Shifting Biomarkers: The Future of Expediting and Refining Drug Delivery

Shifting Biomarkers: The Future of Expediting and Refining Drug Delivery

“Well-defined and clinically valid biomarkers will overcome many of the limitations of conducting studies on rare diseases.”

In April 2010, Kuvan® was approved for the treatment of phenylketonuria (PKU), an inherited disorder that causes elevated levels of phenylalanine in the blood.1 Patients with PKU lack an enzyme known as phenylalanine hydroxylase, which breaks down the phenylalanine we consume in food.2 The conventional treatment for PKU is lifelong dietary restrictions that often leave the patients malnourished. The discovery of the pharmaceutical solution for PKU, Kuvan®, marked a milestone in orphan drug approval and delivery. The approval of Kuvan® relied on the drug’s ability to make measurable and significant changes to a biomarker for PKU rather than the drug’s ability to directly impact clinical outcomes.3 Prior to 2010, there were significant clinical outcome data supporting the relationship between phenylalanine levels in the blood and severe symptoms such as seizure, intellectual disability, and stunted growth. Kuvan® was shown to reduce serum phenylalanine levels, the biomarker for PKU, and was thus approved for clinical use. The use of biomarkers as a surrogate endpoint to inform the diagnosis and treatment of rare pathologies are at the forefront of drug development. Well-defined and clinically valid biomarkers will overcome many of the limitations of conducting studies on rare diseases.3 The application of biomarkers has the potential to accelerate drug development both within Canada and internationally.

Biomarkers are biological characteristics that can be objectively measured and evaluated as an indicator of a biological, pathogenic, or therapeutic process. There are three main categories of biomarkers, as defined by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.4

  1. Prognostic: baseline categorization by the degree of risk for disease occurrence/progression
  2. Predicative: baseline characteristics that categorizes patients by likelihood for response
  3. Pharmacologic: dynamic biological response after a pharmaceutical intervention

  Figure 1: A dysfunctional anion channel, which causes the CF pathology.

Figure 1: A dysfunctional anion channel, which causes the CF pathology.

A single disease can be defined and monitored through different types of biomarkers. For instance, in the case of cystic fibrosis (CF), the G551D mutation and forced expiratory volume in 1 second (FEV1) are both biomarkers at different levels in the manifestation of the disease.4 CF is the result of many different mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which miscodes the anion protein channels the CFTR gene codes for. CFTR is responsible for transporting chloride in and out of epithelial cells, which regulates the movement of solution ions and water across the cell. When these channels are dysfunctional, dehydrated mucous collects on the apical surface of the cell, causing inflammation (Figure 1). G551D is the third most common CF mutation and is a predicative biomarker because knowing the specific CF mutation allows a clinician to predict whether a drug like Ivacaftor would be effective for that individual patient.5 Ivacaftor is a potentiator that assists in the folding of the CFTR protein to increase protein functionality.6 In a randomized controlled trial, it was demonstrated that subjects experienced a 7.5% improvement in absolute change in FEV1 after eight weeks, which is significantly better than placebo.6 In this study, FEV1 was used as a pharmacologic biomarker that measured the dynamic changes to the body because of Ivacaftor administration. FEV1 was used to measure improvement in lung function, which is drastically affected in patients with CF. As demonstrated, biomarkers can be used to identify the primary cause or track the primary and secondary pathophysiologic changes at the genetic, RNA, protein, and metabolite levels.3 Furthermore, biomarkers can also be used to track primary clinical effect and quality of life through biopsies, X-ray imaging, and clinical function tests.3

Biomarkers are expected to make a tremendous impact in pediatric drug administration. It is estimated that 90% of neonates and 40-60% of children have used off-label drugs, meaning that they are using a dosage that is not described or substantiated by rigid clinical trials.7 Children are often excluded from pharmaceutical studies for both practical and ethical reasons. Therefore, biomarkers can act as surrogate endpoints to survival, allowing scientists to examine and monitor clinical efficiency. In the case of Gaucher disease, which is a lysosomal storage disorder, scientists can use a biomarker like glucocerebrosidase, a lysosomal storage enzyme that is deficient in Gaucher disease, to monitor disease progression. This will allow clinicians to be able to identify whether the pharmaceutical intervention is able to delay the progression of the disease without having to wait for symptoms like damage to the brain, heart, kidneys, and peripheral nerves to manifest.7 Better understanding of pediatric dosing regimens will open an entire field of research on the complex interrelationships between developmental changes and changes in biomarker response to therapy.


“Biomarkers hold tremendous promise in refining pediatric drug regimens and accelerating the discovery of drugs for rare diseases.”

Another important use of biomarkers is in facilitating the accelerated approval of orphan drugs used to treat rare diseases. Although Canada has no established national policies or legislative framework for drug regulatory development and market approval, Health Canada proposes to recognize orphan drug designations by other international regulatory agencies like the Food and Drug Administration (FDA).8 In 2012, the FDA approved the use of the accelerated approval pathway for rare diseases, which had been formally used to expedite the development of drugs to treat cancer and HIV.3 Conventionally, the regulatory approval of a new drug is based on a benefit-risk ratio that examines whether a drug can induce an improvement in clinical function measured by tangible changes in how the patient feels and functions. However, the accelerated pathways will allow drug approvals based on the drug’s impact on surrogate outcomes, which are biomarkers that are related to disease, but not necessarily the direct outcome of the disease. Due to a low prevalence of rare diseases, studies must include a significant fraction of the total population of patients to have sufficient power, meaning that the study will be able to detect a statistically significant change. Thus, it is extremely valuable in rare disease research because many rare diseases have extremely small or heterogeneous patient populations. Enrolling anyone accessible with the disease makes the study population heterogeneous in terms of age, severity, the presence of clinical symptoms, and disease progression. Furthermore, the lack of understanding of disease etiology means that many patients have subclinical progression, leading to substantial irreversible damage by the time of prognosis.3 A combination of these factors makes the use of clinical endpoints challenging. Under the new accelerated system, different biomarkers can be used to classify the disease at the gene, cellular, tissue, organ, and integrated system levels to better understand the final outcome.

Biomarkers allow scientists and clinicians to characterize factors that influence disease outcome. Being able to universally and objectively diagnose, measure disease progression, and monitor drug response, biomarkers hold tremendous promise in refining pediatric drug regimens and accelerating the discovery of drugs for rare diseases.


Works Cited:

1. Biomarin. Kuvan (sapropterin dihydrochloride) Tablets and Powder for Oral Solution for PKU. http://www.biomarin.com/products/kuvan. Published 2017.

2. Burton BK, Kar S, Kirkpatrick P. Sapropterin. Nat Rev Drug Discov. 2008;7(3):199-200. doi:10.1038/nrd2540.

3. Kakkis ED, O’Donovan M, Cox G, et al. Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints. Orphanet J Rare Dis. 2015;10(1):16. doi:10.1186/s13023-014-0195-4.

4. Roundtable #2 Biomarkers in Drug Development for Rare Diseases. In: Bethesda: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development; 2013. www.ctsicn.org/sites/default/files/attachments/RT%232 Zajicek.pdf.

5. Bompadre SG, Li M, Hwang TC. Mechanism of G551D-CFTR (cystic fibrosis transmembrane conductance regulator) potentiation by a high affinity ATP analog. J Biol Chem. 2008;283(9):5364-5369. doi:10.1074/jbc.M709417200.

6. Kuk K, Taylor-Cousar JL. Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015;7(4):152-159. doi:10.1177/1753465815601934.

7. Bai JPF, Barrett JS, Burckart GJ, Meibohm B, Sachs HC, Yao L. Strategic biomarkers for drug development in treating rare diseases and diseases in neonates and infants. AAPS J. 2013;15(2):447-454. doi:10.1208/s12248-013-9452-z.

8. Canadian Agency for Drugs and Technologies in Health CADTH. Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment Perspectives. Environ Scan. 2016;2013(42):0-33.


Cite This Article:

Zhang B., Chan G., Palczewski K., Lewis K., Ho J. Shifting Biomarkers: The Future of Expediting and Refining Drug Delivery. Illustrated by L. Nguyen. Rare Disease Review. April 2018. DOI:10.13140/RG.2.2.16349.92642.

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