Celerion

Author: Celerion

  • NASH Pathway to Approval – Light at the End of the Tunnel

    Not long ago, there was very little regulatory guidance or recommendations regarding a pathway for nonalcoholic steatohepatitis (NASH) drug approval. NASH is a chronic hepatic disease that can lead to cirrhosis, liver failure and need for transplant, and currently there is no FDA-approved treatment for NASH, creating a large unmet need for patients. On the bright side, there is a bountiful pipeline of drugs in development for this disease. Many investigational products are being developed under an accelerated process that uses surrogate endpoints such as tissue biopsy results for initial approval followed by clinical outcome measures for full approval. However, it was not until recently that the acceptable endpoint definitions and consensus on patient I/E criteria were described. Academic and industry led partnerships have spearheaded discussion forums for all stakeholders to advance the regulatory science of NASH. To this end, hepatic focused research societies such as the Liver Forum, AASLD and EASL have developed a set of study design considerations for NASH trials. In addition, both the FDA and EMA released draft guidance documents within the past year, providing a clear pathway to approval.

    Society Insight

    The Liver Forum helped define key terminology for NASH clinical trial endpoints such as NASH resolution. While previous Phase IIb trials may have used more lenient criteria, it is now widely accepted that NASH resolution is defined as a histological ballooning injury store of 0, inflammation score of 0-1 and steatosis score of 0-3 according the NAFLD Activity Score (NAS).  More recently, meeting proceedings from a joint AASLD/EASL Workshop addressed standards for reporting results from NAFLD clinical trials. They suggest reporting absolute change in primary and secondary endpoints rather than percent change only as well as absolute number and proportion of patients that improved, remained stable, or worsened on treatment and placebo. Another key recommendation is to report the performance of noninvasive imaging and soluble biomarkers in relation to histological biopsy results. This information is needed to eventually replace the liver biopsy with a simpler, noninvasive measurement.

    Regulatory Authority Recommendations

    The FDA released two sets of draft guidance for NASH drug development, distinguishing between non-cirrhotic (fibrosis stages 1-3) and cirrhotic (stage 4) disease states.  Recommended early phase endpoints for non-cirrhotic NASH include imaging changes in AST and ALT, imaging measures of liver stiffness or hepatic fat content or disease-specific biomarkers such as de novo lipogenesis fractional rates. Participant inclusion criteria for these early studies can be based on histological diagnosis of NASH or a combination of biochemical criteria and/or imaging evidence of steatosis in addition to known risk factors for NASH. For late phase studies, clinical endpoints include NASH resolution with no worsening of fibrosis and/or ≥1 stage improvement in the fibrosis stage with no worsening of NASH for pre-cirrhotic NASH indication. Cirrhotic NASH endpoints for Phase III studies are ≥1 stage improvement in the fibrosis stage with no worsening of NASH, rates of hepatic decompensation events and MELD progression. Hard endpoints are captured as all-cause mortality, liver transplant and hospitalization rates.

    In late 2018, the EMA issued considerations for drugs to treat NASH in a reflection paper. In contrast to the FDA guidance, the European authority takes a more judicious view by recommending co-primary endpoints of both NASH resolution and fibrosis improvement for anti-inflammatory drugs; and 2-stage improvement in fibrosis for anti-fibrotic therapies.

    Hurdles to Overcome

    There are still many challenges to face for NASH drug development. High screen failure rates of 40-60% are not uncommon for clinical trials with biopsy requirements. Steps to mitigate screen fails include robust patient pre-screening with non-invasive techniques such as FibroScan or opting for imaging-based inclusion criteria over biopsy-proven NASH (for Phase IIa studies).

    Another issue to contend with is the large placebo response for histological endpoints. A meta-analysis by Han et al. found that one quarter of patients given placebo had an improvement in NAS by ≥2 points, and improvements in fibrosis scores of approximately 20%. Spontaneous disease regression can contribute to the observed placebo response. External influencing factors may include diet, exercise, and modest amounts of alcohol consumption during the trial. A lead-in period prior to the baseline biopsy may minimize the placebo effect. Meanwhile, 2-stage fibrosis improvement would drastically reduce the placebo response and could be considered as a secondary endpoint to negate false negative studies.

    While the liver biopsy remains the reference standard for disease diagnosis, the ultimate goal is to have a noninvasive soluble biomarker to stage the disease, akin to HbA1c for diabetes and cholesterol for cardiovascular disease.  Biomarkers of inflammatory cytokines, apoptosis (cytokeratin 18) and fibrotic factors show promise, however more validation is required.

    The Road Ahead

    Despite these challenges, there is a light at the end of the tunnel! Clarification of agency expectations and unified definitions has certainly helped to foster the influx of NASH drugs in development. However, the true test will come from a review of upcoming new drug applications. The first approval for a NASH treatment is anticipated by the end of the year, with more to follow suit in 2020.

  • Celerion Celebrates 50th Anniversary of First Clinical Trial

    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.

  • Newsletter: Q2 2019

  • Backing the Biosimilar Boon

    Biological therapies such as peptides, enzymes and antibodies have changed the face of medicine, providing crucial treatment for a number of devastating inflammatory, endocrine and oncological diseases. However, these drugs often come with a hefty price tag due to the complicated nature of manufacturing biological products which are derived from living systems. In an effort to reduce drug prices, especially among biologicals, the Biologics Price Competition and Innovation Act was passed in 2010, creating a regulatory framework for biosimilar drugs to advance on to the market.

    Biosimilars are not an exact copy but are similar to the originally approved biological product. While innovator products must demonstrate pharmacokinetic (PK), dose finding, efficacy, safety and clinical benefit/risk for approval; a biosimilar product follows an abbreviated pathway and must demonstrate equivalent PK, toxicity, similarity, and no clinical change compared to the innovator. With this framework, the goal is to introduce cost-effective alternatives to innovator biological drugs that can help improve patient access to these treatments.

    The Biosimilar Model:
    Robust, vigorous analytical characterization, justification of cell lines, examination of post-translation products, and preclinical studies are emphasized in the biosimilar paradigm. Most biosimilar programs only require one Phase I or III study, reducing cohort sizes and study time from traditional drug approval processes. Immunogenicity data must be collected in patients, however this can be descriptive in nature and is not required to be powered.

    In lieu of a comparative efficacy study, pharmacodynamic (PD) biomarkers related to the mechanism of action can be evaluated as a study outcome. For example, picture a biosimilar product like recombinant insulin binding to a cell receptor to initiate a chain of signaling events. PD biomarkers such as glucose concentrations from these early events of the signaling cascade tend to be more sensitive, while late PD biomarkers like HbA1c are related to clinical outcome yet tend to have lower sensitivity. Therefore, early PD biomarkers are recommended as they are apt to illustrate how a drug behaves and can be applied to simulate PK/PD dose response. Both PK and PD biomarkers are required to be within margins to show equivalency, for the FDA these margins are 80-125%. When no good PD biomarker is available for an indication, clinical endpoints should be the same as the innovator product.

    The FDA’s Action Plan:
    While the EU has benefited from biosimilars for close to 15 years, with 45 approved products and marked reductions in drug prices [1], the US has been slow to embrace this technology. To date, 19 biosimilars have been approved in the US, however 7 products are still not on the market mainly due to patent litigation [1]. In an effort to cut-red tape, increase drug competition and reduce prices for patients, the FDA released their Biosimilar Action Plan in June 2018. This plan outlines their four-pronged approach to expedite biosimilar product development through; increasing efficiency in the approval process, clarifying regulatory guidance, providing educational support for patients and prescribers, and supporting market competition. Progress towards these goals is evident through 60 biosimilar development programs, a newly released final guidance for interchangeability, and plans to license biosimilar and interchangeable insulin products.

    Optimizing Biosimilar Product Development:
    The following study design recommendations are aimed to optimize biosimilar programs when planning for multiple authorities or indications, or for interchangeability designation.

    Multiple Jurisdictions – Consider a 3-way crossover study with US and EU innovator and reference product to establish bridging for various markets.

    Extrapolation – Consider running the study in the most homogenous patient group, this will improve sensitivity. Once approved for one indication, approval can be extrapolated to all other approved indications with justification based on totality of evidence.

    Interchangeability– Refers to pharmacists switching between products without the consent of the prescriber. In the EU, interchangeability of a product is dictated by member states. Elsewhere, Australia has recently granted interchangeability designation for adalimumab biosimilar products [2] . In the US, interchangeability of a biosimilar should be demonstrated in a randomized two-arm (switching vs non-switching) clinical study with a reference product lead-in period. In a crossover design, the switching arm should have at least 2 or more product switches. One major challenge with interchangeability study design is that many antibody biosimilars have long half-lives and which would require a long cross-over study. However, the added statistical power of the cross-over design may well be worth the long study duration. In addition, during such trials, it is important to closely monitor for safety and adverse immune responses. Alternative approach is an integrated study design to demonstrate no clinically meaningful difference between reference and the biosimilar product and evaluate the impact of switching.

    Turn-key Solutions for Biosimilar Programs:
    As a global leader in analytical and clinical studies for biological drug development, Celerion provides turn-key solutions for a number of biosimilar programs.

    • Adalimumab – Anti-TNFα biological for the treatment of arthritis, plaque psoriasis, ankylosing spondylitis, Crohn’s disease, and ulcerative colitis
    • Rituximab – CD20 antagonist for autoimmune diseases
    • Teripartide – Recombinant human parathyroid hormone for osteoporosis
    • Ustekinumba– IL-12/23 inhibitors for psoriasis
    • See our full list of validated bioanalytical assays at www.celerion.com/assays

    Conclusion:
    Altogether, biosimilars are primed to make a significant impact on access to vital medicines worldwide. Currently, of the marketed biosimilar products available in the US the cost for these products is an estimated 17-57% less than the originator price. With new, efficient tools to support biosimilar development, the FDA aims to see even more meaningful impact on drug prices.

    References:
    1. Sarpatwari A, Barenie R, Curfman G, Darrow JJ, Kesselheim AS. The US Biosimilar Market: Stunted Growth and Possible Reforms. Clin Pharmacol Ther. 2019;105(1):92-100.
    2. JULY 2018 PBAC MEETING –POSITIVE RECOMMENDATION. https://www.pbs.gov.au/industry/listing/elements/pbac-meetings/pbac-outcomes/2018-07/positive-recommendations-07-2018.pdf. Accessed 2 April 2019.

  • Celerion Recognized as a Leading Contract Research Organization for the 4th Consecutive Year

  • Newsletter: Q1 2019

  • Newsletter: Q2 2018

  • 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/

     

     

  • 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.

    1. 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.

    1. 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.

    1. 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.

    1. 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/

  • Newsletter: Q3/Q4 2018