as ligand ID 9001 for BIA-10-2474. In addition,
this is now name-mapped in PubChem via our submission. While the only document mapping was
to a Bial patent, this included 388 analogues for interested parties to follow up. However, no IC50s
were reported for the purified human enzyme, only % inhibition from a crude rat brain preparation.
To expand key topics beyond what we typically capture according to our curation rules (see the
database FAQ) we make use of blog posts. In this case we have used this avenue to highlight low
activity analogues (i.e. SAR pairs) for Bial leads, JNJ-42165279 and PF-04457845. In addition we
have connected patents to access extended SAR results. This information is valuable for the in
silico modelling community since it provides comparator controls and sets for pharmacophore
alignments. A set of links related to this abstract can be found as the NC-IUPHAR “Hot Topics”
bulletin http://www.guidetopharmacology.org/hotTopics.jsp#FAAH.

3. Outline
• Context of the BIA 10-2474 tragedy
• Data gaps
• The GtoPdb response
• FAAH related database entries
• Extending connections
• Blog utility
• GtoPdb plans
• Wider issues
• Conclusions
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4. Introduction
• BIA 10-2747 is an Fatty Acid Amide Hydrolase (FAAH) inhibitor
developed by Bial, Portugal as a potential analgesic
• On 6th of Jan 2016, during a Phase I trial in Rennes run by BioTrial, 6
male patients started the 50 mg per day, high dose arm
• On Jan 10th Jan, after cumulative dosing, one was hospitalised, went
into a coma and died on the 17th of Jan
• The remaining five were hospitalised
• The trial was halted on 11th of Jan, publically announced on 15th Jan
• Brain MRI showed variable haemorrhagic and necrotic lesions in the
fatality and four of the remaining five, with possible chronic damage
• 84 volunteers given lower doses showed no symptoms
• Other FAAH inhibitors have completed Phase I without safety issues
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5. Persistent data gaps
• Protocol registered on 16th October last year (EudraCT No. 2015-001799-
24) but not indexed in the search interface
• Protocol released by ANSM on 22nd Jan and Le Figaro on 24th
• Until then BIA 10-2474 was blinded with only a Bial portfolio listing, no
structure, no papers, no trials entry
• The protocol specified a structure from WO2010074588
• The patent remains (as of 27 March) the only source of in vitro data
• The patent has no activity measurements against purified human FAAH
• French “Temporary Specialist Scientific Committee” meeting report of 15
February details safety testing but extrapolates to unlikely in vitro
potencies and irreversibility not supported by results
• Many questions remain, including the multi-species tox outcomes and
metabolite identification
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6. Primary patent filing: patchy data
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7. GtoPdb remit and response
• Our Wellcome-funded mission is described in : “The IUPHAR/BPS
Guide to PHARMACOLOGY in 2016: towards curated quantitative
interactions between 1300 protein targets and 6000 ligands” PMID
26464438
• We had already captured clinical FAAH inhibitors
• We initially surfaced the BIA 10-2474 structure in our 4th February
release, as ligand 9001
• PubChem submission on the 5th (SID 310264779) added name-to-
structure mapping into CID 46831476
• Since WO2010074588 only had % inhibition from crude rodent extracts,
it did not pass our curation stringency for target mapping
• However, in the interests of surfacing important relationships, we “bent
our rules” by estimating an IC50 and adding the link to Swiss-Prot
O00519 (will appear in our March release)
• Given intense interest in FAAH inhibition we utilised curators
comments, a personal blog and our “Hot Topics” to provide ancillary
information not typically covered by curation
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8. GtoPdb entry for BIA10-2474
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http://guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9001

9. Capturing FAAH inhibitors and dual inhibitors
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http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1400

10. FAAH2
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http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1401

11. Extending connections, metadata and context
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GtoPdb
“Hot tips”
Personal
blog
GtoPdb
Blog
GtoPdb
records and
curators
comments
Social media

12. “Hot Topics” a useful dissemination route
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http://www.guidetopharmacology.org/hotTopics.jsp#FAAH

13. Personal blog: useful
cross-pointing to
ancillary data
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http://cdsouthan.blogspot.se/2016/
01/the-unfortunate-case-of-bia-10-
2474.html

14. Using the blog for SAR controls
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• We typically only curate lead compounds for GtoPdb ligand entries
• Blog specifies low-activity analogues useful for in silico modelling and
comparative testing
• Can also cross-points to patent SAR data sets, including other Bial patents

15. Blog adds bioinformatics context
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16. GtoPdb plans
• Continue to update FAAH inhibitors and their x-reactivity, based on data
curated from papers and patents
• Grapple with unit incompatibilities (e.g. % inhib. vs Ki vs IC50 vs Kinact)
• Updates will be surfaced via approximately quarterly database releases
and new ligand structures submitted to PubChem
• Consider non-published but provenanced data, if parties contact us
• Continue to use blog posts to surface useful data going beyond our
curated relationships (e.g. low activity analogues and new patents)
• Will continue to support parties involved with modelling and/or
experimental x-screening related to mechanistic toxicology of BIA 10-
2474, including benchmarking against other FAAH leads
• Eventual documented insights into the molecular pathology will be
pointed to via curators comments, blog posts and Hot Topics
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17. Wider data-related issues
• Experiments to illuminate mechanistic causality (and, crucially, avoidance)
need to be performed outside Bial by other teams with FAAH expertise
• FAAH drug development is likely to cease until this happens
• Given that Bial has not only at least a Kg of BIA 10-2474 but also ~350
analogues (including radiolabelled) the scientific imperative is to distribute
these to engaging parties (unprecedented, but then so is the tragedy)
• As a response to this event and mounting pressure for transparency, drug
development organisations should rethink blinding lead structures by codes
(e.g. V158866, at Phase II, is still blinded)
• They should be encouraged (mandated?) to publish detailed journal reports of
in vitro and in vivo characterisation that facilitate curation into open
pharmacology sources such as GtoPdb and subsequent data mining
• Incidents like this bring the questionable patenting practices of obfuscation
and data-thin applications into sharp focus
• Clinical trial databases have proliferated globally but have yet to meet
expectations for compliance and translational data mining of results
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18. Conclusions
• The BIA 10-2474 disaster raises issues and will have global consequences
• Data paucity has fuelled speculation across the web
• Since GtoPdb’s remit includes clinical compound capture, we filled data
gaps from patents
• We chose to “rule bend” to add target connectivity value
• Beyond database records per se we used ancillary options to surface more
data for the modelling community
• Insights into molecular toxicology need to be verified at the community level
• The longer it takes to close information gaps, the greater the risk of
reputational damage reflecting across the entire industry
• GtoPdb is well positioned to capture and link new data, ideally from the
peer-reviewed literature
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19. Acknowledgments and sources: questions welcome
• The GtoPdb team, Elena Faccenda, Joanna L. Sharman, Adam J.
Pawson, Simon D. Harding and Jamie A Davies
• Stephen PH Alexander, Chair of NC-IUPHAR
• CS and SA appreciated the diligent reporting of news outlets we were
interviewed by and/or attributed quotes
• We also appreciated the active dissemination of our various
surfacing's on social media (e.g. re-tweets )
• The anonymous Wikipedian for corroborative cross-pointing to
GtoPdb and the personal blog
• Documentation on the ANSM (French National Agency for Medicines
and Health Products Safety) website section
http://ansm.sante.fr/Dossiers/Essai-Clinique-Bial-Biotrial/Essai-clinique-BIA-
102474-101-du-laboratoire-BIAL/%28offset%29/0
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