Beyond Vaccines: Tackling Severe Covid-19 Disease
Paul Whittaker • 18 April 2021
SEVERE COVID-19 DISEASE
Around 20% of people infected with SARS-CoV-2 develop severe disease symptoms requiring hospitalisation and, in some cases, intensive care support for critical respiratory disease and/or multi-organ failure (Fig. 1.).
Fig. 1. COVID-19 symptomatology time course and approved drug treatments. COVID-19 symptoms become apparent around 5 days after initial virus exposure. Symptoms peak, on average, 5 days later and, for the majority (>60%) of people, COVID-19 symptoms are mild to moderate in severity. Although symptoms subside for 4 in 5 of these mild/moderate cases after another 5 days, 1 in 5 people can experience persistent symptoms for 12 weeks or more (long COVID). Twenty percent of infected individuals require hospitalisation with hypoxaemia caused by viral pneumonia. Of these hospitalised patients, 1 in 5 develop acute respiratory distress syndrome (ARDS) and/or multi-organ failure requiring intensive care. Up to 40% of critical care patients can die. Around 17% of infected people never develop any symptoms of COVID-19 at any time. So far, the only approved therapies are the anti-viral drug remdesivir and the immunomodulatory drugs dexamethasone and tocilizumab, used singly or in combination, for patients hospitalised with severe COVID-19. In randomised clinical trials remdesivir reduces time to recovery, whereas dexamethasone and tocilizumab reduce mortality in hypoxaemic patients receiving oxygen support, as well as reducing time to recovery and/or mortality, particularly when used in combination. Abbreviations: p.o. – by mouth; and i.v. -intravenous
The rollout of the AstraZeneca-Oxford and Pfizer-BioNtech SARS-CoV-2 vaccines is already having a major impact on the incidence of severe COVID-19 in the UK. Hopefully, similar effects will be seen as vaccines are rolled out in the EU and globally. However, despite the success in developing highly effective vaccines, there is still a need to develop other therapies. These include, antiviral drugs to directly target the SARS-CoV-2 virus, block virus entry/exit, or inhibit virus replication, as well as immunomodulatory drugs to prevent, or attenuate severe COVID-19. Developing these therapies is important given: vaccine hesitancy; the proportion of people in the world who have still to be vaccinated; and the continuing emergence of virus variants.
ANTI-VIRAL DRUGS
So far, remdesivir is the only anti-viral drug approved for treating Covid-19. Its use is limited to clinical settings (Fig. 1.), where it is reported to reduce time to recovery in hospitalised patients. A number of anti-viral drugs are currently being investigated for use in COVID-19. Interestingly, clinical trials of unapproved monoclonal antibody therapies in non-hospitalised adults with mild to moderate COVID-19 symptoms at high risk for progressing to severe COVID-19 have demonstrated reductions in hospitalisations and deaths. Potent, small molecule anti-viral drugs that could be given orally soon after symptom development, or after a positive RT-PCR test, to prevent hospitalisation in individuals at high risk of developing severe COVID-19, would be a valuable addition to the COVID-19 armamentarium.
IMMUNOMODULATORY DRUGS
Markers of inflammation are predictive of critical illness and mortality in COVID-19, and dysregulation of the host immune response is a key feature in individuals with severe disease, particularly those requiring critical care for COVID-19 ARDS. Analysis of data collected from COVID-19 patients already on immunomodulatory drugs for other diseases suggests that such drugs may provide protection from severe disease. In addition, a recent randomised controlled trial showed that early administration of the inhaled corticosteroid budesonide reduced the need for urgent medical care and reduced COVID-19 recovery time. Although children present with milder symptoms compared to adults, rare cases of a very severe multisystem inflammatory syndrome in children (MIS-C) have been reported. However, the hyper-inflammation observed in MIS-C differs from that seen in adults with severe COVID-19. Therefore, it may be that therapies for severe COVID-19 in adults and MIS-C may need to have different immunomodulatory profiles.
The value of immunomodulators in improving clinical outcomes in severe COVID-19 has been directly demonstrated by the RECOVERY trial. Administering the cheap and readily available corticosteroid dexamethasone to hospitalised severe COVID-19 patients with hypoxaemia (Fig. 1.) lowered mortality in those receiving invasive and non-invasive oxygen support, but not in non-hypoxaemic patients receiving no respiratory support. Although guidelines indicate reserving dexamethasone administration for patients requiring supplemental oxygen, a published study suggests that hypoxaemia should not be a trigger for dexamethasone usage unless the patient has been hospitalised for >72 hours. Key features in determining the timing of dexamethasone dosing are likely to be viral load and the level of inflammation in individual patients (Fig. 2.).
The RECOVERY trial also demonstrated that giving the more expensive humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody, tocilizumab, to patients hospitalised with severe COVID-19 (Fig. 1.) reduces the risk of death, shortens time until discharge, and reduces the need for mechanical ventilation. However, it is worth noting that there have been conflicting results from several randomised clinical trials of tocilizumab in COVID-19.
Importantly, the benefits of tocilizumab are seen on top of those provided by dexamethasone. Combination treatment reduces mortality for hypoxic patients requiring non-invasive and invasive mechanical ventilation. As a result, UK and US clinical guidelines now recommend the use of tocilizumab and dexamethasone in the treatment of hypoxaemic patients with severe COVID-19 requiring ventilation, but not for patients without hypoxaemia, or with significant immunosuppression. Although the RECOVERY trial did not explore optimal timing, dose, or duration, data from a Spanish study indicates that administering tocilizumab in combination with dexamethasone at hospital admission results in better outcomes than giving it 24 hours later.
The impressive results using tocilizumab and dexamethasone currently set the standard for severe COVID-19 immunomodulatory therapies, however, there is still scope for the development of other classes of immunomodulators with different mechanisms of action and different (or superior) side effect profiles, especially given the complexity of the innate and adaptive immune responses in severe COVID-19 and cytokine and cytokine receptor pleiotropy and redundancy.
A number of potential immunomodulatory therapies for severe COVID-19 have been suggested including, anti-cytokines, non-specific immune modulators, and specific signalling pathway modulators affecting pro-inflammatory cytokine production. Existing small molecule immunomodulatory drugs, or biologics targeting specific cytokines other than IL-6, developed for autoimmune or other inflammatory diseases, are being tested for being suitable for re-purposing as therapies for severe COVID-19. Alternative immunomodulators could lead to improved clinical outcomes (Fig. 2.), particularly in subsets of severe COVID-19 patients who do not respond to tocilizumab and dexamethasone therapy, or have specific co-morbidities, or different inflammatory profiles. Because systemic inflammation is important in driving pulmonary and extra-pulmonary damage in severe COVID-19, immunomodulatory drugs would be expected to be beneficial in addressing this aspect of the disease.
Could immunomodulators be useful in preventing or treating long COVID? Whether immunomodulators, potent anti-viral drugs, or a combination of the two, can have a positive impact on this post-COVID syndrome is unclear at the present time. This is because it is not known if the burden of health loss due to long COVID is a result of: long-term persistence of the virus; long term sequelae resulting from disruption of individuals’ immune and inflammatory responses; or due to something else entirely.
Fig. 2. Immunomodulatory drug treatment for severe COVID-19. The goal of immunomodulatory therapy in severe COVID-19 is to halt the patient’s journey along the severe disease trajectory and to re-direct them down the resolution trajectory instead. This reduces mortality, length of hospital stay, the need for ventilation and progression to critical illness. The degree and speed with which normal, or at least improved function, is restored will vary between different patients, depending on age and co-morbidities, but improvements will have a positive impact on clinical outcomes and healthcare resource usage and costs. In addition to the drug itself, dosage, timing, and duration of treatment are all likely to be important in terms of controlling severe COVID-19 disease progression, as well as minimising drug side effects. Administration of immunomodulatory drugs too early could negatively impact the host anti-viral response and actually encourage viral replication and spread in the respiratory tract, whereas effectively attenuating (not ablating) excess inflammation will be beneficial, as clinical studies using dexamethasone and tocilizumab have shown. The identification of blood biomarkers that distinguish between protective and damaging inflammatory mediator levels could be used to guide the timing of dosing. It is likely that early treatment of symptomatic/virus positive high risk individuals with a potent anti-viral drug to reduce viral load, followed by immunomodulatory therapy to attenuate hyperinflammation, if required, will be the most effective therapeutic strategy.
PROGNOSTIC BIOMARKERS
Early detection of severe COVID-19 will enable prioritization of high-risk individuals for treatment, positively impacting healthcare resource usage and costs. Factors including age, comorbidities, immune response, radiographic findings, laboratory markers, and indicators of organ dysfunction may individually, or collectively, predict worse outcomes. Although the U.S. Food and Drug Administration has issued an emergency use authorization for a machine learning-based device that may be used to indicate SARS-CoV-2 infection in certain asymptomatic individuals, no biomarker tests for severe COVID-19 have been authorised. However, blood proteins; cardiac injury markers; levels of COVID-19-neutralizing antibodies; markers of complement activation and endothelial damage; immune signatures; and cytokine levels, including GM-CSF, all have potential for use as biomarkers of COVID-19 severity. Given the range of clinical, molecular and biochemical readouts and bioinformatics tools available, my feeling is that the best biomarkers will be prognostic algorithms which predict COVID-19 severity by combining these different readouts to allow personalised immunomodulatory treatment strategies that reflect the underlying multifactorial pathophysiological mechanisms in different patients.
CONCLUSIONS
Despite the success of vaccination and social distancing measures in reducing COVID-19 incidence in the UK, as of 18th March 2021 there have been 127,508 COVID-19 related deaths. Globally there have been 3,009,215 deaths. These figures are still rising as the disease continues to have a major impact on human health and re-shapes social, economic and healthcare systems globally. The effects will continue to be felt for some time as SARS-CoV-2 likely becomes endemic.
Although vaccines will continue to be the primary tool in protecting the world’s population from SARS-CoV-2 infection and COVID-19 disease, there is still a need for the development of anti-viral and immunomodulatory drugs to contain the effects of the virus in individuals who develop severe disease symptoms and require hospitalisation. The results obtained with remdesivir, dexamethasone and tocilizumab in clinical trials demonstrate the value of these therapeutics in positively impacting clinical care and disease outcomes. However, there is a lot of scope for improvement, particularly for patients who do not respond to these therapies.
In addition to the drugs themselves, timing of drug dosing will be very important. Too early, and there is likely to be a negative effect on protective host immunity, encouraging virus replication and spread through the respiratory tract. Too late, and the ability to prevent or modify severe disease progression and limit long-term complications such as lung fibrosis and extra-pulmonary organ damage will be compromised. Blood biomarkers as well as clinical parameters will be an important tool for guiding clinical decisions on the timing and duration of drug dosing. Prognostic algorithms that combine clinical and physiological parameters, together with biochemical and immunological markers will be required, given the syndromic nature of COVID-19. For people at high risk of developing severe COVID-19, the use of data from wearable devices appears to be an effective way of monitoring high risk individuals to enable early anti-viral and immunomodulator treatment that may remove or reduce the need for hospitalisation and the need for critical care.
Clearly the benefits of reducing the need for hospitalisation, the length of hospital stay and the need for clinical intervention are enormous, particularly given the pressures that COVID-19 has placed on healthcare systems and the way it has impacted the treatment for non-COVID-19 disease. Finally, anti-viral and immunomodulatory drugs developed to treat COVID-19 could potentially be re-purposed in future pandemics resulting from different viruses.
A collection of links to information sources relevant to the coronavirus pandemic. From disease and healthcare information, to drug therapies and diagnostics, as well as epidemiology and clinical trials in progress. Association of British Pharmaceutical Industries Up-to-date information on what the pharmaceutical industry is doing to tackle the outbreak Diagnostics webinar slides British Broadcasting Corporation BBC Horizon programme investigating the scientific facts and figures behind the Coronavirus pandemic as at 9th April 2020 British Medical Association COVID-19 Guidance Official guidance for doctors British Medical Journal Coronavirus Hub Support for health professionals and researchers with practical guidance, latest news, comment and research British Society for Antimicrobial Chemotherapy Information and the latest guidance from health bodies, academic publications and other professional societies British Thoracic Society COVID-19 Information Information, guidance and resources to support the respiratory community Centers for Disease Control and Prevention Coronavirus disease portal - up to date genomics and precision health information on coronavirus US government public health information Cochrane Library COVID-19 Information Cochrane Reviews and related content from the Cochrane Library relating to the COVID-19 pandemic COVID-19 Diagnostics Resources Diagnostics resource centre is designed to support policymakers and healthcare providers with up-to-date information on tests and testing for SARS-CoV-2 Resource page to facilitate information sharing and provide technical expertise to teams developing COVID-19 tests Drug Target Review Latest news and updates relating to COVID-19 drug discovery efforts European Respiratory Society COVID-19 Resource Centre European Respiratory Society (ERS) and European Lung Foundation (ELF) resources on SARS-CoV-2 and COVID-19 as it is published International Severe Acute respiratory and Emerging Infection Consortium (ISARIC) COVID-19 Resources COVID-19 clinical research resources Medical Research Centre for Epidemiological Analysis and Modelling of Infectious Diseases All output from the Imperial College COVID-19 Response Team, including publicly published online reports, planning tools, scientific resources, publications and video updates Public Health England PHE COVID-19 dashboard Royal College of Pathologists Latest information available on COVID-19 relevant to the practice of pathology Royal Society of Biology How the RSB is responding to the COVID-19 pandemic, by area of activity Bulletin covering the latest news and science behind the outbreak and the response Royal Society of Medicine Roundup of official guidance and information, tools and helpful resources on COVID-19 for healthcare professionals Resources on COVID-19 national trials University of Oxford Centre for Evidence-Based Medicine Rapid reviews of primary care questions relating to the coronavirus pandemic, updated regularly US National Institutes of Health Latest research information from NIH Wiley Online Library Articles related to the current COVID-19 outbreak, as well as a collection of journal articles and book chapters on coronavirus research freely available to the global scientific community
Image Source “ By the help of microscopes, there is nothing so small, as to escape our inquiry; hence there is a new visible world discovered to the understanding. ” Robert Hooke , 1635 - 1703. The history of microscopes is one of ever higher magnification, enabling scientists to pry deeper and deeper into the minute details of nature invisible to the naked eye. Now microscopy is playing a key role in visualising the molecular architecture of proteins and macromolecular complexes; information which is critical to understanding biomolecular function and discovering new drugs. X-ray crystallography has been the most widely used technique for obtaining atomic level detail, but it does require a large amount of sample and the generation of crystals, which can be problematic. Nuclear magnetic resonance (NMR) does not require crystallization, but it does require large amounts of sample and isotopic enrichment and the technique has generally been restricted to small proteins, single protein domains, or small RNAs. Single-particle cryo-electron microscopy (cryo-EM) is a structural biology technique, first developed back in the 1970s, which does not require crystallization, or large amounts of sample. Using a flash-freezing process that fixes proteins in thin films of ice, cryo-EM avoids the problems of crystallization. Then, thousands of 2-D images of proteins caught in random orientations are stitched together to reveal the 3D structure. Advances in detector technology and software algorithms now mean that cryo-EM can be used for the determination of biomolecular structures at near-atomic resolution , including proteins and macromolecular assemblies “intractable” to X-ray crystallography and NMR. In an application relevant to the current COVID-19 pandemic, cryo-EM has recently been used to study the functional evolution of coronavirus spike proteins and provide a structural basis for the inhibition of coronavirus replication by Remdesivir . Cryo-EM is now being used for a range of applications from studying eukaryotic DNA replication, to structure-based drug discovery (SBDD), as showcased during a recent ELRIG webinar on this topic, held on 2nd April 2020 entitled “From Blob-ology to Near Atomic Resolution Structures: Current Uses of Cryo-EM within Biological Research”. While the number of protein structures being determined by cryo-EM is booming , the cost of a microscope (up to £5/$7 million), the need for custom laboratory facilities and the associated operational costs, means that many structural biologists have no access to this technology. Jason Van-Rooyen explained how The Electron Bio-Imaging Centre ( eBIC ) at Diamond in Oxfordshire provides state-of-the-art cryo-EM equipment and expertise, as well as molecular and cellular cryo-electron tomography for use by academic and industrial scientific groups . Use of the eBIC cryo-EM facility has resulted in 113 publications at the time of writing this article, ranging from the determination of cryo-EM structures of the Escherichia coli RecBCD complex to the cryo–EM structure of RagA/RagC in complex with mTORC1 . Planned, are the provision of a Dual Beam Scanning Electron Microscope (SEM) and Focused Ion Beam (FIB) system for the generation of thin lamellae of cellular samples for cryo-electron tomography, as well as electron crystallography for structure determination. The eukaryotic genome must be accurately duplicated in an a timely manner during the S (synthesis) phase of each cell division cycle . As the genomic DNA in eukaryotic cells is packaged into nucleosome arrays , the nucleosomes need to be dismantled ahead of the advancing DNA replication fork and reassembled again once the DNA has been duplicated. A key component in this highly regulated biological process is the replisome , a large, multiprotein complex, comprising an array of DNA unwinding ( helicase ) and synthesis ( primase / polymerase ) functions, whose assembly is closely linked to cell cycle phase. Initiation of DNA replication takes place when pre-replication complexes (pre-RCs) comprising the origin recognition complex (ORC) , chromatin licensing and DNA replication factor 1 (Cdt1) and cell division cycle 6 (Cdc6) are assembled at multiple DNA replication start sites ( origins ) in the genome during G1 phase. Origins of replication are subsequently licensed by loading of the inactive mini-chromosome maintenance protein complex (MCM) DNA unwinding (helicase) motor onto DNA, which is then activated in a series of steps during S phase to form functional replisomes. It is believed that the activated MCM melts the double helix and unwinds the DNA at the replication fork, allowing the replicative polymerases to do their work. Alessandro Costa ( The Francis Crick Institute ) described how cryo-EM is being used to understand the molecular basis of DNA engagement by the MCM and the mechanics of the helicase motor. Using purified yeast proteins in a reconstituted DNA replication system, his team have used single-particle cryo-EM to study the mechanisms of MCM helicase loading onto DNA and MCM-driven DNA melting and untwisting during origin licensing . DNA fork progression depends on the energy derived from ATP hydrolysis by the MCM motor, however, it is unclear how this is achieved. Using cryo-EM, sub-nanometre resolution structures of the CMG helicase trapped on a DNA replication fork have been determined and combined with single-molecule FRET measurements to suggest a replication fork unwinding mechanism. Further studies on the mechanism of helicase activation show that activated helicases are bound to unwound single DNA strands and pass each other within the replication origin as they translocate in opposite directions along the DNA strands in a process driven by different helicase conformational states. Three different polymerases act sequentially on the leading-strand template to establish DNA replication. Cryo-EM has been used to study the structure and dynamics of the main leading-strand polymerase bound to the CMG helicase and how polymerase binding changes both helicase structure and fork-junction engagement . Pfizer was the first pharmaceutical company to adopt cryo-EM in-house. Due to its ability to visualize protein structures and ligand interactions , cryo-EM has been increasingly adopted by the pharmaceutical industry as a tool to facilitate structure-based and fragment-based drug discovery. Cryo-EM is one of several technologies that AstraZeneca has invested in, as they push to develop novel drug targets. The DNA damage response is one of AZ’s strategic areas within oncology and Taiana Maia de Oliveira described how single-particle cryo-EM has been used to reveal insights into the structure of the DNA damage sensor phosphatidylinositol 3-kinase related kinase (PIKK) protein family, which controls the response of cells to stress and nutrient status. In collaboration with the MRC Laboratory of Molecular Biology , and using facilities at the Cambridge Pharmaceutical Cryo-EM Consortium , AZ researchers used cryo-EM to define the world’s first protein structures for human ataxia telangiectasia mutated (ATM) and the structure of ATM in different functional states. Because of its large size (350 kDa), previous attempts to obtain a high resolution structure of ATM with other techniques proved impossible. ATM is a key trigger protein in the DNA damage repair response, involved in tumorigenesis and survival of cancer cells and, as a result, a prime therapeutic target for oncology. This structural work revealed that ATM functions as a “molecular switch”. In the asymmetric (“on”) ATM dimer state, the active site is open and can bind substrate, whereas in the symmetric (“off”) state the active site is closed and substrate binding is blocked. Both open and closed ATM molecules co-exist in the sample protein samples, explaining why catalytic activity of ATM can be seen even under basal conditions and indicating that activators and inhibitors may work by altering the equilibrium between the two dimer populations. AZ have also used cryo-EM to elucidate the mechanism of RET activation with a view to targeting this mechanism in neurodegenerative disease and diabetes. Conclusion Once derided as being “Blobology” because of the lack of definition in its blurry images, cryo-EM has rapidly become one of the hottest new approaches in biological research, with many calling it a “resolution revolution” . In the last few years there has been an exponential growth in the number of images being uploaded to The Electron Microscopy Data Bank , with the quality of the images rivalling those obtained using X-ray crystallography. As was demonstrated during the ELRIG webinar, cryo-EM is well-suited to providing high resolution structural information to aid both academic and industrial projects. Successful applications in small molecule drug discovery will certainly gather pace as pharma seek to exploit the power of this technology to deduce the structures of therapeutically relevant protein targets, as well as provide information on binding site and ligand interactions , to enable the study of drug-target interactions. In due course, we can expect cryo-EM to be applied to a variety of areas in the pharmaceutical industry, including vaccines, protein degradation, gene therapy, biologics, epitope mapping and antibody-antigen interactions. Technological improvements in direct electron detection , image collection and image analysis , enabled the successes of cryo-EM, but there are still a number of methodological aspects that could be improved , including validating the accuracy of cryo-EM structures and developing data standards . Automation of many steps from sample preparation to data pre-processing will improve the efficiency and productivity of cryo-EM and, hopefully, take specimen preparation for cryo-EM from a trial and error “art” to a controlled and reproducible process making it easier to use and providing robust protocols from beginning to end. The development of graphene supports also promises improvements in the reliability of specimen preparation and image quality. There is also a drive to make cryo-EM more affordable using machines that operate at lower voltages. Finally, for readers interested in learning more about the practicalities of cryo-EM, a good starting point is the MRC Laboratory of Molecular Biology electron microscopy webpage .
Healthcare organisations such as the NHS face unrivalled challenges, from improving access and care for patients, to increasing efficiency and reducing costs. Medical and healthcare innovation is seen as having a key role in driving these improvements , particularly in the NHS . Twice a year the Royal Society of Medicine (RSM) holds a day of presentations and discussions around new ideas and developments in medicine and healthcare. The presenters range from early stage entrepreneurs, to those who are embedding innovations in a clinical setting. The variety of topics covered is always stimulating and provides an early insight into how medicine and healthcare are likely to be shaped in the future. In this article I will be reviewing the two RSM Medical Innovations summits I attended in 2019 on 6th March and 21st September . Patient Monitoring Patient monitoring is an essential part of clinical and disease management. It allows an assessment of the progress/regression of a disease, or the development of complications. Poor monitoring can lead to poor disease control. With all its innovations and possibilities, digital technology has the capability to capture and quantify the physical, mental and social wellbeing of patients, as well as aid in disease management. Digital technology provides an opportunity to deliver patient triage in new ways. Using data from wireless-enabled implanted cardiac devices received via the CareLink network, Matt Cook and Roel Bogaarts ( Medtronic ) explained how the FOCUSON team monitors and triages incoming data to aid hospital clinical teams. Clinical teams receive alerts via telephone, email, or the FOCUSON Platform. As a result they are able to devote more time to patients, particularly those in need of urgent care. The use of algorithms and software ( artificial intelligence, AI ) has great potential for helping clinicians understand complex medical data sets and help guide clinical decision making. Letizia Gionfrida ( Arthronica ) revealed how AI is being used for the assessment and management of chronic rheumatic conditions so that examinations can be performed remotely using a laptop or smartphone camera, to reduce, or eliminate, the need for face-to-face consultations. Elina Naydenova ( Feebris ) described how AI is being used to improve diagnosis in vulnerable patient groups (the young and the elderly) by analysing data from a wide range of point-of-care devices (digital stethoscopes, wearables etc.) to extract clinical information that can be used by healthcare professionals to facilitate early diagnosis. Wearable sensors (wearables) are smart electronic devices worn next to the skin that can collect physiological and environmental data that can be used for immediate user feedback, or downstream analysis. Wearables are increasingly being used to collect and process physiological parameters for digital health information . In terms of the evaluation of human movement, sensors can be used to provide feedback to the user that they can use to modify their movements and improve their daily life. Nuala Barker ( Walk With Path ) talked about two wearables to improve patient mobility: a shoe attachment ( Path Finder ) to improve movement and gait in patients with neurodegenerative diseases such as Parkinson’s disease and; a shoe insole that provides haptic feedback to patients at risk of falls due to diseases such as peripheral neuropathy ( Path Feel ). Patient Self Help Patient self-care is important not only for preventing future health problems (e.g. heart disease and lung cancer), but also in managing the course of long-term conditions. Chris Edson ( OurPath ) explained how smart technology and behavioural science are being combined to help patients replace bad habits with good ones. Nutritional advice and planning are combined with smart scales and a step tracker to facilitate behavioural change and monitor progress. The OurPath online habit change platform has now been commissioned by the NHS . Knowledge is power, as the saying goes. Patient knowledge can improve health outcomes and enable patients to actively participate in disease control and treatment. However, the knowledge needs to be evidence-based and relevant to the patient. Seb Tucknott ( IBDrelief ) has developed an online portal to provide information and support for sufferers of inflammatory bowel disease (IBD) . IBD, which includes Crohn’s disease and ulcerative colitis, is generally managed through strong drugs and/or surgery. For millions of people worldwide, everyday life can be a struggle as sufferers deal with a range of debilitating symptoms which impact their quality of life. The IBDRelief portal is based on research Seb carried out to help him deal with the symptoms of IBD following his diagnosis in 2008 and is aimed at helping sufferers learn how to control their symptoms alongside their medical treatment, as well as connect with other sufferers and share experiences. Mental Health Mental health disorders are complex and challenging, as well as placing an increasing burden on healthcare globally . Digital health interventions (DHIs) , which include smartphone apps, computer‐assisted therapy and wearable technologies, have enormous potential for the treatment for mental health disorders by improving accessibility, clinical effectiveness and personalisation of mental health interventions . Data obtained by digital sensors and wearables can be used as digital biomarkers to assess the mental states of individuals, but the effectiveness has still to be proven clinically. Individuals with autism are at increased risk of having co-occurring mental health conditions such as anxiety and depression . Many of those affected find that existing psychological and drug-based treatments for their conditions have limited impact. Based on research into the ways interoception can influence emotions and behaviour, Sarah Garfinkel ( University of Sussex ) presented an innovative approach to help people with autism who develop an anxiety disorder. This approach aims to help sufferers manage the stress they feel in response to unexpected changes, by tuning into their own heartbeat to reduce anxiety levels. This treatment, known as interoception-directed therapy , is computer based and uses a finger monitor to measure users’ heartbeats as they move through a series of tests and training exercises. A clinical trial is being conducted to understand how effective this approach can be in the short and long term. If effective, the potential is immense and there are plans to develop an app version. Given their ubiquitous digital activity, the use of DHIs may be preferred by children and young people. Richard Andrews ( Healios ) introduced ThinkNinja , a downloadable app designed to help 11-18 year olds learn about mental health and wellbeing and develop skills to help them build resilience and stay well. Built using the principles of cognitive behavioural therapy , the user is coached by the AI-powered app and the skills of a clinical psychologist, to help them deal with a range of mental health issues. Currently, ThinkNinja is a commissioned service only, available in the UK via the NHS, schools, local authorities and charities working with young people. Cancer Cancer screening can save lives by finding cancers at an early stage, or even preventing them. The UK currently has three screening programmes for bowel, breast and cervical cancer. Skin cancer is one of the most common cancers. When diagnosed and treated early, melanoma is curable. Rotimi Fadiya ( PRSM Medical ) introduced The sKan , a low-cost non-invasive handheld device for diagnosing melanoma that provides a quantitative assessment. The technology is based on research showing that cancerous cells are warmer than normal cells. The sKan’s thermistors monitor cancerous cells' heat emissions in real time, creating a heat map showing which cells recover more quickly from thermal shock, indicating the presence of melanoma. The device is still being developed with a view to clinical testing and regulatory approval. Breast cancer is the most common type of cancer in the UK. Early stage detection with suitable treatment can reduce mortality, so there is a lot of interest in developing faster and lower cost ways of diagnosing breast cancer earlier . Francisco J Gonzalez ( Higia Technologies ) described how the Eva bra is being developed for the early detection of breast cancer. Eva uses thermal sensing and artificial intelligence to identify abnormal temperatures in the breast that can correlate to tumour growth so that users are alerted to any disturbing changes. The Eva bra is in early development. It is worth noting that thermal imaging for cancer screening is a controversial area . Radiotherapy is generally considered the most effective cancer treatment after surgery. Proton beam therapy is a type of radiotherapy that uses a beam of high energy protons generated by a cyclotron to treat specific types of cancer (e.g. brain, head and neck cancers). Gillian Wheatfield ( Christie Hospital, Manchester ) explained how precise targeting of the proton beam reduces damage to surrounding healthy tissue and vital organs (e.g. the spinal cord). In the UK, The Christie Centre which opened in 2018, currently provides high energy proton beam therapy, with a second centre at University College London Hospital due to open in 2021. Surgery The convergence of surgical expertise and digital technologies via imaging, virtual and augmented reality (VR and AR), 3-D reconstruction, simulation, 3-D printing, navigation guided surgery and robotic assisted surgery techniques, promises to transform future surgical care . Advancements in VR and AR are starting to impact surgical training. In 2014 around 13,000 medical students, professionals, and interested lay people from more than 100 countries watched an operation live via a camera on a Google Glass worn by colorectal surgeon Shafi Ahmed , while he was performing surgery to remove cancerous tissue from the liver and bowel of a 78 year old patient in London. This was the first time Google Glass had been used during an operation in the UK and demonstrated how a broadcast could reach anybody with an internet connection. In 2016, Ahmed performed surgery on a cancer patient that was streamed live online, using 360-degree virtual reality video and viewed by 55,000 people in 140 countries. Now he is leading an effort to build a fully digital hospital in Bolivia. Robotic surgery, or robot-assisted surgery is a type of minimally invasive surgery which allows surgeons to perform complex procedures with more precision, flexibility and control than is possible using conventional techniques. Compared to open (large incision) surgery, robotic surgery is claimed to cause less trauma, minimal scarring and needs less recovery time. Mark Slack ( CMR Surgical ) described the Versius surgical robotic system which is a rival to the da Vinci system used in some hospitals in the UK. Versius, is a portable modular system of robot arms with a small footprint that can be wheeled into an operating theatre. In a typical scenario, three or more robots are used to perform a range of procedures, with one arm holding an imaging probe and the others equipped with surgical instruments. The surgeon uses gaming style controllers and a 3D display screen at a console in the theatre to perform the procedure. The underpinning innovation for the system is the robotic arm which allows seven degrees of movement . Versius has now been used for operations in the UK . Katerina Spranger and Liya Asner explained how Oxford Heartbeat has developed computational tools to facilitate surgical planning for minimally invasive surgery. Aneurysm surgery requires precise spatial understanding of the vascular anatomy and surrounding tissue to visualise the surgical intervention and pre-define the surgical steps. By reconstructing accurate 3-D anatomy from pre-operative scan data she presented an example of how this approach can be used in planning for aneurysm endovascular stent surgery by helping surgeons choose the best stent and placement for the patient. Potentially, this could reduce waste of devices, complications and costs. Disease The European Union defines a disease as rare if it affects fewer than 1 in 2,000 people. Due to the limited market size and the cost, development of treatments for rare diseases continues to be challenging, despite the incentives in the Orphan Drug Acts of various countries worldwide . The defective gene underlying Duchenne’s Muscular Dystrophy (DMD) was identified in the mid-1980s , however, it took around 30 years for the first approved therapy for DMD to appear and these work only in patients with specific mutations. Josie Godfrey and Fleur Chandler explained how Duchenne UK has brought 8 pharmaceutical companies together through Project Hercules to pool data and resources to accelerate the discovery and development of new therapies for Duchenne’s Muscular Dystrophy (DMD). Initiatives similar to Project HERCULES for other rare diseases could have similar benefits for accelerating the development of new therapies. Over 5% of the world’s population suffers from hearing loss and this figure is expected to rise to 10% by the year 2050. Krishan Ramdoo ( Tympa Health ) described a smartphone-based hearing health assessment system aimed at simplifying the clinical pathway for patients and professionals by improving the communication between GPs and ENT specialists to bridge primary and secondary care. The Tympa system combines: an otoscope for assessing ear health; earwax removal by micro-suction; a screening hearing test; the creation of a digital hearing record with integrated machine learning; and the capability for remote consultation with an ENT specialist. Tympa is currently undergoing trials with the NHS and being rolled out in the Boots Hearingcare network. Eye diseases affecting the cornea are a major cause of blindness worldwide. Around 5 million people suffer total blindness due to corneal scarring . Corneal transplantation is the treatment of choice for loss of corneal function, however, it is limited by the supply of corneal donors. Bioprinting using bioinks is an emerging technology for the fabrication of functional tissue constructs to replace injured or diseased tissues. Che Connon (Newcastle University and Atelerix ) talked about efforts to plug the gap between supply and demand for corneas for transplant surgery by embedding live, functional corneal cells in a hydrogel to create cell-laden bioinks for 3-D bioprinting of a corneal stroma equivalent . When combined with continuous bioprocessing of stromal cells and 4-D tissue engineering using localised cell activators, bioprinting could potentially be used to ensure an unlimited supply of corneas in the future. Drug Discovery and Development Stem cell therapy , also known as regenerative medicine , aims to promote the repair of diseased, dysfunctional, or injured tissue using stem cells . For several decades, stem cell therapy has been used to treat people with conditions such as leukaemia and lymphoma , but its use to treat other diseases is unproven and a cause of concern for regulatory bodies . Osman Kibar explained how Samumed is developing regenerative therapies based on small molecule drugs targeting the Wnt pathway , which is one of the key signalling pathways for controlling the differentiation of adult stem cells. Dysregulation of the Wnt pathway in tissues invariably leads to disease in that tissue, so Wnt pathway modulation has potential as a therapy for degenerative diseases. Although targeting a key cell signalling pathway such as Wnt can be problematic , Samumed are developing a pipeline of treatments for a range of diseases from osteoarthritis to idiopathic pulmonary fibrosis based on drug targets upstream of Wnt receptors, rather than Wnt receptors on the cell membrane. Clinical trials are a vital part of the drug development process. There are tens of thousands of clinical trials taking place globally, each requiring the recruitment of eligible patients for their success, but this has become an increasing challenge. Maya Zlatanova revealed how the FindMeCure Foundation is bringing clinical trials and patients closer together by educating patients about clinical trials and has developed a searchable database of clinical trials so that patients can learn what trials are available that provide access to innovative therapies. On the converse, via Trialhub , FindMeCure provides data to help clinical trial organisers with regards to country and site selection, as well as patient recruitment and engagement. So far, this free service has helped nearly 400,000 patients in their search for clinical trials. Medical Education Advances in medical education have long played a vital part in informing clinical practice. Given the importance of nutrition to human health and the benefits that dietary patterns can have on cardiovascular disease risk and overall mortality , there is a belief that nutrition training should be a compulsory part of medical education, as a way of tackling the increasing burden of chronic lifestyle-related disease in the UK and worldwide. There is also a growing interest in culinary medicine as a way for clinicians to engage better with their patients on lifestyle-related disease. Iain Broadley and Ally Joffee described how Nutritank , an information and innovation hub for food, nutrition and lifestyle medicine, was set up to encourage UK medical schools to increase the levels of nutrition and lifestyle education in their curricula. Nutritank is now part of the NNEdPro network and offers a number of resources for medical students and healthcare professionals. Innovation Innovation is critical in enabling the NHS to deliver better outcomes for patients. However, ensuring the adoption and spread of innovations can be challenging. Chris Chaney discussed the work of CW Innovation in delivering new initiatives and improvements from a smartphone app that provides advice to new parents, to work with the Chelsea and Westminster Hospital Burns Unit on the in-house production of bespoke face masks and splints, for facial scar healing. They are also working with Digital Health London to speed up the adoption of digital health innovation in the NHS. Medical progress is dependent upon the successful translation of basic science discoveries into new medical devices, diagnostics, and therapeutics. “Technology transfer” is the process by which new innovations flow from the laboratory bench to commercial entities and then to market . Since its founding in 2000, Cleveland Clinic Innovations (CCI) , the commercialization arm of The Cleveland Clinic , has translated 3400+ inventions in health IT , medical devices , therapeutics and diagnostics , and delivery solutions into 800+ granted patents, 450+ licenses and 40+ spin-offs. Peter O’Neil revealed how CCI maintains its innovation pipeline using its INVENT (Ideas; Need; Viability; Enhancement; Negotiations; Translation) process and a team of market analysts, subject matter experts and former medical industry leaders to mine, assess, and commercialize new innovations. Industry is increasingly looking to work with small venture capital -backed companies, or universities, to capitalise on their early research capabilities. Funding of early-stage translational research is important for the delivery of investment-worthy opportunities to the venture capital community. However, there are a limited number of investors willing to offer the sums involved. Steve Rockman chatted about how Merism Capital provide seed investment to health & education start-ups. Design is an iterative process in which a prototype solution, selected from a variety of potential solutions to a problem, is tested and revised as needed. In patient-centred design , this process is focused on the patient and their specific needs and considers a range of other factors, such as the environment and economics of the patient’s situation. Nicole Parks and Dipanjan Chatterjee described Medtronic’s approach to patient-centred design via their Applied Innovation Lab (AIL) approach. Much of AIL’s work is focussed on experience design and solution design rather than creating prototypes of new medical devices or apps. We will all die and we will all have to die somewhere. Of the 500,000 or so people who die each year in the UK, around half of these deaths occur in hospital . Yet 70% of people would like to die at home . Having an advance care plan is an effective way of giving people control over where they end their life and is an important part of end of life care . Ivor Williams ( The Helix Centre ), talked about how human-centred design had been used to tackle care planning for emergency hospital admissions ( ReSPECT ) and a digital platform designed to help individuals and families create an advance care plan ( Amber Care Plans ) that can be shared with family, carers and GPs. Conclusion The RSM Innovation meetings are always worth attending. The format of the meetings and the breadth of innovations presented make for a very interesting and stimulating day. What is clear from the 2019 meetings is that digital technology and artificial intelligence are driving healthcare innovation in a wide range of areas, from patient monitoring, to new disease treatments, to improving surgical procedures. The opportunities that are now available for individuals to use digital technology to become active participants in managing both their health and their diseases are exciting and welcome developments. The potential of using data from wearables as digital biomarkers for the assessment of the mental health status of individuals could be a powerful and much needed tool as more and more people suffer mental health issues in society. The use of patient-centred design to improve the patient experience, particularly with regards to end of life care is also welcome, as disease can often be viewed as a scientific and/or technological problem to be solved, while overlooking the “humanness” of the situation. Unfortunately, the 20th RSM Innovation Summit scheduled for 25th April 2020 has now been cancelled because of the current corona virus pandemic, but hopefully it will go ahead later on in the year.
The COVID-19 pandemic which recently originated in China has had a significant impact on the populations , healthcare systems and economies of many countries worldwide. People who get infected appear to vary in their response to the virus , from being asymptomatic or having mild symptoms, to having severe respiratory symptoms which require hospitalisation and can even result in death. Unfortunately, the elderly and people with co-morbidities are often to be found in the latter group, although deaths of people in their twenties or teens have been recorded . Severe responses to respiratory virus infections are often characterised by an exaggerated inflammatory response in which pro-inflammatory cytokine release from damaged lung cells attracts a variety of activated immune cells to the lungs which then cause further lung damage. This appears to also be the case for severe COVID-19 infections . Controlling this excessive immune response will be important in the control of severe disease. However, the aim would be to attenuate the response, rather than ablate it. Total ablation of inflammation would likely promote disease mortality, whereas attenuation should provide protection against the damaging effects caused by excess inflammatory responses, whilst preserving essential innate host defence activities to help clear the virus. As a result, the damaging effects of the excessive inflammatory response would be blunted, but its protective and disease pro-resolution effects would be preserved. Currently, Clinicaltrials.gov lists 239 trials that are planned, or in recruitment, as academic and industrial groups race to develop therapies for COVID-19-induced disease. Most of these are aimed at testing vaccines or anti-viral drugs. None appear to be aimed at testing inhibitors of p38MAPK as immunomodulators for use in severe COVID-19. However, I think such inhibitors have potential and deserve consideration for testing. Several years ago, whilst working at hVIVO, I set up and ran a programme aimed at identifying immunomodulatory drug targets for the treatment of influenza-infected patients who are hospitalised with severe symptoms. The result was a drug repurposing strategy based around p38MAPK inhibitors. Full details can be found in these two submitted patent applications . For various commercial and financial (not scientific) reasons, although a clinically tested p38MAPK inhibitor was in-licensed, the concept was never tested in clinical studies. Given the similarities between severe COVID-19 and severe influenza and the desperate need for drug treatments for hospitalised patients, I do think p38MAPK inhibitor treatment is worth trialling alongside other approaches. Please contact me if you would like to discuss further. Note added 20-MAR-2021: The first of the patent applications referred to above, EP3478322 , was granted a European patent on 30th December 2020. Note Added 06 -MAR-2024: European, US and Japanese patents have now been granted for EP3478322 .
The reductionist target-driven approach to drug discovery, fuelled by sequencing of the human genome, omics technologies and genetic studies has not been as successful in generating new therapies as was initially hoped. Sixty percent of drugs fail in clinical trials due to lack of efficacy, because the underlying therapeutic concept is flawed. This weakness in hypothesis generation is due to gaps in understanding of the underlying human disease biology and drug target validation. So I was interested to attend the ELRIG Drug Discovery 2019 conference entitled “Looking Back to the Future”, held at the ACC in Liverpool on 5-6 November 2019 and catch up on the latest thinking and approaches to tackling these issues. With 8 topic-specific tracks across two days, plus plenary talks, poster sessions and an exhibition featuring 100 companies showcasing their latest drug discovery aids, I was only able to attend a selection of what was on offer. So in this post, I will be concentrating on the talks I attended in sessions dealing with artificial intelligence, cellular models of disease and biomarker strategies in drug discovery. But first, I’ll start with the three plenary talks by Mene Pangalos ( AstraZeneca ), Fiona Marshall ( MSD UK Discovery Centre ) and Melanie Lee ( LifeArc ), who each gave their perspectives on the current issues faced in the discovery of new drugs and how improvements might be made. Plenary Talks Astra Zeneca’s 5Rs framework has already resulted in a 4-fold improvement in clinical trial success rates. In the first plenary talk of the conference, Mene Pangalos explained how AZ aim to improve on this, by rigorous drug target selection and validation using data science and artificial intelligence , as well as technologies such as CRISPR and multi-modal molecular mass spectrometry imaging . Artificial intelligence, in particular, is being leveraged across the drug discovery process in a number of areas in an attempt to make the design-make-test-analyse (DMTA) cycle more efficient and effective. AZ are also expanding the number of therapeutic modalities beyond the trinity of small molecule, antibody and peptide approaches, to include anticalin proteins , proteolysis targeting chimeras ( PROTACs ), antisense and bicyclic peptides , amongst others. Neurodegenerative diseases such as Alzheimer’s disease (AD) have been particularly challenging for the development of new drugs. Only 2 classes of drugs are currently approved for therapeutic use in AD ( acetylcholinesterase inhibitors and NMDA receptor antagonists ). These drugs are able to lessen symptoms (e.g. memory loss and confusion), but are not disease modifying. Fiona Marshall explained how lack of progress in developing new AD therapies is largely due to poor mechanistic understanding of AD, as well as poor predictably of disease models. Drugs based on the genetics-driven amyloid hypothesis have failed to show efficacy in clinical studies , and a recent report suggests that high levels of brain amyloid alone are not sufficient to cause AD. As a result, clinical trials testing possible interventions aimed at other drug targets are currently in progress. Whether the failure of trials of anti-amyloid drugs was due to selecting the wrong drug dosages, the wrong patients, or other reasons, is unclear. However, future success will require biomarkers , neuroimaging and brain activity monitoring for testing drugs with the right mechanism of action in the right patients at the right stage of the disease. The translation of drugs from pre-clinical to clinical testing is clearly an inefficient process that will undoubtedly benefit from well validated therapeutic opportunities. However, Melanie Lee cautioned that, in addition, future products will also need to carry richer data packages, including information on which patient sub-groups to target, as well as companion diagnostics. There will also be an emphasis on diagnosing patients earlier in their disease course, as current points of intervention tend to be late in the disease trajectory. So, in addition to targeted interventions, surveillance screening will be very important. For example, Oncimmune’s Early CDT-Lung test can detect lung cancer 4 or more years before clinical diagnosis. Future improvements in the diagnosis, treatment and outcomes for patients may also come from using crowd sourcing approaches . Cellular Models of Disease The lack of preclinical models that faithfully mimic key aspects of human disease biology in patients has long been an Achilles heel of the drug discovery process. The Holy Grail is to have models that are more capable of predicting clinical success and drug side effects. Organoids derived from adult stem cells, differentiated embryonic stem cells, pluripotent stem cells (iPSCs) and precision genome engineering via CRISPR, offer new opportunities for the generation of diseased and healthy cell types that mimic at least some aspects of the disease in vitro . There is a lot of excitement about using patient-derived iPSCs to overcome the constraints of limited access to viable human tissue and poorly translatable animal models, by enabling the generation of large, reproducible quantities of biologically relevant cells from healthy and diseased individuals. Paul Andrews ( National Phenotypic Screening Centre ), reviewed how phenotypic screening by high content imaging of organoids and iPSC-derived cells is being used to marry “old style” (physiology-driven) and “new style” (target-driven) drug discovery approaches. Phenotypic screening makes no assumptions about the target and limited assumptions about the mechanism of action. The use of iPSCs in phenotypic screening will be aided by: the development of best practices for iPSC disease models ; mapping cell phenotypes to genotypes with single cell genomics ; studying how genetic variations affect cell behaviour by integrating different omics data sets from human iPSCs ; developing well characterised collections of iPSC cell lines for the research community and; developing a collection of cellular reference maps for all the cell types in the human body. There are no effective therapies to treat Glioblastoma (GBM), which is the most common type of brain tumour. Surgery, radiotherapy and chemotherapy, even when combined, only increase survival by a year, on average. Developing clinically effective treatments has been a challenge, despite increasing genomic and genetic knowledge. Steven Pollard ( Centre for Regenerative Medicine, Edinburgh ) discussed how patient-derived models, genome editing and high content phenotypic screening are being used to accelerate drug discovery for GBM. GBM stem cells (which have molecular hallmarks of neural stem cells) and non-transformed neural stem cells have been used as patient-derived models to identify tumour-specific vulnerabilities via genetic screens, or cell-based drug discovery. In addition, the glioma cellular genetics resource is generating a toolkit of cellular reagents and data to expedite research into the biology and treatment of GBM. Wendy Rowan outlined GSKs approach to developing fit-for-purpose cellular models, by scoring models against sets of criteria, so that the most appropriate model(s) can be selected for the research question(s) being asked. Full characterisation of cellular models with respect to how well they model healthy and diseased human tissue physiology using “due diligence checklists” is now seen by GSK as being key to improving drug discovery. For any given drug target, several cellular models may be used to progress the target from validation to candidate selection. GSK are developing cellular models based on organoids , iPSCs and even assessing organ/body-on-a-chip approaches, based on microfluidic technology. Artificial Intelligence (AI) and Machine Learning (ML) As mentioned earlier, AstraZeneca are incorporating AI throughout the drug discovery process. Werngard Czechtizky explained how AZ are incorporating AI into medicinal chemistry by developing algorithms for reaction/route prediction, chemical space generation and affinity/property prediction for low molecular weight compounds, in the first instance, before potentially expanding out to other therapeutic modalities. The aim of doing this is to reduce costs, time, resources and the number of compounds tested (from around 2000 compounds to less than 500) in a 2-3 year time horizon. In terms of hit to lead optimisation , ML is being used for augmented design, predicting synthesis, analytics, and automated DMTA. The extraction of biologically meaningful signals from large diverse omic data sets for target discovery is a major challenge. Michael Barnes ( William Harvey Research Institute ) described how ML and AI are being used to support drug discovery and drug repositioning from genome wide association study data using a tensor-flow framework. Over a thousand genetic loci affecting blood pressure have been identified . These data have been used to teach a tensor-flow algorithm to identify new BP genes. In human population genetics, ML is being used to identify benign human knockouts from exome sequencing data , as potentially safer drug targets with fewer side effects. In personalised healthcare, ML is being used to develop multi-omic predictors of response to biologic therapies . Biomarker Strategies for Drug Discovery Oncology leads the field in the development of biomarkers for drug development and clinical testing. Development of biomarkers for other disease indications lags behind, facing challenges ranging from sample access and quality, to the resolution and sensitivity of detection technologies and the difficulties of measuring low abundance proteins in plasma. In this session, technological approaches to biomarker detection and measurement were reviewed by a range of speakers from industry and academia. Label-free detection methods utilize molecular biophysical properties to monitor molecular presence, or molecular activity. The main advantage of label-free detection is the elimination of tags, dyes, specialized reagents, or engineered cells. This means that more direct information can be acquired about molecular events, minimising artefacts created by the use of labels. Molecular events can also be tracked in real-time, and native cells can be used for greater biological relevance. Peter O’Toole ( University of York ) reviewed how label-free microscopy, can be used to complement and enhance omic and biochemical data by providing minimal perturbations to cellular systems, as well as being quantitative and allowing prolonged live cell imaging. Ptychography (a computational method of microscopic imaging ) does not rely on the object absorbing radiation, so if visible light is used to illuminate the object then cells do not need to be stained, or labelled to create contrast. This allows the collection of cell morphological data during apoptosis and cell division, as well as the observation of the behaviour of cells at the individual level. Understanding the distribution, metabolism and accumulation of drugs in the body is a fundamental part of drug development. Multi-modal molecular mass spectrometry imaging (MSI) allows label-free analysis of endogenous and exogenous compounds ex-vivo by imaging the surface of tissue sections taken from fresh-frozen samples. Gregory Hamm explained how AZ is using MSI to study the abundance and spatial distribution of drugs and their metabolites within biological tissue samples and is also being used for model characterisation . Idiopathic pulmonary fibrosis (IPF) is a lung disease that results in scarring of the lungs and causes progressive and irreversible decline in lung function, with an average life expectancy of 4 years after diagnosis. Currently, only Nintedanib and Perfenidone have been approved for the treatment of IPF, despite numerous phase II and III trials in the past 25 years . This failure is due to: a lack of understanding of the disease mechanism; lack of predictability of preclinical animal models and; the lack of biomarkers to diagnose the disease and monitor response to drug therapy. Sally Price described how the development of biomarkers for IPF is a strategic focus for the Medicines Discovery Catapult , in efforts to develop novel anti-fibrotics . The MDC is working on developing new models such as organ on a chip and 3D organoid models, as well as applying a range of technologies to identify and develop biomarkers for fibrosis. Simon Cruwys ( TherapeutAix ) talked about how a fibrosis extracellular matrix biomarker panel in serum had been used to develop an ex vivo tissue model of IPF . Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND), or Lou Gehrig's disease, is a clinically heterogeneous neurodegenerative disease which causes the death of neurons controlling voluntary muscles. Most sufferers eventually lose the ability to walk, use their hands, speak, swallow, and breathe. Andrea Malaspina ( Queen Mary University of London ) discussed the search for biomarkers for ALS . The development of new therapies for ALS has been limited by a poor understanding of the molecular mechanisms underlying the disease , resulting in the failure of a large number of clinical studies. Proteomic experiments in individuals with a significant difference in prognosis and survival at different time points in disease progression have identified potential biomarkers , such as neurofilaments and proteins involved in the humoral response to axonal proteins and in axonal regeneration. Natural history studies , clinical trials and a biological repository are being used as sources of tissue for biomarker identification and qualification. With regard to Parkinson’s disease , depression, loss of sense of smell and constipation are clinical features that often prelude PD symptoms . Therefore, clinical observations are being used to identify biomarkers that track these symptoms in patients for use in preventive neurology. Although a cell’s proteome contains a lot of biologically and therapeutically useful information, proteome analysis has lagged behind genome and transcriptome analysis. This is due to the complexity of the proteomes of mammalian cells, tissues and body fluids and the wide dynamic range of protein concentrations that are encountered. The emergence of newer sophisticated mass spectrometry (MS) technology in the past decade, with higher resolution and faster scan rates, has enabled smoother and quicker identification of complex proteomes with shorter analysis periods. As a result, Ian Pike ( Proteome Sciences Plc ) explained, mass spectrometry-based proteomic platforms are being increasingly used for: therapeutic protein analysis; target identification and deconvolution; biomarker ID; analysis of target engagement; systems biology and; clinical studies. Ian presented a couple of case studies where MS had been applied to the study of pancreatic cancer and for plasma biomarker discovery in IPF . Finishing the Biomarker session, Chantal Bazzenet ( Evotec ) talked about the portfolio of assays that Evotec have developed to aid the development of therapies for Huntington’s disease . Patients suffer uncontrolled movements, emotional problems, and loss of cognition. This progressive brain disorder is caused by aggregation of Huntingtin (HTT) protein . The wild-type protein is monomeric, but the mutated protein is aggregated and accumulates in neurons, affecting normal neuronal functioning. Evotec have developed assays to measure total and mutated Huntingtin (HTT) protein in mouse and human tissues. Comment Discovering new drugs is challenging and that will continue to be the case for the foreseeable future. Central to the whole drug discovery process is establishing the biological and disease relevance of a particular drug target. However, it is sobering to consider that it took over two decades after the defective genes causing cystic fibrosis (CF) and Duchenne’s muscular dystrophy (DMD) were identified, before the first FDA approved drugs ( Ivacaftor for CF and Eteplirsen for DMD ) were available to treat subsets of patients carrying specific mutations. My personal view is that target validation should called target qualification, as the drug target is not truly validated until it is shown that therapies based on the drug target hypothesis actually work in clinical trials. As I mentioned in the introduction to this post, this is not the case for 60% of pre-clinically “validated” targets... In concert with the efforts to produce better drug targets and therapeutic hypotheses, it is clear that biomarkers for disease characterisation, early detection of disease, determining the trajectory of disease progression, patient selection for drug testing and, patient response to therapy, will be just as important for future clinical success as validated qualified drug targets. Interventions at earlier stages of the disease process are also required so that new drug therapies for common complex diseases are disease-modifying, or even curative, rather than just being symptomatic. What is clear, is that modern drug discovery requires a multi-disciplinary approach employing a number of different technologies, from omics, to CRISPR gene editing, plus everything in between. In turn, this means that ever more complex data sets are being generated that present challenges, not just in analysis, but in interpretation and knowledge extraction. AI will certainly have a key role to play in the data science arena, as well as making the DMTA cycle more efficient and effective. However, the hypothesis-free approach that typifies the omics era of drug discovery can mean that the wrong datasets are generated and analysed, so no matter how “smart” the algorithm used for data analysis, the outputs will not be therapeutically relevant. Therefore, the focus on rigour and quality being pursued by pharma companies such as AZ in everything, from understanding the disease biology, to better target validation qualification, can only be a good thing. What the impact on clinical success rates will be is uncertain at this stage, so it really is a case of watch this space…
Highlights of the inaugural CRISPR in Drug Discovery conference organised by ELRIG and held at the Kings Centre, Oxford, February 27-28 2019
