Cancer  

Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy (I-SPY 2) 

I-SPY 2 will be a groundbreaking, large-scale five-year scientific collaboration that will test new breast cancer drugs in 800 patients diagnosed with rapidly growing, localized stage 2 or 3 breast cancers that have a high risk of recurrence. They will be tested in the neoadjuvant setting, in which chemotherapy is given to patients to reduce tumor size before surgery. This allows researchers to follow the response of the tumor to the treatment in a rapid, six-month period before surgery, which saves several years compared with testing drugs after surgery.  

I-SPY 2 embodies “personalized medicine” in action: its approach will enable breast cancer treatments to be selected and tested based on whether they work more effectively in individual “types” of patients, as determined by measuring specific biomarkers in each patient’s tumors. Because I-SPY 2 is designed to test which drugs work most effectively in specific types of individuals, it promises to sharply reduce the number of patients required for follow-on trials of those drugs utilized in the project.  Furthermore, an innovative adaptive trial design will enable researchers to use early data from one set of patients to guide decisions about which treatments might be more useful for patients later in the trial, and eliminate ineffective treatments more quickly A distinctive feature of the trial is that it will screen multiple drugs from multiple companies—up to 12 different cancer drugs over the course of the trial. In order to do this, FNIH received a master Investigational New Drug (IND) approval from the FDA—which allows the I-SPY TRIAL team to graduate, drop and add drugs seamlessly throughout the course of the trial without having to stop the trial to write a whole new protocol. This will dramatically reduce the time it takes to move from one drug to another in the trial. 

These innovations, together with significant organizational efficiencies for this project, promise to speed and reduce the cost of drug development and advance regulatory approval of drugs that are specifically targeted to work more effectively in individual patients.   

Immunity & Inflammation 

PET Imaging of Inflammation in Rheumatoid Arthritis  

PET Imaging of Inflammation in Rheumatoid Arthritis focuses on determining the potential clinical utility of PET imaging using the [¹⁸F]PBR06 TSPO-specific radioligand as a biomarker to indicate active inflammation in rheumatoid arthritis and to correlate the expression of TSPO with the efficacy of disease-modifying anti-rheumatic drugs (DMARD) in rheumatoid arthritis patients. This 14-month project will work to determine the test-retest reliability of [¹⁸F]PBR06 TSPO imaging; and test the hypothesis that TSPO expression is highest in active rheumatoid arthritis patients, lower in patients in remission of rheumatoid arthritis, and lowest in healthy subjects. If successful, this project would qualify this PET radioligand as a biomarker of rheumatoid arthritis disease activity. 

Metabolic Disorders 

Establish Guidelines and Initial Diagnostic Criteria for the Association of Sarcopenia with Clinically Important Weakness – Evidence for Treatment Benefit  

The loss of skeletal muscle for the average normally healthy person amounts to about 20% between about 30 and 70 years of age. This loss may accelerate as aging progresses. Common among older adults, Sarcopenia has a number of serious consequences such as weakness, reduced mobility, functional disability, increased mortality and negative effects on comorbid conditions, such as glycemic control in diabetes.  It is currently unrecognized as a disease state within the healthcare industry because there is a lack of uniform criteria for its diagnosis and severity.  

Even in geriatric practice, the diagnosis of Sarcopenia is still subjective and qualitative, and lacks widely accepted standard criteria.  This lack of objective criteria has limited attempts to develop interventions that can improve muscle strength more than exercise alone.  Analogous to osteoporosis, Sarcopenia has the potential to be diagnosed using a widely accepted test that measures bone mineral density, Dual Energy X-ray Absorptiometry (DEXA). 

Approval of therapies for Sarcopenia depends on the creation of clear indications for treatment (i.e., specific guidelines for diagnosis).   The goal of this project is to develop the consensus guidelines for the diagnosis of Sarcopenia and will involve secondary analyses of existing data in order to develop a body of evidence that can support a definition of a clinical indication of clinically important weakness related to low muscle mass.  The evidence would then be presented at a conference organized by FNIH and attended by representatives from other professional organizations with an interest in the health care of older adults.  The final recommendations and the supporting evidence would be published for wide dissemination of the results. The hope is that the consensus definition would serve the purposes of all interested stakeholders from academia, government, industry and the non-profit sector.   

Mathematical Modeling of Atherosclerosis to Predict Cardiac Events

This three-year effort is designed to capitalize on the significant number and varied types of biomarkers that have already been studied in atherosclerosis.  While the ability to predict cardiovascular outcomes based on low-density lipoprotein (LDL) lowering is very good, the mechanisms for non-LDL lack consensus within Phase 2 biomarkers that can provide a reliable predictor of outcome in Phase 3, and thus the development of drugs for atherosclerosis is at a critical junction.  

The Mathematical Modeling Atherosclerosis project aims to 1) be able to identify a clinically meaningful change in the atherosclerotic process of disease burden within 6 months (or less) of treatment through the use of one or more biomarkers, and 2) identify subjects at higher risk of a Major Adverse Cardiac Event (MACE) beyond the estimate provided by current risk engines.  

Ultimately, the project will successfully integrate different measures (such as soluble biomarkers and imaging) into a mathematical model of atherosclerosis that unites facets including the pathobiology of related and contributory disorders (hypertension, diabetes, obesity, inflammation and thrombosis).  

Clinical Studies to Evaluate and Qualify Kidney Safety Biomarkers

It is not uncommon for candidate compounds in drug development to cause histopathologic lesions in the kidney in animal toxicology studies that are used to support the safe conduct of clinical trials.  Those kidney findings may be seen in a single species and at times and doses where there are no measurable changes in serum creatinine (sCr) or BUN, the two conventional biomarkers for monitoring changes in kidney function.  In order to not expose patients in clinical trials to potential risk, such compounds are often abandoned, leading to significant delays in drug development timelines, or even to loss of drug candidates despite the fact that the human relevance of such findings seen in a single species is uncertain and unlikely.  A panel of several new biomarkers has been formally qualified for regulatory decision making in such animal toxicology studies, demonstrating their ability to outperform sCr and BUN for monitoring the early onset and reversal of kidney tubular injuries, even at very minimal stages of injury.   

Convincing data are lacking that will provide both regulatory and industry clinicians with assurances that these new biomarkers can consistently and reliably enhance clinical trial safety and behave similarly in humans by demonstrating their ability to similarly outperform sCr and BUN in the clinic as more sensitive and earlier biomarkers of drug-induced kidney injuries.   

The two studies are expected to provide data to qualify clinical utility biomarkers of acute tubular injury for patients with largely uncomplicated and normal baseline kidney function. Qualified kidney safety biomarkers that can outperform sCr and BUN for monitoring acute drug-induced renal tubular injury will enable industry and regulatory decisions regarding the appropriateness of the use of such biomarkers to predict and monitor human renal safety of compounds dosed to the relevant clinical exposures with benefit from being tested in early clinical trials. The data from this research are expected to inform the utility of these biomarkers in highly controlled settings of Phase 1 and 2 trials. The data are also expected to provide practical thresholds of changes in these biomarkers that signify stopping criteria to halt dosing or dose selection.  

Neuroscience 

Alzheimer’s Disease Targeted Cerebrospinal Fluid Proteomics

The lack of tools for early diagnosis and disease progression in Alzheimer’s disease (AD) continue to be major hurdles in AD drug development.  Identification and validation of cost-effective, non-invasive tools to identify early AD and to monitor treatment effects in mild-moderate AD patients could revolutionize current clinical trial practice.  Treatment prior to the onset of dementia may also ensure intervention occurs prior to irreversible neuropathology. 

This project will carry out a targeted proteomics project to qualify Cerebrospinal Fluid-based (CSF-based) tools to diagnose patients with AD and to monitor disease progression over a one-year period and is the second of a two-phase effort that will seek to qualify two multiplexed panels in both plasma and CSF, utilizing samples collected through the Alzheimer’s Disease Neuroimaging Initiative (ADNI).  The specific aims of this project include: 

Aim I:  To qualify a 151 analyte multiplex immunoassay panel as a tool to diagnose and monitor disease progression in the ADNI cohort. 

Aim II:  To examine Beta-Site APP Cleaving Enzyme (BACE) levels and enzymatic activity in CSF in the ADNI cohort. 

Aim III:  To qualify a 30 analyte mass spectroscopy (MRM) panel as a tool to diagnose and monitor disease progression in the ADNI cohort. 

The CSF multiplex analysis from Aim I is planned to begin in early 2010, with subsequent completion of Aims II and III by the end of 2010.  

Functional Imaging and Biomarkers for Pain and Analgesia 

Chronic pain is a significant public health problem that affects the quality of life and accounts for considerable direct healthcare costs, as well as indirect costs, such as the loss of workplace productivity.  It is estimated that lost work due to pain costs Americans over $60 billion annually (Stewart et al., 2001).  At present, pain assessment is based almost exclusively on patient self-reports (e.g. Visual Analogue Scale), which are limited by the relationship between biological nociceptive (pain-related) processes and patients' verbal and/or written descriptions of pain.  Furthermore, currently prescribed analgesic agents are successful in treating chronic pain only 30% of the time. Therefore, the identification and development of biomarkers that could serve as objective, quantitative measures of pain-related processes, and of the impact of analgesics on pain would represent a major advancement to the field.   

The goal of this study is to use functional magnetic resonance imaging (fMRI) of the brain to determine objective, image-based measures of analgesic effects and disease state that may provide the basis for further development of a biomarker for analgesics for chronic (neuropathic) pain.  While other imaging types such as Positron Emission Tomography (PET) have been used effectively for brain function and for drug-receptor binding, PET requires the manufacture of specific ligands for measures of specific drug-receptor interactions and also exposes subjects to radiation that limits the number of times they can be scanned.  Conversely, fMRI is better suited for biomarker development since it non-invasively measures brain function without using radiation, has high spatial resolution, produces compelling images of brain activation, and fMRI responses have been shown in a large number of studies to be sensitive to modulation by pharmacological agents.