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How biomarkers and bioanalytics are changing R&D

Biomarkers have been causing a paradigm shift in how HCPs treat patients for some time – now they are bringing the pharma industry a new gold standard for clinical research.

Thomas Turi, chief scientific officer at Nexelis, tells us how a biomarker-led R&D approach is transforming drug development in disease areas like non-alcoholic steatohepatitis (NASH) and cancer, and provides best-practice tips for companies looking to harness this approach.

Biomarkers have already guided our understanding of several cancers and led to the development of several precision medicines. Recent approvals in highly heterogenous tumours, such as non-small cell lung cancer, are now targeting smaller patient populations – representing just a single-digit percentage of patients with aggressive cancers and poor prognosis.

Unsurprisingly, some major pharmaceutical companies are in the process of revamping their entire R&D approach to focus on biomarkers, and see such technology as the key to discovering new, breakthrough treatment options that also have the potential to transform care by allowing patients to undergo less exhaustive testing.

Developing a biomarker strategy for clinical trials

One key piece of advice for pharma companies moving in this direction is to involve CRO biomarker strategists early on, to help determine what the target is, and the potential mechanism associated with it, which will ultimately allow for a better trial experience for both companies and patients.

“As biomarker analysis becomes more complicated, it’s important to find the balance between selecting appropriate endpoints to inform decision making and sparing patients the burden of a lot of repeated or invasive sampling procedures”, Turi says. “Partnering with companies that specialise in biomarker testing at the early stages of trial design can greatly improve efficiency and efficacy, thus sparing patients extensive testing”.

Biomarkers exist for different purposes, and strategists can identify the appropriate biomarkers that will help patients and HCPs choose beneficial treatment options.

“One type of biomarker can help stratify patient populations or determine which are the most appropriate patients to treat. This is especially helpful in a heterogeneous disease, where it allows clinicians the ability to better define the disease population”, says Turi.

“Another type of biomarker can stage patients accordingly within their disease. While other biomarkers may indicate the likelihood of disease progression”, Turi added.

“Despite the wealth of information and data on biomarkers, many disease indications lack informative markers. Thus, many sponsors undertake exploratory biomarker discovery studies. One of the big challenges of multiplex-type approaches and biomarker discovery or identification is overfitting of data and making sure you haven’t biased your analysis”, says Turi. “In addition, having a robust strategy where biomarker discovery, confirmation and validation are linked is essential to yield informative markers”.

Identifying a set of biomarkers from a given study is quite easy and can help identify candidate biomarkers, but what’s important is finding an informative biomarker by going through the qualification and validation of it.

Partnering with an experienced clinical research organisation (CRO) and clinical reference laboratory (CRL) is critical in biomarker testing as well. Turi states that it’s beneficial to utilise CRO and CRL knowledge working in specific disease areas as well as their scientific and technical experts, who can provide insights that will inevitably advance programmes.

“A CRL partner or laboratory will be a thought partner as you continue to progress your development programme – someone who can engage early and has the resources and expertise in bioanalytics as well as the reach to support you throughout a small, focused phase 1 study to a global clinical trial.”

All successful partnerships start with clear and open communication and transparency at the programmatic level as well as the scientific and technical levels. A fruitful research partnership is key to ensuring patients get the best results possible, which is why strategists are so important in biomarker-led R&D programmes.

“Biomarker strategy is essential when considering the idea of sparing patients from the trials and tribulations of multiplex, multivariant analyses throughout phase 1.”

Taking a patient-centric approach to biomarkers

Some companies take a shotgun approach to analyses, which can overburden patients by trying to include many kinds of markers, but it’s important to have the qualities, resources, and expertise needed for a focused biomarker-driven research programme to improve the overall experience for patients and researchers.

Turi states, “You need to be patient centric – the individual at the centre of the trial – and think about their journey through their disease. Study subjects try to help themselves and the broader patient population by volunteering for a clinical trial. We should never lose sight of who actually drives these trials – the patient”.

Currently, researchers are thinking of how biomarker-led approaches to clinical research can support the development of new treatment options, especially in heterogenous diseases such as NASH and non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic steatohepatitis, better known as NASH, is a type of non-alcoholic fatty liver disease and a condition that causes inflammation and accumulation of fat and fibrous (scar) tissue in the liver. About 3% to 12% of adults in the United States have NASH. In such a prevalent disease, having prognostic markers or risk stratification markers would be useful.

“We don’t have a true understanding of the underlying molecular mechanisms that contribute to NAFLD and subsequently NASH. So, we don’t have a true aetiology of it”.

“Currently, the best recognised markers for identifying NAFLD and NASH is through liver biopsy, a highly invasive procedure that really is based on a pathologist’s interpretation,” Turi states. “In order to stage one’s disease, serial biopsy may be necessary, which attributes greater burden and potential risk to patients”.

“There are some blood-based biomarkers used for staging or identifying NASH that require analysing multiple biomarkers and then translation into a score. However, these assay may not always provide a good indication of where a patient truly is in their progression of the disease or whether a patient will progress in their disease”, Turi adds.

Therefore, creation of therapies for NASH remains a challenge because the current understanding of the pathogenesis of NASH, while much improved, remains unclear. A biomarker-led research approach could be critical for the potential discovery and development of a NASH treatment.

Supporting the future development of biomarkers

Although there’s no general database of informative biomarkers at the moment, many companies are working to analyse them with appropriate tools and technologies that identify potential candidates.

“The NIH, the Critical Path Initiative, and many others have provided guidance on how one can take steps not only to identify biomarkers, but also to provide appropriate context on their use. It’s a long process to generate the evidence to demonstrate that it truly is an informative biomarker that can be used for decision making”.

Turi notes that, ultimately, more biomarker-led research will be incorporated within trial settings in the future to improve the overall clinical strategy. Biomarkers will be used to select patients who are most likely to respond to treatment, and more researchers will make biomarker-guided decisions and use biomarker selection, and biomarkers will become broader and more prevalent in treating disease areas outside of oncology.

“Biomarker scientists and translational scientists are becoming more critical and vital to the success of drug development programmes. As people come up with more novel trial designs – adaptive-type trials, where you can change approaches and treatments within a given trial, move patients from one arm of the trial to the next – it will become more evidence-based. Biomarkers will be central in those decision-making processes.”

About the interviewee

Thomas Turi

Thomas Turi, Ph.D. is part of the executive leadership at Nexelis, where he is chief scientific officer. He has 25 years’ pharmaceutical and contract research leadership experience, during which two of Dr Turi’s accomplishments were establishing the Biomarker Center of Excellence for Covance and serving as senior director of translation biomarkers and mechanistic biology at Pfizer. He has also previously served on the Board of Directors for Cellcarta (formerly Caprion Proteomics) and led several external partnerships, including those with Rules Based Medicine, Celera, Incyte and Affymetrix. He has also served on grant and programme project review boards for NASA’s Section for Biotechnology and Tissue Engineering.

About Nexelis

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With unrivaled expertise in immunology, five operating sites in North America and Europe, and a translational offer of services covering the needs of the pharmaceutical industry from the lead selection to the late clinical stage, Nexelis is a leading provider of assay development and advanced laboratory testing services in the infectious, metabolic and oncologic fields. Its versatile team of scientists, working with state-of-the-art technology platforms, were instrumental in the development, qualification, validation, and large-scale sample testing of assays that supported the FDA filing of almost 100 new molecular entities, including blockbuster vaccines and biologics, anti-viral drugs, immunotherapy, gene and cell therapy products.

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