Intelligent use of suitable biomarkers
How quickly does a pharmaceutical substance exert its effect? What mechanisms does it use to exert its effect on people and how long does it remain active? In a team headed by Prof. Dr. Martin Elmlinger, Nycomed GmbH has developed an efficient biomarker discovery concept specially adapted to the company’s requirements and designed to clarify such questions. The concept is specifically geared to the phases and requirements of the company’s projects. Every year, the company develops five new biomarker tests with the objective of speeding up the time to market of new drugs.
"Maximum safety and optimal effect" is the motto of Martin Elmlinger and his team of 12 in the Department of Biomarker Development at the research-oriented pharmaceutical company Nycomed. The team, which consists of biologists, technicians, chemists and mathematicians, uses measurable parameters such as biochemical molecules or body functions in order to measure the relationship between a drug's actual effective dose and its degradation in the human body, as well as to describe these relationships mathematically. In order to achieve this, the team bases its investigations on the fact that a patient's disease processes are reflected on the molecular level. In their investigation of potential new drug candidates, the biomarkers used are identified in blood samples or excretions such as urine or saliva.
"Blood is still the most common material used for such investigations. It is easily accessible and contains a wide variety of cell types that react specifically to pharmaceutical substances, just like other body cells," said Martin Elmlinger. In principle, biomarkers can be measured in all tissues and body fluids. Martin Elmlinger explains that saliva tests or tests based on joint space fluid, which is an excellent investigational material for rheumatoid arthritis-related biomarkers despite its limited quantity, have not yet reached total maturity. In contrast, the lung fluid of patients suffering from lung diseases such as asthma or COPD provides very significant information. However, the recovery of lung fluid using bronchoscopy is very difficult and associated with risks for the patient. In cancer patients, direct histopathological measurements of tissue samples are used to obtain information about cancer-related biomarkers.
"Every year, our small but highly efficient laboratory team develops up to five new biomarker tests that are also used in clinical studies," said Martin Elmlinger who also holds a professorship at the University of Tübingen. Elmlinger's team is currently working on 12 projects focusing on substances that are in different stages of development. A small number of these substances is still in late preclinical development; the majority of drugs are currently being tested in initial human trials by Nycomed GmbH's clinical development departments. About one third of the projects focuses on the development of biomarker concepts for pharmaceutical substances that are close to market, and that are currently being tested in large clinical trials. Biomarkers play an essential role here, as they do with drugs that are already on the market, since they often help to expand the application spectrum of an already approved pharmaceutical substance.
Focus on application instead of pure basic science
Martin Elmlinger and his team have developed concepts for the entire range of development phases. The line of approach of the Biomarker Development Department was clearly defined at the outset, and the focus is firmly on pure application aspects in drug development and not on basic science. “Our approach is knowledge-based; we use the knowledge obtained in our own research departments (e.g., biology) but also base our investigations on scientific biomarker-related publications in the fields of medicine, biology and pharmacology,” said Martin Elmlinger.
Depending on the developmental stage a drug has reached, Martin Elmlinger and his team use the following types of biomarkers: in early development projects (preclinical to clinical phase 1a projects), drug-specific biomarker tests that reflect the drugs’ principle of action (target) are developed and validated. Nycomed GmbH usually carries out these tests using isolated fresh blood from voluntary donors. “We use target-related markers like these to investigate the drugs’ early pharmacodynamic effects, for example the speed of the drug effect. Major focus is also put on how a certain dose affects the primary effect of the drugs,” explains Prof. Martin Elmlinger. The primary drug effects assessed from changes in biomarker concentration following the administration of a certain drug are then correlated by Nycomed’s pharmacometricians with the drug concentrations occurring at the time the biomarker concentration is determined.
This correlation is used as the basis for mathematical models describing the dynamics of a given pharmaceutical substance. They either help to assist in decisions regarding the frequency and dose of drugs required to treat a certain disease or provide information on whether reasonable administration is at all possible. “For example, it would not make sense to develop a drug that needs to be administered as an infusion several times a day. An important goal of the Nycomed developers is to develop drugs that do not need to be administered orally (tablets) more than once or twice a day. If the application of the drug is too complicated, then errors tend to occur, which potentially impede the success of the therapy,” emphasises Martin Elmlinger.
Disease biomarkers and stratification biomarkers
Nycomed GmbH develops biomarker concepts that enable the determination of target-related markers and disease biomarkers in clinical phase 2 (evaluates how well the new drug works) or advanced clinical testing phases. Advanced clinical trials test the application of the drugs on suitable patients as well as on patients participating in large clinical patient trials (phase 3 trials and patient trials following the market introduction of the drug in order to expand the therapeutic field of the drug under investigation (phase 4 trials)). "These trials are carried out in order to help us assess the clinical therapeutic effects of a drug and to clarify the molecular mode of action of the drug under investigation," said Martin Elmlinger.
Nycomed's Biomarker Development Department uses stratification biomarkers, i.e. gene signatures or special gene patterns in order to be able to better select suitable patients for the treatment of a certain disease or suitable volunteers who do not suffer from metabolic anomalies. "Although this might later restrict the breadth of the population that can benefit from certain drug treatments, these biomarkers provide us with information on the safety and optimal spectrum of the drug's activity," explains Elmlinger who was responsible for setting up Nycomed's (formerly ALTANA Pharma) Biomarker Development Department.
Only very tricky tests are carried out in-house
Elmlinger established a biomarker strategy that bears his signature. The Nycomed Biomarker Development Department pursues a strategy that does not involve a pure research approach which would require a lot of people, time and money. “We work on an entirely knowledge-based basis and pursue a strongly cross-functional orientation of our staff at the same time as focusing strongly on drug development projects,” said Elmlinger. All pure routine biomarker services are spun out in new companies, only the very tricky laboratory tests are developed in-house and they are then transferred to a service partner for routine measurements. The concept of the Biomarker Development Department is thus strictly adapted to the structures, timelines and budget of the company.
In order to enable the rapid market launch of new drugs, Nycomed investigates as many parameters as possible in a single clinical study. “This helps us learn as much as possible about the drug as quickly as possible, which in turn enables us to tighten the clinical development programmes,” said Elmlinger. Elmlinger and his team use immunological tests (ELISA, multiplex ELISA, immunoblot, immunocyto- and histochemistry), DNA and RNA expression studies using chip-based technologies (e.g., Illumina, Affymetrix), mass spectrometry and gas chromatography for their biomarker discovery activities. Target-related biomarkers are usually tested in in vitro test systems involving full blood.
Manufacturing method determines procedural method
When looking for and analysing biomarkers, Prof. Martin Elmlinger and his team use different procedural methods, depending on the type of drugs used. When looking for biomarkers relating to classical chemical drugs such as Nycomed’s Pantozol that is used for the treatment of reflux, the Nycomed team uses a different method from that used for focusing on genetically engineered biochemical drugs. “In the case of genetically engineered biochemical drugs, safety is paramount, and many safety biomarkers are determined in order to obtain early information about unusual immunological reactions,” said Elmlinger. Since the recombinant antibodies are often involved in immunological reactions, in vitro experiments need to exclude their immunomodulatory effect. Nycomed runs comprehensive in vitro tests that are largely based on biomarkers. “The development of classical chemical drugs, which also includes our new Daxas® drug for the treatment of COPD patients for which we have applied for marketing authorisation, is also based on biomarker tests. Daxas was optimised and developed using state-of-the-art technologies such as biomarkers and pharmacokinetics,” said the head of Nycomed’s Biomarker Development Department.
Between preclinical research and clinical development
The translation of pharmacological data obtained from biomarker tests on animals to the situation in humans is an essential and hugely challenging part of Elmlinger’s work. Although many biomarkers can easily be measured in preclinical models, the true challenge lies in finding out whether the biomarkers that have been shown to be representative of a certain disease in animals, also provide reliable answers in humans. “Translational development is aimed at reducing the incalculability of drug effects, especially when moving from animal models to humans,” said Prof. Dr. Martin Elmlinger. In order to reduce the incalculability of drug effects, Nycomed’s human studies on biomarkers initially pursue a more explorative, though still knowledge-based biomarker discovery approach.
“We put together a larger set of in-house and commercial biomarker tests, based on knowledge gained from animal experiments as well as on information on animal and human tests published in scientific literature,” said Prof. Martin Elmlinger. These marker sets are then tested, leading to the selection of useful markers that can subsequently be analysed in larger clinical trials and on actual patients. Elmlinger’s team pursued this strategy in their search for specific markers for chronic obstructive pulmonary disease (COPD), a common disease associated with chronic inflammation and the gradual destruction of the lung epithelium. “The diagnostic inflammation marker hCRP (human C-reactive protein), which is also used for the diagnosis of other inflammatory diseases, has proven very helpful,” said the head of Nycomed’s Biomarker Development Department. With regard to many diseases, the findings gained in animal models cannot always be equally well transferred to the situation in humans. Appropriate animal models are still not available for many human diseases.
Prof. Martin W. Elmlinger, Ph.D.
Director Biomarker Development (RDP/BD)
Byk-Gulden Straße 2