Drug discover – Drug development

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

It is not only 1 trial that a company has to do -> it is 2 trials to make sure the firs trial is not chance.

EMA – drug approval

FDA – in the states

 Allows to get drug to market

 Very expensive process – cost around $1-4bn (which is outside any of the grant funding
capacities)

Might start with high-throughput screening -> 250 compounds (look at the diagram on the slides)

Each phase will cost more and more money because you have an industry of people behind pushing
the drug forward

You need to think about drug supply – have chem and manufacturing in addition to the cost of the
drug development -> may cost an additional few million pounds.
Academia – produce knowledge

Pharm – produce treatment

The essential feature that allows the drug development process is the patent process – give pharm
company the protection to produce the drug forward

Academia sets the process for the govt and the industry – do not care much about the cost

In terms of drug development we have regulation processes – each trial has to be independently
monitored

- Contract research organisation does this

- If a drug fails, you can cut this out without affecting the core business side

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

Academic produce scientific papers – pharm produces patents which is where a large amount of
these papers are found

Pharm companies gives research funds and access to reagants for the academics – but when this
happens the findings are given to the pharma companies

Creates IP (intellectual property) that can be protected -> contract made that can have a
confidentiality agreement (1 way or 2 way)

There is a general gaggign period where you cant say anything

Material transfer agreement – restricts what you do and controls how you use them  works in a
defined protocol

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 – gives protection to exploit ideas – comes in various ways – allows to work
without competition for a certain amount of time
When patent:

- Restricted to inventors, not workers

- They have to 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

University business

- 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

Patents give protection for around 20 years, and are published 18months after filled -> then starts to
accumulate cost

20 years might not be enough as it might take most of those years to develop the drug

Patent cost is a lot due to legal cost translation (have to translate to individual language e.g.
Japanese cost £15-20,000.

Can you patent worldwide or just in certain markets?

You really have to find a partner within 18months as once cost accumulates, you will not be able to
afford it.

Need to ensure you have non-public disclosure without filing

- As soon as it is in the public domain: it is difficult to patent – do not talk about it

- This differs in the country you are in e.g. in the US you can talk and still patent it
- This is good because it limits awareness to competition and prevent replication of ideas
- Embargo PhD thesis

Often visibible before publication

Company info outlet is often not published – but it is not peered or reviewed

Espace.net – patent database

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 chem is brick dust – completely insoluble

If you look at its properties it was v.hydrophobic, interacts with p450 (so many drug drug
interactions), also binds to p-glycop (molecule on the enothelium 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

Investigational new drug

Have to show there is animal pham + toxi to show that the drug is safe

Phase 0 – primary screen – allows to sort many drugs out

Secondary – simple animal model

Tertiary screen – more complex

Starts with in vitro assay -> animal models without checking for any toxicology or focus on the model

Phase 1 – 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 – this is where basic research transition to market

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 shemes
to help support early studies to overcome the valley into tgotting pharm companies on board

- They have limited funds but they aim to exploit your ip

- And if you have a lack of business accument they will exploit it more

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

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

read the article on the slides

- The drug is making $4 bn a year

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