Non-Alcoholic Steatohepatitis: Limited Available Treatment Options but Promising Drugs in Development and Recent Progress Towards a Regulatory Approval Pathway

Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing world-wide in parallel to the increase of the obesity epidemic. Insulin resistance (IR) and the accumulation of triglyceride-derived 103072_liver bw1toxic lipid metabolites play a key role in its pathogenesis. Multiple biomarkers are being evaluated for the non-invasive diagnosis of NASH. However, a percutaneous liver biopsy is still the gold standard method; the minimal diagnostic criteria include the presence of >5% macrovesicular steatosis, inflammation, and liver cell ballooning. Several pharmaceutical agents have been evaluated for the treatment of NASH; however, no single therapy has been approved so far. Due to the increasing prevalence and the health burden, there is a high need to develop therapeutic strategies for patients with NASH targeting both those with early-stage disease as well as those with advanced liver fibrosis.
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Creating your Biomarker Strategy from Discovery to Development

Biomarker strategy - graphic of molecules bunched together.
In the effort to reduce attrition rates and improve approval rates of new molecular entities by regulatory agencies, there’s no doubt that biomarkers can make a big impact. But it’s not as simple as tacking on additional studies. Biomarker development requires an insightful strategy and consideration of specific opportunities and needs throughout the drug development pipeline.

A quality biomarker starts at the source—the sample itself. Sample collection and handling protocols must be standardized to specify the minimum volume requirement in the proper container along with the most optimal temperature during transportation and storage. These requirements should be backed and driven by validated processes. To further ensure biomarker stability, it’s equally critical to include the maximum allowed time in transportation. Continue reading

Less Gambling, More Science: Phase II Under Scrutiny

neuro

Failures of Phase III programs after successful Phase II programs is probably the worst outcome of a clinical development program, as it failed in the most costly way. Nevertheless, these failures occur not infrequently. In psychiatry, highly publicized Phase II success stories ended in discontinuations of development programs, such as the NK1-antagonist program in depression several years ago. More recently, other examples have emerged. Some skip the Phase II process altogether with designs, which are supposed to provide “pivotal” data for regulatory purposes in large Phase III-like studies, which are just labeled as Phase II. These failures do not come out of the blue. Sometimes it is important to go back to basics and consider the purpose of Phase II trials.

What is the purpose of a Phase II trial?

The purpose of Phase II trials, besides gaining insights into the safety of a compound, is broadly exploratory, i.e. to generate data, which help with the design of the pivotal Phase III program. In a therapeutic area, a reasonably performed Phase II study can provide insights into clinical and biological patient characteristics, which match the properties of the drug under study.  With an increased interest in personalized medicine, these boundaries between patient populations have to be understood in order to be successful. This approach is in direct contradiction to the urge to generate a “pivotal” Phase II outcome. Continue reading

Understanding the Clinical Impact of Having a Companion Diagnostics Strategy

Understanding the Clinical Impact of Having a Companion Diagnostics Strategy

As the pace of companion diagnostic innovation continues to accelerate, the drug development industry faces several headwinds. Numerous patent ‘cliffs’ are affecting the sales of blockbuster drugs; competition is increasing for a limited clinical trial population in increasingly global trials; and health outcomes pressures from patients, payers and healthcare providers are transforming the drug development process.

Over the past 10 years, advances in analytical technologies have provided new tools to identify patients who are more likely to positively respond to a certain drug or, conversely, experience a negative reaction to the particular therapy. These tools, known as companion diagnostics, are laboratory tests for biomarkers that, once commercialized, are designed to be an accompaniment to the safe and effective use of a particular therapy. Continue reading

Examining Tau Phosphorylation as a Potential Alzheimer’s Disease Biomarker

tauWe are always on the lookout to apply the latest research to our work and contribute additional findings to the scientific community. This month we will present a poster studying the regulation of Tau phosphorylation at the upcoming 2013 Society for Neuroscience conference in San Diego.

The interest in this research was first sparked at last year’s 2012 Alzheimer’s Association International conference in Vancouver, Canada, where we heard discussions on the effects of anesthesia on Alzheimer’s disease (AD) patients. Continue reading

The Role of the CRO in Frontloading Cardiovascular Safety

The Role of the CRO in Frontloading Cardiovascular SafetyCardiovascular safety remains a leading cause of drug attrition during preclinical and clinical development, accounting for discontinuation of approximately one third of marketed drugs.

These liabilities, which pertain to both cardiovascular- and non-cardiovascular-targeted drugs, can be identified during early development by addressing cardiovascular safety endpoints prior to the selection of a drug candidate, a process known as ‘frontloading’. Although not mandated by the key regulatory guidance for safety pharmacology (ICH S7A; US FDA, 2001), an increasing number of companies choose to conduct early non-GLP cardiovascular safety studies in support of decisions on the progression of their compounds. Continue reading

Biomarker Development for Parkinson’s Disease

Biomarker Development for Parkinson’s Disease

Parkinson’s Disease (PD) is a chronic neurodegenerative disease with no known cure, no certain cause, and no clinically available test for simple diagnosis. Research advances have been made, but there still remains a huge unmet need for diagnostic and disease progression biomarkers.

Research on this disease is focused on the changes that occur in the brain. Research has shown that the nerve cells in the brains of Parkinson’s patients have abnormal protein deposits that may disrupt normal brain function and cause Parkinsonian symptoms, such as tremor, slowness of movement, and rigidity, among others. Continue reading

Accelerating Candidate Selection: Solutions for Lead Optimization Pharmacology & Toxicology

Lead optimization (LO) is one of the most expensive and time-consuming stages of the drug development process due to the number of programs running simultaneously and the number of molecules within each of those programs. Covance’s Lead Optimization Pharmacology & Toxicology services are designed to help you select the best molecule for candidate selection and further development. Our ability to integrate service lines, such as pharmacology, biomarkers, imaging and safety, and thoughtfully add endpoints to studies, maximizes the number of questions being answered in each study leading to improved probability of technical success. The following video gives an overview of our Lead Optimization Pharmacology & Toxicology services and the benefits of choosing Covance as your LO partner.

Using Next-Generation Sequencing to Detect Epigenetic Alterations – The Impact on Clinical Oncology

Using Next Generation Sequencing to Detect Epigenetic Alterations - The Impact on Clinical Oncology

How can identical twins, with the same genetic makeup, experience different diseases? Scientists believe this is due to epigenetic marks or chemical tags that play a role in controlling the activities of genes. The study of the epigenetic landscape has already generated recent breakthroughs in the detection, treatment and prognosis of many diseases, including cancer.

These breakthroughs are due in part to large-scale mapping efforts of cancer genomes coupled with the rapidly dropping costs of high-throughput next-generation sequencing technologies. Identification of mutations and epigenetic analysis are the next frontier for finding reliable biomarkers and developing targeted therapies.

Next-generation sequencing platforms are particularly powerful for mutational and epigenetic studies due to their ability to quickly analyze the entire genome through multiple methods of sequencing, such as DNA, RNA, miRNA, whole genome, exome, targeted, ChIP-Seq, methylome and epigenome. As a result, researchers obtain comprehensive, clinically relevant data sets.

With these resulting data, computational biologists can mine both open source data sets along with data sets from clinical trials to narrow down options for prospective biomarkers. Continue reading

Obtaining Early Insights Into Safety and Efficacy: The Benefits of Preclinical In Vivo Imaging

The benefits of preclinical in vivo imagingFirst established as a standard practice in clinics, in vivo imaging also benefits translational or preclinical research. For the past 25 years, many studies have relied on in vivo imaging as a method to quantify treatment response and gain early insights on efficacy. Now, as the technology advances, researchers can expect to benefit from greater spatial resolution and software advancements that allow faster, cost-effective translation of study results.

“Imaging often gives you unique information that can’t be obtained any other way.  The phenomena that you would observe preclinically may be the same disease state in the clinical trial,” says Michael Cockman, Senior Scientist and Manager of the Imaging Center at Covance. “It’s common to hear from a client who wants to test a type of imaging, called a modality, in a particular disease state to find out if it is appropriate for clinical development later.” Continue reading