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Biomarkers are important tools in drug development and are used throughout pharmaceutical research. This review focuses on molecular biomarkers in drug development. It contains sections on how biomarkers are used to assess target engagement, pharmacodynamics, safety, and proof-of-concept. It also covers the use of biomarkers as surrogate end points and patient selection/companion diagnostics and provides insights into clinical biomarker discovery and biomarker development/validation with regulatory implications. To survey biomarkers used in drug development--acknowledging that many pharmaceutical development biomarkers are not published--we performed a focused PubMed search employing \"biomarker\" and the names of the largest pharmaceutical companies as keywords and filtering on clinical trials and publications in the last 10 years. This yielded almost 500 entries, the majority of which included disease-related (approximately 60%) or prognostic/predictive (approximately 20%) biomarkers. A notable portion (approximately 8%) included HER2 (human epidermal growth factor receptor 2) testing, highlighting the utility of biomarkers for patient selection. The remaining publications included target engagement, safety, and drug metabolism biomarkers. Oncology, cardiovascular disease, and osteoporosis were the areas with the most citations, followed by diabetes and Alzheimer disease. Judicious biomarker use can improve pharmaceutical development efficiency by helping to select patients most appropriate for treatment using a given mechanism, optimize dose selection, and provide earlier confidence in accelerating or discontinuing compounds in clinical development. Optimal application of biomarker technology requires understanding of candidate drug pharmacology, detailed modeling of biomarker readouts relative to pharmacokinetics, rigorous validation and qualification of biomarker assays, and creative application of these elements to drug development problems.

To evaluate the disease biomarker response of venglustat in patients with Fabry disease (FD), utilizing data from a single-arm phase 2 study of venglustat and a placebo-controlled phase 3 study of agalsidase beta through historical control and case-matched analyses. Eleven venglustat-treated male patients with classic FD in the phase 2 study were matched with placebo- or agalsidase beta-treated patients from the phase 3 study based on propensity scores at baseline. Changes from baseline in plasma globotriaosylceramide (GL-3 or Gb3) concentrations were analyzed at approximately 6-36 months. Venglustat treatment resulted in greater significant reductions in plasma GL-3 concentrations at 6 months from baseline vs. placebo (mean difference -2.56 μg/mL, p < 0.001), and at 24 and 36 months from baseline vs. agalsidase beta (mean difference -1.8 μg/mL, p < 0.05 and -2.35 μg/mL, p < 0.01, respectively). GL-3 concentrations continued to decline with venglustat for up to 3 years without plateauing. Venglustat showed significantly greater reductions in plasma GL-3 concentrations than placebo after 6 months and agalsidase beta after 24 and 36 months. These findings support the potential of long-term venglustat treatment to reduce GL-3 accumulation in patients with classic FD. Further studies are needed to confirm clinical benefit.

Disease modifying treatments for Alzheimer's disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.

Background: The diagnosis of diseases leading to brain injury, such as stroke, Alzheimer disease, and Parkinson disease, can often be problematic. In this study, we pursued the discovery of biomarkers that might be specific and sensitive to brain injury. Methods: We performed gene array analyses on a mouse model to look for biomarkers that are both preferentially and abundantly produced in the brain. Via bioinformatics databases, we identified the human homologs of genes that appeared abundant in brain but not in other tissues. We then confirmed protein production of the genes via Western blot of various tissue homogenates and assayed for one of the markers, visinin-like protein 1 (VLP-1), in plasma from patients after ischemic stroke. Results: Twenty-nine genes that were preferentially and abundantly expressed in the mouse brain were identified; of these 29 genes, 26 had human homologs. We focused on 17 of these genes and their protein products on the basis of their molecular characteristics, novelty, and/or availability of antibodies. Western blot showed strong signals in brain homogenates for 13 of these proteins. Tissue specificity was tested by Western blot on a human tissue array, and a sensitive and quantitative sandwich immunoassay was developed for the most abundant gene product observed in our search, VLP-1. VLP-1 was detected in plasma of patients after stroke and in cerebrospinal fluid of a rat model of stroke. Conclusions: The use of relative mRNA production appears to be a valid method of identifying possible biomarkers of tissue injury. The tissue specificity suggested by gene expression was confirmed by Western blot. One of the biomarkers identified, VLP-1, was increased in a rat model of stroke and in plasma of patients after stroke. More extensive, prospective studies of the candidate biomarkers identified appear warranted.

background: Definitive diagnosis of Alzheimer disease (AD) can be made only by histopathological examination of brain tissue, prompting the search for premortem disease biomarkers. We sought to determine if the novel brain injury biomarker, visinin-like protein 1 (VLP-1), is altered in the CSF of AD patients compared with controls, and to compare its values to the other well-studied CSF biomarkers 42-amino acid amyloid-β peptide (Aβ1–42), total Tau (tTau), and hyperphosphorylated Tau (pTau). methods: Using ELISA, we measured concentrations of Aβ1–42, tTau, pTau, and VLP-1 in CSF samples from 33 AD patients and 24 controls. We compared the diagnostic performance of these biomarkers using ROC curves. results: CSF VLP-1 concentrations were significantly higher in AD patients [median (interquartile range) 365 (166) ng/L] compared with controls [244 (142.5) ng/L]. Although the diagnostic performance of VLP-1 alone was comparable to that of Aβ, tTau, or pTau alone, the combination of the 4 biomarkers demonstrated better performance than each individually. VLP-1 concentrations were higher in AD subjects with APOE ε4/ε4 genotype [599 (240) ng/L] compared with ε3/ε4 [376 (127) ng/L] and ε3/ε3 [280 (115.5) ng/L] genotypes. Furthermore, VLP-1 values demonstrated a high degree of correlation with pTau (r = 0.809) and tTau (r = 0.635) but not Aβ1–42 (r = −0.233). VLP-1 was the only biomarker that correlated with MMSE score (r = −0.384, P = 0.030). conclusions: These results suggest that neuronal injury markers such as VLP-1 may have utility as biomarkers for AD.

Current guidelines for managing Philadelphia-positive chronic myeloid leukemia include monitoring the expression of the BCR-ABL1 (breakpoint cluster region/c-abl oncogene 1, non-receptor tyrosine kinase) fusion gene by quantitative reverse-transcription PCR (RT-qPCR). Our goal was to establish and validate reference panels to mitigate the interlaboratory imprecision of quantitative BCR-ABL1 measurements and to facilitate global standardization on the international scale (IS). Four-level secondary reference panels were manufactured under controlled and validated processes with synthetic Armored RNA Quant molecules (Asuragen) calibrated to reference standards from the WHO and the NIST. Performance was evaluated in IS reference laboratories and with non-IS-standardized RT-qPCR methods. For most methods, percent ratios for BCR-ABL1 e13a2 and e14a2 relative to ABL1 or BCR were robust at 4 different levels and linear over 3 logarithms, from 10% to 0.01% on the IS. The intraassay and interassay imprecision was <2-fold overall. Performance was stable across 3 consecutive lots, in multiple laboratories, and over a period of 18 months to date. International field trials demonstrated the commutability of the reagents and their accurate alignment to the IS within the intra- and interlaboratory imprecision of IS-standardized methods. The synthetic calibrator panels are robust, reproducibly manufactured, analytically calibrated to the WHO primary standards, and compatible with most BCR-ABL1 RT-qPCR assay designs. The broad availability of secondary reference reagents will further facilitate interlaboratory comparative studies and independent quality assessment programs, which are of paramount importance for worldwide standardization of BCR-ABL1 monitoring results and the optimization of current and new therapeutic approaches for chronic myeloid leukemia.

Familial adenomatous polyposis (FAP) is a precancerous, colorectal disease characterized by hundreds to thousands of adenomatous polyps caused by mutations in the tumor suppressor gene adenomatous polyposis coli (APC). Approximately 30% of these mutations are premature termination codons (PTC), resulting in the production of a truncated, dysfunctional APC protein. Consequently, the β-catenin degradation complex fails to form in the cytoplasm, leading to elevated nuclear levels of β-catenin and unregulated β-catenin/wnt-pathway signaling. We present in vitro and in vivo data demonstrating that the novel macrolide, ZKN-0013, promotes read through of premature stop codons, leading to functional restoration of full-length APC protein. Human colorectal carcinoma SW403 and SW1417 cells harboring PTC mutations in the APC gene showed reduced levels of nuclear β-catenin and c-myc upon treatment with ZKN-0013, indicating that the macrolide-mediated read through of premature stop codons produced bioactive APC protein and inhibited the β-catenin/wnt-pathway. In a mouse model of adenomatous polyposis coli, treatment of APCmin mice with ZKN-0013 caused a significant decrease in intestinal polyps, adenomas, and associated anemia, resulting in increased survival. Immunohistochemistry revealed decreased nuclear β-catenin staining in the epithelial cells of the polyps in ZKN-0013-treated APCmin mice, confirming the impact on the β-catenin/wnt-pathway. These results indicate that ZKN-0013 may have therapeutic potential for the treatment of FAP caused by nonsense mutations in the APC gene.Key messages• ZKN-0013 inhibited the growth of human colon carcinoma cells with APC nonsense mutations.• ZKN-0013 promoted read through of premature stop codons in the APC gene.• In APCmin mice, ZKN-0013 treatment reduced intestinal polyps and their progression to adenomas.• ZKN-0013 treatment in APCmin mice resulted in reduced anemia and increased survival.

Biomarkers of tissue injury have evolved empirically over the last 50-–100 years. With the advent of immunoassays and discovery tools such as RNA expression and proteomics, more systematic approaches to the discovery of biomarkers can be expected in the future. This review discusses the evolution of biomarkers of muscle, liver, heart and brain injury and illustrates that a modern discovery tool, such as mRNA profiling, would have predicted the biomarkers for cardiac injury (heart attacks) that actually evolved over 50  years by empiric approaches. We also discuss how novel biomarkers for brain injury were identified using RNA expression approaches. It is our prediction that there will be a growth in the number of valuable biomarkers for identifying cell and organ injury in the next 5-–10  years.

The promise of targeted therapies in molecularly defined subsets of cancer has led to a transformation of the process of drug development in oncology. To target cancer successfully and precisely requires high-quality translational data. Such data can be generated by the use of biomarkers that answer key questions in drug development. Translational data for aiding in decision-making and driving cancer drug development can be generated by systematic assessments with biomarkers. Types of biomarkers that support decisions include: pharmacodynamic assessments for selecting the best compound or dosage; assessment of early tumor response with tissue biomarkers and imaging, mutation, and other assessment strategies for patient selection; and the use of markers of organ injury to detect toxicity and improve safety. Tactics used to generate biomarker data include fit-for-purpose assay validation and real-time biomarker assessments. Successfully translated and clinically informative biomarkers can mature into novel companion diagnostic tests that expand the practice of laboratory medicine. Systematic biomarker assessments are a key component of the clinical development of targeted therapies for cancer. The success of these biomarker assessments requires applying basic principles of laboratory medicine to generate the data required to make informed decisions. Successful biomarkers can transition into diagnostic tests that expand the laboratory medicine armamentarium.

Owing to these differences, a gap may result in optimal matching of the right patient to the right drug when medical practice changes rapidly. [...]changes to the system are essential for enabling rapid translation of scientific evidence into high-quality clinical practice and thereby improvements in patient care. Alternatively, it would be highly desirable to have a mechanism for facilitating the rapid availability of commutable calibrators and standards that serve as external quality controls for the assay, as has been proposed for BCR-ABL (breakpoint cluster region-c-abl oncogene 1, non-receptor tyrosine kinase) transcript-level quantification (16 ).