The Screening Cascade

Start with 100-100s compounds -> put through assays -> after 2-3years = 1 molecule

A process by which the effects of large numbers of molecules are evaluated, first in simple
assays and then in increasingly complex assays, each testing for a particular biological
property - this filter out unwanted molecules and enables structure-activity relationships to
be understood - until a molecule is obtained with properties thought to enable it to become
a successful drug
 Improves selectivity and potency via filtering

RECEPTOR - site of mediator action

Extracellular Intracellular
G-protein coupled receptor Nuclear
Ligand gated ion channel Enzyme
Receptor tyrosine kinase
(enzyme linked)

Ion channels and Carrier proteins

- Involved in post receptor signalling: also, sites of drug action

STEP 1 - FIND A MOLECULE TO WORK WITH

HTS - Liquid transfer via pin arrays/automated cell profiling and compound screening
Focused screen
Physiological screen
NMR screen

GTPγS assay - Cell membranes; + 35S-γ-GTP

Process of association is used in the gtpys assay – suitable/easy assay to conduct
Tell you nothing about the function – antagonist/agonist – what type
But it is useful as a first step

Fluorescent Imaging Plate Reader (FLIPR) Assay

Relies on G-proteins R when coupled to Gq proteins stimulate intracellular Ca2+ flux
Changes measured using calcium-sensitive dyes and a fluorescence plate reader
 Ca2+ entering cells bind to intra-cellular Fluo-3 & results in increased fluorescent
emission at 520 nm
Still tells nothing about how R operates in native environment

Orthologue – check for receptor activity – use mouse/rat

Because you are going to test bio properties in vivo rather than
in human – need to know if it works in a mouse, if there is
toxicity before even testing on larger animals (humans)
- Need to know if will work in native cell

Human & rodent κ opioid receptors share ~94% aa sequence

homology but residues involved in intracellular signalling not
conserved
SoC Criteria
Initiation of additional chemistry to establish detailed SAR and optimise a series

It is possible to plan a meaningful chemistry strategy and there is potential to capture

intellectual property

The lead molecule has reasonable potency

The lead molecule has acceptable selectivity of action for the target receptor, compared
with family members and with potential liability issues suggested by the structure of the
molecule
The lead molecule has activity at the rat orthologue
= Assays are in place to move forward

Now have lead molecule that can be optimised

STEP 2 - takes 2 years and a full team of expertise

Motilin – lead molecule that was achieved by HTS by discovery of GPR38

STRUCTURE-ACTIVITY RELATIONSHIPS (SAR)

Relationship between the chemical or 3D structure of a molecule and its biological activity.

Today SAR are more high-throughput -> Modified the two r positions, by inserting dif groups
The analysis of SAR enables the determination of the chemical group responsible for
evoking a target biological effect in the organism. This allows modification of the effect
or the potency of a bioactive compound (typically a drug) by changing its chemical structure.

Patent ‘space’ – test molecules which are variations of desired candidate molecules
Patent ‘busting’ – occurs frequently

Receptor Pharmacology

Affinity
tenacity with which a drug binds to a receptor – LEARN THE EQUATION

Ligands reside at a point of minimal energy within a binding locus of a protein

• ratio of the rate the ligand leaves the protein surface (Koff)
• and the rate it approaches the protein surface (Kon)
 • Binding affinity influenced by non-covalent intermolecular interactions such as
hydrogen bonding, electrostatic interactions, hydrophobic and Van der Waals forces
between the two molecules

Affinity/ Affinity Constant

This ratio is the equilibrium constant of the ligand-protein complex
• Keq = Koff/Kon
• defines the molar concentration of ligand at the protein where 50% of the protein
has ligand bound to it
The “affinity” or attraction of the ligand for the protein is the reciprocal of K eq

(the higher the affinity, the lower this concentration will be)

Binding affinity is typically measured and reported by the equilibrium dissociation constant
(KD), which is used to evaluate and rank order strengths of bimolecular interactions. The
smaller the KD value, the greater the binding affinity of the ligand for its target.

Ligand
 Any chemical which combines with a receptor
Antagonist
 A drug that reduces the action of another ligand/drug, generally an agonist
Agonist
 A ligand that binds to a receptor and alters the receptor state, resulting in a
biological response

Competitive (reversible) antagonists

Bind to the receptor without evoking a measurable
response (no efficacy)

Binding not permanent - the antagonist COMPETES with

agonist molecules
Increasing the concentration of antagonist increasingly
prevents agonist molecules from binding – and vice
versa

An antagonist will block the excess ligand binding to the

receptor to dampen the effect.

Competitive antagonism
Binds to same receptor as the agonist

Shift response curve to the right when use antagonist –

can calculate conc. Ratio to know what concentration of
antagonist is required

Non-competitive receptor Antagonists

Effectively irreversible
• Chemically modifies receptor to prevent agonist
binding (covalent bond)
• Binding so tightly (high affinity) that rate of
dissociation is effectively zero at relevant time scales
• Bind to different site, reducing binding of agonist by allosteric mechanism
Receptor Agonists

G proteins bind the guanine nucleotides GDP and GTP. Three different subunits associated
with the inner surface of the plasma membrane and transmembrane receptors
•Gα, which carries the binding site for the nucleotide. At least 20 different kinds of Gα
molecules are found in mammalian cells.
•Gβ
•Gγ

In the inactive state, Gα has GDP in its binding site.

•When a hormone or other ligand binds to the associated GPCR, an allosteric change takes
place in the receptor (that is, its tertiary structure changes).
•This triggers an allosteric change in Gα causing
•GDP to leave and be replaced by GTP.
•GTP activates Gα causing it to dissociate from GβGγ (which remain linked as a dimer).
•Activated Gα in turn activates an effector molecule.

In a common example (shown here), the effector molecule is adenylyl cyclase - an enzyme
in the inner face of the plasma membrane which catalyzes the conversion of ATP into the
"second messenger" cyclic AMP (cAMP).
Activated Gα is a GTPase so it quickly converts its GTP to GDP. This conversion, coupled with
the return of the Gβ and Gγ subunits, restores the G protein to its inactive state.

Potency
 The amount (weight) of drug required to produce a given effect
Efficacy
 The degree to which an agonist evokes a cellular response
 intrinsic activity refers to the effect of the agonist at the receptor itself, rather than
the overall effect on the tissue (multiplication of response)

Measuring potency
EC50
 The molar concentration of an agonist that produces 50% of the maximal possible
effect of that agonist
 Other % values (EC20, EC40, etc) can be specified
pEC50
The negative logarithm to base 10 of the EC50 of an agonist
Useful to:
 Compare potencies of drugs
 Estimate margin of safety, relative to other actions of the drug

Agonist A is more “potent” than agonist B - but both full agonists

POTENCY depends on:
• Drug factors – efficacy and affinity
• System factors – receptor number & efficiency of
coupling
System factors can cancel out differences in drug factors

Blue (a) is more potent than B – can define this by

looking at both EC50s
Partial agonist
 Has affinity for the receptor but low efficacy
 It will not produce a maximum response

Inverse agonist
Binds to the receptor but induces negative efficacy – negative effect for the receptor
The receptor must have constitutive activity in the absence of a ligand

Two-state receptor model and inverse agonism

INVERSE AGONISTS
 have higher affinity for the active state of the receptor
 shift the equilibrium back to the inactive state

Active and Inactive receptors in equilibrium Active and Inactive receptors in equilibrium

Activation of G protein-coupled receptors

GPCR doesn’t always couple to G-

proteins -> can bind to arrestin
pathway

Morphine binds so that receptor

bind to g-P but also to arresting
pathway
-> causes side effects seen with
morphine – if you can separate
these, you might be able to avoid
side effects and the way analgesics
are used.

Biased Agonism
Thermal energy drives protein (receptor) into preferred energy wells

 Particular ligands enrich a particular conformation

 Some conformations (energy wells) have preferred affinity for cell signalling proteins
 Function is linked to these conformations

Functional Selectivity and Biased Receptor Signaling ; Kenakin T, JPET 336:296–302, 2011

 agonists stabilise unique active states to create a signal “biased” towards specific
cellular pathways
 You can make it be selective – force receptor to communicate with G-protein or
arrestin pathway
 may activate pathway for desired clinical response without adverse effects
 large potential for biased agonist-disease links

Kenakin & Christopoulos, 2013, Natue Rev Drug Disc, 12, 205-16

Biased signalling in disease

Clinical use unclear -> potential drugs e.g. µ-opioid agonists which treat pain without
respiratory depression

Kenakin & Christopoulos,

2013, Nature Rev Drug Disc,
12, 205-16

Example: morphine as an analgesic

Activates the µ opioid receptor, a GPCR
Adverse events include respiratory depression, sedation, nausea, vomiting, constipation
Also euphoria and physical dependence

Tolerance can develop requiring dose escalation

TRV130 – Trevena - DeWire S, Yamashita D, Rominger D, Liu G, Cowan C, Graczyk T et al. A

G Protein-Biased Ligand at the -Opioid Receptor Is Potently Analgesic with Reduced
Gastrointestinal and Respiratory Dysfunction Compared with Morphine. 2018.

 screened their internal chemical library

 measured G protein coupling (inhibition of forskolin-stimulated cAMP accumulation)
and ß-arrestin-2 recruitment to hMOR (enzyme complementation)
 identified several active compounds -> lead molecules -> HTS
 optimised for potency, ligand bias, and selectivity

Now a potent G-protein biased ligand at hMOR (human MOR)

 HEK293 cells expressing human MOR
 ß-arrestin-2 recruitment
• measured by chemiluminescent ß-galactosidase activity
 G protein coupling
• measured by inhibition of cAMP accumulation
-> showed potent agonist in GPCR assay similar to that of morphine to turn on GP pathway
-> but the trv130 have poor ability/reduced the b-arrestin pathway due to bias

TRV130 competitively binds to the hMOR

TRV130 competitively displaced EC50 of DAMGO-stimulated ß-arrestin-2 recruitment,
consistent with competitive mechanism of action
TRV130 vs. morphine in the 56°C hot plate assay in mice, which involves both spinal and
supraspinal responses
Both showed maximal efficacy – showed that TRV130 can act as an analgesic in mice.
- Mouse put on hot plate, but causes mouse to lift the paw – standard test of pain
- Can also reduce the requirement to remove the paw by usage of morphine or trv4.

 TRV130 reached peak analgesia at 5 min

 TRV130 reached peak analgesia at 30 min
 duration of action for TRV130 and morphine similar at approximately 90 min

Claimed to have made molecule that doesn’t look like morphine and doesn’t act as
morphine does to turn on b-arrestin pathway to ↓ resp + GI function. The trv has reduced
the ability to activate b-arrestin pathway; increased analgesia.

TRV130 causes less gastrointestinal dysfunction than morphine at equivalent analgesic

doses

TRV130 exhibits less respiratory suppression than morphine in rats

 Morphine increased pCO2 at doses 4-fold and 8-fold over the hot plate ED50
 TRV130 did not cause this severe level of respiratory suppression even at 8-fold over
the equi-analgesic dose

Phase 1b trial - Soergel D, Subach R, Burnham N, Lark M, James I, Sadler B et al. Biased
agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target
adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover
study in healthy volunteers. Pain. 2014;155(9):1829-1835.
30 healthy men received single IV injections of TRV130 (1.5, 3, or 4.5 mg), placebo or
morphine (10 mg) in a randomized, double-blind, crossover study

Summary: Compared to morphine, TRV130 elicited higher peak analgesia, with faster
onset and similar duration of action
 Respiratory drive reduction greater after morphine than any TRV130 dose
 TRV130 generally well tolerated, and exposure was dose proportional

TRV130 produced a transient reduction in respiratory drive whereas the effect of morphine
persisted
Degree of respiratory drive was the same long term but didn’t last as long as there was only
a transient reduction

Potential for lower incidence of nausea with TRV130

Phase 2a trial - Viscusi E, Webster L, Kuss M, Daniels S, Bolognese J, Zuckerman S et al. A

randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor,
for the intravenous treatment of acute pain. PAIN. 2016;157(1):264-272.

The molecule has lower ability to cause side effects when compared to morphine e.g. resp
depression and tolerance
integrated mean (SD) % change from baseline in oxygen saturation over 0 - 24.5 h was
numerically smaller for TRV130 than morphine”

OLINVO™ (oliceridine injection) = TRV130

New Drug Application filed
Big pharma
Learning objectives:
 How do we identify what molecular target we should develop a drug to?
 Drug discovery process
 Screening
 Modelling
 Translation
 Biomarker strategy
 Risks

Patient centricity
 Core to the development of new therapeutics is the current unmet medical need in a
given disease
 Linked to this is also the commercial value of a new therapeutic. A recent Tufts
Center for the Study of Drug Development report claimed cost of developing a
prescription drug that gains market approval at $2.6 billion (a 145% increase over
estimate from 2003)
 Caveats exist of course, and primary motivation of all pharmaceutical
companies is to reduce this by reducing attrition (which is factored
into this analysis)
Target Discovery
Disease Mechanism
The disease mechanism defines the possible cause or causes of a particular disorder, as well
as the path or phenotype of the disease. Understanding the disease mechanism directs
research and formulates a possible treatment to slow or reverse the disease process. It also
predicts a change of the disease pattern and its implications.

Disease mechanisms can be broadly classified into the following groups:

 Defects in distinct genes—genetic disorders
 Infection by bacteria, fungi, or viruses
 Immune/autoimmune disease
 Trauma and acute disease based on injury or organ failure
 Multicausal disease

Disease Genes
Disease genes have been identified based on hereditary patterns even before the
knowledge of the DNA sequences of the human genome. Following an original founder
mutation, these genetically inherited diseases run in families; examples include
phenylketonuria, cystic fibrosis, Huntington disease, Fanconi's anemia, and autosomal-
dominant familial Alzheimer's (FAD).

The specific gene defects or mutations that bring about a hereditary disorder have been
identified for a number of diseases. Progress in DNA sequencing technology has enabled
rapid identification of disease genes through genetic screening. Early intervention is possible
for a limited number of hereditary diseases.
A large fraction of disease, however, is not based on the mutation of a single gene, but
rather on a number of genes that together determine a person's risk of developing a
particular disease. For example, certain mutations in the BRCA gene family raise the risk for
cancer. However, this risk does not always equal 100 percent certainty, and individuals
bearing certain BRCA mutations may never develop cancer. Certain allelic variants can
increase susceptibility for diseases, such as the ApoE4 allele does for Alzheimer's.
 Environmental factors such as diet, toxic exposures, trauma, stress, and other life
experiences are assumed to interact with genetic susceptibility factors to result in disease.
Thus, drug targets may include molecular pathways related to environmental factors.

Multi-causal
 Disease gene – those that are directly related to the disease, it can be multi-component
(cancer – has risk factors, IBD – having a genetic signature give you a high risk, but the genes
associated only counts for 8% of patients) – this is due to impact of environment on gene
mutations
 Target types – classical receptors – mainstay of drug discovery -> GPCR – about 50% of drugs
target these
 Proteins + emnzyme (kinases)
 Dna, rna, ribosomal targets

Target identification is multifactorial - Hughes et al., 2011

Look at current body of literature of

what is known about the disease

There are exceptions to this. – e.g.

accidental findings

But all of the factors in the diagram

are involved

Do not rely on other peoples’ (academic)

data Prinz et al, 2011; Nature Rev Drug Discovery
Reproduced 1 (7%) Reproducibility of published data in 67 in-house projects
Inconsistencies 11 (26%) - Only 1 study was reproducible

The pharma wants to reproduce what is in the literature -> took all the studies in literature
that were related and looked for consistency in those done internally and, in the papers,

In pharma – reproduce to show that drugs will work in system that is published
Failure to reproduce is sig. -> ¼ of projects are dropped due to inconsistencies

‘Drugability’ - How easily a given target can sustainably be accessed by a drug

 Cellular location Transport mechanisms
- GPCRs are usually on outside of cells. Many current drug targets are GPCRs
 Resistance development – e.g. HIV protease
 Side effects – No point of treating someone if the benefit balance is impaired
challenge because not just of the risk of lack of modulating the target, but when you do
safety you are developing a therapeutic index -> if you do not have the efficacy window
compared to the toxic window then it is difficult to test
- e.g. Salbutamol (beta 2 receptor agonist)
 Target Validation
 demonstration that a molecular target is critically involved in a disease process, and that
modulation of the target is likely to have a therapeutic effect
- usually done in-vitro then in-vivo
- e.g. Knock-out transgenic animal models

 Challenge because not just of the risk of lack of modulating the target, but when you do
safety you are developing a therapeutic index -> if you do not have the efficacy window
compared to the toxic window then it is difficult to test

Assay Development

 In vivo/Animal Models  allows to define pharmacology and biological efficacy in parallel

Problem = no animal model of disease that accurately represents the clinical disease
 Pharmacology and biological efficacy in parallel
 In vitro/Cell-based - Ethical, whole cells or cell fractions, >10K/week
 HTS – High-Throughput-Screening - take large compound library and run against target of
interest
 Parallel Assays - use multi-well assay plates (96-, 384-well), >100K compounds/week
 uHTS – Ultra-High-Throughput-Screening, usually run in 1536-well assay plates, cost
effective, complex assay development, >1,000K compounds/week
 Costs – automated systems with high capital investment and running costs
 Really difficult via HTS and cell-based formats to optimise the compound
 Therefore, need to look at crystal structure of the peptide
 Low Affinity Binding - low throughput, e.g. NMR and X-Ray Crystallography

How is a compound identified? - Hughes et al., 2011

Lack of compound passed into in

vivo assays, 10-100  candidate
stage will have 1-2 assets left
within a process of year.

Then you scale up manufacturing

and do additional toxicology
studies (2 week study takes 6
months to run due to detailed
analysis required).

Primary assays

 Once target is identified need to develop assay to screen compounds in

 Usual method is to insert the gene of interest into a cell line to induce heterologous
expression of the target
 Particularly of value for G-protein coupled receptors and ion channels
 Alternative is to use cell lines which endogenously express target
 For protein targets (such as kinases) primary screen is cell free before moving to a
cell line expressing target
GPCR agonist -Assay development
Activation of GPCR can be detected in multiple ways – can also look at “bias signalling”
which may be beneficial for biology

LHS – concentration response

curve – increase concentration of
glp-1 agonist = effect on ratio
(fluorescence) – increases allow to
optimise the curve

RHS – shows where things fit in the

pathway – looks at the excitation
through the camp pathway – can
look at different parts by using
different assays

Automation and throughput key to rapid identification of lead chemical series

 Compound library consists of compounds synthesised in house, or through

commercial sources filtered for “drugability” – e.g. No known reactive groups.
 Key resource that large pharma have over smaller biotechs is diversity of library
 BUT always looking to increase chemical diversity further and partner with additional
companies / biotechs for bespoke projects
 Compounds housed in storage bank @ 1 or 10mM stocks in neat DMSO at -80oC to
preserve compound integrity

Sample store  subsets made into assay ready plates  HTS  Single plate data

Primary Screen Results – Distribution

Plate visualization shows no edge effects, and hits spread across the plate

When run -> you get a median that should be near 0

Then you have biological noise
If looking at agonist – you are looking at 2 sd to the right (50% of activation of a target)
Blockers – 2 sd to the left
Then you look at compounds that will go in
these regions
If 2 sd from normal, it is likely to be effective
- You can be stricter by using 3 sd, then
can move down to 2d

Screening and Hits to Leads

Rational Approach
- Low affinity binding

Fragment screening helps in getting novel patentable leads in a short time. The picture
shows how a fragment is grown in the target binding site. In two cycles the binding affinity
of this fragment was increased 100-fold

Low affinity binding

e.g. of using structure of protein that you interact with and build a design
Structure activity relationship – refining the lead to get a candidate molecule for clinical
development
 Small changes in molecular structure can have dramatic effects on potency
 Use of x-ray crystal structural information can show where compounds bind to the
receptor which significantly enhances drug design

Academic study looking at GPR40

Black curve – micromolar drug – never an actual drug due to its size
small changes with lipophilic fluorine ad chlorine additions tend to
change the effect

Log screening – subtly different – middle compound lost some

efficacy (shift left (due to ↓ potency) and down)

Demonstration of Donepezil binding to human acetylcholinesterase

 Limitation is that crystal structures of many targets not available
 Particularly true for GPCRs and ion channels
 Need to already have a compound that is able to bind to the target

Crystal structures of protein-protein interactions

Using crystallography - enables to see p-p interactions and model it -> certain people are
specialised for different protein models
Allows for structure-based design on poorly tractable targets

 Enhancement of technology has enabled protein: protein interactions to be

successfully modelled.
 Opens up new opportunities for structure-based design on typically poorly tractable
targets

Translation from single cell assay to function – 1. in vitro

 Activity identified in cell-based assay is only a surrogate for the target in the cell and
system of interest.
 Assays need to be developed at target tissues to confirm biological activity translates
from the “artificial” cell-based system

e.g. 5HT4 – for controlled peristalsis. 5-HT4 agonists can modulate gastrointestinal motility
through an action on neurones within the enteric nervous system

- Stimulate tissue and see effect

- Then see what the drug does to the
contraction (facilitate or inhibit)
- Then compared to cell-based activity
- Can also be lungs, kidney, liver -> set
up cell-based system to what you are
trying to target
 Translation of functional in vitro activity to in vivo function
 Aim of drug discovery is to discover candidate compounds that have activity in an
intact human
 Need to identify assays that can predict the activity required in human disease
 Caveat: Diseases in human are multi-factorial and there are no true animal
models of disease
 In vivo models aim to look at specific components of the function of the
receptor in the organ system of interest

Good translation of effect from isolated tissue to in

vivo function
- Effective dose and conc and from this data ->
translate the info into a free fraction to see from
the blood of the animals, what is conc in the blood,
and the unbound conc.
- As plasma proteins bind to the blood and the drugs
bound to the plasma proteins will be unable to work

Lead Optimisation
 Complex, non-linear process of refining the chemical
structure of a limited number of Lead compounds to
improve drug characteristics with the goal of producing
a preclinical drug candidate.
 This stage frequently represents the bottleneck of a drug
discovery program.
 Continuous, multi-step process based on knowledge
gained at each stage

The objective of this drug discovery phase is to synthesize lead compounds, new analogues
with improved potency, reduced off-target activities, and physiochemical/metabolic
properties suggestive of reasonable in vivo pharmacokinetics. This optimization is
accomplished through chemical modification of the hit structure, with modifications chosen
by employing knowledge of the structure-activity relationship (SAR) as well as structure-
based design if structural information about the target is available.

 ADME
 Absorption
 Distribution
 Metabolism
 Excretion
 Investigate toxicity
 ADMET
 ADMETox
Additional screening
 Selectivity for target
- Other related proteins in family
- General selectivity (broad ligand profiling)
 Pharmacokinetics
- Distribution – drug needs to get to target
 CNS penetration
 Cell penetration
- Drug half life
 Acceptable dosing frequency in patient group
- Route of metabolism and excretion
- Potential for drug-drug interactions
 Toxicology
- On target toxicology
 Can the target be safely modulated?
- Off target toxicology
 What other effects does the compound have?
 Therapeutic Index

Top – good example of where you give the drug and have exposure, rises, and decreases
due to decay – ends up with cmax (highest conc) – how much of that curve is needed for
biological effect + can you stain it without toxicity
 Therapeutic index
 In this example, although the index is taken at 50:50, it is now changed to Emax vs
E20 (toxicity)

An example of translation from idea to clinical candidate

Nav1.7 blocker for somatic pain

Genetic mutation of the target nav1.7 - publication was important as it stated that there
are 3 Na+ channels critical for pain
- Found that mutation = pain reception affected
- Inc. in excitability – gave painful hand + feet
- Diff mutation – pain syndrome dominated in face and rectal region

2 diff mutation of 1 gene = diff localisation of pain

- 3rd mutation – channel does not work – cannot feel any pain – first diagnosed in
India – people tend to have altered tongues, ocular issues and need high
maintenance to allow development
- 2nd image – where mutations are

- 3rd image – electrophysiology the effects of mutations

A – control
Mutated – multiple AP with the same impulse
Null mutation – no AP

CNV1014802 – from GSK  focused on the drug and not influenced by politics and
company redirecting – this is why biotech’s are perceived to be better

Did a trigeminal pain study – red is normal actions, then blue with the compound
- Trigeminal nerve was very sensitive to this compound so made sense to target it
Biomarker assay development
 Biomarkers significantly increase probability of drug candidates making it to market
 Biomarkers are key to identifying that the drug is dosed at the correct level to
produce the desired level of target occupancy

Biomarker example – anti-TNFs

 TNF-a is an important pro-inflammatory cytokine

 Therapeutic efficacy in IBD and other inflammatory
conditions rely on sufficient binding of anti-TNF antibodies
to circulating TNF-a and 1 reason for treatment failure is
high clearance of the antibody in some patients
 Elisa kits are now available which can detect unbound
levels of TNF-a at disease relevant concentrations
- Were used to prove functional binding during clinical
trials
- Potential to be used for a personalised medicine
approach

Increased probability of success of new compound to launch if biomarkers are used

 Identification of biomarkers enables:
- Patient enrichment / personalised medicine approach
- Proof of target engagement

RHS – second bar – 78 compounds that have been lost because

companies have reprioritised their focus and so loses a potential
therapeutic drug
- Hard because of business decisions and monetary limits
-
Toxicology is the initial cause of failing -> but as the phase
continues it becomes safety as the limiting factor

If you can’t have a human model or have access to human disease tissue – use hiPSCs –
enables to look at disease pathways and look at functions as they are functionally active
cells. Repurposing if the best way to utilise a failed drug
Once molecular target identified and validated, upwards of 10 years before new medicine
launched

New technologies and screening methods lead to increased drugs?

 With the exception of the odd spike, drug approvals have remained constant for the
last 20 years
 This is in spite of:
- Increased R& D expenditure
- Full genome sequencing
- Genetic markers of disease being indentified
- Improvements in biomarkers (of both disease and drug effect)
- Reasons?

Reasons for failure – a cross-industry perspective

Toxicology remains a significant hurdle for successful compound progression

Over 40% failures at phase 2 are driven through lack of efficacy (if exclude company
portfolio rationalisation)
- What can be done to reduce attrition further?

Use of hiPSCs to transform the current clinical trial model? - Matsa et al. 2016 Physiol Rev

Real potential for testing specific mechanism and its relevance to an individual cell process
in disease. Particularly relevant for monogenic changes

iPSC has a fundamental problem when testing diseases of aging as they are by design
immature and rarely even phenotypically equivalent to day 1 neonate i.e. 9 months post
differentiation.

Summary
 Drug discovery is a complex process requiring many years of investment with only
a 10% probability of success even once in clinical phase
 New screening methods and technologies have increased understanding of drug-
target interactions and optimised drug design
 Significant challenges remain
- Translation of efficacy
- Safety
- Use of biomarkers to stratify patients and determine drug effects reduces
attrition
 Chose best modality (small molecule / biologic) based upon target
DEVELOPMENT FROM INSIDE ACADEMIA
Academic entrepreneur – SME – Big Pharma

The problem is: only big pharm companies that can delivery new pharmaceuticals for
chronic diseases because of the resources requires to undertake the processes
As an academic we can develop ideas – but do not have the resources to develop the drug
or the knowledge -> basic science invention + clinical science from phase II to III trials

How are drugs developed?

Grant-based academic invention -> go through cycles of trying to gather money
- Define target, uncover new biology, and new disease mech for pharm
- Develop tools to assess efficacy and target
- Eventually reach valley of death

The process is like a game of snake and ladders with more snakes,
Can divide into no. of processes:

Phase 0 – invention and pre-clinical animal studies

Phase 1 – trials in healthy individuals – drug safety
Phase 2 – in people with disease – to get hint of efficacy
Phase 3 – people with disease – to prove efficacy
Drug approval

COST $1-2 BILLION DOLLARS

SCIENTIFIC PAPERS - INNOVATIONS & PATENTS (INCOME GENERATION)
PHARMA RESEARCH FUNDS & ACCESS TO REAGENTS

Once drug made -> have to go through a cost effectiveness process before going to nhs to
be used in patients
The cost of 3,000 and 30,000 is set by the govt advisors which makes it difficult for
academics to be fully involved in the trial
To monitor the trial, it cost 50,000,000 – there is no academic group that can afford to do
this or be involved in development all the way to the clinics.

CONTRACTS
CONFIDENTIALITY AGREEMENT
(One way/Two Way)
Gagging Period

MATERIAL TRANSFER AGREEMENT restricts what you do and controls how you use them
Protocol
Obligations
Publication Issues
Rule of Law

They will state a rule of law – the problem with academic is that they lack lawyers and so if it
goes wrong, that is when you have the problem
Need to be legally minded
INTELLECTUAL PROPERTY
INTELLECTUAL PROPERTY is the overall term that refers to all forms of idea protection:

• Patents - Authority or licence conferring a right or title for a set period to exclude
others from making, using, or selling an invention
• Design Rights - Rights to protect Visual Design of Object
• Copyright - Exclusive rights to original work
• Trade Marks - Sign of Expression of a Product

Gives protection to exploit ideas – comes in various ways – allows to work without
competition for a certain amount of time

- Top slice (take 30% of the cost) -> sliding scale of royalties
- When things are developed, need to have an agreement policy before patent filing
and making money

PATENTS
INVENTORSHIP
Academic Papers Containing Many Authors

Patents are Restricted to Inventors (not workers)

• PATENTABILITY
• NOVELTY
• INVENTIVE (EU)/NON-OBVIOUSNESS (US) - Different from the “Prior Art”
• USEFUL/INDUSTRIAL APPLICATION - Not obvious to someone skilled in the “Art”

PATENTS PUBLISH IN 18 MONTHS

- Restricted to inventors, not workers

- They must define if the idea is patentable, novel -> if it is useful
- Is it not obvious to someone skilled in the art – can it be created without specific
knowledge

NON-PUBLIC DISCLOSURE BEFORE FILING

PUBLICATION BLOCKS - Prevent Early View to Competition
Limit awareness to idea to limit competition
Veto it
EMBARGO PhD THESIS
Approach to science
pharm – invention and opportunity -> pharmacokinetics + toxicology
- Doses response
- Essential record keeping – essential for patentability
- Ideally wants – reproducibility

Academics – mechanism science – concerned about the publication -> do not care about
translation – treatment route, won’t use oral route
- Dose response not reported
- Pharmacokinetic + toxicology not reported
- Many people who work in academic do not have idea of human condition and its
transability that they are modelling

e.g. optic neuritis

- can use as type system to see if we can protect nerved from damage
- made na+ channel blocker
The chemistry is brick dust – completely insoluble
If you look at its properties it was very hydrophobic, interacts with p450 (so many drug-drug
interactions), also binds to p-glycoprotein (molecule on the endothelium that excludes
drugs entering the brain – not good for the purpose of the drug)
However, if you innovate it, when looking at p-glyco. it is not present in lesions, so we can
use the drugs to selectively target lesions, and when inject the compound you can see it
going through the lesion. – gave a mechanism to selectively target the drug through a tissue
- Didn’t go anywhere because of the valley of death

DRUG DEVELOPMENT PIPELINE

INVESTIGATIONAL NEW DRUG (IND) FILING (PHASEI & BEYOND)
• Animal Pharmacology and Toxicology Studies:
Assessment as to whether the product is reasonably safe
• Manufacturing Information - adequately produce and supply consistent batches of
the drug.
• Clinical Protocols and Investigator Information - Detailed protocols for proposed
clinical studies to assess whether the initial-phase trials will expose subjects to
unnecessary risks.

NEW DRUG APPLICATION (NDA) FILING (LICENSING) PHASE IV & BEYOND

• Drug is safe and effective in its proposed use(s). Benefits outweigh the risks.
• Drug labelling (package insert) is appropriate, and what it should contain.
• Manufacturing is adequate to preserve the drug's identity, strength, quality, and
purity.

Phase 0 – primary screen – allows to sort

many drugs out

Secondary – simple animal model

Tertiary screen – more complex

 Phase I – toxicology will affect the timing of phase
1, e.g. if 3 months of toxicology – need to do 3
months of phase 1

 Increase the dose slowly and wait before

administering on more people
 Check for toxicology and safety
 Then have multiple ascending dose studies –
depends on pharmacokinetics – dictates how often
you need to dose people

Phase II – 60-200 people – you will

register the trial (if not done, then
journals cannot publish them)
Need to define primary and
secondary outcome – prevents
changing your outcome at the end
 25% of trials change the
endpoint once the trial has finished

Phase III – outcome needs to be

clinical
 Need to look for dose response
and have a primary outcome within
2-3 years
 Then do post-marketing studies
in phase IV

VALLEY OF DEATH

It is difficult to get grants to develop commercial products

Commercial companies do not want to buy early studies so
most of their money will go into advanced studies.
As a consequence of valley of death -> bioseed funds +
business arms of charities and govt schemes to help
support early studies to overcome the valley into to getting
pharm companies on board
- They have limited funds, but they aim to exploit your IP
and if you have a lack of business acumens they will exploit
it more

PEDDLING

USE OF ACADEMIC MEDIA TO PUBLISIZE THE IMPORTANCE OF THE PROJECTS

HELP GENERATE FUNDS
• MEETINGS LARGE & SMALL
• SCIENCE ARTICLES TO PROMOTE IP-COMPANY
 • MEDIA & SOCIAL MEDIA
• USING ACADEMIC RESOURCES TO PUSH THE PROJECT FORWARD

VENTURE CAPITAL
• INFLUENCE
• QUICK PROFIT
• SHORT-TERM INVESTMENT
PREFERENCE INVESTOR SHARES PAID BEFORE OTHER SHARE HOLDERS (X TIMES
PREFERENCE)

UNIVERSITY BUSINESS/INTEREST FIRST BUYER COMPANY REQUIREMENTS

VENTURE CAPITAL REQUIREMENTS
SCIENTIST ENTREPRENEURS COMPANY DIRECTOR REQUIREMENTS
• REDUCED INFLUENCE UNIVERSITY BUSINESS REQUIREMENTS
• SHARE DILUTION versus
SCIENTIST ENTREPRENEUR
Investment terms
 TIME-RIGHTS - X% of your time allocated to Projects per week.
 FIELD OF STUDY RIGHTS - Rights to exploit your work in fields of Study
 NON-COMPETE CLAUSE - Your Academic Work can compete against
 Commercial Interest - Restriction of Field of Work, without approval. You cannot work with
other companies, without approval Companies will not work/deal with you.
 CONFLICT OF INTEREST

Academic repurposing
- Take drug that is active in another field and reuse it in another disease
- E.g. take drug in cancer -> use for MS (lack of effect in most cases)
- Do phase 1, 2 -> hope for adoption in use
- No financial backing
REPURPOSING: (PHASE I & SAFETY INFORMATION KNOWN)
PHASE II & ONE PHASE THREE TRIAL

Pharmaceutical repurposing
REPURPOSING: DE-RISKED DEVELOPMENT WITH NEW PATENT FILED
PHASE II & TWO PHASE THREE TRIALS
REGULATORY APPROVAL
LICENSE & FINANCIAL GAIN

Pharm repurposing
- Take product active in another disease -> reinvent it to get new patent filed
- Phase II and 2 phase III trial
- Most likely see monetary gain
 Table – all the other drugs were originally
non-MS drugs that were repurposed
e.g. campath was an anticancer drug – gave
lower dose, increased price -> MS
the downside of drug repurposing is that it
limits access to drugs as the price increases
– makes it difficult for people to get access
to them

From academic laboratory to the market: Disclosed and undisclosed narratives of

commercialization – Adi Sapir 2017
- The paper aims to shed light on the transformation processes by which intellectual-
property-based commercialization activities have become widely institutionalized in
universities all over the world, and on the complexities, ambiguities and tensions
surrounding this transition.
- COPAXONE-1 (GLATIRAMER ACETATE) IS LEADING SELLER IN MS MARKET $4 BILLION
A YEAR SALES

There are failures to translate in particular in pre-clinical phase

 PRE-CLINICAL FAILURE - Baker D & Amor S. Mult Scler Relat Disord. 2014;3(5):555-64.

• Model does not reflect human disease biology

• Drug does not target biology relevant to human application
• Lack of appreciation of human disease - Mechanism is all Important. Meet an pwD
• Dogma & overstating effect - Relevance of Slight Delay of a Few Days, Slight
Diminution
• Model used in a way that does not reflect human indication - Prophylactic/Therapy
• Drug doses are not used in at physiological doses - “Stress Effect”
• Drugs are not delivered in a way appropriate to how used in humans - “Route &
Timing”
• Studies are not transparent & not reproducible (Ineffective Study Design) -
Reporting Issues
 CLINICAL FAILURE
• Lack of clear understanding of human pathology
• Drug is seldom investigated by scientists developing the Idea.
• Over-interpretation of significance of pre-clinical studies
• Drug is not used at a dose relevant to the pre-clinical studies
• Population does not respond as predicted. (Ineffective Trial Design) - “Placebo
Effect”
• Dose-limiting side-effects - Less Circuitry so Less Compensation Capacity
• Study Underpowered, too short or unrealistic expectations
• Measurement Instruments Inadequate Clinical
Outcomes and Surrogate Markers
• Wrong Group of People studied (IneffectiveTrial
Design)
• Commercial Interests

Animal Studies
Sample Size Calculations: <5%
Randomization <20%
Blinding <30%
Summary

ACADEMICS:
GOOD PRE-CLINICAL INPUT
INVENTION/TARGET DISCOVERY
ASSAY DEVELOPMENT

GOOD IN CLINICAL DEVELOPMENT INPUT

CLINICAL TRIALS
PATIENT RESOURCE FOR TRIALS
ADVISORS TO PHARMA

MOST BUSINESS NAIVE

MOST FOLLOW DOGMA
MOST LACK KNOWLEDGE OF DRUG DEVELOPMENT & DRUGABILITY
LACK RESOURCE
Drug discovery in small-to medium enterprises (SMEs)

Life arc - Bridges gap between research and Pharma.

• An academic and non-profit charitable philosophy, which are institutions – basic
research, academics having an understanding of the fundamental aspects of biology
• Business orientated and constrained pharmaceutical biotechnology – translation of
the biology and chemistry into therapeutics
• Charitable status – money made goes back into research and funds future projects.
Has to report to the Charity Commission. Due to its charitable status, it can focus on
diseases with an unmet need.

Challenges to the UK pharmaceuticals sector

This graph shows the fact that

expenditure increases dramatically,
whilst the number of new chemical
entities being developed is
decreasing. As a result of the high
cost to develop less drugs, large
pharmaceutical companies don’t
fund projects that won’t return a
profit.

Ethical problem – there are still

patients with diseases that need
treatment

The reason for the graph is that

Pharma wants to see targets before
the start of development, so that
they can pick projects that is likely to succeed.

LifeArc helps the academic to deal with these targets –translation and validation.
An early-stage academic target, with some investment, can be pushed so that it becomes
interesting for Pharma, and becomes less of a risk.
This is useful for Pharma, because they don’t need to spend the money and they receive
targets that have a lower chance of late-stage attrition.
So, LifeArc acts as an industry-academia colloaboration.

“Valley of death”
 Translational gap between basic research and human efficacy
• Compounds fail in the clinic
• Lack of efficacy and/or unexpected AE
 “Reproducibility crisis”. Between 65% and 90%, of the academic literature is not
reproducible (Bayer/ Amgen).
• Targeting the wrong things?
• Academia/ Industry not on the same page?
 “Academic drug discovery centres”
• De-risk targets and develop chemical starting points.
Valley of death – where academics don’t have enough money to make their projects
interesting for Pharma. Pharma won’t provide funding because it is too early to start
investing. There is a period in between, where the project needs a small amount of funding
to make it interesting for Pharma, but Pharma won’t fund it + the academics can’t afford it.
This is where LifeArc comes in.

Compounds fail in the clinic. They fail because of a lack of efficacy and/or unexpected
adverse events. These occur at the late stage.
Reproducibility crisis means that between 65% and 90% of publications cannot be
reproduced. This is because it is very difficult to completely replicate studies from one lab to
another. This does not mean that the data from publications are wrong. Pharma, when
taking a project, will carry out wet diligence, where they will try to reproduce the pre-
clinical data. This is one of the challenges of translating science from an academic
environment into Pharma.
De-risking targets means choosing projects that are likely to succeed.

Centre for Therapeutics Discovery (CTD)

• Small Molecule
• Drug Discovery
• Antibody Engineering
• Antibody drug conjugates
• Structural biology

Real world DD processes

• LifeArc Drug Discovery centres on translation of scientific ideas into practical
biological/chemical strategies for therapy
• The process is surprisingly consistent across academia, biotech’s, SME’s and large
pharma

This takes a long time and takes a lot of money.

Pharma spends most of their money at the pre-
clinical stages, so they want to know at the lead
identification stage that they are selecting
projects that will succeed.

Progressing projects into Drug Discovery - (Swinney, 2013)

THE DD process is not linear

• An idea is formulated, and then the process of

candidate discovery is carried out, to reach a
drug candidate.
• The development arm is what Pharma does. It
makes sure that the drug can get to its site of
action, and makes sure that its pharmacokinetic
profile is what is required.
• Target product profile (TTP) is a planning tool for
therapeutic candidates based on FDA Guidance
for Industry and Review Staff Target Product
Profile — A Strategic Development Process Tool.
• What is tolerable
• What does the FDA require
 • What are patients prepared to take
• What are the adverse events
• Therapeutic index – efficacious dose vs toxic dose

A single idea might have around 10 different routes to finish.

R&D – Registration and Development. This is the complete cycle.

An arsenal of technologies and disciplines

HTS (high throughput screening) – small molecules are profiled at single concentrations in
vitro assay.
Encoded library technology – pieces of DNA with a compound attached to them. In a few
tubes, billions of compounds can be tested with high sensitivity.
Translation of the assays into a molecule that is drug-like and has therapeutic potential:
• Rational drug design
• Compound libraries
• Medicinal chemistry
• ADME – does the liver digest the
compound, is the drug at the target site at
the desired concentration
• Assay development
• Antibody engineering – chemically
synthesise antibodies that can be
fractioned off and replace chemical groups
and regions, Fab/Fc regions.

Translation is pivotal within the drug discovery process

• In the drug discovery end, we start with an identified protein. This protein will need
to be expressed, or a mutation is found that is important for a condition.

• Profile the compound versus the protein.

• It has no physiological constraints, no physiological predictability. Compound might
bind, but the effective is unknown. It might make the protein behave worse.
• Profile the protein in a more physiological condition e.g. whole cell culture.
• Need to understand what the protein does in the network. Whole organs may be
used for this. Rodent and animal models are typically used. These are useful but
have limitations e.g. hard to determine if a mouse has schizophrenia, and the
difference in severity of schizophrenia over the course of a few weeks. The
translation between the animal condition and the human condition is difficult.

Moving from the pre-clinical part to the

clinical part is ultimately the translation
of the pre-clinical data to the clinical
setting. In the clinical setting, there is
physiological predictability, however
only one compound can be tested at
any one time.
LifeArc therapeutic focus and target classes
LifeArc focuses on a number of different target classes:
• Soluble enzymes – kinases, proteases, nucleases, phosphatases
• Cell surface proteins - Cell surface receptors, GPCRs, ion channels, gene reporter
• Protein:protein interactions - Transcription factors, DNA repair complexes,
• Unknown target

More new drugs identified via Phenotypic screens (Swinney, 2013)

Molecular Mechanism of Action

Phenotypic screening:
• System-based approach – phenotypic approach, distinguishing efficacy from toxicity
e.g. kills cancer cells but not healthy cells – good for developing a therapy.
• Target-based approach – identify target first, and then test for what condition it
might be involved in
• Most drugs that are successful are system-based and have undergone empirical
observation.
• Incorporate disease relevant pathways
- Over-expression / siRNA
• Allows for the identification of unknown (hidden) drug activities

Translation:
GPCR – signals secondary messengers, has a phenotypic output and we know what we
want to see.

In this case:
Tissue bath assay
• Compound X is the test compound against natural ligands
• Downward inflection means contractility
• Concentration-dependency present, compound X is a partial agonist compared to
the natural ligand
• Looking further down the pathway, there is a different pharmacology.

Camp 2nd messenger

• Compound X is now a full agonist
• There is a difference in the potency, which is not evident in the tissue bath assay
• Very small error bars = very precise assay
• But it gives a different pharmacology
• Similar to the signalling pathway in the
phenotypic response

Now we know the receptor signals through cAMP

through adenylate cyclase. It also signals through
Gq subnuit, due to the calcium response.
Different pharmacology when looking at the
calcium assay, identifying that the compound X
doesn’t work at all.
Measuring the phenotypic response, the
pharmacology is different. There is some partiality,
and a difference in potency.
Assay in more intact systems with ‘high content’
• Ensure modulation of activity of target protein impacts disease as expected (target
validation)
• Focus on disease relevant cell-based assays to optimise potential drugs
- Range from simple assays measuring intra-cellular activity or secretion of a bioactive
agent from cells, to phenotypic screening

The graph with multiple lines is the result of measuring pharmacology in

an intact system – you pick up many errors and impacts.
• These are networks that are resulting in the phenotypes
• Very difficult to reproduce
Have to repeat this to make sure that it is statistically significant.

Development of therapeutic antibodies

 Areas of expertise
– Antibody Generation
– Protein Production
– Biophysical Characterization
– Humanization
– Affinity Maturation
– Antibody Drug Conjugation

 Required capabilities
– Molecular cloning (PCR, digests, ligation, electrophoresis, DNA preps)
– Tissue Culture
– Mammalian Transfection, Protein Expression and Purification
– QC: SDS-PAGE, Western Blot, ELISA, Flow Cytometry, SPR, Bli, DLS, SEC-MALS,
cIEF etc.
– Phage Display: Panning

Medicinal chemistry
• Significant ex-Pharma experience
• Over 150 years and 15+ clinical candidates
• Access to latest synthesis technology
• Additional synthesis capacity in Asia and UK
• In house in vitro ADME/DMPK support
• State of the art in silico design
• Supported by structural biology at Leicester University

Important to understand the structure of the proteins that are interacting.

• In silico screening can occur if the structure has high resolution, and the folding
mechanism is known in its dynamic configuration
• Computational docking of compounds
Works well, very high impact as long as the protein can be solubilised ( = crystal structure)
• In the absence of a crystal structure, it is not useful
• Surface proteins are difficult to get a crystal structure because it is outside of its
native state, so it doesn’t fold well
 Resources
Limited resource capacity
• Low bandwidth – how big the capacity is,
how many compounds you can get
through, how many targets you can get
through the portfolio
• Cannot target many therapeutic areas
and a diverse range of targets – difficult
to achieve with this FTE (full time
equivalent – one person’s worth of time,
or a tenth of ten people time)

Actively managing a portfolio (resource)

A method to overcome the challenges of many targets = portfolio
• Where to spend money and time spent on projects.
• Bottom left - Spikes identify how much effort a project takes, changes with time
• Managing resources is very difficult – specific jobs requires specific people

How can the drive to potentially de-risk

targets for Pharma, whilst maintaining an
appropriate level of support be overcome?
• Address the attrition – most things
will fail, but it is important to try and
enable the science to show what will
fail as early as possible, so that we can
focus on other, potentially successful,
things.
• Balance the attrition against the
critical mass of resource
• If you take a long time, the landscape
will change to

What drives target choice?

These are things that need to be considered when a proposal is brought from an academic.
From a Pharma perspective – is there an avenue of intellectual property that can be secured

Small companies –
secure intellectual
property for the
academic, takes care of
the law side

The criteria for project

inclusion are many and
varied and often
specific.
Perspectives/opinions
are equally varied
e.g. different scientists
or different parts of the
company
Active management of the LifeArc portfolio
These are the criteria that LifeArc need to
establish with the academic prior to working
with the academic
Clarity of intent
• Must not be published in an article
• How will the academic be funded e.g.
royalty scheme

Project Structure Academics

• LifeArc Resources provided free of charge
• PI always included in project team
• Agreement provides revenue share back
to PI  Sliding scale
• Takes into account background IP
• IP jointly owned
• PI is free to publish (if project team agree)
• LifeArc can defer publication if conflict with commercial strategy
• LifeArc normally has commercialisation rights

Benefits to Academics
• Access to drug discovery capability free of charge
• No loss of control of own work
• Potential to access tool compounds and Abs for publications
• Share of upside post-partnering
• Possible access to industry funding downstream

Project Structure Pharma/Biotech

Collaborations
• Milestones and target profile defined up front
• Partner joins project team
• Partner may provide compounds and/or resources
• Defined points for transfer of project to partner
Partnering
• Risk sharing
• Upfront, milestones and royalty

Benefits to Pharma/Biotech
• Access to huge network of academic research
• Early sight of cutting edge science
• De-risking early stage targets at limited risk and resource exposure
• Ability to shape project selection and direction
• Potential to trawl network for specific solutions
• Access to academic expertise
• Flexible deal terms

LifeArc Pipeline
20 projects at any time - 12 small molecules; 6 antibodies; 2 Antibody-drug conjugates
Overall 5-7 are late stage
13-15 are typically in early phase validation stage

Primary disease areas = cancer, fibrosis, pain, AD, autoimmune disease, Cushing’s disease
Project sources - Call for Targets

Call for targets – if you are an academic, they will

want to discuss ideas.
• Works with consortiums.
• Goes to discuss with Pharma – identify
potential ideas that they would like to work
on. Shows that they are interested. Pull-
back system = Pharma is pulling ideas from
academics.

Project Selection - Triage

If it can’t be rejected at that point

• Full review carried out – literature searches, works with academics
• LifeArc does this part – checks the FT (freedom to operate) makes sure that every
part of the project, such as the cell lines that might have been obtained from
another academic – this will interfere with the drug discovery because the original
academic has read-through into the drug discovery, so you have to remake reagents.
Drug discovery license from companies that supply reagents.
If full review is good, it is sent to external experts to review.
• Academics
• Pharma partners
• Key opinion leaders
Experimental due diligence
• Wet chemistry
• Studies to reach a feasibility to show if it worked or not
• Reproduce data
 Approved projects

Pharma Alliances
Neurodegeneration – a problem
• Over 20 years there has only 4 drugs that treat the symptoms, not underlying cause.
• 123 clinical failures – an enormous amount of money in failed targets
• By 2030, it costs $2 trillion just to treat people, not cure them

Very difficult to achieve

• People are likely to get Alzheimer’s at 20 years of age, but no symptoms
• Need to be taking prophylactic treatments, for something you might get, that might
work, 30 years before it appears
• Patients won’t do this
• Hard to make a clinical trial for this

A partnership to translate fundamental discovery

Pot of money
• Call for targets – academics bring
targets for dementia specifically
• The partners assess the targets

Advantage of the partnership

• Pharma will do some of the tasks
that are outside of the budget, such
as generating antibodies that are
necessary for the project, animal
models, understanding of a
structure

Very powerful partnership – de-risking

targets

Keytruda Immuno-oncology breakthrough

• Binds PD-1 and unmasks tumour cells - harnesses power of immune system
• Delivering patient impact:
– Malignant melanoma – FDA APPROVED
– NSCLC – FDA APPROVED
– Head and Neck – Under FDA Review
– Over 200 clinical trials ongoing covering 30 different tumour types
– Over 100 trials on combinations with Keytruda
• 834 melanoma patients, tumours shrank in 33-34% of patients
• Overall survival for patients treated was between 67-70%
• 280 patients suffering from metastatic NSCLC expressing PD-L1 on > 50% tumour
cells showed tumour shrinkage in 41% of cases
These images show the impact of Keytruda
• Image A (left) has a tumour
• Image A (right) is after treatment, the tumour has gone. Complete
response within 1 year
• Image B (left) is a tumour that is life-threatening
• Image B (right) is the stable disease after 1 year, so the tumour has
stabilised, not getting worse

• Costs £15-20 million to fund LifeArc

• In the late 1990s-early 2000s, came to LifeArc with the PD-1 checkpoint
inhibitor, asking to humanise it
• No upfront payment, instead chose royalties
• Now it receives £500 million for 6 months work
• However, this is only less than 1% of what Pharma will generate from drugs
• These profits will go back into research to fund other projects

LifeArc can reinvest £500M back into research

Drug Discovery and Repositioning

Here is the generic drug discovery process, particularly for small molecules.
• Start with a phase of target ID and validation
• Bioinformatics and data are involved here
Hit and Lead ID
• Once a target molecule has been identified that you want to screen
• High-throughput screening takes place
• Select a range of hits, and select a lead, which is the best candidate molecule
Lead to candidate
• Chemists optimise the lead molecule to make it more orally available, safer, and
pharmacologically more desirable
• Animal models used to predict safety and to predict efficacy
Phase I
• Division between o adverspreclinical and clinical research
• Molecule placed into humans for the first time
• Has to be done stringently
• Evaluates the safety and pharmacology of the drug only, not the efficacy
• Takes place in 20-100 healthy human volunteers
• Has to be safe with ne events before moving onwards
Phase II
• Separated into A and B
• Focused on determining the dosing of the drug and the efficacy of the drug
• Takes place in patients for the first time, several hundred patients
• Small number of patients, so may not detect adverse events
• At the end of phase IIB, is the Proof of concept – show that the drug works in
patients with the disease
• At this stage, millions of pounds will have been spent
Phase III
• After Proof of concept has been established
• Large comparative study, often comparing the drug against other drugs on the
market
 • Have to show that the drug is superior to other drugs on the market, in terms of
safety and efficacy
• Many drugs fail here
• At the end of phase III, if good efficacy and safety is shown, the regulators approve
the drug, and it goes on the market.
• The first few years of marketing the drug is known as Phase IV, and is part of the
drug trial
• Pharmacovigilance takes place, which picks up adverse events that might be rare and
related to that drug. The label of the drug might be altered at that time.
• Drugs can still fail at this time.
With biologic development, such as monoclonal antibody drugs, this process is shorter. The
first three stages are shorter, as it is defining the monoclonal antibody for the target, and
generally it is quicker to target. This is the same for the repositioning of the drug, where an
existing safe drug is put into a new disease indication, the process moves to phase II.

Target validation - How to Validate a target

Often target validation is described as:
• Validate the target
• Go into high throughput screen
• In vitro and in vivo assays
• Clinical studies
This is inaccurate. Although a lot of target
validation is done early, target validation is
an ongoing process, and a target is only
validated once it is working in the clinic for a
number of years and in people.

Cox-2 inhibitors
Good example of target validation is the selective cox-2 target class.
These are important pain targets. Cox-2 inhibitors were on the market in the 1990s, with
Vioxx being the most famous of these. They were heavily marketed by direct marketing.
People with osteoarthritis or minor pain were marketed these painkillers. These painkillers
were very effective.

However, there were some issues.

COX-2 inhibitors are working on a fundamental piece of

biology. They are working on the equilibrium in the
platelets, between thromboxane and prostacyclin.

If COX-2 inhibitors are placed into the vessel, the biology

of the pathway is disrupted. This makes the blood more
clottable, the platelets aggregates and constriction of the
blood vessels occurs. Often this would occur to small
vessels, resulting in cardiovascular events such as strokes
and heart attacks, particularly if there is an underlying
cardiovascular disease.
This would have been predicted, if the biology was well understood. Around 2000, reports
from doctors showed that people that took COX-2 inhibitors had a higher rate of heart
attacks than you would expect in the demographic.

Financially, this had a big impact on drug companies, particularly Merck. The pharmaceutical
sector declined because the drug was withdrawn in the EU and the US.
Further on, class actions occurred which affected the company’s reputation.

Target Validation: The first rule

"All things are poison, and nothing is without poison; only the dose permits something not to
be poisonous “- Paracelsus, 1493-1541

Perspectives on target validation and safety

Biology – the analysis that is done to look at target validation and safety
This is the overall biological paradigm of early target validation.
• Take a disease model e.g. cancer cell lines or clinical samples such as blood and
tissues, or knockout mice
• Do a series of studies, such as genomics, proteomics and genetic studies
• Look for genes that have been altered in the disease state
• Prioritise these genes to see if these would be suitable as targets
• Once the candidates have been identified, more studies can be carried out, such as
knock-down of the target using RNAi or knock-out studies using knockout animals
• When there is confidence with the target, high throughput screening would occur
Pathway Informatics & Target Discovery
One of the big contextual parts of looking at a target, is pathways relating to that target.
Once a target has been identified in a genomic experiment, in an ideal world for drug
discovery, the pathway would be linear with the target in the centre of the pathway.

Modulation of the target would lead to the desired downstream effects.

In reality, targets and pathways are highly complex. There is lots of cross-talk. Modulation of
the target could have unforeseen effects, and also modulation of the target might not be
enough to shut down the particular process.

Target discovery focused on identification of a pathway and macromolecular target involved

in disease. The assumption is:
• One target  One consequence

In reality:
The target is usually one component of a complicated biochemical network
• A target acting as a single critical node may,control or influence many processes.
• Network interactions can be redundant. “Work arounds” limit efficacy of a drug.
• Drugs can interact with multiple targets.
• Efficacy and safety are often a consequence of interaction with multiple targets

Pathway Pleiotropy & Redundancy

Example of a simplified pathway system, an oncology example.
• Oncogene target that wanted to be blocked
• Inhibitor is placed upstream to block the
oncogene target
• However, the target pathway is complex
• Blocking the target might have an off-target
effect, which might be a harmful side effect
• Equally, tumours may find a work-around.
So, blocking the target gene will result in
the tumour finding a work-around that still
activates the oncogene. So, this inhibitor
will only be partially effective.

Combination therapy can be considered, which is often done in cancer.

• Completely shut down a target
• It is holistic, and can’t be sure that everything is shut down

Pathway Analysis: STITCH -> Tool to look at a pathway complex. STITCH is used to look at a
list of genes and their pathways.

Pathway Analysis: ENRICHR -> Tool to look at a pathway complex. ENRICHR can be used to
look at a list of genes and identify common pathways.

e.g. gene expression experiment.

• Another approach for target gene discovery, rather than looking at a single target,
you might want to look at which target pathways are upregulated in disease state.
• ENRICHR can be used for this.
 Target
Genome Wide Association Studies are the primary genetic form of study, used to study the
genetics of complex diseases. First case of a reasonably successful GWAS was the Wellcome
trust case/control consortium in 2007.
• This shows the nature of different of
complex diseases.
• Seven diseases are shown with different
genetic properties.
• The alternating blue colours are each
chromosome in a Manhattan plot.
• The green peaks are genome wide
significant signals.
• This shows that bipolar disorder had
very little signal in it. This is highly
complex disease, with only 2000 cases
present. The study isn’t powered to
detect anything.
• Coronary artery disease had a single
signal.

• Crohn’s disease had several very strong

associations across the genome.
• It showed 10 genome wide significant signals.
• If you take the 10 signal genes, and place it into the ENICHR tool, one of the pathways
that comes up is autophagy. Almost all of the peaks contain genes that are involved in
autophagy, which is a process by which cells clear up debris. This tells us that in Crohn’s
disease, which is irritable bowel syndrome (a defect of the gut), there is defective
cellular clean up, which shows that the gut is not self-cleaning.
• This identifies a mechanism for a disease from straight genetic study in humans.
• Although the time it was published there were drugs to upregulate autophagy, this
immediately gave a hypothesis that you could use drugs like Rapamyicn, which is a drug
known to upregulate autophagy, to treat Crohn’s disease
• Rheumatoid arthritis and type 1 diabetes are both autoimmune conditions. They both have
a big peak on chromosome 6, which represents the HLA gene which is important for
immunity. HLA is present in a large amount of diseases, which shows that immunity is
important in a range of complex diseases.

Target ID by GWAS - Autophagy - A Crohn’s disease mechanism

Here, GWAS didn’t just identify targets, it also

identified mechanisms. The autophagy
mechanism in Crohn’s disease has been a point
of interest and heavily investigated.

One of the issues is that drugs like Rapamycin is

quite toxic, so they might be effective, but
should not be used on a long-term basis.
Drug discovery needs to be looked at for drugs
that would be more suitable for chronic use.
Therapeutic opportunities from GWAS
Gathered GWAS association data.
At the time, there was 800 publications of GWAS associations.
This correlated with 991 genes that were associated with disease.
• How many genes were druggable with a small molecule drug, and how many could
be targeted with a biologic molecule, known as a biopharmable gene?
• An average of 15% of genes are druggable, and 25% of genes are biopharmable.
• 212 genes were druggable, and 469 genes were biopharmable.
• The resulting percentages were higher than the expected percentages.
• This suggests that genes associated with complex diseases, are more likely to be
drug targets as well as modulatable.

The reason of the study was to look for drug validation evidence and drug repositioning
opportunities.
• Took 155 GWAS genes that are already being studied – done by comparing the 991
GWAS genes with the Pharmaprojects, which is a database of all the current drug
discovery projects
• Matched indication – if the gene is
associated with diabetes, they
looked at what was being worked
on in the industry for that gene.
• If it was diabetes as well, it went
into YES. 65 genes had the disease
association and the drug discovery
project having the same indication.
• 93 genes were mismatched – the
gene might be associated with
diabetes, but it might be worked
on for Alzheimer's disease.
• This could be a new
indication for the drug.

Target Indication Aligns

Sanseau et al. Nat Biotechnol. 2012,

30(4):317-20.)
 Here are two interesting lines of evidence from this study.

• We can see genes that align, meaning that the indication of the project aligns, such as
HMGCR which is the target of statins, the most effective drug used in the clinic. The
indication of the drug is lowering cholesterol, and the GWAS trait was cholesterol level.
So it shows that we can identify the target with genetics.
• Other cases include IL12B being associated with psoriasis, and its GWAS trait is psoriasis as
well. Ustekinumab has shown to be effective in treating this.
• Likewise in Crohn’s disease, Ustekinumab is in Phase 2 trials, so it gives some strength to
carry on using Ustekinumab, and carry on trials using Ustekinumab in Crohn’s disease.

Where the drug indications don’t align, this suggests that drugs could be repositioned to a
new indication.
For example, there is association between Crohn’s disease and TNFSF11, which is a TNF-
cofactor. There is a monoclonal antibody against this protein that has been used for
treatment in osteoporosis/bone cancer, so it is possible that this also be useful in treating
Crohn’s disease.

GWAS > Drug: Mode of action is key

The direction of effect needs to be considered alongside the GWAS indication.

• An example is the NR3C2, which is a salt channel that is
associated in hypertension in GWAS.
• There is a known agonist, fludrocortisone, that
indicates the cerebral salt-wasting syndrome.
• The side effects of this agonist, it causes hypertension.
• This suggests that we don’t want to agonise this,
instead we want to antagonise this
• The hypothesis is that the antagonist will inhibit and
reduce hypertension
• This is potentially the repositioning opportunity.

There are no known antagonists of this target

• ChEMBL database shows small molecules that are tool compounds
• Use to test mouse models with the disease
This is how genetics can be used to validate targets and reposition drugs.

Health and population effects of rare gene knockouts in adult humans with related
parents
 Complete gene knockouts are highly informative about gene function
 We Exome sequenced 3,222 British Pakistani adults with high parental relatedness
 Subjects were healthy and reproductively fit
 Extensive regions of autozygosity were identified

Narasimhan et al (2016) Health and population effects of rare gene knockouts in adult humans with related
parents. Science. 2016 Apr 22;352(6284):474-7

BornInBradford is a cohort study where the Bradford population, a third of which is a

British-Pakistani population, was analysed.
• This population is known to have a high rate of first-cousin marriages, so genetically
are interested – there is a higher rate of consanguinity in that population.
• The reason for sequencing this population was because the BornInBradford
population were recruited in maternity clinics, so when people in Bradford had a
 child, the adult parent would have their health history check to see if they would join
the study, and then the children would be followed up with a study. So, this is a birth
cohort, with an adult element.

• They had extensive regions of autozygosity – where you inherit both strands of the
chromosome from the same ancestor.
• This means there are regions where there is no heterozygosity, and all
variants are homozygous.
• Looking at a Caucasian population, like the Caucasian population in the 1000
Genome Project, they have on average 4-5 regions in their genome of 1 Megabase
size, that by chance, are autozygous.
• The BornInBradford cohort, although the majority are on the bottom left of the
graph, there are outliers that have 30-40 regions of 6-7 Megabases where the
regions are homozygous.
• We all carry disease-causing mutations in the heterozygous state, however it has no
health effect. Individuals with large areas with homozygous variants are likely to
have health effects as a result of those variants.

Narasimhan et al (2016) Science. 2016 Apr 22;352(6284):474-7

• Looked at the regions, sequenced them, and looked for loss of function (LOF)
mutations.
• There was 1,111 loss of function mutations. This included 781 genes
• Among those, 53 were known Mendelian disease genes, meaning that 53 of these
genes are supposed to cause rare
Mendelian disorders. However, this
was not happening in that population,
which meant that the gene causing
Mendelian disorders were wrong and
that they are not Mendelian disease
genes, or another reason could be
that it has a low penetrance and has
not emerged, or some other reason.
• From the point of view of
druggability, there were 110 genes
that can be drugged, and 137 genes
that are predicted to be druggable

Genes with benign LOF are less connected

 What does LOF tell us about gene function in a drug discovery context?
 Genes with LOF variants have less interactions with other genes (based on STRING db)
- less connected in pathways
- Gain of Function variants tend to be more connected in pathways

 They have 7 protein-protein interactions with other genes in the database

 The average gene has 14 protein-protein interactions
 Compared to the gain-of-function mutations that activate a protein and causes a disease,
they are much more connected, with an average of 47 protein-protein interactions
 Do genes with “Benign LOF” mutations make better, safer drug targets?
- 30% of Born in Bradford LOF genes that entered development were approved by
regulators
- Background success rate of 14%
• This means that these targets are half as connected, but twice as likely to reach the
end of the drug discovery process and succeed, and to a regulator

- Growing population variation resources will make human KO studies viable for most drug
discovery

So, these genes are:

• Less connected
• Can be modulated
• Are still involved in the disease
• Not involved in a variety of pathways
• Safe to target

Similarity
Avandia – A familiar pharmacovigilance story
• Avandia is a very effective diabetes drug. Appeared to be safe on the market,
however it was only after it was taken by millions of people, did cardiac risk emerged
for this drug.
• Avandia raised the risk of heart attack.

Why PPARG agonists cause cardiac events?

Type II diabetes target -> nuclear hormone receptor
Highly expressed in adipocytes
Rosiglitazone (Avandia) was a blockbuster for GSK until emergence of cardiotoxicity

The mechanism:
• Unlike COX-2 inhibitors, where the risk of cardiovascular risk could have been
predicted because of platelet biology, Avandia works on PPAR-gamma.
• This, on the face of it, looks like the perfect target
• PPAR-gamma is massively expressed in adipocytes. This is an excellent target area
for diabetes. Not usually expressed in any other tissues, it is usually has very low
levels of expression.

How could there be cardiac events?

• Look for off-target effects

PPAR protein family

• The image shown is a dendrogram of all the nuclear hormone
receptors, so they are all related.
• PPAR-gamma is on the bottom green circle. It has 2 closely-
related homologs, PPAR-alpha and PPAR-delta.
• The bottom image is an alignment of these proteins, in the
area of where the Avandia agonist binds.
• There are large areas where there is high protein homology,
which suggests the protein structure is similar, so this might be
the case that the agonist is binding to these proteins.
• This was the case. It binds with lower efficacy.
Target Expression -> look at the expression of similar proteins using these tools
GTEX
- Tissue expression
- Expression genetics (eQTL)
EBI Gene Expression Atlas
- Comprehensive view of public expression data
NCBI GEO
- Comprehensive view of public expression data

PPARG agonists
Chembl query shows Avandia activity at PPARG homologues
Notably all are expressed at higher levels than PPARG in heart according to EBI Gene
Expression Atlas
- PPAR-gamma is not expressed in a cardiovascular system, but PPAR-alpha and
PPAR-delta is highly expressed.

If we line up the expression of the three proteins:

- Although the drug might be 10x more effective

when bound to PPAR-gamma, and the drug is
much less effective in PPAR-alpha and PPAR-
delta, but PPAR-alpha and PPAR-delta are much
more highly expressed in the heart
- This means that there is exposure to the heart,
and so there is an effect on the cardiac and
vascular tissue

Polypharmacology - One Drug, Many Targets

 Drugs metaphorically known as “magic bullets”, but “magic shotgun”
 may be more appropriate
 Drugs often exhibit polypharmacology binding multiple targets
 The chart shows the known affinity (Ki) values of antipsychotic drugs for a panel of
receptors. Low Ki=high receptor affinities
 Variation at any of receptor could influence drug action

Keiser, M. J. et al. Nature 462, 175–181 (2009). Hopkins AL. Nature 462,167-8 (2009)

• The image shows anti-psychotic drugs

• The heat map shows the strength of action of an anti-psychotic drug on the different
hormone receptors, such as serotonin receptors, dopamine receptors and
adrenergic receptors.
• Most psychiatric drugs work on 25-30 targets
• This in part, is why they work, because they work on a very wide range of targets,
but it is also why they a lot of severe side effects
What Makes a Good Animal Model?
• A good animal model should have the following characteristics:
• Should closely reproduce the disease or condition under study
• Should be an industry/academic accepted model
• The data should be robust enough to be duplicated by a 3rd party
• Should show statistical significance – feasible to use sufficiently large number of
animals to demonstrate statistical significance
• The data endpoints should be convincing enough to justify transition into man

ANIMAL  HUMAN

When trying to predict how effective and safe a drug will be, animal models need to be
used. This is a checklist of what is needed in a good animal model to successfully transition a
target into humans.
• When doing an animal experiment, it is important to do a power calculation to show
that there is enough animals to show power and statistical significance, to show the
result is valid. It is also used to show that you are not using more animals than is
needed to be used.

The TGN1412 (CD28-superMAB) disaster

• TGN1412 is a super monoclonal antibody. It is a dual agonist to two receptors on two

cells and is a CD28 T cell co-activator.
• It is used for leukaemia and potentially for rheumatoid arthritis.
• This drug was effective in animal models with no adverse events.
• Human trials in Northwick Park led to serious side effects because of poor testing.
• They lined up six healthy volunteers and injected them all consecutively, so that they
had no chance to observe the subjects.
• Most of the subjects developed symptoms within the first 20 minutes.
• They developed a cytokine storm.
• What happened is that they miscalculated the dosing when it was being transitioned
from animals to humans.
• This meant that they cytokine system in the subjects into overdrive, ending up with a
huge immune system shock, and serious adverse events, such as the loss of
extremities such as fingers and toes. None died however.
Selecting Species for Preclinical Studies
First thought that perhaps the animal models were not good models for use.
• The reason for this is the evolutionary pressures on animals.
• If histones were the drug target, which are essential to genome function, a pufferfish
could be used for a good model for human histone function.
• This is because these proteins are under extreme negative selection, so there is not
much difference between fish histones and human histones.
• If alanine:glyoxylate aminotransferase was the drug target, which is important in the
processing of meat in a carnivorous diet.
• This is under extensive positive selection in cats. So if a cat was used as a model of
this protein, it would provide inaccurate data.
• The function of this protein in cats is completely different to the function of the
protein in humans, so the two are not suitable as models for each other.

This is the consideration when working with a target in another species, we should look at
the actual sequence of the target, and any evidence of selection in that target.
Intellectual Property – Foundations of Patents Law
Patent
 A bargain between the state and the inventor
 The inventor has to supply full and complete disclosure of the invention
 A limited monopoly on a product or process or use
 State awards 20 year right to exclude others from making or using the invention as
described in the specifications
 Contrast to trademarks, copyright, design, etc rights.

Some of the decision in the cases – one side is a scientist trying to explain what it is, and the
other is the court/lawyers making the patent, in between there are trade scientists.
Have to convert the invention into written language – this is where the law gets wonky – so
things can go wrong

Patents are territorial

 Patents are territorial.
 A French brevet d’invention has no effect outside France.
 A UK patent has no effect outside the UK.
 A person has to apply for patent protection in each country in the world.

Only exist for 1 country – there is no community patent

You apply in the EU patent office and indicate which countries you want to patent for –
more countries – higher the fee, and the greater no. of translations required (this might
affect the written items due to errors in translation)
World intellectual property in Geneva

Filing and Grant of a Patent

 Date of filing – (Priority date if no priority claimed)
 Preliminary Examination – formal examination
 Search
 Publication (18 months from priority date)
 Substantive Examination – on patentability– “a conversation” between examiner and
applicant  Grant

Most important date for lawyers is the date of filing (priority date – date where it is filed
anywhere on the planet) -> can go 6mnths later and claim the same date of filing – have this
date for up to 12 months.
- Can claim 1st Jan as data filing until the 31st Dec
Date important to make sure that if competitor submits on the same date -> they will work
into hours, minutes to check which was filed first.

First to file system – first to file rather than first to invent. The latter is difficult because
when is an invention actually an invention.
Lab books are signed, and counter signed at all times
The US is now first date of filing. – this also means that sometimes you get a situation where
the inventor does not file first, but the corporation does – who is entitled to own the
patent?

Date of filing and priority date are interchangeable

Countries that are too poor to have patent databases will send to HYPO
Japanese patent office and us patent office will search throughout the 3 main databases
- Sometimes difficult with new data because there is no previous data to search
against
Patent examiners might send it back if not understandable – need to be clear in explanation
Us patent e.g. petrol motion machine – see if you are trying to claim a field of science or a
theory (not patentable). Usually wait until the patent is granted before an invalidity claim is
put into place by opposing company

Basic requirements
o Novelty - ie the invention is new
o Inventive step - ie the invention is not obvious
o Capable of industrial application; and
o Not excluded subject matter

Novelty, inventive, industrial application

(+ subject matter per say – at some point patent will not protect the subject matter even if
they follow the first 3 requirements)

Novelty – has to be new – not available by any means (pictures, advertisements, oral
disclosures) anywhere in the world – what is the state of the art -> everything before date of
filing is state of art

Novelty
 Section 2, UK Patents Act, Art. 54, EPC, Art.27(1), TRIPS
 Article 54 -
 (1) An invention shall be considered to be new if it does not form part of the
state of the art.
 (2) The state of the art shall be held to comprise everything made available to
the public by means of a written or oral description, by use in any other way,
before the date of filing of the European patent application.
 prior state of art = everything made available to the public (whether in the United
Kingdom or elsewhere) by means of written or oral description, by use or any other
way before filing date of application
 Objective, universal test - not relevant whether inventor knew about prior art or not;
all known prior art everywhere
 New Use of an old thing allowed - if new result; new use or purpose
 New Advantage of an old thing - Mobil Oil III

Prior state – can be difficult as opposition can create obscure publications that could
describe what you are saying a few years ago – PhD thesis is often brought up as invalid
data against a case. The court and judges have to make the decision

Concept of novelty and terminology

 The following are patentable - new things (products) / new processes / new uses for
old things / new advantages of old things used in an old way / selection patents
 Priority date: The date on which the novelty of the invention is judged
 Prior Art: This means something which existed in the state of the art before the
priority date of the invention
 Anticipated: This means some piece of prior art exists which affects the novelty of
the invention

Disclosed to the Public/Confidentiality/NDA

 To anticipate an invention must be available to the public:
 “to form part of the state of the art, the information given by the use must have
been available to at least one member of the public who was free in law and
equity to use it” PLG Research Ltd v Ardon [1993] FSR 197, 226
  “if the information, whether in documentary form or in the form of the
invention itself, has been communicated to a single member of the public
without inhibiting fetter that is enough to amount to a making available to the
public…” Bristol Myers Co’s App [1969] RPC 146, 155
 Possible fetters: non-disclosure agreement or duty of confidence

Mobil Oil III (EPO, 1991)

“A claim to the use of a known compound for a particular (novel) purpose, which is based
on a technical effect which is described in the patent, should be interpreted as including that
technical effect as a functional technical feature, and is accordingly not open to objection
under Article 54(1) EPC provided that such technical feature has not previously been made
available to the public.”

Used to have produce a new product to be novel vs using a known compound but using it
for a new purpose
- This makes it diff to draw the line what is novel
- Compound used in lubricant patent to reduce friction
- As patent was going to expire, they made a second application saying the same
compound in lubricant can be used to reduce rust
- Court allowed this
- But the reason for reducing rust was possible due to reduction in friction

What if invention is openly used in public, but is not specifically known about?
 Merrell Dow - active substance openly used but effect not known about - Held
chemical substance does not need to be identifiable - it was still available in public
 Traditional knowledge example - Amazonian Indians who believed that effect of the
cinchona bark on malaria was due to the “spirit of the bark” - however, would we
say Indians knew about quinine even though they did not know its chemical
structure or that cure for malaria was due to chemistry, and not spirits?

Patent in prodrug – discovered that therapeutic effect was caused by metabolites -> got
patent on metabolite. They thought the legal patent would last further than the 20 years on
the original patent – question was what effect the disclosure of the original patent would
have on the novelty of the second patent

Judge posed a question: what we need to say to say something is new.

This was by no means a simple matter -> devised a discussion about Amazonian Indians but
in 19th century a scientist isolated quinine to be used for treatment.
Does patent law require disclosure of actual chemistry?
Amazonians knew about quinine and the second patent did not add anything to the actual
art of the compound – there was no practical disclosure and therefore the 2nd patent was
thrown out

It was a reach-through claim since the 2nd patent just tried to extend the patent yrs and
extend its original idea. In UK law you do not have to know the chemistry, you only need to
know the effect. State of the art is what we know now

Inventive Step / Obviousness

Section 3, UK Patents Act 1977/Article 56, European Patent Convention - Inventive step
“An invention shall be considered as involving an inventive step if, having regard to the state
of the art, it is not obvious to a person skilled in the art. If the state of the art also includes
documents within the meaning of Article 54, paragraph 3, these documents shall not be
considered in deciding whether there has been an inventive step.”
More difficult hurdle to cross
- Who is the person skilled in the art? -> is stated that the person is not a genius but
not a moron, but has a lot of unimaginative knowledge in that sector – no ability to
invent – the person cannot know too much, or info will be obvious in hindsight
- It is not a single person, it can be a team working together. They are assumed to
have read everything in the field up to date but not know everything
- An ordinary person skilled in the art
- How do you start the process? The court has a 4-step way of doing this

European Patent Office (EPO) - “inventive step” test

 The problem-solution approach
 What is prior art?
 What is technical problem to be solved, in light of prior art?
 Whether claimed solution is “obvious to the person skilled in art”?

United Kingdom Approach - Windsurfing/Pozzoli Test

 Windsurfing International v Tabur Marine (GB) [1985] RPC 59
 Prior art = “straight” boom

The invention is a curved stick – if it is too stiff and continues to curve it will crack – this is
why it is curved. The state of the art is a straight stick -> curve it

UK-Windsurfing test
 Identify the notional “person skilled in the art”
 Identify the relevant common general knowledge of the person
 Identify the inventive concept in patent
 Identify the differences, if any, between the prior state of the art and inventive
concept, or the claims
 Viewed without any knowledge of current invention, Court has to decide whether
these differences constitute steps which would have been obvious to the skilled
man, or whether they require any degree of invention
 (Confirmed in Pozzoli Spa v BDMO[2007] EWCA Civ 588, 2007)

People who know about windsurfing and its tech are the notional person
Identify the common knowledge – has to give by two side and the judge has to decide
where he will go.
Inventive concept -> the judge has to know the only inventive concept – in the e.g. it was
the boom, and it was curved
Take state of art (straight boom), and claim (curved), and view without any knowledge ->
however the decision is somewhat subjective.

Excluded Subject Matter

Not everything can be patented

- Computer programmes are per say (by itself)
- Business models/methods
- DNA strand – later explained

In US, everything made is patentable – the amazon 1 click -> but in UK it

would not be because it is an algorithm
Mouse with ear – can you patent biological living material?
To a certain extent you can
Oncogene inserted mouse – claimed that the mammalian organism with inserted oncogene
– nothing against this in US law, when it went to Canadian and EU law there was arguments
against morality

European Patent Convention

Article 52(2), EPC: The following are not regarded as inventions
(a) discoveries, scientific theories and mathematical methods;
(b) aesthetic creations;
(c) schemes, rules and methods for performing mental acts, playing games or doing
business, and programs for computers;
(d) presentations of information.

Article 53, EPC - The following are not patentable (paraphrased)

(a) inventions the commercial exploitation of which would be contrary to “ordre public” or
morality; [...]
(b) plant or animal varieties or essentially biological processes for the production of plants
or animals; this provision shall not apply to microbiological processes or the products
thereof;
(c) methods for treatment of the human or animal body by surgery or therapy and
diagnostic methods practised on the human or animal body; [...]

a) In EU it was not allowed to be patented

- Part of the problem of the claim was that they claimed the method of inserting the
gene, and the successive products of test – but EU stated that this was claiming a
whole species
- Is it immoral to transform an animal for it to get cancer – they came up with a
balancing test of weighing up suffering of the mouse to the benefit
- Concluded it was moral as suffering was outweighed by the benefits.
- Over the years, the scope of the patent was reduced -> this refers from rodents and
to mice – this should have been done from the start as there is no reason to suppose
that what works for mice could not work for dolphins
Did expt on baldness on mice.
Most people would not know how much a mouse suffers from being bald – the benefits
were much reduced by this as baldness was not as serious as cancer – patent was not
allowed for this
b) Maybe written by diplomats
c) Methods of treatment – the purpose behind this is to not have situation where surgeons
can be sued because of patentability and unable to carry out an operation. Also exclusion
that allows pharmacists to do a compound product required for a disease.
Swiss claim – came out a way to patent known drugs in a way for second use and third
medical use
You do need a very good patent agent and written language
- Minute you type something physical – it becomes patentable – programme are difficult to
patent because of this

T 356/93 Plant cells/PLANT GENETIC SYSTEMS [1995] OJ EPO 545

 “It is generally accepted that the concept of ‘ordre public’ covers the protection of
public security and the physical integrity of individuals as part of society. This
concept encompasses also the protection of the environment.
Accordingly…inventions the exploitation of which is likely to breach public peace or
social order (for example, through acts of terrorism) or the seriously prejudice the
environment are to be excluded from patentability as being contrary to ‘ordre
public’.
  The concept of morality is related to the belief that some behaviour is right and
acceptable whereas other behaviour is wrong, this belief being founded on the
totality of the accepted norms which are deep routed in a particular culture. For
the purposes of the EPC, the culture in question is the culture inherent in European
society and civilisation. Accordingly…inventions the exploitation of which is not in
conformity with conventionally accepted standards of conduct pertaining to this
culture are to be excluded from patentability as being contrary to morality.”

Onco-Mouse
 T 19/90 Oncomouse/HARVARD [1990] OJ EPO 476 a balancing test was introduced:
 “a careful weighing up of the suffering of animals and possible risks to the
environment on the one hand, and the invention’s usefulness to mankind on the
other.”

Stem-cell patents?
Oliver Brüstle v Greenpeace (Case C-34/10, Court of Justice of the EU, 18 October 2011)

Article 6(2)(c), Directive 98/44/EC, on the protection of biotechnological inventions:

1. Inventions shall be considered unpatentable where their commercial exploitation
would be contrary to ordre public or morality; however, exploitation shall not be deemed to
be so contrary merely because it is prohibited by law or regulation.
2. [...] the following, in particular, shall be considered unpatentable:
(c) uses of human embryos for industrial or commercial purposes;

Too controversial for any repeal

Article 6 is important – use of human embryos
The court tried to understand the difference between diff types of embryos whether they
were totipotent and pluripotent, and tried to make distinctions in law at what stage it was
regarded as an embryo to be allowed to patent -> required ethical boards
- But Poland is a catholic country and part of the EU and stated that any part of the
embryonic stage was not patentable – every country can put in a position
- Many lawyers do not understand the judgement – can use embryos for diagnostics
and therapeutics and can patent – but cannot patent them for scientific research.

The use of human embryos for therapeutic or diagnostic purposes which are applied to the
human embryo and are useful to it is patentable (for example to correct a malformation and
improve the chances of life)
but
their use for purposes of scientific research is not patentable

- Can you patent cell lines? – but it comes from your body? -> under patent law yes,
but the ethical law says no as needs informed consent
- The first cell line was done on cancer patient’s tumour and was immortalised – this
was 66 years ago, and this was very controversial, but ethics changed over time.
- She was from a poor African family and a lot of money has been generated using
from cells and results derived from her tumour – but her family never received any
of the reward – controversial

A Patent Application
 An application contains - [section 14(2) of PA 1977 EPC Art 78(1)]
o A request for the grant of a patent;
 o A description of the invention - description needs to disclose the invention in
a manner which is clear enough and compete enough for the invention to be
performed by a person skilled in the art. IMPORTANT LEGALLY
o The claims - IMPORTANT LEGALLY
o Any drawings;
o An abstract.

It is about knowledge – just because you know about is it okay to say it is in the prior state?
Can patent bits of humans – but if you do it without prior consent of the owner = sue
The most important things are the descriptions and claim
Descriptions – what was done, what was known and describe it so that the person skilled in
the art can replicate it looking at your information
- For many patents you do not show everything – state “in the range of” – keeps
things back as this is done in licensing part to make the data a trade secret
- E.g. best at range of 70-90; but it actually best at 84 temp.
The description is done with patent agent and inventor
The law only looks at the claim
-> after patent is for 20 years

Rights and Scope of Protection

 Exclusive right to make product/use process
 What are essential elements of the invention?
 Duration of rights - 20 years from the date of filing

Infringement of a patent
 where the invention is a product, he makes, disposes of, offers to dispose of, uses
or imports the product or keeps it whether for disposal or otherwise;
 where the invention is a process, he uses the process, or he offers it for use in the
United Kingdom when he knows, or it is obvious to a reasonable person in the
circumstances, that its use there without the consent of the proprietor would be an
infringement of the patent;
 where the invention is a process, he disposes of, offers to dispose of, uses or
imports any product obtained directly by means of that process or keeps any such
product whether for disposal or otherwise.

Rights and Scope of Protection - Construction of Claims

 Scope of protection = construction of claims
 Protocol of Article 69, EPC
 Doctrine of equivalents

European Patent Convention, Protocol

 Article 1 (General Principles) - Article 69 should not be interpreted in the sense that
the extent of the protection conferred by a European patent is to be understood as
that defined by the strict, literal meaning of the wording used in the claims, the
description and drawings being employed only for the purpose of resolving an
ambiguity found in the claims. Neither should it be interpreted in the sense that the
claims serve only as a guideline and that the actual protection conferred may extend
to what, from a consideration of the description and drawings by a person skilled in
the art, the patentee has contemplated. On the contrary, it is to be interpreted as
defining a position between these extremes which combines a fair protection for the
patentee with a reasonable degree of certainty for third parties.
 Article 2 (Equivalents) - For the purpose of determining the extent of protection
conferred by a European patent, due account shall be taken of any element which
is equivalent to an element specified in the claims.’
 Catnic Components Ltd. v. Hill & Smith Ltd. (1982) R.P.C. 183 (House of Lords)
Simple patent
 Fig. 1 – patent used word “extend vertically” – what does this mean – 90 degrees, or
between 80-90 -> they actually did it 6 degrees off
 Doctrine of equivalents – language cannot
restrict the invention because it is only
language - The doctrine of equivalents is a
legal rule in many (but not all) of the
world's patent systems that allows a court to
hold a party liable for patent
infringement even though the infringing
device or process does not fall within the
literal scope of a patent claim,
 90 degree/vertically – they actually mean
that it should have leeway -> gives judge and
court to extend what is written.
 The judge claimed that the person did not
actually mean 90, but rather 90ish.

Lord Diplock, in Catnic:

 “....it seems to me that the expression "extending vertically" as descriptive of the
position of what in use will be the upright member of a trapezoid-shaped box girder,
is perfectly capable of meaning positioned near enough to the exact geometrical
vertical to enable it in actual use to perform satisfactorily all the functions that it
could perform if it were precisely vertical; and having regard to those considerations
to which I have just referred that is the sense in which in my opinion "extending
vertically" would be understood by a builder familiar with building operation.”
 “Or, putting the same thing in another way, it would be obvious to him that the
patentee did not intend to make exact verticality in the positioning of the back plate
as essential feature of the invention claimed."

Improver v Remington
The Improver case was between producer of a depilatory device called “EPILADY”
 Improver had a patent on a depilatory device called “EPILADY”. Remington
was sued when they produced and marketed their “Smooth and Silky”
competing device. This struggle was in many jurisdictions and is
internationally usually referred to as the “EPILADY” case.
 In EPILADY, a helical coil spring is bent, and rotated at high speeds. In this
way, unwanted hair could enter the gaps in the coil at the convex point,
clamped upon, and then plucked.

Epilady – 8 decisions made on it – for lady’s hair

Fig 2 – infrigment – not a coil; Fig 1 - a coil
They went through all the parts to see if it was an infringement
Came with:
Rubber, rubber
Heat, heat
Pulling by static, pulling by static

Although they look different, they had the same materials and methods to remove hair
painlessly - High heat using rubber involving static
Person skilled in the art – is it infringement?
Remington’s “infringing” device
 The Remington device had rubber rolls with slits. The rubber roll was bent
so that the slits at the convex, outer side would open to form gaps.
 When rotated at high speed in this bent position, unwanted hair could
enter into the open gaps, be clamped and plucked,
 Issue: Does Remington infringe Improver?
 Are they equivalent? In function and technique?

Correct approach to claims interpretation?

United Kingdom
 Hoffmann J. held that the skilled reader would have understood from the language
of the claim (helical spring) that the patentee intended that strict compliance with
the primary meaning was an essential requirement of the invention. He did not look
at the claim, though, for this finding but held that the description named a variety of
alternatives for features of the invention (e.g. a kind of drive for the device, a kind of
gears between the drive and the helical spring) but did not mention at any place that
there would be an alternative for the helical spring. The skilled reader would see that
Improver just wanted protection for the helical spring, and nothing else.

Germany
 In the German counterpart case, the – at that time - two questions were asked, i.e. is
there technical equivalence, and can the skilled person realize this technical
equivalence? In Germany, it was held that there was infringement - based on
doctrine of equivalents.

Exceptions and Limitations

 Private and non-commercial use - An act is not an infringement of the patent
provided it is done privately and for purposes which are non-commercial.
 Experimental purposes - Experiments undertaken solely to demonstrate to a third
party that a product works or to provide information to a third party, which can
include a regulatory authority, are not experimental use
 Extemporaneous preparation on prescription - act which consists of the
extemporaneous preparation in a pharmacy of a medicine for an individual in
accordance with a prescription given by a registered medical or dental practitioner
or consists of dealing with medicines so prepared is not infringing
 An act which consists of the use by a farmer of the product of his harvest for
propagation or multiplication by him on his own holding, where there has been a
sale of plant propagating material to the farmer by the proprietor of the patent or
with his consent for agricultural use does not infringe. - There is an equitable
remuneration scheme in place.

The exceptions tend to be narrow - Experimental usage tends to be narrow

Minute the commercial comes in, the exceptions are removed
Sometimes make batches around the same time of patent soon expiring -> then flood the
market with the surplus amount
- Cannot make it in countries where there are other patents or sell it – need to wait
for 20 years to expire

Exceptions and Limitations - Bolar Exemption

 it consists of –
o an act done in conducting a study, test or trial
o necessary for and conducted for the purposes of a medicinal product assessment
o which would otherwise constitute an infringement of a patent for an invention
 o is to be regarded as done for experimental purposes relating to the subject-
matter of the invention
o This exception will allow all necessary trials and health technology assessments
for all drugs (novel as well as generic) and all applications for marketing approval
(European as well as non- European).

Ownership and Employee Inventions

❖ Basic rule of entitlement - first to file and not first to invent
❖ Inventor is entitled to invention - unless contract etc.
❖ Employer owns inventions made by employee during the course of normal duties-
employer
❖ Co-ownership

If you work in a company, your employers hold the patent

Anything creates by an employee within course of employer, all intellectual rights belong to
the employer

e.g. in early 90s a tea lady invented something for hoover – but she was employed – but she
was doing this outside of the course of hear employment (inventing was not her actual role)
You are entitled to compensation only if the employee is important for the company.
As an inventor, you are entitled to be named on the application – legal right of co-
ownership.
 An introduction to pharmacovigilance
Authorisation process

Detailed supporting dossier -> comes as email

attachment – large dossier
- Different parts of this are assessed by
toxicologist (to inspect animal studies
data), pharmacist, physician (look at
clinical trial results)
- Physician works with statistician
These assessments are then reviewed by expert
committee. Competent authority in EU is the
European commissions

Basis of authorisation decisions

3 criteria only:
• Safety - is it safe, or safe enough in context of disease
• Quality - high quality – does it contain what it states – active and other constituents
• Efficacy - does it work in clinical trials
-> effectiveness is used for healthcare assessment companies like NICE

Cost is not taken into account – allows to not focus on cost-effectiveness

Decision to use the drug is done by NICE
Risk-benefit evaluation is a key issue – is the ultimate judgement – benefits outweigh risk

How does authorisation work?

Basic legal framework:
• A medicine may not be marketed without an authorisation
• Attached to the authorisation is the Summary of Product Characteristics (SPC)
• A medicine may only be advertised in accordance with the SPC
• Individuals and companies who offend may be prosecuted

Legal document attached to it 2 other things

1. Patient information leaflet – tells side effects – this is a legal document and are
actively approved
2. More scientific version – SPC – part of the legal documentation granted to company
– mainly aimed at doctors – summary of product characteristics
If the drug is approved only after the original drug has failed – can be prosecuted

The Regulators’ Dilemma

As time ↑ more patients get exposed, we learn more
about the drug

If you have a particular disease that is unpleasant, life

threatening – orphan diseases (rare) – pressure from
regulators and patient groups to get the treatment
approved asap even though there is little information
of the drug being safe or efficient.

Green line – marked authorization

 Benefit-Risk balance is key
Risk-benefit analysis: Process of weighing up and balancing all the available evidence on
risks and benefits on the same scale. It varies depending on the indication and population.
Need to promote public health in relation to medicines while ensuring the patients
protection towards potential adverse drug reactions
 Pharmacovigilance

If risk is greater, then it is taken off the market

10 days ago, MS treatment caused inflammation in people’s brain and was removed from
the market through an autoimmune mechanism – caused encephalitis
18months ago, this drug was proven to be better than previous, now it is not the case
- Benefit risk is important at each step -> always want to target this

UK vs EU vs international regulation
• UK regulator: MHRA (Medicines and Healthcare Products Regulatory Agency)
• EU Regulator: European Medicines Agency (and European Commission)
• WHO: supports Member States with standards, information, guidelines etc.

Who – not formally a regulatory agency – it is a support regulator of how to do

pharmacovigilance, general guidelines, and providing information

Who is who EU in medicines oversight

• EMA – development of medicines / authorisation of new innovative medicines / EU level
pharmacovigilance + ‘decisions’ on major benefit risk questions / coordination of EU
activities / EU databases
• National Agencies - oversight of national manufacturing / national pharmacovigilance /
authorisation of national generics / clinical trials approval / inspection and enforcement
• Marketing authorisation holders;
• healthcare professionals;
• patients

National agencies – if manufacturing part in uk, the uk agency goes to inspect it and gives
authorisation to manufacture
Makes decisions that are only relevant to the uk market
-> also authorise national generic medicines – where patent has run out and data protection
has run out
-> inspects both manufacturing sites and clinical trials

Enforcement is done by ex-policemen to stop illegal activity in terms of medicine

e.g. something being sold in Camden market, but the ingredients are pharmaceutical – and
people are claiming it is causing damage to health – this is illegal
Marketing authorisation holder – holders of a license – pharmaceutical companies
Healthcare professionals – prescribing and dispensing drugs

Key legal references (EU level)

• Directive 2001/83/EU – basic legislation laying down the rules on authorisation,
pharmacovigilance, manufacturing, inspections, advertising and marketing
• Regulation 726/2004/EU – establishes the EMA and the centralised procedure (one
authorisation for the entire EU)
 Why do we need Pharmacovigilance and how is it organised in Europe?
What is pharmacovigilance?
‘The science and activities relating to the detection, assessment, understanding and
prevention of adverse drug effects or any other drug related problem’ WHO 2002
- KNOW THIS!!!

Assure that any aspect which could impact the safety profile of a medicine is detected and
assessed and that necessary measures are taken.
Should know to quote the bold text
- Simple: assuring that any aspect that could affect the safety profile of drug is
detected and assessed – monitoring the safety aspects of a drug

Scandals which have marked the history of pharmacovigilance

-mediator – anti-diabetic treatment (suppressed the appetite) but was an amphetamine –
but have been taken off the market. This drug stayed on the market for a long time, and all
the senior members were fired as the system did not work.

- Key reason why we need the aforementioned

Rosiglitazone – cardiovascular risk for anti-diabetes meds – removed from EU, but remains
on US at strict regulation -> early signs shown but still approved, but later showed large
numbers of affected and death
Medalione - Antidiabetic treatment for fat – the company that made this med also
produced amphetamine
- Should have removed in the late 90s but was not removed for a while

Possible MCQ
• What we know at the time of authorisation:
 Dossier of evidence submitted by the companies on safety, quality and efficacy; Full
assessment by the regulators
• What we do not know: Full safety profile in normal clinical practice (e.g. Rare
adverse drug reactions (ADRs), Delayed ADRs, ADRs from chronic exposure, ADRs in
special populations, ADRs from ‘off-label’ use)
• Pre-marketing data have important limitations:
 Pre-clinical data: low predictive value
 Clinical trial data provide provisional evidence of safety but:
• Too small (~ 1500 patients);
• Limited duration
• Do not represent the real world

The dossier – we know about the efficacy of the product as the design of clinical trials is
driven by detecting the properties of the drug,
Full safety is not known – if trial is done on 2000 patients, even if side effects seen in 1 in
1000, then you do not know if it was due to chance or because of the drug
Or if the trial was done for a year, but side effect was shown after a few year – you could
not measure this during the trial.
Adverse drug reactions -> do not take place in pregnant women, fragile people, children – so
you will not know how the drug performs in these people in trials
This is given in controlled manner e.g. diabetes, non smoker and less than 65 for
hypotension treatment – but patients who do not fit this may use the drug outside the trial,
so side effects will not be known for this
 Burden of adverse drug reactions - (EC Impact Assessment 2008)
Medicines save lives and relieve suffering, but:
• 5% of all hospital admissions are for ADRs,
• 5% of all hospital patients suffer an ADR,
• ADRs are the 5th most common cause of hospital death
• Estimated 197,000 deaths per year in EU from ADRs
• EU Societal cost of ADRs Euro 79 Billion / year

Pharmacovigilance can reduce the death and suffering caused by adverse reactions

Pharmacovigilance: Objectives
• Identify previously unrecognised hazards
• Evaluate changes in risks and benefits and improve the safety of marketed medicines
• Take action to promote safer use to optimise the safe and effective use of medicines
• Provide optimal information to users

Pharmacovigilance: prerequisites
1. Functioning state (law and order)
• Responsibilities can then be laid down by law
2. Functioning healthcare system
• Operations can be embedded in the healthcare system
3. Science and resources (people, data, knowledge etc)
Relevant to the consideration of pharmacovigilance in the EU compared to less developed
states……

Need to have functioning state – law and order of these

Functioning healthcare system – for most meds in EU are judged that you need intervention
of healthcare professional – if you don’t then you don’t have good safety monitoring and
collection of the data from pharm and doctors
Science and resoruces – need people to provide access to data and analyse the data to
provide the information to doctors and professionals

Pharmacovigilance in countries with stringent regulators: the actors

Two most imp in terms of the law are company and regulator
Clearly in healthcare system it is about the last 3

Pharmacovigilance process steps

Think about pharmacovigilance as a process
1. Risk management planning – when product comes in for authorisation, we authorise
all products with a plan to collect data and minimise risk. For some meds, it is
important to know the risks especially with toxic and those that might be harmful in
pregnancy (put in measure to prevent women from being pregnant when using the
drug) – use contraception
2. Collect data – reports sent in by doctors, patients, pharmacist
3. Detect safety ‘signals’ – to detect previously known effects of the drug
4. Evaluate risk
5. Benefit-risk assessment
6. Take action if there is a risk
7. Communicate this – put on website, write to doctors, sent out info to the patient
groups, European MS society e.g.
8. Audits
 - Certain no. of patients might have rebound of MS, or difficult to treat and are
prescribed combination of treatments
- Need to take action and look to see if there is a benefit and their health outcome

Data sources in pharmacovigilance

• Non-clinical studies - animal or laboratory test
e.g. test for mutagenesis, carcinogenesis tends to be non-clinical
• Clinical trials
• Epidemiological (observational) studies - case control or cohort studies – look at
treatment used and look over time, or look at previous results of patient and see
their progression
• Spontaneous reports of suspected adverse drug reactions
• Systematic reviews and meta-analysis of observational data
• Systematic reviews and meta-analysis of clinical trials

ADR – if you take too many ibuprofen and you get inflammation of stomach
Spontaneous report – when patient gives report that they have had a side effect
Where there is a large no. of clinical trial done to look at if something is caused by the
treatment or the underlying disease is very difficult -> put all of trials into meta-analysis to
improve chances of detection cause.

Critical role of reports of suspected adverse reactions

Reports of suspected ADRs:
• Reports from patients and professionals (= Yellow Card in UK)
• Are received by national agencies and by companies (by law)
• National agencies and companies report on to EudraVigilance
• EMA (through EudraVigilance) makes the report available for analysis by EMA expert safety
staff and expert safety staff in the national agencies respecting data protection – these are
used for ‘signal detection’ and evaluating safety issues to identify way to reduce harm
• EMA makes a subset of data available to the general public

Critical role of reports of suspected adverse reactions

Reports of suspected ADRs:
• Main source of safety issues / evidence of harm leading to action to protect public health
• national data sets too small to detect safety issues well – research shows Eudravigilance
detects issues years earlier (Alvarez et al). Eudravigilance – European data processing
network
• Issues may be detected many decades after product enters market

There is a critical role of reports of suspected adverse reactions

- You have the right to report ADRs to MHRA
- Reports are the yellow card scheme – the national agencies look at the data and see
if they can have detected previously unregonised results

Pharmacovigilance: Eudravigilance
• EU data processing network and management system for reporting and evaluating
suspected adverse reactions during the development and following the marketing
authorisation of medicinal products in the European Economic Area (since 2001)
• Over 13 million adverse reaction reports received and processed (1.5 million new
reports per year)
• Access to EV data to the public via the European Database of Suspected Adverse
Drug Reactions reports

Information to be reported includes:

 Patient identification (initials, sexe, age, country)
 Suspected product(s) identification (name, dosage, route of administration, therapy date
and duration…
 Reaction description including seriousness and time to onset
 Concomitant drugs and patient history

Increase in reporting due to better awareness among the general public of the importance
of adverse reaction reporting, resulting in part from the new EU pharmacovigilance
legislation, which introduced direct reporting of adverse reactions by patients and
consumers in all Member States

Actions to reduce risks

• Inform patients via warnings in product information
• Stop use (contra-indicate) in at-risk patients
• Reduce the top dose (if dose dependent risk)
• Introduce monitoring for early warning signs (e.g. blood tests or x-rays)
• Restrict the use to only the most severe patients
• Withdraw the product.

What can we do if we discover a risk? We try to minimise risk

Done by:
- Impowering patients if they want to take a risk – inform them of the warning
- Reduce top dose – often side effects are dose dependent
- E.g. ibuprofen – large amounts = gastritis – reduce the top dose – but this means
reducing the maximal response of the drug
- Monitoring early warning signs – often done
If we measure the liver function to test for inflammation – but very rarely are there studies
supporting the use for it. But it is still done because it is unlikely to do the patient harm that
they have early mild hepatitis
X-rays for lung fibrosis – baseline before treatment, and every year do a scan for detection
progression
- Restrict use of the most severe patients

Communicating on benefit risk

• Product package
• Product leaflet
• Summary of Product Characteristics
 • Letter (email etc) to doctors / pharmacists
• Educational material (brochures / training) for patients or healthcare professionals
• Websites
• Apps

Drug taken off the market daclizumab (brand name Zinbryta)

Therapeutic humanized monoclonal antibody which was used for the treatment of adults
with relapsing forms of multiple sclerosis (MS). Daclizumab works by binding to CD25, the
alpha subunit of the IL-2 receptor of T-cells.
- The European Medicines Agency has suspended the licence of a multiple sclerosis
drug after 12 reports of serious inflammatory brain disorders, three of them fatal.

• Aniello Santoro, Georgy Genov, Almath Spooner, June Raine & Peter Arlett. Promoting and Protecting
Public Health: How the European Union Pharmacovigilance System Works. Drug Safety 2017. 40:855-
869; 10.1007/s40264-017-0572-8
• Arlett, et al. The European Medicines Agency’s use of prioritised independent research for best
evidence in regulatory action on diclofenac. Pharmacoepidemiology and Drug Safety.
Pharmacoepidemiology and Drug Safety. Volume 23, Issue 4, pages 431–434, April 2014.DOI:
10.1002/pds.3594
• Arlett et al. Nature Reviews Drug Discovery 13,395–397(2014). Proactively managing the risk of
marketed drugs: experience with the EMA Pharmacovigilance Risk Assessment Committee.