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  • COVID-19, Kawasaki and the Cytokine Storm

    COVID-19, Kawasaki and the Cytokine Storm

    by Sabina Paglialunga, PhD – Director, Scientific Affairs, Celerion

    SARS-CoV-2 symptoms include fever, cough and shortness of breath. The disease is especially hard on vulnerable populations such as the elderly and those with underlying health conditions like obesity and hypertension. Now, developing reports indicate that children may also be at great risk than originally thought.  

    Into the Eye of the Storm

    The virus primarily enters the body via the respiratory tract, and into lung cells through ACE2 receptors.  To counteract, the body mounts an immune response to defend against the foreign virus.  However, this attack tends to occur several days after initial infection, by when significant amount of viral shedding has already occurred, contributing to the wide spread of the disease.  As part of the defense process, there is an influx of immune cells, which include macrophages and T cells to the respiratory tract, leading to an overall systemic upregulation of pro-inflammatory cytokines (e.g. IL-6, IL-1β, TNFα) as well as interferon (IFN) signaling and production anti-viral factors. The resulting immune response drives B cells to create antibodies against SARS-CoV-2. These antibodies recognize the virus, neutralize and clear it from the body.  

    While many infected individuals are asymptomatic or present with mild symptoms. Since the ACE2 receptors are also expressed in gastrointestinal tissues, abdominal symptoms are associated with COVID-19.  More severe cases will result in pneumonia, sepsis, acute respiratory distress syndrome (ARDS) requiring hospitalization and even death. Researchers have found that a hyper-immune response is associated with the most severe COVID-19 cases. Early studies from China reported patients in intensive care units (ICU) had dramatically elevated levels of IL-6, IL-10 and TNFα, accompanied by a reduction in CD4+ and CD8+ T cells [1]. This hyper-, pro-inflammatory state is often referred to as the cytokine storm or cytokine release syndrome (CRS). In this state, pro-inflammatory cytokines are released in excess amounts, creating an exaggerated cytokine response.  This can lead to not only damage to the virus and infected host cell but also healthy cells too. In the lungs, destruction of areole cells can result in hypoxia and ARDS, which may lead to death.  Similar finding of increased levels in IL-2, IL-7, G-CSF, CXCL10, MCP-1, MIP-1α, and CXCL10, CCL7 were subsequently reported, suggesting the hyper-inflammation associated with severe COVID-19 exacerbates lung damage [2, 3]. The cytokine storm is thought to be driven by IL-6 [4]. In that respect, the virus also infects monocytes, macrophages and dendritic cells that can result in their activation and further secretion of IL-6. 

    Navigating the Current Pandemic with Past Coronavirus Experience 

    The raging cytokine storm also contributed to morbidity in patients infected with other Coronaviruses. There are seven known human coronaviruses.  The 229E, HKU1, NL63, OC43 strains are associated with the common cold, however more virulent forms  have resulted in major past outbreaks; SARS (Severe Acute Respiratory Syndrome) in 2002 and MERS (Middle Eastern Respiratory Syndrome) in 2012. SARS, MERS and COVID-19 viruses originated in bats then transitioned in an intermediate host before jumping to humans (reviewed in [5, 6]). The SARS-CoV-2 virus shares similar sequence identity to the SARS virus (SARS-CoV) and may provide insight into the current pandemic and cytokine storm. 

    SARS-CoV-2 binds ACE2 receptors more efficiently than the SARS-CoV 2003 strain but less efficiently than the strain first identified in 2002, as mutations in SARS-CoV created a less virulent form. It is too early to tell how or if any mutations in SARS-CoV-2 will affect infection and mortality rates. The reproductive number (R0), number of cases directly generated by one infected individual, as well as complication and mortality rates for SARS, MERS and COVID-19 is listed in Table 1. While the infection rate of COVID-19 is much greater than SARS and MERS, the mortality rate is expected to be lower. On the other hand, ARDS-specific complication of COVID-19 is anticipated to be similar to SARS and MERS. 

    Table 1. Virulence of SARS, MERS & COVID-19

    Characteristics SARS MERS COVID-19*
    Reproductive number (R0)  1.7 – 1.9 <1.0 2.0 – 2.5
    ICU admission (% cases) 23 – 24% 53 – 89% 24%
    ARDS-specific complication (% cases) 20%  20 – 30%  18 – 30% 
    Mortality rate 14 – 15% 35% 2 – 4%

    Adapted from [5-7].  *Current estimated values.  

     

    A key lesson learned from previous outbreaks is how Coronaviruses commandeer the host cells immune response unleashing the cytokine storm. Both SARS-CoV and MERS-CoV encode accessory proteins known to antagonize IFN and suppress its signaling [8]. Diminished IFN response, allows for unchecked and rapid viral replication in which a surge of cytokines and chemokines are eventually and robustly released in a last ditch attempt to kill the virus contributing to the cytokine storm. Moreover, this dampening of the IFN response is strongly associated with disease severity [9].   In a second strike, the SARS-CoV virus also encoded accessory proteins that activate NLRP3 inflammasome, which drives IL-1β and promotes expression of other pro-inflammatory cytokines such as TNFα and IL-6 (reviewed in [6]). These strategic viral battle maneuvers are postulated to contribute to the cytokine storm that is being observed with the current COVID-19 pandemic.

    The Next Wave: Kawasaki Disease-like Symptoms in Children

    While early reports suggested that children were spared from COVID-19, a number of significant severe COVID-19 cases in pediatric populations have emerged [10, 11].  More urgently, is the rise of multisystem inflammatory syndrome in children (MIS-C) clusters arising in the US and EU associated with COVID-19. As of May 12, 2020 there were over 50 cases reported in New York City alone. With the current situation escalating rapidly, on May 14, 2020 the CDC issued a health advisory for MIS-C.  The disorder is associated with active infection or antibodies against SARS-CoV-2 [12], or COVID-19 exposure within 4 weeks prior to the onset of symptoms. Clinically, MIS-C is defined as persistent fever, requiring hospitalization with multisystem involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological) and Kawasaki disease-like symptoms. 

    Kawasaki disease is a rare, vasculitis disorder affecting young children that can lead to coronary artery aneurysm, thrombosis and sudden death if left unchecked. It is the leading cause of acquired heart disease in pediatric populations in developed countries. Disease diagnosis is established by presence of persistent fever along with four of five signs and symptoms; bilateral conjunctivitis, strawberry tongue and/or dried cracked lips, polymorphous exanthema, cervical lymphadenopathy, swelling of hands and feet. While the exact etiology is still not fully understood, it is thought that Kawasaki disease may arise from an infectious trigger (bacterial or viral), resulting in upregulation of the immune system in a genetically susceptible individual (reviewed in [13]). 

    Kawasaki disease has been previously reported with acute viral infection of the respiratory system, resulting in dysregulated immune response as observed in with the cytokine storm [13]. A children’s hospital retrospective review of Kawasaki disease admission from 2009 to 2013 linked the disease with rhinovirus and parainfluenza and to a lesser extent human coronaviruses strains 229E, NL63, OC43 [14]. Therefore, it is conceivable that SARS-CoV-2 may represent the infectious trigger during the current crisis. Similar to the cytokine storm described above, Kawasaki disease patients also have remarkably increased CRP, IL-6, IL-10 and IFNγ [13], and potential involvement of an acute B cell response [15].  Indeed, the first case of Kawasaki disease with concurrent COVID-19 infection was reported in a 6-month old infant with elevated CRP. The patient also had a continuous fever, lack of appetite, mild congestion, and met the classic Kawasaki disease criteria [16]. In addition, RT-PCR testing confirmed positive result for COVID-19 infection. 

    While the incidence of past Kawasaki disease cases tended to be seasonal and were more prevalent in Asian countries and Asian races in the US [13]. Genome-wide association studies have identified candidate loci [17], however the genetic factors contributing to pathogenesis of the disease are not fully understood. Moreover, it is still too early to determine if genetic susceptibility plays a role in the rash MIS-C observed in the current COVID-19 pandemic as children of many ethnicities have reported disease symptoms [12, 16]. 

    Quieting the Storm: Immunosuppressant Drugs

    Since disease severity appears to be driven by a cytokine surge, it suggests that anti-inflammatory treatments may quell the cytokine storm and improve disease prognosis.  During the SARS outbreak, immunosuppressants such as corticosteroids resulted in more harm than good and are therefore not recommended for the treatment of COVID-19 [18]. For that reason, clinicians are expanding their toolbox and looking to therapies targeting pro-inflammatory cytokine. Tocilizumab, a marketed IL-6 receptor antagonist, is indicated for CSR, and was recently reported to improve COVID-19 patient outcomes in a small open-label study in China. Further randomized controlled trials are now underway with Tocilizumab, as well as with other  direct IL-6 antagonists such as Siltuximab and Sarilumab and indirect inhibitors such as Ruxolitinib. Additional immunosuppressant drugs such as anti-IL-1 anti-IL-17, anti-TNFα are also currently being explored as potential treatment under the compassionate use authority or off-label, with randomized clinical trials starting soon.  A recent GlobalData* database search retrieved nearly 75 COVID-19 planned or ongoing trials with interleukin inhibitors. Moreover, there may be a role for novel anti-inflammatory drugs in COVID-19 treatment.  Across all stages of development, sponsors are promptly advancing their program to help the fight. In response and support of this effort, the FDA issued guidance for industry on developing treatment and preventative COVID-19 drugs. While, immunosuppressant drugs will not be a cure for COVID-19, only a vaccine or anti-viral drug can annihilate the virus, anti-inflammatory therapies can play an important role in reducing the need for ventilators and preventing mortality.  

    For children presenting with classic Kawasaki disease criteria, treatment guidelines include intravenous immunoglobulin and high dose aspirin [16]. Refectory Kawasaki disease may be treated with corticosteroids, although this approach remains controversial due to the risks associated with steroids [13]. Alternative therapies aiming to suppress the pro-inflammatory state include TNFα inhibitors such as Infliximab, Abciximab and Etanercept. Overall, treatment with these anti-inflammatory drugs led to improved outcome, reduction in fever and reduced risk of coronary artery aneurysms (reviewed in [13]. It remains to be seen how TNFα inhibitors will be deployed in the current pandemic. 

    Biomarkers beaming like a Lighthouse

    Another area under intense investigation is the use of biomarkers. Cardiac biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) indicate cardiac stress can be useful to assess cardiac risk associated with Kawasaki disease. Furthermore, identifying early prognostic biomarkers of COVID-19 severity is important for clinicians to initiate therapy before critical care is needed.  Low lymphocyte count as well as the serum levels of D-dimers, ferritin, CRP and IL-6 may help stratify mild from severe cases [19, 20]. C-reactive protein (CRP), an acute-phase inflammatory protein synthesized by IL-6-dependent signaling and indicator of IL-6 bioactivity. CRP can be used to predict the cytokine storm severity and monitor IL-6 blockade efficacy [21]. Therefore, monitoring chemokines and inflammatory cytokines may not only be helpful to risk stratify for disease severity but also demonstrate target engagement and proof-of-mechanism for immunosuppressant and anti-inflammatory drugs in development. 

    A Fleet of Bioanalytical Platforms 

    In addition to measuring cytokines in serum, COVID-19 testing will help launch us out of social isolation.  A SARS-CoV-2 qPCR test can confirm the presence of the virus and antibody testing can determine if someone was already exposed and may have immunity to SARS-CoV-2. For clinical trials, it is important that these assays meet stringent validation criteria as well as demonstrate good sensitivity and specificity.  

    Utilizing an advanced array of bioanalytical tools, Celerion provides full bioanalytical solutions for small and large molecule assays as well as genetic and cell-based assays. For the health and safety of our participants and staff, we provide COVID-19 testing at our Clinical Pharmacology Units in Lincoln, NE, Phoenix, AZ and Belfast, UK. These tests are validated and performed in our very own Bioanalytical laboratory.  Critical to the current pandemic, we offer analytically validated cytokine and chemokine assays utilizing a sophisticated automated electrochemiluminescence (ECL) platform. 

    View our list of analytically validated COVID-19 biomarkers here: https://www.celerion.com/2020/04/27/capturing-the-cytokine-storm-using-biomarkers-in-covid-19-trials 

    Celerion is on Deck!

    As a full-service CRO and leader in early phase drug development, Celerion is ready to serve our biotech and pharma partners develop life-saving treatments during these extraordinary times. Our mission is to focus every day on helping our clients get their drugs to market, so that they touch the lives of our family, friends and people in need around the world.

    References

    1. Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest. 2020.
    2. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.
    3. Yang YS, C.; Li, J.; et al. . Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome. medRxiv. 2020.
    4. Moore BJB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020.
    5. Petrosillo N, Viceconte G, Ergonul O, Ippolito G, Petersen E. COVID-19, SARS and MERS: are they closely related? Clin Microbiol Infect. 2020.
    6. Fung SY, Yuen KS, Ye ZW, Chan CP, Jin DY. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect. 2020;9(1):558-70.
    7. Ruan S. Likelihood of survival of coronavirus disease 2019. Lancet Infect Dis. 2020.
    8. Wong LY, Lui PY, Jin DY. A molecular arms race between host innate antiviral response and emerging human coronaviruses. Virol Sin. 2016;31(1):12-23.
    9. Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020;38(1):1-9.
    10. Shekerdemian LS, Mahmood NR, Wolfe KK, Riggs BJ, Ross CE, McKiernan CA et al. Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units. JAMA Pediatr. 2020.
    11. Mehta NS, Mytton OT, Mullins EWS, Fowler TA, Falconer CL, Murphy OB et al. SARS-CoV-2 (COVID-19): What do we know about children? A systematic review. Clin Infect Dis. 2020.
    12. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020.
    13. Agarwal S, Agrawal DK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin Immunol. 2017;13(3):247-58.
    14. Turnier JL, Anderson MS, Heizer HR, Jone PN, Glode MP, Dominguez SR. Concurrent Respiratory Viruses and Kawasaki Disease. Pediatrics. 2015;136(3):e609-14.
    15. Lindquist ME, Hicar MD. B Cells and Antibodies in Kawasaki Disease. Int J Mol Sci. 2019;20(8).
    16. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J et al. COVID-19 and Kawasaki Disease: Novel Virus and Novel Case. Hosp Pediatr. 2020.
    17. Elakabawi K, Lin J, Jiao F, Guo N, Yuan Z. Kawasaki Disease: Global Burden and Genetic Background. Cardiol Res. 2020;11(1):9-14.
    18. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-5.
    19. Velavan TP, Meyer CG. Mild versus severe COVID-19: laboratory markers. Int J Infect Dis. 2020.
    20. Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020.
    21. Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020:102452.

    *GlobalData search: Infectious disease therapy area; Coronavirus disease 2019 (COVID-19) indication; planned, ongoing not recruiting, ongoing recruiting, ongoing recruiting by invitation trial status; L04AC Interleukin inhibitors ATC classification. Search date 01May2020. GlobalData, John Carpenter House, UK.

    Acknowledgments

    Thank you to Celerion scientists Aernout van Haarst, Sumit Kar, Fred Pritchard, Michelle Combs and Lorraine Rusch for editorial assistance.

  • Capturing the Cytokine Storm: Using Biomarkers in COVID-19 Trials

    Capturing the Cytokine Storm: Using Biomarkers in COVID-19 Trials

    Sumit KarBy Sumit Kar, Lead Scientist – Biomarkers, Celerion

    Cytokine biomarkers are released in the body after SARS-CoV-2 viral particles are presented by antigen presenting cells initiating a cytokine storm.1 Cytokine storm, known clinically as haemophagocytic lymphohistiocytosis or cytokine release syndrome, is mostly seen after viral infections, and leads to constant fever, increased ferritin, and multi-organ failure including acute respiratory distress syndrome (ARDS). For this reason, anti-inflammatory drugs, such as some targeting IL-6, are being tested as therapies for COVID-19 to prevent ARDS, the most common reason for fatality in patients suffering from COVID-19.

    SARS-CoV-2 studies show alterations in serum IL-2, IL-6, IL-7, granulocyte-colony stimulating factor, IP-10, MCP-1, MIP1-α, and TNF-α, which are positively correlated with COVID-19 disease severity.1 The exact cytokine profile varies between studies. In previous viral challenge trials with neutralizing antibody therapies (e.g. for influenza), only IP-10 and IFN-g were reduced after drug dosing.2 The specific cytokines needed for SARS-COV-2 trials are yet to be well-characterized. Therefore, larger multiplex panels measuring several markers together are recommended for speed – especially those that are well characterized for reliability (e.g. Meso Scale Discovery® (MSD) V-Plex Assays).

    Use Cases of Cytokines for COVID-19 Clinical Trials

    These cytokine biomarkers can be monitored in SARS-COV-2 trials for vaccines, antivirals, and antibody therapies. Cytokines can be measured for patient enrollment, mechanism of action, and treatment effect contexts of use. For example, drugs trying to prevent ARDS should measure cytokines as a secondary endpoint and to show their mechanism of action. At Celerion, we validate all biomarkers fit-for-purpose based on their context of use in the study following the latest regulatory guidelines.

    Celerion’s Cytokine Assays

    At Celerion, we have validated MSD Cytokine Panels with up to 10 cytokines and chemokines for quantification via automated electrochemiluminescence (ECL). The panels can be custom designed according to need while maintaining the performance of the assay.

    Celerion MSD Validated Cytokine Panels (human serum)
    Panel 1: IFN-g, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-a
    Panel 2: Eotaxin, Eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, MDC, MIP-1a, MIP-1b, TARC
    Panel 3: GM-CSF, IL-12/IL-23p40, IL-15, IL-16, IL-17A, IL-1α, IL-5, IL-7, TNF-β, VEGF-A

    Exploring Cytokine Profiles in other Matrices

    Respiratory specific matrices (i.e., bronchoalveolar lavage fluid (BALF), sputum and saliva) can be a reservoir of cytokine upregulation upon viral exposure via inhalation.3 Celerion has extensive experience measuring biomarkers in these respiratory matrices using the latest technology, which quantitates cytokines at ultra-low concentrations via Quanterix® Simoa and MSD S-Plex platforms.

    References

    1. Mehta P, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet. 396(10229), 2020

    2. McBride JM, Lim JJ, Burgess T, Deng R, Derby MA, Maia M, Horn P, Siddiqui O, Sheinson D, Chen-Harris H, Newton EM, Fillos D, Nazzal D, Rosenberger CM, Ohlson MB, Lambkin-Williams R, Fathi H, Harris JM, Tavel JA. Phase 2 randomized trial of the safety and efficacy of MHAA4549A, a broadly neutralizing monoclonal antibody, in a human influenza a virus challenge model. Antimicrob Agents Chemother 61:e01154-17, 2017

    3. Horiuchi T, et al. Biomarker profiles of BALF in ALI/ARDS due to pandemic (H1N1) 2009 influenza. European Respiratory Journal. 38 (Suppl 55), 2017

    Acknowledgements

    Special thank you to Celerion scientists Curtis Sheldon, Amanda Daugherty, and Aernout van Haarst for their editorial assistance.

  • Pharmabiotics – Spreading Culture to Therapeutic Drugs

    In the therapeutic toolbox, there is a multitude of drug categories. For decades, small molecules have been the cornerstone of pharmacology. In recent years, biological products have ushered in a wave of therapies, and forged the path for other cell- and genetic- based treatments. Greater understanding of the microbiome in association with dysbiosis and associated diseases have led to the advancement of pharmabiotics.

    How Microbes can Treat Diseases

    Pharmabiotics or live biotherapeutic products (LBP) refers to live microbes administered to patients to treat a disease. Gut dysbiosis is an imbalance of digestive track bacteria species that may contribute to a host of diseases including depression, Alzheimer’s disease, diabetes, irritable bowel disease (IBD) and nonalcoholic fatty liver disease (NAFLD) and even cancer.  Replenishing the so-called “good” bacteria may return balance and revert or alleviate symptoms of the conditions. Gut-brain-, gut-lung- and gut-liver- axes research has expanded our understanding of the microbiome and fostered a new branch of drug development. Dysbiosis has also been described in other organ systems such as the skin, mouth, vagina and placenta [1], all which may benefit from LBP treatment.

    Pharmabiotics are validated through clinical trials with safety and efficacy endpoints for a given indication and follow the same regulatory pathway to approval as other novel drugs. In that respect, pharmabiotics differ from prebiotic and probiotic products. Prebiotics are fermented fibers that supports the growth of certain gut bacteria, while probiotics are live microorganisms that support or show potential for health benefits. For the most part, these two products are considered a dietary supplement or a medical food and do not require FDA premarket approval.

    LBP can be derived from a human host or genetically modified or engineered to express a specific trait. According to ClinTrials.gov several LBP are in development [2]. This includes pharmabiotics for cancer adjuvant therapy, asthma, IBD and prevention from recurrent infection such as Clostridium difficile and bacterial vaginosis.

    FDA Guidance on Pharmabiotics

    The FDA defines LBP as a product that [3]: i) contains live organisms, such as bacteria; ii) is applicable to the prevention, treatment, or cure of a disease or condition of human beings; and iii) is not a vaccine.

    The FDA guidance, which was updated in 2016, outlines requirements for describing the LPB and the manufacturing process as well as adjuvant substances if necessary. For non-clinical studies, the FDA recommends pharmacological and toxicological studies of the LBP in laboratory animals, or in vitro, to support a proposed clinical trial evaluating the investigational LBP. Similar to small molecule or biological drug development, non-clinical studies for LBP may include general toxicity; target organs or systems of toxicity; teratogenic, carcinogenic, or mutagenic potential of any ingredient in the product; and relationship of dosage and duration to toxic response and pharmacological activity. In addition, during early clinical Phase I studies, emphasis should be placed on subject safety. Early studies with healthy volunteers can be important to identify common LBP-associated adverse events before proceeding to studies in more vulnerable populations, such as those with the disease of interest. Currently, there is no EMA guidance for pharmabiotics as the agency does not regard LBP as a drug; however this stance may change as the field continues to grow.

    LPB Dosing and Monitoring

    Commonly, dosing units for LPB are based on a colony forming unit (CFU). According to the FDA, CFU is the measurement of viable microbial cells that are capable of replicating on agar plates and forming colonies which are then counted [3]. Depending on the targeted tissue, delivery of LBP may be orally ingested, administered via the urogenital track or other methods.

    While traditional PK assessments may not apply to the field of pharmabiotics; microbiota diversity, taxonomic composition as well as the microbiome are important pharmacological endpoints. LPB bacterial strain colonization in stool and fecal metabolomic profile, including short chain fatty acids and bile acids, may be evaluated for LBP targeting gut disorders, while sputum may be obtained for microbe count and bacterial DNA for an asthma indication. Supporting serum biomarkers such as inflammatory cytokines, chemokines, and hormones can also demonstrate systemic pharmacodynamic changes.

    Safety Considerations

    While probiotics are generally considered safe for consumption, there has been reported instances of adverse events which can include systemic infections, deleterious metabolic activities, excessive immune stimulation in susceptible individuals and gene transfer [4].  Pharmabiotics may results in similar adverse effects, therefore close monitoring may be warranted. An excellent recent invited review by LeBegue et al. describes the history and study design considerations for pharmabiotic products [5].

    The Celerion Advantage

    Celerion clinics have experience with LPB and the unique challenges in sampling and handling key matrices such as feces, urine, sputum and other fluids for pharmabiotic studies. Our team of highly skilled Regulatory and Drug Development Service associates can support your LBP from IND through Phase II. In addition, we have a vast database of healthy volunteers as well as access to patient populations such as asthma, NAFLD and irritable bowel disease patients.

    References

    1. Belizario JE, Napolitano M. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches. Front Microbiol. 2015;6:1050.
    2. ClinTrials.gov. Live biotherapeutic products search. https://clinicaltrials.gov/ct2/results?cond=&term=live+biotherapeutic+product&cntry=&state=&city=&dist= Accessed March 9 2020.
    3. Early Clinical Trials With Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information; Guidance for Industry. . Food and Drug Administration; 2016.
    4. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60 Suppl 2:S129-34.
    5. LeBegue CE, Love BL, Wyatt MD. Microbes as Drugs: The Potential of Pharmabiotics. Pharmacotherapy. 2020;40(2):102-6.

     

  • COVID-19 Vaccines in Development

    COVID-19 Vaccines in Development

    COVID-19 is a respiratory illness caused by a novel coronavirus. According to the CDC, symptoms may include fever, coughing and shortness of breath. The virus is highly contagious and can spread between people who are in close contact with one another (within 6 feet) or when an infected person coughs or sneezes spraying respiratory droplets.

    While the world is grinding to a halt to slow the spread of the COVID-19 through social-distancing, self-isolation and quarantine efforts. The race to find a COVID-19 vaccine has just began. As of March 18th 2020, there are 298 clinical trials for COVID-19 and 129 drugs in the pipeline which may potentially treat this disease (GlobalData).

    As we face this ever-growing pandemic, Celerion is ready to work with our pharma and biotech partners to ensure safety and efficacy of COVID-19 vaccine development. Celerion is a leader in vaccine development with infections disease experience. Our track record spans both preventive and therapeutic vaccines, subunit and conjugates across all phases I-IV in more than 20 countries, 300 study centers and 4500 subjects.

    We will get through this, together!!

     

  • Celerion Celebrates a Decade of Translating Science Into Medicine

  • Celerion Expands Clinical Research to Nebraska Innovation Campus

  • Newsletter: Q3/Q4 2019

  • 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