Translational science: The future of medicine

When the term ‘translational medicine’ first came to prominence at the turn of the century, there were suspicions that this concept was simply a rebranding of conventional medical research, describing the process in which scientific discovery at the laboratory bench eventually translates to an effective therapy at the patient’s bedside. The practical application of identifying and developing new therapies has always been a lengthy process. Would giving it a new name make it more efficient for scientists?

However, medical researchers quickly realised that translational science does not merely make existing systems work faster. Rather, researchers recognised that uncovering the next medical advancements requires a two-way flow of information from bench-to-bedside as well as from bedside-to-bench. Improving the feedback between basic researchers and front-line clinicians’ results in more targeted research. This two-way flow of information also allows clinicians to adapt trial designs in response to real-time data, as well as using predictive modelling to increase the success of Phase III clinical trials.

With the successful sequencing of the human genome in 2003, interest in translational medicine further intensified as the medical community looked to translational scientists to guide the next phase of research. Dramatic advances in our understanding of the genetic basis of disease opened the doors for discovering new therapeutic options for many areas of unmet medical need. But which paths would lead to effective therapies and which would turn to dead ends? Translational medicine offered to map a navigation through this maze.

Tools of the trade

Translational scientists quickly developed an array of new techniques, including rational drug design, in which potential therapies are discovered based on knowledge of their biological target. High-throughput technologies and advanced computer modelling have created a new discipline of in silico research that can sift out potential therapeutic molecules with a far greater success rate than that achieved using conventional laboratory analyses.

The identification of biomarkers has created a much closer relationship between diagnostics and treatment with the advent of ‘companion diagnostics’, in which new products are launched alongside accompanying tests to identify the patients most likely to benefit from the therapeutic. This has allowed medical researchers to develop new targeted agents for specific subpopulations of patients. Such a targeted approach has the potential to change a ‘loser’ drug with modest efficacy into a ‘winner’ drug with efficacy adequate to achieve health agency approval. Identification of the responding patient subset can lead to greater treatment effect for individual compounds. Additionally, targeting the appropriate patient population can help identify those patients at greater risk for significant safety events, which could reduce health agency concerns. Pharmacodynamic (PD) markers are now routinely used to monitor treatment response, allowing clinical outcomes to be linked to drug mechanism of action (MOA), and doses optimised at a much earlier stage in drug development.

It is this research that promises to help deliver personalised healthcare through more effective solutions tailored to address the needs of neglected disease indications, where patient populations are small and perhaps previously considered insufficiently lucrative for investment. Previously discarded molecules may find themselves back under scrutiny as their biological targets are identified. The personalised approach is a response to the demands of patients for more choices rather than a ‘one-size fits all’ model to treatment. Through this more tailored approach, researchers are increasingly identifying the right medicine for the right patient at the right time.

The business case

Along with scientific endeavour and patient care, economic and business factors have also been driving the growth of translational medicine.

One of the primary keys among these is the recent strategic shift among major pharmaceutical companies from small molecules to biologic compounds. In search of new products to expand research and development pipelines, many companies have dramatically increased their biotech capabilities, resulting in a slew of new and exciting products under investigation.

There is a clear business incentive to construct a more focused approach to research that yields better outcomes. Currently, an innovative molecule takes a 15 year journey from discovery to launch at a cost in excess of one billion US dollars (about EUR 740 million). Only one in 5,000 to 10,000 compounds synthesised ever becomes a commercial product1. In the US, less than one per cent of newly discovered molecules targeting a newly discovered disease mechanism receive FDA approval2. Even those products that make it to human clinical trials face a sobering attrition rate – fewer than 30 per cent ever get marketing approval, according to the trial-tracking company Centerwatch3. Translational medicine aims to create early go/no go criteria through which pre-clinical data can be assessed and followed up or discarded accordingly.

Evidence of success

Charged with meeting the demand for more personalised healthcare and improving return on investment in the pharmaceutical industry, translational scientists must live up to high expectations. Recent successes offer insightful case studies for the utility of this approach.

Scientists have made great strides in personalised medicine for several cancer types. For example, the monoclonal antibody trastuzumab has been shown to improve survival and response to chemotherapy in breast cancer patients whose tumours overexpress the human epidermal growth factor receptor type 2 (HER2). Between 20 per cent and 30 per cent of patients with invasive breast tumours exhibit such over-expression. Through companion diagnostics, including immuno – histochemistry (IHC) and fluorescent in situ hybridisation (FISH), clinicians can identify those patients who have HER2 over-expression and, thus, will most likely respond to treatment with trastuzumab. For the remaining 70 per cent of patients, treatment with trastuzumab will likely not be efficacious.

Traditionally, therapies with a ‘failure rate’ of 70 per cent or more would not often be viewed as a commercial success. But with testing, trastuzumab is now widely used in the right subpopulation of patients. More importantly, this means that patients without HER2 overexpression, who will likely receive little to no benefit from trastuzumab, can be given alternative therapies earlier.

Rational drug design and high throughput technologies were both at the forefront of the development of imatinib, a drug that has now been targeted toward at least two different cancer-causing genetic mutations. Researchers initially developed imatinib after discovering a link between a rare cancer called chronic myelogenous leukaemia (CML) and a chromosomal abnormality known as the Philadelphia translocation. This translocation causes an oncogenic gene fusion known as bcr-abl. Using high throughput technology, investigators searched specifically for a molecule that would inhibit the bcr-abl protein and eventually developed imatinib. Later research uncovered additional benefits with imatinib, including efficacy against gastrointestinal stromal tumours (GIST) in patients who tested positive for the c-kit or CD117 genetic mutation.

Biomarkers are now commonly used to improve the specificity of treatment in a range of other cancers, as well as other disease areas. For example, improved response rates to the monoclonal antibody cetuximab and panitumab have been seen in metastatic colorectal cancer patients whose tumours express wild type KRAS versus those that carry the KRAS mutation. In non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) gene mutations and increased EGFR copy number predict response to the tyrosine kinase inhibitor gefitinib.

The MedImmune approach

While MedImmune is not the only one applying translational science to its research efforts, the company has developed a unique way of effectively using the promise of the pharmacogenomics and translational medicine.

Our unique approach is well illustrated by the development of sifalimumab, which is in Phase II trials for the treatment of Systemic Lupus Erythematosus (SLE). This is a classic example of companion diagnostics, in that the drug is being developed in conjunction with its own diagnostic test.

Sifalimumab is a fully human antiinterferon- α (IFN-α) IgG1κ monoclonal antibody that binds to most of the IFN-α subtypes with high affinity but does not bind to the other type I IFN family members. It works by inhibiting IFN-α signalling through the IFN-α receptor (IFNAR). This monoclonal antibody is of interest in SLE as it is known that lupus disease activity is associated with elevated serum levels of IFN-α4. There is also evidence that showed increased expression of type I IFN-inducible transcripts in blood and tissues from SLE patients5. Furthermore, there is a correlation between IFN levels and expression of type I IFN-induced transcripts and SLE disease activity6.

To determine sifalimumab’s efficacy in SLE, we first need to develop a panel of PD markers to evaluate the MOA of the drug in clinical trials. By transcript profiling studies of the blood from healthy donors and two independent SLE patient cohorts, we developed a 21 type I IFNinducible transcript panel that could be conveniently measured using TaqMan quantitative polymerase chain reaction assays. Using this PD marker set, our scientists embarked on a Phase I clinical trial in 62 SLE patients. The results of this trial demonstrated a safety profile that supported continued clinical development. We also observed that sifalimumab showed a dose-dependent inhibition of the type I IFN-inducible transcripts in SLE, demonstrating clear biological activity of sifalimumab in SLE.

Other exciting compounds in MedImmune’s translational medicine pipeline include a monoclonal antibody (MEDI-575) to plateletderived growth factor receptor alpha (PDGFRα) that has shown promise in certain cancers. MEDI-575 is in clinical development in patients with advanced solid tumours, and has been shown to inhibit signalling from PDGFRα on cancer cells and supportive stroma. Importantly, the compound does not appear to affect PDGFRβ, the inhibition of which has been associated with clinical toxicities, including extravascular fluid accumulation.

MedImmune is also developing a potent anti-IL-5R antibody known as benralizumab (MEDI-563) for the treatment of inadequately controlled asthma. A novel method/diagnostic tool is being investigated to identify the patient population that will most likely respond to benralizumab, and is based on a peripheral blood sample. Benralizumab will hopefully be the most effective and convenient treatment in reducing the frequency of severe asthma exacerbations, while improving symptoms and quality of life for patients with inadequately controlled eosinophilic-mediated asthma. Benralizumab is being studied for subcutaneous administration with dosing every four to eight weeks. By identifying inadequately controlled patients with eosinophilic-driven asthma using a personalised healthcare approach, and prescribing benralizumab on top of medium to high-dose inhaled corticosteroids and LABA combination therapy, healthcare providers may be able to reduce asthma-related exacerbations and improve symptom control which currently contribute to a the high economic burden of disease, and thereby reduce associated healthcare costs.

Conclusion

Translational science holds great promise for developing new innovations in a range of therapeutic categories, as evidenced by MedImmune’s well-stocked pipeline and other successes. Nevertheless, this area of research is still in its infancy and faces a number of challenges, such as a lack of sufficient funding, high initial start-up costs and certain regulatory barriers.

These obstacles should not stifle the potential growth that this branch of science promises for the medical and patient communities. Through translational science, we should be encouraging reinvestment and reinvestigation of previously discontinued research as information gleaned from the bedside may provide the insights needed at benchside. In a time when the pharmaceutical industry is struggling to meet the ever-increasing demands for innovation, translational science offers the opportunity to reinvigorate research and development, and to deliver the kind of personalised healthcare patients now demand.

References

1. www.ddw-online.com/drug_discovery_business/ 581318/the_healthcare_industrys_evolving_role_in_ translational_research_an_opportunity_for_ competitive_advantage.html

2. www.newsweek.com/2010/05/15/desperatelyseeking- cures.html

3. www.nctimes.com/business/article_d9a6fee5- bec2-596b-b3c1-851940972e27.html

4. Hooks JJ et al. New Engl J Med. 1979;301:5-8

5. Crow M. Arthritis Rheum. 2003;48:2396-2401

6. Dall’era MC et al. Ann Rheum Dis. 2005;64:1692-1697

About the Author

Dr. Bahija Jallal is currently Executive Vice President, Research & Development with oversight for research & development activities based at MedImmune’s Gaithersburg and Cambridge, UK sites. Dr. Jallal joined MedImmune as vice president, translational sciences, in March 2006 and in 2007, her responsibilities were expanded when she was appointed head, preclinical oncology. Prior to joining MedImmune, Dr. Jallal worked with Chiron Corporation where she served as vice president, drug assessment and development, and successfully established the company’s translational medicine group. Prior to Chiron, she worked at Sugen, Inc. where she held positions of increasing responsibility leading to senior director, research. Dr. Jallal received a master’s degree in biology from the Universite de Paris VII in France, and her doctorate in physiology from the University of Pierre & Marie Curie in Paris. She conducted her postdoctoral research at the Max-Planck Institute of Biochemistry in Martinsried, Germany.