BIOMARKERS - Biomarkers: The Guiding Light for R&D in Heterogeneous Diseases

BIOMARKER-LED R&D

While biomarkers have been a long-standing part of R&D and a mainstay of clinical practice for the characterization and diagnosis of disease for decades, they are increasingly playing a crucial role in guiding decisions to improve efficacy and efficiency of clinical trials. Biomarkers can not only provide critical insights into the biological activity of targets and their modulation, but can also guide on the most appropriate patient populations to recruit into studies and inform the selection of trial metrics and endpoints.

The pharmaceutical industry has emerged from a period of poor productivity and overall inefficiency to deliver an unprece­dented number of new drugs. In 2006, after extensive research and consultation, the US Food and Drug Administration issued the Critical Path Report and List.¹ The report outlined a number of priority areas for scientific improvement in the development process, including the development and utilization of biomarkers, as well as modernizing clinical trial methodologies and processes.¹ Incorpo­rating many of the recommendations from the Critical Path Report, throughout the past 5 years, the industry has delivered an average of 46 new approvals per year, more than double the 22 approvals per year delivered between 2006 and 2010.²

Through this marked improvement, biomarkers have demonstrated their inte­gral role in enabling better decisions on advancing compounds with a high prob­ability of success and eliminating nonpro­ductive programs at earlier stages of development. Thus, a biomarker-led R&D approach has become the standard for drug development.

Biomarkers have already guided our understanding of the complex heterogene­ity of several cancers and led to the devel­opment of a number of precision medicines. More recent drug approvals, in highly heterogeneous solid tumors such as colorectal cancer, are now targeting smaller patient populations – representing even single-digit percentages of patients with aggressive cancers and poor prog­noses.³ Unsurprisingly, most major phar­maceutical companies are increasing their investment in biomarker-guided develop­ment.

Practically, this means ensuring a comprehensive biomarker approach is ini­tiated during the preclinical phase of the program and integrated into the overall clinical development strategy. Implemen­tation of the biomarker strategy should begin within the very first patient cohort, evaluating whether there are early signals of efficacy, or potentially early signals of safety issues. This will ultimately allow ear­lier, more informed decisions on whether to proceed into late-stage human trials, thus saving time, money, and resources.

PLUGGING INTO THE RIGHT EXPERTISE AT THE RIGHT TIME

The pharmaceutical industry has made great strides in unlocking the poten­tial of biomarkers in oncology, but how can researchers quickly make the same in­roads in other heterogeneous diseases that have multiple biomarkers at play? One route is to access a partner, such as a clinical research organization (CRO), with deep, relevant therapeutic and bio­marker expertise, and then harness this knowledge at an early stage when design­ing biomarker-led clinical programs.

CROs are in a unique position, with experience supporting clinical develop­ment programs that span a broad spec­trum of disease and mechanistic approaches. Moreover, many of these CROs have expertise in developing robust, complex biomarker assays. Identifying the right laboratory partner with the knowledge and capabilities to design and run these critical assays needed to support the clinical trial design could be the difference between trial success and failure.

It is also important to access this ex­pertise early on. In order to capture as many insights as possible, many trials in­corporate numerous types of markers, and therefore multiple invasive tests for the pa­tient to endure, which can result in an un­necessary burden on the patient. Having the insights, knowledge, and experience to select the most informative and valuable biomarker and utilizing enhanced tech­nologies to interrogate each sample through multiplex assays, can all help to streamline biomarker analysis and de­crease patient burden.

CROs can be seen as thought part­ners, able to lend the right expertise and resources to alleviate the burden for in-house development teams. Accessing a range of biomarker scientists and technical experts, many of whom are core members of any CRO team, complements a spon­sor’s translational medicine expertise, bol­sters early research efforts, and supports a more informed decision-making process. In this way, the right CRO partner provides added value and efficiency to develop­ment programs.

APPLYING A BIOMARKER-LED APPROACH TO NASH

Biomarkers can provide a dynamic and powerful approach to understanding the spectrum of a heterogenous disease, such as in nonalcoholic fatty liver disease (NAFLD). NAFLD causes fat to accumulate in the liver of people who drink little or no alcohol. It is increasingly common around the world, especially in Western nations, and it is set to become the predominant cause of chronic liver disease in many parts of the world. The epidemiology and demographic characteristics of NAFLD vary worldwide.^4,5 In the US, it is the most common form of chronic liver disease, af­fecting about one-quarter of the popula­tion.⁴

Nonalcoholic steatohepatitis (NASH) is a type of NAFLD and a condition that causes inflammation and accumulation of fat and fibrous tissue in the liver; it devel­ops in only in a minority of patients with NAFLD. NASH is thought to be the precur­sor of liver fibrosis, which is associated with morbidity and mortality.⁶ Nearly 16.5 million people in the US are believed to have NASH, with more than 3 million thought to have liver cirrhosis due to NASH.⁷ Globally, one-quarter of the pop­ulation is estimated to have NAFLD.⁸ The incidence of NASH is projected to increase by up to 56% in the next 10 years.⁹

One major challenge in successfully developing an effective treatment is the lack of a noninvasive approach to diag­nosing NASH/NAFLD. Currently, the only means of a diagnosis is through invasive liver biopsies, but the interpretation is often subjective and the patient acceptability is poor.¹⁰ Variability in sampling that results from the limited sample size in combina­tion with the heterogeneity of the disease also limits the chance of a successful and definitive diagnosis.¹⁰ As the prevalence of NASH continues to grow, it is becoming in­creasingly important to identify noninva­sive biomarkers that support both diagnosis and the measurement of disease progression.

Furthermore, reflective of the complex nature of this disease, there are currently no approved treatments. This means that, when a patient goes through the burden­some process of diagnosis, they are then faced with few, or even no, medical effec­tive interventions to help treat this disease. Currently, doctors can only recommend weight loss to treat NASH – according to the National Institute of Diabetes and Di­gestive and Kidney Diseases, weight loss can reduce fat in the liver, inflammation, and fibrosis.¹¹ Experts are not sure why some people with NAFLD progress to hav­ing NASH. The continued lack of under­standing of the underlying molecular mechanisms that contribute to NAFLD, and subsequently NASH, make it increas­ingly difficult to develop a viable therapy.

The significant unmet medical need in NASH has led to substantial interest from the pharmaceutical industry, patient or­ganizations, and physicians on the devel­opment of an effective therapy. Yet the intricacy of the disease creates a complex­ity in the development of clinical studies that can be difficult to address.

A large number of noninvasive bio­markers have been deployed to evaluate NASH status and liver function, and those specifically targeting liver fibrosis provide a novel tool that can both determine a pa­tient’s likely journey with the disease and ascertain treatment efficacy.¹² These types of biomarkers could also be used to risk-stratify patients and improve the prognos­tics of clinical trials, to target the most at-need and at-risk patients, in turn, in­creasing the likelihood of trial success.

Additionally, numerous studies have attempted to identify informative biomark­ers for NASH disease staging, progression, and potential disease regression. Recently, a transcriptomic approach identified a set of promising biomarkers that correlate to disease stage. Additional proteomic analy­sis demonstrated that AKR1B10 and GDF15 are associated with both hepato­cyte ballooning and inflammation scores.¹² These serum-based protein bio­markers can be useful for the confirmation and staging of NASH in future clinical studies. Access to validated assays for these novel and informative biomarkers could also provide valuable insights on the efficacy of emerging therapeutics.

In addition to monitoring drug action or response, biomarkers are increasingly being utilized to guide patient selection, treatment, and management decisions. Prognostic biomarkers can help identify patient populations that are more likely to respond to a given treatment, while safety biomarkers can help avoid administering treatment to patients who might not re­spond, or may be harmed, by a specific treatment. As selection biomarkers are used more frequently in clinical develop­ment (presently, they are only being used in a small proportion of studies), and pa­tient selection is subsequently refined, phase transition success rates in high-prevalence diseases should improve.¹³ The higher success rates for trials involving bio­marker-selected patients suggest the broader industry is already on the right path.¹³

In one recent independent study, high levels of fibrogenesis biomarkers, such as PRO-C3, in patients with NASH are indica­tive of high disease activity and can be used to improve patient response rates in clinical trials. In a study presented at EASL 2018, patients’ specific levels of PRO-C3 were significantly reduced as a result of resmetirom (a selective thyroid hormone receptor-β agonist) treatment. Similar pre­dictive results for resmetirom were pre­sented by Madrigal Pharmaceuticals at the Global NASH Congress 2020 in the exten­sion study.¹⁴ As a result, specific PRO-C3 levels have been listed as inclusion criteria for the Phase 3 NAFLD clinical trials.¹⁴ This new paradigm further demonstrates the utilization of biomarkers in the assessment and treatment of diseases at the earliest possible time could maximize the benefit to patients.¹⁵

Bringing a safe and effective NASH treatment to patients poses many chal­lenges, but through strategic partnerships between pharmaceutical and CROs, lever­aging critical expertise and substantial re­sources, it is achievable.

As our understanding of heteroge­neous diseases evolves, the use and value of biomarkers in research and develop­ment will only continue to increase as we seek to unlock our understanding of these diseases and develop increasingly person­alized treatments.

REFERENCES

1. Woodcock J, Woosley RL. Annu Rev Med 2008; 59:1-12.
2. Mullard A. Nat Rev Drug Discov. 2021;20:85-90.
3. The ASCO Post. Prevalence of KRAS G12C So­matic Mutations by Cancer Type, Race, and Sex. Prevalence of KRAS G12C Somatic Mutations by Cancer Type, Race, and Sex – The ASCO Post. Last accessed October 2021.
4. Mayo Clinic. Nonalcoholic fatty liver disease – Symptoms and causes. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symp­toms-causes/syc-20354567. Lasted accessed October 2021.
5. Loomba R, Sanyal AJ. Nat Rev Gastroenterol He­patol. 2013;10:686-690.
6. National Institute for Health and Care Excellence. Non-alcoholic fatty liver disease (NAFLD): assess­ment and management. https://www.nice.org.uk/guidance/ng49. Last ac­cessed October 2021.
7. NASH Facts. The Latest Treatment Options for NASH in 2020. https://nashfacts.com/latest-treat­ment-options-for-nash-in-2020/. Last accessed October 2021.
8. Cotter TG, Rinella M. Gastroenterology. 2020 May; 158:1851-1864.
9. Huang DQ et al. Nat Rev Gastroenterol Hepatol. 2021;18:223-238.
10. Wong VW et al. Nat Rev Gastroenterol Hepatol. 2018; 15:461-478.
11. National Institute of Diabetes and Digestive and Kidney Diseases. Treatment for NAFLD & NASH. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/treatment. Last accessed October 2021.
12. Govaere O. et al. Sci Transl Med 2020; 12:eaba4448.
13. BIO, Biomedtracker, Amplion. Clinical Develop­ment Success Rates 2006-2015. https://www.bio.org/sites/default/files/legacy/bioorg/docs/Clinical_Development_Suc­cess_Rates_2006-2015_-_BIO,_Biomedtracker,_Amplion_2016.pdf.
14. Nordic Bioscience. Biomarkers for Nash. https://www.nordicbioscience.com/therapeutic-areas/hepatic-diseases/non-alcoholic-steato­hepatitis. Last accessed October 2021.
15. Guest PC. (2017) The Importance of Biomark­ers: The Required Tools of the Trade. In: Bio­markers and Mental Illness.Copernicus, Cham. https://doi.org/10.1007/978-3-319-46088-8-3.

Dr. Thomas Turi joined the executive leadership at Nexelis in the role as Chief Scientific Officer, bringing 25 years of pharmaceutical and contract research leadership experience. Two of his previous accomplishments are when he established the Biomarker Center of Excellence for Covance, and when he served as Senior Director of Translation Biomarkers and Mechanistic Biology at Pfizer. In addition to his current responsibilities, he has served on the Board of Trustees for The Life Sciences Foundation and is a member of the Global Health Research Roundtable of the Indiana Clinical and Translational Sciences Institute. He has previously served on the Board of Directors for Caprion Proteomics and led several external partnerships, including those with Rules Based Medicine, Celera, Incyte, and Affymetrix. He has also served on grant and program project review boards for NASA’s Section for Biotechnology and Tissue Engineering. Dr. Turi earned his bachelor’s degrees in Biochemistry and Chemistry from the University of Illinois at Urbana-Champaign and his PhD in Molecular Genetics from the University of Cincinnati College of Medicine. He completed postdoctoral training at the Yale University School of Medicine applying molecular genetic techniques to investigate the mechanisms of protein transport.