Celerion is proud to celebrate the 50th anniversary of the first clinical trial, conducted at our facilities in Lincoln, Nebraska. The company, originally called Harris Laboratories, conducted its first clinical research study in 1969, becoming one of the first organizations to offer an independent clinical research testing environment.
Author: Celerion
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Innovations in COPD – A Breath of Fresh Air
Chronic obstructive pulmonary disease (COPD) describes a cluster of diseases linked to breathing problems and airflow blockage, such as emphysema and chronic bronchitis. COPD is often associated with cigarette smoking, and prolonged exposure to poor air quality or toxic gaseous pollutants. This chronic disease affects over 3 million people in the US each year, and is currently the third leading cause of death worldwide. COPD results in difficulty breathing due to limited airflow availability in the lungs, and symptoms include shortness of breath, wheezing or chronic coughing. Periods of sustained or severe COPD episodes are referred to as exacerbations. While there is no cure for COPD, current treatments increase bronchodilation (opening of the airways) to provide symptom relief. For nearly 50 years, bronchodilators such as beta-2-adrenoreceptor agonists and muscarinic antagonists have been at the cornerstone of COPD treatments and are available in; short-acting, long-acting, single-, dual- or glucocorticoids combined triple-therapy.
Over the last decade, a surge in COPD research has greatly expanded our understanding of the disease and the key inflammatory players involved in airway blockage. This global initiative has led to the clinical development of over 25 novel drug targets. Roflumilast, a phosphodiesteratse type 4 (PDE4) inhibitor, was the first approved COPD add-on therapy which specifically targets the inflammatory processes underlying COPD. Ongoing research has identified pivotal roles for neutrophils and eosinophils (inflammatory cells) in COPD development, and resulted in a number of exciting drug targets in the pipeline. By addressing the underlying mechanisms responsible for disease development, this may lead to treatments that alter the course of disease progression and possibly a cure for COPD.
Along with new drug targets, the COPD biomarker landscape has also changed. While spirometer and patient-reported outcome remain critical clinical study endpoints, a role for soluble biomarkers to characterize patient populations and demonstrate drug efficacy has emerged. Fibrinogen is a soluble biomarker drug development tool approved by the FDA for COPD patient selection. Plasma fibrinogen levels are elevated in patients with COPD and are likely to experience an exacerbation, a key inclusion criteria for clinical trials aiming to demonstrate a reduction in exacerbation rates. In addition, validated assays for pro-inflammatory cytokines such as TNFa, IL-5, IL-8 and IL-17 are also of interest as increased levels of such cytokines may reflect an upregulation of neutrophilic and eosinophilic immune cell activity, and their attenuation can be indicative of reduced inflammation. Moreover, these biomarkers can be measured in either serum or right at the site of the airway blockage and inflammation, in lung fluid. Sputum collection (coughed up saliva and mucus mixture) and bronchoalveolar lavage (BAL) are two manners to retrieve lung fluid secretions. BAL is a minimally invasive endoscopic technique performed by a trained bronchoscopist to obtain cellular and biochemical components from lung fluid during a saline wash. Various cell types, cytokines and drug concentrations can all be measured to better understand pharmacokinetic – pharmacodynamic relationships.
With the development of new technologies and more sensitive bioanalytical assays, novel, non-invasive breath tests have entered the investigational scene in recent years. For instance, methodologies have been applied in exploratory clinical studies to analyze volatile organic compounds (VOC) in breath, exhaled breath condensate (EBC), and particles in exhaled air (PExA). Due to the nature and origin of VOCs which are derived from the entire body and microbiome, metabolomic analyses of VOCs have been explored as a potential tool to support early diagnosis of a broad range of systemic diseases, but it may also be useful for respiratory disease. For instance, VOC biomarkers have been shown to correlate with sputum markers from inflammatory cells and cell counts in COPD. Distinct patterns have also been associated with COPD disease staging. In contrast to VOC, EBC and PExA analytes are considered respiratory tract-specific, reflecting airway lining fluid and immune cell mediators from the lower airways. Their analysis allows identification and quantification of inorganic anions and cations, proteins, lipids and genes known to play a role in immune response. In addition, drug concentrations can be assessed in EBC and PExA samples.
Altogether, novel biomarkers and non-invasive breath test technologies may help diagnose respiratory pathologies, identify pathogens and distinguish treatable traits. Moreover, these innovations in COPD may provide new insights into inflammatory pathways in relation to pulmonary disease and disease stages. Finally, novel biomarkers in exhaled breath are likely to provide new tools to monitor disease state and treatment effects for specific drug targets.
Links:
Third leading cause of death – https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
Roflumilast – https://www.daliresp.com/
Drug development tool – https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm453496.pdf
Validated assays – https://www.celerion.com/category/assays
Bronchoalverolar lavage (BAL) – http://celerion.com/news/2013/01/09/bronchoscopy-suite
COPD disease staging – https://goldcopd.org/gold-reports/
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Entering the NASH Race: Tips for Early Clinical Development
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that affects over 17 million Americans and this number is growing. NASH can lead to cirrhosis, end-stage liver disease, liver transplant and even hepatocellular carcinoma. Therefore, the need for treatment for this devastating, progressive disease is dire. That said, the NASH drug development landscape is robust. With over 100 compounds in discovery, nearly 80 drugs in clinical trials in which 4 have made it to Phase III; it is anticipated that a NASH drug will be available within the next few years and there will be several drug categories to boot. Potential drug classes include those that target metabolic pathways such as de novo lipogenesis, those that have anti-inflammatory or anti-apoptotic properties and anti-fibrotic compounds. Similar to the diabetes indication, polypharmacy may be one strategy to tackle this progressive, chronic disease.
Although the NASH pipeline is abundant, with no FDA approved treatment as of yet, there is still time to enter the race. For sponsors considering stepping into the ring, here’s a list of suggestions to navigate the course.
- Develop the right plan for your drug.
Demonstrating safety and tolerability in early clinical studies is a must to advance a program forward, but so much more can be captured in these early trials. Pharmacodynamic signals of drug efficacy can be examined in Phase I development through innovative and adaptive study designs which include a patient arm or tailored proof-of-mechanisms studies, like interrogating the de novo lipogenesis pathway for an anti-steatosis drug.
- Identify the right participants for your study.
Participant pre-screening efforts can save sponsors time and money. A clinical research organization with a rich database of well characterized participants can expedite study recruitment and reduce screen failures. The FibroScan® is a fast, painless, non-invasive ultrasound-like device that measures liver stiffness (fibrosis) and hepatic steatosis (fat); both measures are key markers for NASH clinical trials. FibroScan® pre-screening can assist with participant selection for more sophisticated and expensive inclusion criteria such as magnetic resonance imaging (MRI) or elastography (MRE). In addition, the Liver Forum, a consortium of academic leaders, industry and regulators, has recently recommended using the FibroScan® as part of the inclusion criteria for early phase NASH clinical studies.
- Do more with less.
The FibroScan® is not only a valuable tool for study inclusion criteria, this technique has served as a key primary or secondary study endpoints in many NASH clinical studies. Additionally, soluble biomarker panels such as FIB4 and NAFLD Fibrosis Score calculated from clinical chemistries such as AST and ALT, are also inexpensive ways to identify potential participants for clinical studies and monitor drug efficacy.
- Look towards the future.
Current NASH standards of care and management strategies include vitamin E or pioglitazone treatment as these therapies have been shown to be effective in improving the histological features of NASH. Drug-drug interaction studies may be necessary before moving into later phase studies to accommodate patients on standards of care treatment and allowing for a great patient population base to pull from, if safe to do so.
The NASH race to market is well underway; however latecomers entering the NASH indication do not need to fall by the wayside. A strategic early phase drug development plan may help foster the next blockbuster treatment.
Links:
De novo lipogenesis: https://www.celerion.com/wp-content/uploads/2016/09/Celerion_Clinical-assessement-of-hepatic-DNL-in-NAFLD-review_092716-1.pdf
FibroScan: http://www.fibroscan.com/en/
Liver Forum: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906171/
Management strategies: https://doi.org/10.1002/hep.29367
Drug-drug interaction: https://www.celerion.com/services/data-management-and-biometric-services/pkpd-modeling/
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The Next Frontier of Pharmacology: Micro Drug Delivery
Injectable medication can be burdensome for the patient, causing pain and discomfort, and can contribute to compliance issues especially when chronic treatment is required. A promising and emerging area in pharmacology that may alleviate these obstacles is transdermal microneedle drug delivery. Patch microneedles are about the size of a postage stamp and can contain ~30-50 tiny needles smaller than the diameter of a strand of hair. This innovative design limits pain, tissue trauma and infection, and could be applied by minimally-trained personnel, facilitating use in both developed and developing countries.
Patch microneedles are widely gaining traction in the vaccine drug development space. The microneedles penetrate the upper skin layer and rapidly dissolve to deliver the vaccine. Transdermal vaccine delivery is a preferred alternative for those with a fear of needles and is an essential step towards disease eradication worldwide. A critical issue concerning current vaccines reaching rural regions is the lack of refrigeration and a cold supply chain. In this respect, microneedles hold the potential to overcome vaccine wastage due to heat and light exposure as well as volume waste.
This technology is not only being applied to vaccines but across indications from oncology to chronic diseases such as diabetes. Alarmingly, the World Health Organization estimates that only half of all patients with chronic diseases comply with treatment recommendations. Microneedle patches are being developed to address treatment compliance by easing the burden of daily or weekly injections. Through passive drug diffusion, drug delivery could be sustained for 6 months up to 1 year as fixed needles swell within the skin layer to hold the patch in place.
Microneedle patch technology is a promising drug delivery system that may ease patient burden and can facilitate great treatment compliance. A number of current studies in early clinical drug development are underway for a multitude of disease indications. This drug delivery technology has the potential to revolutionize access to treatment, making significant impact on public health worldwide.
