110713 bayerfdgdfgpharma brosch en web

8/10/2019 110713 BayerfdgdfgPharma Brosch en Web

1/16

FROM MOLECULESTO MEDICINE

A journey through research and development


2/16


3/16

Bayer invests considerable resources in theresearch and development of new drugs,with the aim of improving patients qual-ity of life and prolonging lives. We focus ontherapeutic areas with a high unmet medicalneed, areas that require further innovationdespite the progress that has been made as for example in cancer therapy.

It takes about twelve years to develop anew drug. During this time, highly qualifiedscientists from a variety of disciplines workon filtering out a suitable active ingredientfrom an enormous number of compounds.

They study 5,000 to 10,000 compounds,of which only four or five drug candidateseventually remain. These are then tested onhumans in clinical studies. At the end of the

process, only one substance is approvedand becomes available to physicians andpatients. Cooperation in interdepartmen-tal, multidisciplinary teams is an importantrequirement for success in the complexprocess of drug development.

With this brochure, we cordially invite youto join us on a tour of our research anddevelopment departments to gain an insight

into the work of our scientists. In ten chap-ters you can follow a new drug as it developsfrom a molecule to a medicine.

Prof. Dr. Andreas Busch

Head of Global Drug DiscoveryBayer HealthCare

Dr. Kemal MalikHead of Global DevelopmentBayer HealthCare

3


4/16

RNAi analyses makeit possible to identifytarget molecules that

are key to the courseof the disease

The scientists focus their attention on thesignaling pathways of cells which control all

the bodys major functions. Understandingthese biochemical processes in the bodycan yield valuable clues as to how a diseasecan be combated. This is because thesignaling cascades involve proteins that canbe potential sites of action for drugs. Thesetarget sites are usually receptors cellularbinding sites for hormones and other mes-sengers or enzymes, which are respon-sible for the chemical transformation of

substances in the body. Drugs either switchthese proteins off or enhance their function.However, only few protein molecules are

suitable as targets for drugs. It is a difficultand complex task to detect them amongthe countless proteins that are produced bythe body.

Proteins that might be playing a signifi-cant role in the course of a disease can beidentified using DNA chips for example.

This is done by detecting messenger RNA(mRNA). The scientists use RNA interfer-

ence to establish whether these proteinsare suitable as targets. This method makesit possible to switch off individual genes bythe targeted degradation of their mRNA.

As mRNAs code for proteins, any targetprotein can be switched off in this way. Ifthe disease-specific process at the cellularlevel subsequently changes, this suggeststhat the blocked protein might be a suitabledrug target. Careful work is very important

at this stage of the research process, sincethe quality of a target is key to the successof the subsequent work steps.

4


5/16

To find these potential active compounds,the researchers first develop activitytests matched to the respected target thatare suitable for use in the automated andminiaturized process. This can take a

couple of months. They then use highthroughput screening (HTS) to combthrough the in-house compound library(currently containing close to three millionchemical substances) for suitable lead

candidates.Robots fillthousands ofmicrotiterplates on

which up to1536 testscan beperformedsimultane-

ously. In this way, the target is automaticallymixed with quantities of the substances inan assay volume as minute as 50 nanoliters.Since HTS ensures a very high throughput,this process only takes a few weeks.

The scientists use various detectingprocedures to measure the effect on thetarget after binding a compound. They oftenuse highly sensitive CCD cameras to gatherfluorescent light released after a substancehas bound to a target protein. A computer-assisted evaluation of the quantity of lightthen identifies the compounds that have thedesired effect.

The researchers determine the potency ofthe most interesting compounds by testingthem in dilution series. Finally, they furtherexamine the sufficiently potent candidatesfor undesirable effects. The compoundsshould bind only to the target and not toother molecules to minimize potentialadverse effects. The lead candidates thathave now been found are not yet ready for

use, however. They have to be optimized infurther stages of the development process.

Minute amountsof substances are

prepared in microtiterplates by robots

5


6/16

Structural biologists determine the molecu-lar properties of the targets. They investi-gate the position of pockets to which theactive compounds can bind and the interac-tion between these protein pockets and theactive substance. For this purpose they use

X-ray structural analysis, which only can beperformed on crystallized target proteins.However, the generally lengthy crystalliza-tion process does not succeed with everyprotein. The lattice structure of a crystallizedprotein diffracts the X-ray beam in a char-acteristic way. Structural biologists can readthe electron density and thus the positionof the atoms from the diffraction pattern. Inthis way they can draw conclusions on the

three-dimensional molecular structure.

Computational chemists use this informa-tion to fi nd further substances that fi t thebinding pockets of the target proteins. Todo this, they use computerized screeningprocesses to search through virtual com-pound libraries. In this way they can identifymolecules that have not yet been synthe-sized and others that can be purchased

from external vendors. The subsequentstage of lead optimization also benefi tsfrom computational chemistry.

Computer calculations can thus be usednot only to predict which molecular modifica-tions of a substance are likely to improveits capacity to bind to the target, but also

which biophysical or toxic properties mightbe associated with a structural transformation.

This enables the synthetic chemists to dotheir work in the laboratory in a more targetedmanner. However, the natural fl exibility ofprotein structures makes reliable predictionsdiffi cult ultimately, it is always the experi-ment actually conducted that counts.

Three-dimensionalmolecule model of an

anticoagulant

6


7/16

Chemists workingtogether on optimizinga substance

In addition to having the desired effect,a substance must meet other criteria. Ifpossible, it should bind only to the targetand not to other molecules in the body tominimize adverse effects. It must not break

down before it has a chance to have itseffect, and it must be soluble in water toget into the body at all.

In order to createmolecules with suchproperties, chemistsvary the lead candidatesby adding or removingvarious chemical groups

or by modifying themolecular structure.They fi rst systematically

create hundreds or even thousands of differ-ent variations using automated processes.

These are then further screened to fi lter outcandidates that are most likely to meet therequirements. This process is supported bycomputer simulations which are provided bythe colleagues from Computational Chemis-

try. These improved lead compounds arethen subjected to repeated biological tests.These give the medicinal chemists ideas forfurther optimization steps.

The alternating process of chemical opti-mization and testing usually takes severalyears. Researchers often make hundredsof modifi cations to a lead compound in thecourse of its development. The experience

of medicinal chemists is very important inthis work. When they improve one desiredproperty of a molecule, this sometimesworsen others. When the scientists arefi nally convinced that they have found acompound that exhibits the desired proper-ties, they apply also for a patent. Preclinicaldevelopment can now begin.

7


8/16

Pharmacology is divided into pharmaco-dynamics and pharmacokinetics. Pharmaco-dynamics investigates whether the compoundsalready proven binding capacity to thetarget molecule has a physiological effect,i.e. whether the active compound really iscapable of treating the disease. Pharmaco-

kinetics studies the absorption, distribution,metabolism and excretion of a drug. It canhappen that an active compound is prema-turely broken down in the stomach or liverand never reaches its true destination, oreven that metabolism converts it into a toxicsubstance. Such knowledge is indispensablefor developing a form of administration. Toxi-cologists investigate whether the substancehas a toxic effect on the body and whether

it is capable of causing cancer, genetic muta-tions or damage to unborn children. Thedose is critically important here. Pharmaco-logists and toxicologists therefore determinewhat is known as the therapeutic window.

This is the span between the minimum doseat which a therapeutic effect becomes justvisible and the maximum dose at which thereis no toxic effect.

The scientists in preclinical developmenthave three courses of action at their dispo-sal. First they use computer programs insilico to simulate processes to dismiss anyunsuitable candidates. They subsequentlytest the active compounds in test tubes orpetri dishes in vitro on cell and tissuecultures or with bacteria. Finally, animalexperiments in vivo are vital to understan-ding the complex interactions that take place

in an entire organism. These studies arerequired by law and are governed by strictguidelines and state controls.

5.

At the preclinical developmentstage, pharmacologists andtoxicologists test the new activesubstances under various experi-mental conditions

8


9/16

Testing and manufacturing

formulations for suitably packingthe active substance

Factors to be considered in the develop-ment of a suitable form of administration be it a tablet, an ointment or a patch

include patient acceptance and the specifi crequirements of the active ingredient. Inac-tive ingredients which can make up most ofa drugs volume serve as carriers for theactive compound. Maize starch or lactose,for example, are used in tablets, whilewater-oil emulsions are used in ointments.

The administration form also infl uences adrugs therapeutic effect. It determines how

the active ingredient enters the body, whereand in what dosage it is released, and thetime it takes to be absorbed. For example,compounds that need to be released intothe body slowly and continuously can beincorporated into additives that are notreadily soluble. Active ingredients that wouldnot survive passage through the liver aretransported via a patch or injections directlyinto the blood circulation. In addition, the

mode of administration must ensure that thepatient will be able to dose the drug safelyand handle it easily.

Galenics experts are also responsible for adrugs storage safety. They ensure that theactive ingredients content remains con-stant, the product remains chemically stable

throughout its shelf life, and that it maintainsits purity. Another requirement is that theformulation can be manufactured on anindustrial scale. Beginning with a prototype,the next step is to reproduce it on a labora-tory scale.

By scaling up production in several stepsat the test facility, the scientists fi nally reachlarge-scale production. The newly devel-

oped drug formulation is initially used andtested in clinical trials before it can reach themarket as an approved drug.

6.

9


10/16


11/16


12/16

A persons genetic disposition influencesthe absorption, metabolism and effect ofa drug in the body. These processes aregoverned by certain protein molecules such

as enzymes and receptors. The informationstored in our genetic material (DNA) providesthe blueprint for these proteins. Inherited

variations in thesequence of an indi-

viduals DNA buildingblocks calledsingle nucleotidepolymorphisms orSNPs can influ-ence whether certainprotein molecules

are present or missing and affect their activ-ity. Scientists use systems called microarraysto study these genetic characteristics, which

are specific to individuals, and gene expres-sion. They allow more than a million genevariations to be examined simultaneously.

Researchers are trying to identify biomarkerswhich measure the differences betweenhealthy and diseased cells and also betweenindividuals. Biomarkers can also be used asbenchmarks to measure the success of atherapy. Pharmacogenomics therefore offers

the future promise of treatments in which theactive ingredient and the dosage are tailoredto the individual patients needs. In this way,the maximum possible therapeutic successcould be achieved with a minimum ofadverse effects. Test procedures are alreadyavailable which enable scientists to makereasonable predictions on whether individualdrugs will have a desired effect on a patient.Pharmacogenomic advances can also make

clinical trials simpler and safer, because theymake it possible to recruit study participantsin a targeted manner patients who arehighly likely to respond to the compound tobe tested and unlikely to suffer seriousadverse effects.

Using genetic data raises ethical and legalissues. For researched-based pharmaceuti-cal companies, sensitive handling of genetic

information and compliance with strict data-protection regulations form the basis of theirscientific work.

9.

Tissue samples are analyzedin order to decipher the DNAand the individual blueprint forthe proteins

12


13/16

The documentation submitted to a regulato-

ry agency by the pharmaceutical companycontains all the data generated during thedevelopment and test phases. This dossierwith the results from chemical-pharmaceu-tical, toxicological and clinical trials maysometimes amount to capacities of morethan 13GB or 500.000 pages. The regula-tory agency reviews the documentation tosee whether it provides sufficient evidenceto prove the efficacy, safety and quality of

the drug for the proposed indication.

Regulatory Affairs is also involved earlier,during a drugs development process. Theyensure that, wherever possible, all the nec-essary steps for approval are considered al-ready at an early stage. Indeed, most drugsachieve approval in this way, although insome cases it is subject to conditions,e.g. restricting the number of indications

or requiring warning notices.

As a rule, pharmaceutical companiesstrive to market their products world-wide. To do so, they require approvalfor each individual country. This is grant-ed in Germany by the Federal Institutefor Drugs and Medical Devices (BfArM),in the USA by the Food and Drug Admin-istration (FDA). In the European Union, the

EMA is responsible for central approval,which is valid for all member states. Phar-maceutical manufacturers usually first apply

for approval in the USA and Europe. If it

is granted there, they also apply in theremaining countries. A simplified procedureis then generally sufficient. Approval marksthe successful completion of a long pro-cess. After a development process lastingeight to ten years, and a approval processlasting up to two years (depending on thecountry), the drug is finally available to pa-tients all over the world.

10.

All data and findingsare documented in orderto compile the dossier

13


14/16

Publisher

Bayer Pharma AGCorporate CommunicationsMuellerstrasse 17813353 Berlin

Germanywww.bayerpharma.com

Contact

Dr. Kerstin CrusiusTel.: +49 30 468 [email protected]

Picture credits

kurhan / Shutterstock.compatrickheagney / iStockphoto.comRubberball / iStockphoto


15/16

DE LA MOLCULE AUMDICAMENT

DALLA MOLECOLAAL FARMACO

VOM MOLEKL ZUMMEDIKAMENT

FROM MOLECULES

TO MEDICINE

DE LAS MOLCULAS ALOS MEDICAMENTOS

The Bayer sciencemagazine research

Bayer appsProcesses in Researchand Developement

From Moleculesto Medicine (film)

MOLEKLDEN ILACA


16/16

For more information visit us on

www.bayerpharma.com

110713 bayerfdgdfgpharma brosch en web

Documents