An explanation of the drug discovery process

ProteoGenix July 9, 2018

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From the lab to the patient: a drug story An explanation of the drug discovery process
When a new drug finally earns the right to integrate your pill dispenser, it already has a fulfilled life. It takes an average of 14 years for a new compound to reach the pharmaceutical market, from its conception to its approval.

Why does it last so long?

In order to be validated, each drug has to pass a large number of tests. It has been estimated that only 1 in 5000 drug candidates succeeds to overcome all the steps that bring it to your drugstore!

Here is a short overview of the prenatal life and birth of a new drug.

1. Research and development – Choosing the right battle 

Each future drug starts its conceptual existence in a research lab.

The first step of its early life relies on the identification and definition of the medical needs, leading to the disease selection. This choice can be motivated by various scientific, strategic and economic factors. Pharmaceutical industries often focus on the disease prevalence and potential revenue, whereas academic institutions are also likely to concentrate their efforts on rare diseases, depending on the available grant fundings and on personal interests.

Once selected, a common method is to first conduct research on the disease mechanisms in order to identify the most appropriate drug target (target identification). This latter can be defined as a relevant molecule, generally a protein, on which the future drug should bind to produce its effect. Various biochemical, genetic or computational approaches can be used and combined to compare the differences between healthy subjects and patients. They permit to find out the genes and subsequent proteins involved in the disease, and their pathways.

Once identified, the potential target needs to be validated (target validation) by various tests in order to confirm it is truly appropriate and sufficient to fight the disorder.

The next step usually consists in developing a compound that can bind to the target and produce the desired effect. First, various molecules are tested by assay in order to identify the hits, in other words, all the molecules able to bind with the target. Out of these, it is then possible to screen those which have the best effects on the target, also called the leads (lead selection). These molecules can be small chemicals, proteins or more specifically monoclonal antibodies. To finish, the leads are optimized (lead optimization). This process can require further peptide, small molecule, protein or antibody drug development steps, in order to improve their properties and to make them more drug-like. The number of biotherapies (proteins and antibodies) at preclinical stage, clinical stage or on the market is growing very fast. The types of biomolecules are more and more complex. The most common ones include vaccines, monoclonal antibodies, bispecific antibodies (more than 100 existing formats) and antibody drug conjugates (ADC)...

Lead optimization of biomolecules may involve several techniques such as monoclonal antibody humanization and antibody affinity maturation. These are usually performed through several antibody engineering rounds, intended to modify the DNA sequence of the biomolecule.

All these stages take between 3 and 6 years on average.

2.      The preclinical studies - Formation and maturation of a drug embryo 

The drug candidates are then tested during pre-clinical studies, aiming to provide efficacy and safety information. This constitutes a necessary step before human tests.

During preclinical studies, the experiments are conducted both in vitro (i.e. within test tubes or cell cultures) and in vivo on at least two mammalian non-human species - usually a rodent and a non-rodent one. The effects of the drug on the organism (pharmacodynamics) and the way the organism affects the drug (pharmacokinetics) are analyzed. The respect of the Good Laboratory Practices, defined by the European Union, is required at every stage in order to ensure the quality, validity and ethical sustainability of the whole process.

The preclinical studies last on average 1 year and are needed to afford efficacy, data dosing, and toxicity levels. When achieved and succeeded, the drug candidate is ready to access to the clinical studies.

3.      The clinical studies - Ready to confront with the real world? 

Things are getting serious. The candidate drug which succeeded the preclinical tests is now going to be tested on humans. This will ensure it is efficient on the disease of interest, appropriate and, most of all, safe.

The clinical studies are typically divided into 3 phases that will be successively explained below.

Phase I – Is the drug harmless for humans (non-toxic), and at which maximal dose?

During this phase, the candidate drug is tested on healthy humans. The aims are to evaluate its potential toxicity and its evolution within the organism, in comparison with the animal model. The study includes generally between 20 and 100 volunteers and lasts several months. If a safe dose founds the treatment, the drug passes on phase 2. It is assumed that about 70% of the drug candidates succeed at this step.

Phase II – Is the drug efficient and safe for the patients of interest?

The drug is tested on the dose perimeter considered as safe during phase 1 trials, but this time on a few hundreds of patients suffering from the disease of interest. This experiment provides additional safety information to the researchers such as the optimal dose to administrate, and permits to evaluate the efficacy of the drug compared to a placebo (a no-effect substance). If the drug is assumed to provide a safe and beneficial effect to the patient, it gets to the third (and last) clinical phase. On average, only 1 of 3 drugs passes this stage, which can last 2 years.

Phase III – Is the drug still safe and efficient at larger scales, and confronted with other parameters?

Many criteria are studied during this phase: the drug is administrated to thousands of patients. Its tolerance and efficacy is compared to the reference treatment if there is one, or with a placebo. The possible interactions with other treatments are also analyzed. It leads to a more precise evaluation of the risk-benefit of the drug. This phase is known for being the most difficult, expensive and time-consuming.

4.      Approval and marketing – The birth of a medicine 

When a candidate drug finally succeeds in all these phases, it is very close to being considered as a new medicine…

But before that, it has to be evaluated and approved by regulatory authorities. 25% of the submissions still fail at this stage, which may last 1 or 2 years.

The birth of a drug in the market does not mean that its examination is over: it will still be monitored, in order to identify potentially undetected side effects in the general population. The drug follows phase IV trials (mainly “post-marketing surveillance” trials), which purpose is to evaluate its long-term effects. This process lasts as long as the drug is marketed.

To be continued... 

Success has its price: a single drug reaching the market costs on average more than a billion dollars to produce. It tends to increase due to the complexity of the new biotherapies (monoclonal antibodies, bispecific antibodies, antibody drug conjugates, CAR T-cells therapies…)! This exorbitant amount can be explained by various factors, including the technologies used during the development phases, the thousands of volunteers involved during the clinical tests, and the ever reinforcing regulations of health agencies.

The steps of the drug discovery process. Credit: www.proteogenix.science
From the lab to the patient: a drug story An explanation of the drug discovery process

The high failure rate and the huge time spent are also responsible and are not on their way to decline. Indeed, the recent decrease in the number of accepted molecules per year suggests that the development phase is taking more and more time.

This bad news could be, in fact, a blessing in disguise: it appears that industries are partly redirecting their activities to focus on so far unstudied targets and drugs. These projects are more time-consuming and risky, but could lead to really high-valuable results, and to the fruitful emergence of new treatments during the next years potentially saving many more lives.

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References and Sources

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