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