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New stromal cell treatment trial for chronic inflammatory diseases

People with chronic inflammatory diseases are taking part in a new cell therapy clinical trial that one participant said made them feel “miles better”.

The POLARISE trial, being organised by BHP founder-member the University of Birmingham and funded by a grant from Innovate UK is testing a type of cell therapy – stromal cells – to see whether they can resolve symptoms and inflammation in patients with certain autoimmune diseases including rheumatoid arthritis and primary sclerosing cholangitis.

A Phase 2 trial, POLARISE will investigate the safety and activity of ORBCEL – a stromal cell therapy that has been developed by Orbsen Therapeutics Ltd. Stromal cells are rare cells found naturally in the human body where they stimulate resolution of injury and inflammation via a natural healing process called efferocytosis. Stromal cells are also allogeneic – which means they can be purified from one donor and given to multiple patients without causing allergic reactions – so there is no need for donor matching.

These rare stromal cells are ethically sourced and purified from human donor tissue and expanded to therapeutic doses at the University of Birmingham’s Medicines Manufacturing Facility (MMF).

The ORBCEL therapy is administered intravenously across two visits with subsequent hospital appointments to check on the progress of their condition during a two-year trial period.

Philip Newsome, Professor of Hepatology and Honorary Consultant Hepatologist at the University of Birmingham is leading the POLARISE trial, and explained: “Stromal cells are an exciting potential treatment for inflammatory diseases. These diseases are debilitating and very hard to treat as the body has switched a natural defence system for dealing with threats to one that starts attacking itself. It’s therefore critical to find ways to support the body to naturally deal with inflammation rather than turn off the defences which can lead to all sorts of infections. Early results from previous trials using Orbsen’s ORBCEL stromal cell therapy are encouraging and we’re hopeful that the treatment will be beneficial for some patients.”

Stromal cells such as Orbsen’s ORBCEL therapy can be purified from bone marrow or umbilical cord tissues donated by healthy individuals with donor consent under ethical approval by the Anthony Nolan Trust. While each single bone marrow or umbilical cord contains only few thousand stromal cells – these cells can be purified by Orbsen’s technology to undergo controlled expansion in cleanroom bio-reactors to produce a thousand allogenic doses of ORBCEL from each tissue.

Within the Innovate UK-funded Advanced Therapies Treatment Centre (ATTC) Consortium and POLARISE trial – these tissues are transported from the Anthony Nolan centres to the Advanced Therapies Facility (ATF) at the University of Birmingham – where Orbsen and ATF staff collaborated to purify and manufacture doses of Orbsen’s Stromal cell therapy – ORBCEL- using patented technologies and Terumo’s Quantum Cell Expansion Bioreactors.

Orbsen Therapeutics Chief Scientific Officer, Steve Elliman said: “We are delighted to continue our significant and productive clinical collaborations with Prof. Newsome, the University of Birmingham – and the Anthony Nolan Trust – to determine the safety and efficacy of our ORBCEL therapies in patients with chronic inflammatory diseases.

“These First in Human (FIH) trials are difficult to undertake and deliver – even more so during the COVID19 pandemic. These trials are not possible without brave patients – like Hannah Dines – who volunteer to participate in these rigorous safety trials. And so, we take this opportunity to thank the patients, nurses and clinical teams who work so hard to complete these invaluable studies.

“We look forward to completing these important safety trials and look forward to examine how ORBCEL can encourage resolution of symptoms in patients with chronic inflammatory disease.”

The Innovate UK-funded POLARISE trial represent the third major clinical trial collaboration between The University of Birmingham and Orbsen Therapeutics to assess the safety and efficacy of Orbsen’s ORBCEL therapy. Professor Phil Newsome is also leading the EU FP7 funded MERLIN clinical trial that is assessing ORBCEL as a therapy for patients with autoimmune liver diseases. The MERLIN trial is complete and is expected to report in the first half of 2024.

Orbsen is also collaborating with Prof Paul Cockwell at the University of Birmingham and Professor Giuseppe Remuzzi at the Mario Negri to assess the safety of ORBCEL as a therapy for Chronic Kidney Disease caused by Type 2 diabetes, in a Phase 1/2 clinical trial called NEPHSTROM. Professors Cockwell and Remuzzi recently published the first results from NEPHSTROM in the prestigious Journal of the American Society of Nephrology (JASN). In the NEPHSTROM trial publication in JASN, a low dose of ORBCEL was reported to be safe and promote stabilization of kidney function over 18 months in patients suffering with Progressive Chronic Kidney Disease and type 2 diabetes.

Patient story – Hannah Dines, Rio 2016 Paralympian

Self-confessed ‘type A person’, Hannah Dines is one for setting mad goals. Born with cerebral palsy, freelance writer and sportswoman Hannah trained and raced for Great Britain in para-cycling including racing at the Rio 2016 Paralympic games, and now represents GB in adaptive surfing.

However, in 2021 during the buildup to the delayed Tokyo games Hannah was diagnosed with a chronic inflammatory disease called Primary Sclerosing Cholangitis (PSC) in which the bile ducts in the liver get progressively narrower can lead to liver failure and impacts other organs like the spleen, intestines and bowel.

Hannah explains: “I was diagnosed with PSC after struggling with major fatigue and worsening of my spasticity from my cerebral palsy. I would train and feel very ill but do it anyway. I love moving my body and during the training I still felt that joy. Still, I began to fear the symptoms that would come after. I used to call it having an ‘exercise hangover’ though I rarely drank alcohol and was in my twenties. I would ensure I had at least four hours after training to collapse in bed, too tired to even watch TV, feeling too ill to sleep, known as malaise.”

“By the point of diagnosis though I was really ill and sleepy every day, I couldn’t focus but I kept pushing with my training, a part time job and then bed. Finally, a clinical doctor took my blood to put me on an alternative spasticity medication that required a liver function test. That’s when I was sent to a liver clinic and they took a liver biopsy right away and found out my sclerosis was pretty serious.

“It made all my symptoms make sense and because I was young and sporty no-one misdiagnosed me with fatty liver or alcoholism, which was nice, even if it didn’t really lessen the impact of having PSC.”

After receiving her diagnosis, qualified physiologist Hannah knew she wanted to try and take part in a clinical trial although received a series of rejections due to the advanced nature of her PSC.

Hannah continues: “I was recommended for POLARISE and I didn’t hesitate. The day after my first dose I felt incredible and not just because the clinicians administering the drugs were so nice. This effect lasted a couple of days and I truly felt released from PSC.”

“I was still competing at a sport: adaptive surfing and I booked all my contests because I knew I wouldn’t need to cancel. I laughed out loud on an aeroplane because I felt real energy for the first time in years. It was probably the steroids or a placebo effect but my liver function tests also got much better.

“My second dose was a little underwhelming compared to my first, but I still felt miles better. My “malaise” and feeling kind of “dead” had gone away.

“I used to obsess over my blood values and stopped checking them. I started setting goals more than two months in advance, which I had decided not to do after a year of having to cancel everything. We’re now six months and I still big hits of malaise but just to know that respite might be possible like at the start of my trial…that’s really special..

“All I can do is hope the findings are positive and this can become a regular treatment for people with PSC. No matter the result of POLARISE it has given me real hope for the future.”

Not letting PSC stop her, Hannah has taken up adaptive surfing and last year represented GB at the world championships, finishing fourth in her category and supporting Team GB to their most successful championships yet.

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Center of Excellence Award Renewal for Allergy, Asthma and Immunology Center

The Allergy, Asthma, and Clinical Immunology Center in Birmingham has been successful in renewing its Center of Excellence status for another four-year term – re-affirming the Center’s international recognition for multidisciplinary scientific and clinical innovation – following a successful bid led by Professor Mamidipudi Thirumala Krishna, representing Birmingham Health Partners.

Renowned for its innovative services to accelerate education and research, the Institute of Immunology and Immunotherapy, and the School of Pharmacy at the University of Birmingham in collaboration with the West Midlands Allergy and Immunology service at University Hospitals Birmingham (UHB) NHS Foundation Trust has once again been designated as a World Allergy Organisation (WAO) Center of Excellence.

There are currently 82 Centers worldwide, and only three other similar Centers of Excellence in the UK.

According to the World Allergy Organisation (WAO), their Centers of Excellence accelerate multidisciplinary science and clinical innovation, training, and advocacy worldwide to deliver world-class education, research, and training to stakeholders in asthma, allergy, and clinical immunology.

Professor Mamidipudi Thirumala Krishna said: “This continued recognition of our Center of Excellence signifies our commitment to delivering world-class clinical services, fostering excellence in education and research, and nurturing collaborative relationships both nationally and internationally and contributing to global health.”

Professor Ben Willcox, Director of the Institute of Immunology and Immunotherapy at the University of Birmingham, commented: “We are proud to see our Center of Excellence renewed, guided by the visionary leadership of Professor Krishna. We have over 50 years of experience in world-leading immunology research, and this Center’s status renewal is testament to that.”

Professor Anthony Cox, Head of the School of Pharmacy and Professor in Clinical Pharmacy and Drug Safety, said: “Great news that the World Allergy Organisation Center of Excellence has been extended. The School of Pharmacy is proud to be working with the center on issues related to allergy and medicines – including inappropriately identified drug allergies which have a considerable impact on patient safety and the rational use of medicines.”

Dr Richard Baretto, Clinical Service Lead for the Department of Allergy and Immunology at UHB, added: “This prestigious award from the World Allergy Organisation is testament to the efforts of all the members of the clinical teams, providing excellent care for our patients with allergic disease. It emboldens us all to strive for continued improvement in our service through regular review, research and innovation.”

Professor Adel Mansur, Lead for Birmingham Regional Severe Asthma Service, commented: “On behalf of the Birmingham Regional Severe Asthma Service I am delighted of the news of extending our status as World Allergy Organisation Center of Excellence, recognising the excellent work done in Birmingham. Over the last three years tremendous work and development have been achieved to further strengthen our Center in areas of research, education and training and to lead on clinical excellence in allergy, asthma and clinical immunology.”

“We have adopted various initiatives to improve our patients outcomes, access and equity of service delivery and provide conducive environment for our trainees to learn and develop skills and further their career.  Our national and international contribution to research and education in these fields are also important developments and targets to progress further over the next 4 years which I look forward to with excitement.”

Dr Gareth Walters, NHS consultant in occupational respiratory medicine and interstitial lung diseases in Birmingham, also added: “On behalf of the Birmingham Regional NHS Occupational Lung Disease Service , we are very pleased that our status as a World Allergy Organization Center of Excellence has been renewed for a further 4 years. This is testament to the hard work and dedication of our multi-disciplinary team, who go above and beyond to diagnose and manage a range of occupational lung diseases.”

The Allergy, Asthma and Immunology Center will continue to lead global healthcare innovation and pursue its commitment to excellence in research and education for another term commencing in 2024 to 2028. 

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Launch of new international medical code for presymptomatic type 1 diabetes

Researchers at BHP founder-member the University of Birmingham have partnered with NHS England to produce a diagnostic code tailored for individuals in the early phases of type 1 diabetes, enhancing patient prospects for timely healthcare and access to cutting-edge treatments.

Today marks the introduction for a new SNOMED CT code specifically for presymptomatic type 1 diabetes, which will be integrated into the standardised and multilingual set of clinical healthcare terminology. SNOMED codes are crucial in electronic health records, being used to identify a person’s underlying medical conditions. This system acts as the most precise and extensive list in clinical health terminology globally.

Type 1 diabetes progresses gradually through three stages, with the initial two stages termed presymptomatic type 1 diabetes. Individuals in this phase exhibit biological markers, or autoantibodies, indicating the onset of the immune attack that targets insulin-producing beta cells. Given the absence of symptoms, detection relies heavily on screening initiatives such as the ELSA study, a trial led by Professor Parth Narendran at the University of Birmingham,  screening children for type 1 diabetes. Screening initiatives such as these will allow for early identification.

Lauren Quinn, who co-leads the ELSA study and assisted in the development of the of the SNOMED code, commented: “The introduction of this SNOMED code facilitates clinical care and follow-up for individuals with presymptomatic type 1 diabetes. It also allows researchers to identify people who could benefit from novel therapies to delay the onset of type 1 diabetes and recruit them to clinical trials of immunotherapies.”

“This will transform type 1 diabetes research by fast-tracking recruitment, unravelling how the condition develops and progresses, and bringing us closer to licensed disease-modifying treatments in type 1 diabetes.”

Dr. David Shukla, a GP and Clinical Research Fellow involved in code development, highlighted its practical implications: “The inclusion of a code for the diagnosis of presymptomatic type 1 diabetes will highlight to healthcare professionals involved in their care the individuals who are at high risk of developing type 1 diabetes. This will help ensure that when these people progress and develop symptomatic type 1 diabetes, it will be picked up and treated at a much earlier stage.”

“This reduces the risk of them presenting or being diagnosed late and developing diabetic ketoacidosis, an emergency complication of type 1 diabetes that can be fatal. This timely pick up and initiation of prompt treatment will lead to substantial improvements in their diabetes and future care.”

Hilary Nathan, Director of Policy and Communications at JDRF UK, added: “This recognition of presymptomatic type 1 diabetes with a SNOMED code is a crucial step towards the implementation of population screening programmes for early detection of type 1 diabetes. Early detection leads to short and long-term health benefits, improved quality of life and cost savings for healthcare providers.”

“The new code will unlock better monitoring, follow-up and education for people in the earliest stages of type 1. It will also help facilitate recruitment into clinical trials of emerging treatments, enabling people developing type 1 diabetes to access therapies that have the potential to claw back valuable time free from the burdens of type 1 diabetes management.”

The code for type 1 diabetes in SNOMED is ‘Diabetes mellitus type 1 – 46635009’. The new code presymptomatic type 1 diabetes, known as ‘‘Presymptomatic diabetes mellitus type 1 – 1290118005′, has now been introduced for inclusion in individuals’ electronic health records. 

These codes are now part of the ‘Health conditions’ category in the NHS app, allowing individuals and their families to access them as well. 

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New Inflammatory Bowel Disease testing protocol could speed up diagnosis

Patients with suspected inflammatory bowel disease (IBD) could benefit from improved testing protocols that could reduce the need (and lengthy wait) for potentially unnecessary colonoscopies, a new study has found.

In a paper published in Frontline Gastroenterology, researchers from the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC) tested a new protocol to improve IBD diagnosis combining clinical history with multiple home stool tests.

In the two-year study involving 767 participants, patients were triaged and had repeated faecal calprotectin (FCP) tests. The research team found that the use of serial FCP tests were able to strongly predict possible IBD as well as Crohn’s Disease and Ulcerative Colitis, and observed that a second FCP test was a strong indicator of a potential need for further investigation including colonoscopy; although the researchers observed that only 20% of patients had two samples submitted prior to referral to secondary care.

Dr Peter Rimmer from the NIHR Birmingham Biomedical Research Centre and corresponding author of the study said: “Patients who experience symptoms associated with inflammatory bowel diseases often have a long wait until getting a diagnosis, and current testing is under immense strain.

“Using a comprehensive 13-point symptom checker and multiple FCP tests, we have been able to identify much more accurately patients who had IBD and other diseases. The rollout of this protocol could reduce the time taken to get a diagnosis and start treatment for IBDs as much more of the screening and testing can be done through primary care. The sensitivity of multiple FCP tests can be used to flag those patients who urgently need referral into secondary care.”

Dr Rachel Cooney, Consultant Gastroenterologist at University Hospitals Birmingham NHS Foundation Trust, researcher at the NIHR Birmingham BRC and co-author of the study, added: “In its simplest form, this study may help improve referral triage for IBD patients.

“But as we plan new care pathways, it could open up new exciting possibilities: with the growing availability of home FCP testing, these tests’ results combined with simple symptom questionnaires could feed into algorithms that allow patients to self-refer to secondary care services, reducing strain on primary care.

“This is something we’re going to explore in a large follow-up study we’re currently initiating.”

The NIHR Birmingham Biomedical Research Centre is hosted by BHP founder-member University Hospitals Birmingham NHS Foundation Trust in partnership with fellow BHP founder-member the University of Birmingham. Its roster of partner organisations also includes BHP members Birmingham Women’s and Children’s NHS Foundation Trust; Sandwell and West Birmingham NHS Trust; and Aston University. 

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Objective biomarker test could predict heart disease risk for patients with common arrhythmia

Patients with atrial fibrillation (AF) – a common heart arrhythmia – could have one blood test to assess their risk of cardiovascular events in the following five years, new research has found.

Published in Cardiovascular Research and presented at the Frontiers in CardioVascular BIology Congress 2024 conference in Amsterdam, the research suggests that a blood-based biomolecule test alone could assess the risk of having a cardiovascular event in the next five years.

The study of 1,586 AF patients found that a cluster of high-risk patients who recorded high levels of 13 biomolecules had five times more cardiovascular events than those in the low-risk cluster.

Professor Larissa Fabritz, from the Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg Eppendorf and an Honorary Professor at BHP founder-member the University of Birmingham said: “These validated findings show that one blood test could be used to help predict the risk of cardiovascular events for patients with atrial fibrillation, helping to differentiate healthcare where it’s most needed. Through a further validation study carried out in Birmingham, we are confident that the blood test can give a useful understanding of those in greatest need of interventions to avoid strokes, acute heart failure and death.”

The international team developed a profile of 13 specific biomarkers that were used to differentiate risk in atrial fibrillation. Using samples from AF patients, they analysed likely target biomarkers and through the trial and validation in the Birmingham BBC-AF registry found that a combination of elevated biomarkers corresponded with risk variation in patients.

The findings are taken from a subset of the EAST – AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) trial which demonstrated that early rhythm control – with antiarrhythmic drugs or atrial fibrillation ablation – delivered within one year after AF diagnosis improves outcomes in 2,789 patients with early AF and cardiovascular risk factors compared to usual care (UC) over a 5-year follow-up time.

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Epilepsy in pregnancy – new project to create personalised care for at-risk mums

Pregnant women with epilepsy could see a major improvement in the care they receive through a new cross-BHP project led by the University of Birmingham with Birmingham Women’s and Children’s Hospitals NHS Foundation Trust (BWC), which also aims to reduce maternal mortality risk.

The EpiSafe project, funded by the National Institute for Health and Care Research over five years, will create and trial an evidence-based, personalised care bundle specifically designed for pregnant women with epilepsy.

The team of researchers, led by Professor Shakila Thangaratinam from the University of Birmingham and BWC, will provide healthcare professionals with the tools and guidance they need to streamline the care they provide and allow for shared decision-making with women regarding their epilepsy and pregnancy.

The EpiSafe project will also study the long-term effects of newer anti-epileptic drugs (AEDs) on children’s development. Many mothers are prescribed these newer AEDs due to concerns with older medications, yet they often discontinue them out of fear of potential harm to their baby.

As part of this study, the researchers across BHP will bridge the knowledge gap by assessing the long-term neurodevelopmental outcomes of children exposed to newer AEDs during pregnancy. This research will empower pregnant women with epilepsy, enabling them to make informed decisions about the safe use of AEDs.

Professor Shakila Thangaratinam, Dame Hilda Lloyd Chair of Maternal and Perinatal Health at the University of Birmingham and Consultant Obstetrician at Birmingham Women’s and Children’s NHS Foundation Trust said:

“Epilepsy continues to be one of the main causes of mothers dying in pregnancy and postpartum period. Sadly, we are not observing a fall in maternal deaths. On the contrary, there has been a doubling of the rates of Sudden Unexpected Death in Epilepsy (SUDEP) in mothers between 2013-15 and 2019-21 in UK and Ireland.

“We know that the primary factors contributing to these poor maternal outcomes are the lack of specialist antenatal care and reduced compliance with anti-seizure medication. The EpiSafe programme of work has the potential to improve the care these women receive and save lives within this high-risk group.”

At the core of the EpiSafe programme are mothers with lived experiences of epilepsy from diverse backgrounds. They will play a pivotal role throughout the lifetime of the programme in shaping the development and roll-out of the EpiSafe bundle. Charity partners on the programme include Epilepsy Research Institute and Epilepsy Action, who will provide invaluable insight and guidance.

Dr John Allotey, Associate Professor in Epidemiology and Women’s Health at the University of Birmingham and project leader said: “By working with diverse groups of women with epilepsy and their families, professional bodies, organisations providing care for pregnant women with epilepsy, as well as dedicated epilepsy charities, we will develop an acceptable, relevant and accessible tool which identifies pregnant women with epilepsy who are at high risk and promotes safe use of AED.”

The project consists of six work packages to create the EpiSafe risk assessment and treatment pathway, that will facilitate early specialist epilepsy care for high-risk women. The team will also evaluate whether EpiSafe will help more women at high-risk access specialist epilepsy care early in pregnancy.

The Epilepsy Research Institute’s Director of Research Partnerships, Dr Caoimhe Twohig-Bennett, said: “The Institute launched last month with Reproduction & Hormones as one of our overarching strategic research theme. We are delighted to be collaborating on the EpiSafe project, to ensure safer care and reduced risks for pregnant women with epilepsy.“Central to the work of the Epilepsy Research Institute is a culture of advocating and actioning the research priorities of people affected by epilepsy through our Shape Network PPIE group. Members of the network have been pivotal in the development of this programme of research, and we look forward to their continued involvement as this important project progresses.”

Rajinder Flora, Assistant Director of NIHR’s Programme Grants for Applied Research (PGfAR), which funds the research, said: “Epilepsy causes 1 in 10 of all deaths during pregnancy in the UK, this new project aims to identify women with epilepsy who are at highest risk of seizures and create a treatment pathway for them.

“Funding research like this is vital to provide evidence-based personalised care for pregnant women with epilepsy”

The EpiSafe team also includes co-applicants from University of Liverpool, University of Manchester, Birmingham City University, University of Aberdeen and Belfast Health and Social Care trust, as well as partnerships with Kings Health Partnership and Murdoch Children’s Research initiative.

The EpiSafe work streams consist of:

  • Gathering all evidence needed to design the EpiSafe bundle,
  • Co-designing and testing the EpiSafe bundle by working with women and healthcare professionals,
  • A randomised controlled trial to see if using the EpiSafe bundle improves care, reduces seizures and complications in mother and baby,
  • Studying the longer-term development of children aged 7-11 exposed to AEDs before birth,
  • Studying the cost of using EpiSafe and its long-term impact, and
  • Planning appropriate involvement and engagement with women with epilepsy and their support networks.

Parliamentary event

At a parliamentary event to launch the project hosted by former Health Minister Baroness Cumberlege – who chaired key report on harmful side effects of some medicine – patients and researchers explained about how important this project is for ensuring that women across the UK get a say in managing epilepsy during pregnancy.

Addressing the event, Baroness Cumberlege said: “Being pregnant is a very important stage for every woman, conscious that if all goes well she is bringing new life into the world. The EpiSafe programme is crucial in creating evidenced based pathways which must ensure the voices and experience of women directly shape solutions. The success of this programme will only be realised if there is meaningful collaboration between researchers, clinicians, and women with epilepsy and their families. Cooperation is vital to spur change.

“All those involved in the care of pregnant women have a duty to safeguard the wellbeing of all mothers with chronic health needs. I will follow the progress of innovations borne from initiatives such as this closely, and with the help of others advocate tirelessly for their swift translation into enhanced standards of care.”