Author: Louise Stanley

Drug combination could overcome tumour resistance in paediatric cancers

Written by Louise Stanley on 21/04/2023. Posted in Cancer outcomes, Clinical trials.

Children with some solid tumours may benefit from receiving a combination of inhibitor drugs, according to interim results of research presented at the American Association of Cancer Research’s Annual Meeting 2023, held April 14-19.

The ongoing research being conducted by an international team including the University of Birmingham suggests that a combination of the PARP inhibitor olaparib (Lynparza) and the investigational ATR inhibitor ceralasertib showed clinical benefit in paediatric patients with solid tumours exhibiting DNA replication stress and/or DNA repair deficiencies.

Dr Susanne Gatz, associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham presented the study.

Dr Gatz said: “To our knowledge, the combination of PARP inhibitors and ATR inhibitors has not been widely investigated in adult tumour types. This is the first proof of principle that the combination is well tolerated and can lead to clinically relevant responses in paediatric cancers.”

AcSé-ESMART is an international European proof-of-concept platform trial intended to match paediatric, adolescent, and young adult patients with relapsed or treatment-refractory cancers with a treatment regimen targeted to their cancer’s mutational profile. Gatz and colleagues, including Birgit Geoerger, MD, PhD, head of the AcSé-ESMART trial, have so far evaluated 15 different treatments, mostly combination strategies, in more than 220 children following mandatory high-throughput genomic profiling of their tumours.

Arm N of AcSé-ESMART is tailored toward patients with malignancies that exhibit defects in DNA replication and damage repair. Impairments in homologous recombination (HR), a type of DNA repair, can sensitize cells to drugs called PARP inhibitors. PARP inhibitors have proven effective against specific adult cancers with HR deficiencies—most notably, mutations in BRCA1 or BRCA2. How to best use PARP inhibitors in paediatric patients where BRCA1/2 mutations are rarely found remains unclear.

Dr Gatz said: “Paediatric cancer cells proliferate rapidly and have some element of replication stress and a dependency on ATR. We think there might be a kind of primary resistance of paediatric cancers to PARP inhibitors and that combination with an ATR inhibitor could potentially overcome that.”

Gatz also explained that paediatric cancers are often driven by complex mechanisms, making it difficult to identify an effective treatment regimen. Single-agent therapies targeting one mutated protein are often insufficient in paediatric patients, necessitating additional research into combination therapies and mechanisms of response.

“So far, it is unclear if the molecular alterations based on which the patients were enrolled in this trial are the sole reasons for response,” Gatz said.

“Further, it may be difficult to identify patterns of response in specific tumour types due to the tumour-agnostic nature of the study. Nevertheless, this study design can give preliminary indications of signals in specific alterations and tumour types and can provide the basis for future clinical trials.”

Gatz and colleagues plan to evaluate biomarkers of response from the raw sequencing data of the enrolled patients, from the expression of key target proteins such as ATM, and from RNA sequencing data.

Gatz noted that these analyses may identify “molecular constellations” indicative of response to olaparib plus ceralasertib.

“There are enormously valuable drugs currently in development and, provided there is a good clinical or preclinical rationale, we need to apply them more creatively to diseases for which the drug is not currently indicated,” Gatz said.

Limitations of this study include a small, non-randomized sample intended primarily as a proof of concept and to determine the optimal dose for study expansion.

The study is as yet unpublished.

West Midlands Innovation Accelerator to Spark Growth and Innovation

Written by Louise Stanley on 21/03/2023. Posted in Birmingham Health Partners.

The Universities of Birmingham and Aston – both BHP members – are to participate in the West Midlands Innovation Accelerator announced this week by the West Midlands Combined Authority.

Designed to bolster the region’s innovation and R&D capability, as well as sparking commercial growth and investment, the Innovation Accelerator will receive a share of a new £100m fund from Innovate UK. This fund, first announced in the Government’s 2022 Levelling up White Paper, will be divided across three regional Innovation Accelerators over the next two years.

Aims of the Innovation Accelerator include accelerating the region’s engineering research & development, boosting inward investment, and reinforcing the West Midlands’ position at the frontier of the UK innovation revolution by enabling businesses to develop new products, processes and services.

The West Midlands Innovation Board has targeted investment on five projects enabling new solutions around Medical and Clean Technologies.

The University of Birmingham is leading the 6D Innovation Accelerator project, bringing together key stakeholders (universities, hospitals, industry and government-funded ‘Catapults’ for manufacturing innovation) to supercharge the region’s ability to accelerate new health and medical technologies. Its aim is to deliver a streamlined programme to help companies navigate “pinch-points” in the process of medical translation.

Professor Liam Grover, of the University of Birmingham’s Healthcare Technologies Institute, said: “Taking health and medical technologies into the market place can be a minefield of regulatory, funding and management issues. We aim to develop clear processes that will help companies navigate the obstacles and deliver marketable products that will enhance people’s lives.”

The 6Ds are:

- - Diagnosis of company needs
  - Definition of major NHS and industry-based challenges to target
  - Development and refinement of prototype products
  - Deployment of innovation in real-world NHS settings
  - Diversification of supply chains, skills and services
  - Demonstration of significant economic and health benefits for our region

The University is also playing a key role in a second project, Digital Innovation Transformative Change (DIATOMIC), led by Connected Places Catapult, the UK’s innovation accelerator for cities, transport and place leadership. Partners include Aston University, Birmingham City Council, Birmingham City University, Greater Birmingham Chambers of Commerce.

DIATOMIC will accelerate place-based innovation in the West Midlands. Harnessing the region’s existing international relationships and through a series of targeted initiatives, it will focus on growing the region’s clean tech, health tech and med tech markets.

Through DIATOMIC civic leaders will be able to set innovation challenges, support local SMEs to respond and benefit the community through the UK’s first inclusive innovation hub. It will also promote the use of data to enable better place-based decision making and develop an impact assessment toolkit.

Announcing the Innovation Accelerator, Andy Street, Mayor of the West Midlands, and chair of the WMCA, said: “I’m delighted to see the Innovation Accelerator fund finally land in our region which will unlock a further £150m of private sector co-investment. The funding will inject momentum into the delivery of the West Midlands Plan for Growth which sets out how we will unlock hundreds of thousands of new jobs and be home to major global companies in this decade.

“One of my key mayoral missions is to restore our status as the fastest growing region outside of London – just as we were pre-pandemic. Innovation is central to achieving that mission.

“We’re already a leading region for UK innovation when it comes to automotive and aerospace – with every £1 of Government spending for Research & Development translating in to £4 of business investment. This latest news will help us to build on our progress to date – with Government’s forthcoming Trailblazer Devolution Deal and proposed programme of Investment Zones set to usher in exciting times ahead.”

Minister of State for Science Research & Innovation at DSIT George Freeman said: “Through Record investment in our UK science, technology & innovation sectors, the Innovation Economy is creating new career opportunities in the campuses, clusters & companies of tomorrow.

“That’s why UKRI is putting clusters at the heart of its of its £25bn budget up to 2025, and why our £100m Innovation Accelerator Program provides £33m each to 3 emerging clusters to attract industrial co-investment and become major, globally competitive centres for research and innovation.

“The West Midlands Cluster is becoming a world class hub of R+D in med tech and clean tech.

“I’m delighted that local leaders have come together to use our £33m to launch such exciting programs with industry and Universities in this exciting area.”

Learning from the pandemic: Birmingham Health Partners publishes rapid evaluation study of remote outpatient appointments

Written by Louise Stanley on 16/03/2023. Posted in Birmingham Health Partners.

Birmingham Health Partners (BHP), the second city’s University-NHS partnership, has called for greater engagement with clinicians and a deeper understanding of patient experience when considering the continued use of remote outpatient appointments post-Covid.

A new report, ‘Learning from the pandemic shift of outpatient services to a remote footing: a rapid evaluation study’, has been published by researchers and clinicians from across the three founding members of BHP (University of Birmingham, Birmingham Women’s and Children’s NHS Foundation Trust and University Hospitals Birmingham NHS Foundation Trust), and offers advice about how remote outpatient consultations might best be used as we ‘return to normal’. The authors set out a suggested approach to making decisions about when a remote outpatient consultation might be appropriate or not; explore the issues facing patients, carers and health professionals; and point to the many operational issues that need to be addressed as new care pathways that embrace both remote and in-person consulting are developed.

The report was co-ordinated by Birmingham Health Partners’ new Rapid Evaluation Service and comprised interviews with a range of BHP staff involved in remote consultations as well as health data gathered on the use of these appointments across both Trusts, and a pragmatic literature review.

Lead author Dr Richard Lewis, Senior Associate at the University of Birmingham’s Health Services Management Centre commented: “While the shift from face-to-face to remote consultations occurred quickly in both Trusts – reaching around half of all consultations at its peak – the proportion of remote consultations has, to some extent, fallen back from pandemic lockdown levels. This research is intended to inform clinicians and managers as they plan how best to organise outpatient services beyond the pandemic, with a mix of in-person and remote consultation offers. There is a risk of missing a unique opportunity to draw on experience of sudden and unplanned changes in outpatient consultations to apply these lessons to more sustained reform of how at least some appointments might be delivered longer term.”

Matt Boazman, Interim Chief Executive of Birmingham Women’s and Children’s NHS Foundation Trust, added: “This study has demonstrated the significant potential for continued innovation in how we deliver care to patients, particularly across outpatients. It also serves to illustrate the importance of ensuring that we fully consider the views of patients and carers who will have different views on consultation formats depending on their personal circumstances. The authors are right to point out the need to pay careful attention to any potential unintended consequences, including the impact on patient-clinician relationships and ensuring that there are robust mechanisms in place to continue to support safeguarding.”

The report can be downloaded here:

- - Full report: Learning from the pandemic shift of outpatient services to a remote footing- a BHP rapid evaluation study
  - Executive Summary

The BHP Rapid Evaluation Service was established in 2022 to provide time-sensitive, formative evidence on innovations in healthcare and capacity building. It carries out rapid and effective service evaluations, often running in parallel with service implementation; helps spread learning to other sites; and helps build local capacity for in-house evaluations.

The Health Services Management Centre (HSMC) at the University of Birmingham is one of the UK’s foremost centres for research, evaluation, teaching and professional development for health and social care organisations. HSMC has established a unique reputation as a ‘critical friend’ of the healthcare community and strives constantly to bridge the gap between research and practice.

New drug can lower brain pressure and treat blinding IIH headaches, finds trial

Written by Louise Stanley on 13/03/2023. Posted in Clinical trials.

Patients with Idiopathic Intercranial Hypertension (IIH) – a condition which causes raised brain pressure and debilitating headaches – could be treated with an injectable peptide used for type 2 diabetes, a new trial has found.

The study, published in the journal Brain, reports on a phase two trial of a drug called exenatide, a GLP-1 receptor agonist, as a potential treatment for IIH.

The IIH Pressure Trial led by a team of neurologists from BHP founder-members the University of Birmingham and University Hospitals Birmingham found that the seven patients who received regular injections of the drug, currently approved for use in Type 2 Diabetes, experienced a drop in pressure in the brain during both short (2.5hrs and 24hrs) and long term (12 weeks) measurements.

The trial also saw significant reductions in the numbers of headaches across the 12 weeks that participants took part, with an average of 7.7 fewer days per month of headaches compared to the baseline, compared to only 1.5 fewer days in the placebo arm.

Alex Sinclair is Professor of Neurology in the Institute of Metabolism and Systems Research at the University of Birmingham, an Honorary Consultant Neurologist at University Hospitals Birmingham NHS Foundation Trust, and Principal Investigator of the study, said: “This is a major trial for the rare and debilitating condition IIH that can lead to people, usually women, going blind and suffering disabling daily headaches. There are no current licenced drugs to treat IIH and hence this result is a major step forward for IIH patients.

“We are delighted to see that the phase two trial resulted in our treatment group having lower brain pressure both immediately and after 12 weeks and nearly 8 fewer headache days across the 12-week period, and that all the women were able to continue the treatment throughout with few adverse effects. We now hope to see a much larger trial of exenatide to literally ease the pressure for the many people around the world suffering with IIH.”

Dr James Mitchell, Lecturer in Neurology at the University of Birmingham and first author of the paper said: “The results of this clinical trial are a shot in the arm for finding clinical treatments for IIH. While we need to do further trials before such a treatment could be available for patients in the future, we are encouraged by the significant results from this trial that made a real difference for those in the treatment arm and this treatment may prove relevant for other conditions resulting in raised brain pressure.”

In this study the drug was given as a twice daily injection into the subcutaneous tissue. To reduce the need for frequent injection in the future, a once-weekly subcutaneous injection called Presendin will be trialled though University of Birmingham Start-up company, Invex Therapeutics.

Shelly Williamson, the Chair of patient charity IIH UK said: “This is such exciting progress. New drug options is vitally important for IIH and this trial brings hope to the millions of patients living with the condition. We very much look forward to the next steps and seeing the drug tested in two large Phase 3 clinical trials.”

The IIH Advance is a Phase 3 clinical trial in Adolescents run in the UK, sponsored by the University of Birmingham and IIH Evolve is running in adults internationally sponsored by Invex Therapeutics. Ultimately the aim is to gain enough evidence to allow the drug to be licensed for use in IIH patients in the future.

Funding boost for Birmingham rare disease research

Written by Louise Stanley on 28/02/2023. Posted in Birmingham Health Partners, Clinical trials, Early diagnosis and detection, Experimental medicine.

BHP founder-member the University of Birmingham has been awarded a £500k Pathfinder Award from the medical research charity LifeArc which will support early-stage projects with a focus on translational development in rare diseases.

The successful projects have now been announced following an internal selection process. Research, conducted by the University of Birmingham and working across Birmingham Health Partners, will begin this spring.

Professor Timothy Barrett, Director of the Centre for Rare Disease Studies (CRDS) Birmingham, commented: “I am thrilled that our Centre for Rare Disease Studies at the University of Birmingham has been successful in securing a LifeArc Pathfinder Award. We are working closely with other organisations from Birmingham Health Partners; Birmingham Children’s and Women’s Hospital and University Hospitals Birmingham; to fund a number of impactful translational research projects through the fund. Our uniquely diverse patient population, and strength in partnership ensures that we are in the best possible position to drive forward research in rare diseases to accelerate progress and ultimately improve patients’ lives.”

Around the world, approximately 300 million people are living with a rare disease. A disease is considered rare if it affects less than 1 in 2000 people. Around 80% of rare diseases have a genetic component. They are often chronic, progressive, degenerative and frequently life-threatening with no existing cure.

Owing to the nature of rare disease, small patient populations make research challenging. Lack of scientific knowledge and quality of information on rare diseases can mean that misdiagnosis is common and treatment options may be limited.

The Centre for Rare Disease Studies supports basic and applied research, in order to build a pipeline of translational research from gene discovery to improving the diagnosis, clinical management and treatment of these disorders.

Research projects that will benefit from the Pathfinder Award include:

- - The NEEDED Study (NanoporE Enhances Diagnosis in rarE Disease), led by Dr Hannah Titheradge, which will investigate the effectiveness of a new type of genome sequencing to identify rare diseases.
  - A proof-of concept study, led by Dr Nekisa Zakeri, which aims to develop a novel ‘off-the-shelf’ T cell immunotherapy capable of providing more effective treatment for patients with a rare liver cancer.
  - The CATCH Study (CArbalivefor the Treatment of CHoleastic Disease), led by Dr Palak Trivedi, looks into whether a new medical device can absorb toxins from the gut to reduce inflammation and scarring in primary sclerosing cholangitis; a rare progressive liver disorder for which no medical treatment has been shown to slow disease progression.
  - Dr Richard Tuxworth and Professor Zubair Ahmed, whose research in DNA damage in nerve cells has already resulted in patent applications covering pathways and mechanisms that could provide new therapies for neurological conditions and spinal cord injury, will now work with Professor Andrew Beggs and Dr Chiara Bardella to investigate the potential for one of these pathways (the ATM-Chk-2 pathway) as a basis for therapies to tackle rare neurological conditions that appear early in childhood.
  - Dr Sovan Sarkar’s study aims to improve the health of patients with rare childhood-onset forms of neurodegeneration by correcting the process of autophagy that normally removes undesirable cellular materials which is detrimental to brain cells called neurons.

Dr Hannah Titheradge, a Consultant in Clinical Genetics at Birmingham Women’s and Children’s NHS Foundation Trust, will investigate the effectiveness of nanopore sequencing – a new type of real time genome sequencing – on a larger group of patients. Previously tested on a very small sample, this new technology showed promise for improving our capability to diagnose rare diseases.

Nanopore sequencing reads more letters in an individual’s genome than the standard sequencing method used to diagnose rare genetic disorders. The NEEDED Study (NanoporE Enhances Diagnosis in rarE Disease) will explore a more detailed approach that could improve the percentage of patients who receive an important genetic diagnosis, which can help those patients and their families face their challenges feeling better informed.

Dr Hannah Titheradge commented: “Receiving a diagnosis can be an uphill challenge for patients with rare diseases and their families. These individuals often wait years for a final diagnosis, having undergone multiple tests and procedures. Having a diagnosis is very important because it helps these individuals better understand their health problems and plan for the future. Some genetic conditions are treatable, and a diagnosis is the first step towards accessing these treatments. We can also understand whether any other family members’ health may be affected. For these reasons, any advance that can be made in improving rare disease diagnostics is invaluable.”

Samira Fakire, Business Manager at LifeArc, added: “We hope that the Pathfinder Award will encourage more researchers to move into the rare disease space and promote the development of a translational culture – pushing more discoveries from the lab into meaningful real-world benefits for patients.”

BHP invests £300k in innovative service improvement projects

Written by Louise Stanley on 27/02/2023. Posted in Birmingham Health Partners.

Birmingham Health Partners (BHP), the second city’s University-NHS partnership, has announced the inaugural recipients of its Seed Fund programme, awarding more than £300,000 to four projects across physiotherapy, drug delivery, perinatal care and ophthalmology.

Launched in 2022, the BHP Seed Fund is designed to support clinical academics and early-career researchers to develop, refine and implement projects which address local health burdens or system challenges. The fund enables interdisciplinary research, aiming to develop service improvements which can have rapid impact on patient experience and outcomes, and which can also be rolled out to other NHS Trusts. With funding contributed by its three founding members – the University of Birmingham, Birmingham Women’s and Children’s Hospitals, and University Hospitals Birmingham – the Seed Fund supports BHP’s culture of embedding research into everyday clinical and healthcare practice.

The successful projects are:

- - Testing a variety of interventions to reduce avoidable readmission to acute hospital care after hip fracture;
  - Developing a novel drug delivery device to reduce recurrence of sarcoma (bone and soft tissue cancer);
  - Reducing racial and ethnic inequalities and improving perinatal outcomes using health data;
  - Developing an Ocular Infection reference database to deal with common eye conditions.

The judging panel were impressed by the scope and variety of all the proposals submitted, noting the particular benefits of the successful projects in terms of patient outcome and cost-effectiveness for the NHS. The projects also demonstrated a clear link back to the five priority themes which have been identified for the West Midlands by BHP in collaboration with local NHS Trusts, namely: health data and AI; engineering into health settings; sustainability; health inequalities; and health systems and evaluation.

Dr Emma Sutton, a clinical-academic physiotherapist at BHP founder-member University Hospitals Birmingham NHS Foundation Trust is one of the awardees and commented: “I am absolutely thrilled to be conducting this important piece of work alongside a fantastic steering group which includes orthogeriatricians, geriatricians, surgeons, methodologists, nurses, physiotherapists, pharmacists, data experts, quality improvement experts and patients. We are all passionate about the care of older people, and we are driven to improve care so that when a person who experiences a hip fracture goes home, they only return to hospital within the first month if it is appropriate and necessary. Working out which re-admissions to hospital are avoidable is crucial, because when an older person is re-admitted to hospital, they are at risk of much poorer outcomes (such as being discharged to residential care instead of their own home). We hope to find a way to identify which readmissions are avoidable, and identify which systems and support could be put in place to ensure that the root causes of these avoidable re-admissions can be tackled.”

Tim Pile, Chair of BHP member the Royal Orthopaedic Hospital, led the judging panel and commented: “In its inaugural year, the BHP Seed Fund received a very high standard of applications, attracting a wide range of proposals from across the partnership. Our awardees all demonstrated tangible patient benefit and excellent potential to scale up and roll out to other Trusts. As each project now begins to move from proof-of-concept through to implementation, we’ll be on hand to provide support and mentoring throughout.”

Applications for future rounds of the Seed Fund and key dates will be posted at www.birminghamhealthpartners.co.uk/bhp-seed-fund/