- ARTIFICIAL INTELLIGENCE
Delivering transformational data analysis for infectious disease drug discovery
Artificial intelligence and the insights it can provide offer a route for infectious diseases to stay in the spotlight and draw interest from R&D investors worldwide. Liam Tremble at Poolbeg Pharma explores how this technology can be applied to data analysisPharmaceutical R&D is becoming increasingly expensive, and returns on investment (ROIs) have been falling over the last several decades, with static levels of new drug approvals since the 1980s. It is estimated to cost over $2 billion to develop a single product and over 90% of products which have a filed investigational new drug application (IND) go on to fail. ROI from the pharma sector has fallen from 10% in 2010 to just 2% in 2018 but has recently started to recover.1-2No sector has been as severely impacted as the infectious disease market. Before COVID-19, almost two decades had passed without substantial improvement in treatment options for a range of viral illnesses, such as influenza.Part of the dilemma of diminished returns is thought to be related to the consistent improvement of each new drug. Subsequently, making incremental improvements in new drug candidates has become more difficult, especially when coupled with the probability that the majority of intuitive drugs, considered likely to succeed, have already been discovered. Now, more than ever, there is a need to look beyond conventional drug development approaches to discover the next generation of therapeutics.In recent years, researchers have been battling against reduced returns by using artificial intelligence (AI) to help guide drug discovery and development within the pharma sector. AI is designed to deal with big datasets from a variety of sources and formats, making it ideally equipped to deal with modern cutting-edge analysis techniques. These range from single-cell transcriptomic sequencing and proteomic analysis, which produce Big Data, to the diverse data types that together describe a disease phenotype.AI is a high-power computing technique, which uses iterative ‘learning’ algorithms to interpret, learn, and discover from underlying patterns in ‘Big’ Data. In addition to traditional Big Data, modern AI providers incorporate machine reading comprehension (MRC) to allow algorithms to learn from unstructured text-based publications, creating formidable ‘intelligent’ machines, which are up to date with the latest literature.The US is the undoubted leader in pharma AI, with over 184 companies and over $12 billion of capital invested in providing AI based tools to aid drug discovery, development, and medical treatment. In silico AI tools exist to identify disease specific targets, interventions against those targets, coupled with the absorption, distribution, metabolism, and excretion (ADME) and toxicology profiles of them, can determine their probability of success in the clinic. Pharma companies are using AI to expand their pipelines and to prioritise existing assets, with many major pharma companies refraining from commercial decisions on their pipelines without the input of AI-based predictive outcomes.The role of AI in infectious disease is particularly pertinent due to the diverse range of factors that can impact the trajectory of infection and immunity. Although conserved responses have been identified in infectious disease, such as the decoupled interferon responses, which distinguish severe and mild viral infections, a multitude of factors such as age, human leukocyte antigen (HLA) type, immunological history, immunological status, volume of pathogen initially experienced, and host comorbidities, can all result in varied responses to a single pathogen.‘Original antigenic sin,’ the process by which immunological history can impede antigen specific responses by ‘antigen trapping’ early in infection, has been identified by vaccine developers as a major obstacle in the design of universal vaccines. Particularly in elderly or immunocompromised individuals, it can be difficult to stimulate a durable vaccine response in a consistent manner due to the multitude of underlying factors. It is likely that elements of personalisation will be needed to drive the effector mechanisms for lasting immunity.
The non-biased ability of AI to integrate multi-omic data makes it an ideal platform to deal with these wide-ranging factors that affect and predict immunity, host response, and recovery in the face of a plethora of infectious diseases. It also makes it the ideal partner in helping to identify the next generation of pharmaceutical products to prevent and treat disease.One of the significant challenges for AIbased discovery is the quality of the data input and the presence of high-powered comprehensive datasets that can be used to validate its findings. Commercial grade platforms often overcome this issue by the integration of gargantuan datasets taken from publicly available information. However, these datasets are often incomplete due to limited publishing of original datasets and data protection legislation, which regulate clinical data.Despite the large-scale support for AIdriven improvement of healthcare delivery, progressive improvements in AI have largely outpaced the development of the regulatory framework surrounding it. Data protection legislation, designed over the past decade to counter the exploitation of personal data by corporate interests, often finds itself at odds with the principles of AI-based learning.AI is beginning to revolutionise the delivery of healthcare. Its ability to integrate and infer from diverse data types, (such as imaging data, clinical notes, demographics, and lab results in real time to produce tools for diagnoses and prognosis), can aid clinical decision-making. The ethical implications of rapidly advancing AI-based contributions to medical treatments have stirred global bodies to develop guidelines and principles for the integration of AI in medical settings.Integration of AI in the drug discovery and drug development process is impacted less by these ethical concerns. However, issues still exist, such as the propagation of ethnic bias in medical treatments due to underlying bias in datasets, which may manifest further differences in healthcare outcomes across underserved minorities and developing nations.Global initiatives, such as the Human Vaccines Project, have been engaged in sustained efforts to characterise the immune system in exquisite detail, with the underlying belief that integration of diverse high depth datasets will produce prognostic and interventional products to improve health outcomes. Single-cell next-generation sequencing, full length protein microarrays, phage display, and cell phenotyping arrays produce Big Data, which can be layered onto host biology.The power of AI will advance exponentially over the coming years. However, in order to accelerate insights, there is the opportunity to progress beyond the gradual accumulation of data snippets and to input bespoke high depth data from infectious disease. High depth analysis of clinical data is cost prohibitive, particularly when the insights of AI may be only the first step in the development of a new product.In light of the COVID-19 pandemic, it is vital that national bodies recognise the potential of AI to prepare for and respond to future challenges. There has been a unique opportunity to provide bespoke data for AIdriven infectious disease research through human challenge trials, in which volunteers are inoculated with an infectious agent in carefully controlled conditions and monitored through health, sickness, and recovery. During this time, daily biological samples can be obtained, revealing local and systemic responses to the challenge on a real-time basis, which can then be coupled to an intervention.Academic institutions such as Imperial College London and Oxford University have championed the technique in recent years, including challenge of healthy volunteers with SARS-CoV-2. A beneficial impact of the high depth data analysis of modern immunological techniques has been the reduction in the number of subjects required for powered and meaningful interpretations.Recent evidence in COVID-19 has shown that germline mutations and HLA types can profoundly influence susceptibility to severe disease. The data highlight the importance of matched genetic, transcriptome, and immunology datasets for training AI algorithms. In the absence of matched HLA data, immunological trends can be misattributed to other mechanisms or signals that may not be detectable behind the background variability that these factors create. The noise of biology will always be present, but it is the responsibility of those using AI for research to produce clean data, which minimise confounding factors and facilitate the next generation of insights.As a scientific community, we have great confidence in the ability of AI to lead the next generation of interventions in the war on infectious disease. However, while AI will not replace the requirement for basic research, our ability to integrate AI cutting-edge analyses into clinical datasets will speed up the development of novel interventions which can improve patient outcomes.The potential for using AI analysis of biological data to quickly and cost effectively identify many more interesting and efficacious drug candidates for infectious diseases with serious unmet needs, is both very real and very exciting.References
Liam Tremble PhD, Project Manager, R&D Operations at Poolbeg Pharma plc (London AIM: POLB) – a clinical stage infectious disease pharmaceutical company, which aims to develop multiple products faster and more cost effectively than the conventional biotech model. Liam, an immunologist, has worked at hVIVO, part of Open Orphan PLC, the provider of human challenge trials with a focus on strategic engagement to enhance recruitment for clinical trials. Prior to that, he was a researcher at the Cork Cancer Centre, Republic of Ireland. He completed his doctoral degree at University College Cork on the role of tumour associated macrophages in melanoma.
liam.tremble@poolbegpharma.com - EXCLUSIVE INTERVIEW
Supporting rare neurological disease patients during COVID-19
PHARMA FILES PEAKS TO The Brain CharityThe pandemic presented numerous challenges for those living with rare neurological diseases. Nanette Mellor, CEO of The Brain Charity, delves into the numerous ways in which the charity is continuing to provide assistance to patients, in areas extending from mental health to logistical support
Pharmafile: What are some of the ways in which The Brain Charity supports those with rare diseases?Nanette Mellor: If you Google your very rare neurological disease, most likely The Brain Charity will be the listing that appears first.One of the key things we do for clients is find them more information about their condition and what a diagnosis means for their life – from research papers, health documents, other charities etc. If your condition is very rare, there may not be a lot of information out there, so this might be difficult to find for yourself.We also put people with rare diseases in touch with others with the same condition through social activities and support groups. Being around others in a similar situation means clients can offer each other practical advice on how they’ve coped with different challenges.Each understand what the other is going through, and can offer a non-judgemental space for sharing.“ If their disability is invisible, they can also feel stigma attached to that in terms of how they are treated, particularly when applying for welfare benefits”What are some of the biggest challenges faced by patients with rare neurological diseases?While the diseases themselves are very different, we find there are several overarching themes in terms of the challenges people tend to face.The first problem is that it’s very difficult for people to get a diagnosis, in some cases it takes years, and in that time frame, they may be given various misdiagnoses or even mistreatments. For this reason, The Brain Charity does offer expert legal advice for any clients who have struggled with misdiagnosis or medical negligence.A lot of people struggle to get a diagnosis if their GP hasn’t come across someone with that very rare condition before. This can be very difficult for them to join the dots. If their symptoms seem confusing, they can be mistaken for being psychosomatic.Another challenge is actually getting information. If they have a rare condition, the likelihood is less research happening into the treatment of their condition as less people are affected. There can also be very little available factual information about causes, symptoms, how it will affect them, which leads to feelings of bewilderment. If their disability is invisible, they can also feel stigma attached to that in terms of how they are treated, particularly when applying for welfare benefits.It can also be difficult for people with rare neurological diseases to find someone to talk to, who understands completely what they are going through. They may never meet someone with the same condition as them, face to face.How was The Brain Charity impacted by the pandemic? What changes did this period bring about?2020 was the most challenging year in The Brain Charity’s history for our clients. Throughout the pandemic, people with neurological conditions have remained some of the most vulnerable in our society, and in desperate need of support.The Brain Charity finished 2020 having seen a rise of more than 50% in demand for our services compared to 2019. Long COVID-19, the rise in mental health problems due to the social isolation caused by the pandemic, and mass unemployment, means this is likely to increase further.At the beginning of lockdown, the charity reached out to its most vulnerable service users to ask how they felt, how they were coping, and if they needed any extra assistance. Many people were shielding and unable to leave the house, and were struggling to access online food deliveries, which led to further anxiety. Others were worried about running out of money.When our centre in Liverpool closed last March, we acted quickly to divert our resources to offer a new food delivery service. We then introduced a broader community service to help people shielding at home. This involved making trips to the shops, picking up prescriptions, keeping gas meters topped up, and even helping with vet visits for pets. Between March and August 2020, a team of 21 staff and volunteers delivered 1,104 food packs across Merseyside, helping an average of 58 people per week.The Brain Charity also launched a telephone befriending service to combat loneliness, to ensure anyone left socially isolated by coronavirus could hear a friendly voice at the end of the phone, or via video call, each week. This is still running, and currently makes more than 50 hour-long calls per week.The number of people coming to our counselling service at the point of suicidal thoughts has also risen by more than half over the last 12 months. We extended provision for our free counselling appointments so more people could be seen, giving clients the option to have a video or telephone appointment if they would prefer, and ensuring our building was COVID-19 safe for face-to-face appointments, too.For many of our service users, The Brain Charity’s regular social events and activities were the highlight of their week, the chance to meet in a safe, welcoming space, free from judgement and discrimination. Moving these online allowed us to open classes and workshops which may previously have only happened in our centre to people as far afield as Newcastle, Scotland, and Cornwall.Our two innovative community-based projects also pivoted to online video-based alternatives: ‘Music Makes Us!’ provides speech and language therapy via song, and physiotherapy via dance to people living with dementia, and The Brain Changer Arts Project provides physiotherapy via dance, and occupational therapy via arts and crafts to children with neurological conditions. This meant more people from across the UK were able to participate. Throughout the pandemic, all our practical help services offering advocacy, info, advice, and welfare benefits support, continued running remotely.
Nanette Mellor, CEO of The Brain Charity has dedicated her career to working for disabled people for over twenty years, and has experience in the field spanning the public, private, and third sector. Her previous role included national responsibility for the design and implementation of Mencap’s grassroots campaigning activity. In 2014, Nanette took up her first CEO role with The Brain Charity. She has recently been voted Social Leader of the Year at the English Woman of the Year Awards (North) 2018.
