Impact case study database

After the success of Neurosolutions, the Warwick spin-out founded in 2001, the research group expanded operations to North America (Cerebrasol; 2010), to meet increasing demand for services from US-based pharmaceutical/biotechnology companies, and Australia (PacificDiscoveryServices; PDS) in 2013, after Spanswick’s joint appointment at Monash. Over the REF assessment period, the group of companies has employed 21 full-time staff based on three sites globally, and 5 PhD students wholly or partly funded by Neurosolutions.

Revenue from contracts in the period 2014 to 2020 exceeded £7M (GBP7,000,000) with a global clientele spanning small academic groups and start-ups through to small-medium enterprise biotechs and major pharmaceutical companies. The group has engaged over 65 companies globally between 2014 to present [5.1]. The research has delivered economic impact through the development of intellectual property and creation of new companies, benefited existing companies by driving or supporting their drug and technology development programmes and enabling the development of new therapeutics. Some indicative examples include:

Development of Eslicarbazepine as a treatment for epilepsy

In 2007 to 2008, Neurosolutions and Cerebrasol conducted preclinical studies of Eslicarbazepine (BIA-2-093) with Portuguese pharmaceutical company Bial, identifying its mechanism of action, utility as an anticonvulsant and its suitability for the treatment of neuropathic pain when compared to the established therapeutics carbamazepine, and oxcarbazepine [5.2]. Multiple phase I, II and III clinical trials were subsequently undertaken with Eslicarbazepine, with the drug completing trials successfully. In early 2009, Bial sold the rights in Europe to the Japanese company Eisai, marketed under the tradename Zebinix. In the US, it is marketed by Sunovion under the tradename Aptiom, receiving approval from the FDA in November 2013 for adults and in 2017 for children. [5.3] In the US, the total revenue generated by sales of Aptiom across the period April 30 2014 to June 30 2020 was 81.3 billion yen equivalent to approximately GBP600,000,000. [5.4] Revenue figures for sales of Zebinix in Europe are not publicly available but are generally estimated to be a multi-million pound sum.

Epilepsy is the fourth most common neurological condition and manifests as unprovoked seizures, which are caused by abnormal firing of impulses from nerve cells in the brain.

Partial-onset seizures, one type of seizure and the most common, are characterized by bursts of electrical activity that are initially focused in specific areas of the brain and may become more widespread, with symptoms varying according to the affected areas. The unpredictable nature of seizures can have a significant impact on those with epilepsy. Reducing the frequency of seizures can greatly lessen the burden of the condition. A recent clinical trial - an open-label extension study conducted in adults completing a phase 3, randomized, double-blind, non-inferiority trial - found that more than 80% of patients using Eslicarbazepine as a monotherapy remained seizure‐free throughout the 2-year study period. [5.5]. The consultancy work conducted by Cerebrasol with BIAL – Portela & Ca S. A. at Warwick Medical School during the period 2007-2008, played a critical role in the clinical development of Eslicarbazepine Acetate, its subsequent approval by regulatory authorities from 2011 onwards (EMA, FDA, SwissMedic) and the availability for adult and pediatric patients afflicted with epilepsy under the trade names of Zebinix and Aptiom. See statement by Bial board member. [5.6].

Novel targets, therapeutics, strategies and technologies for chronic pain.

Extensive research undertaken by Neurosolutions and Cerebrasol in collaboration with Wex Pharmaceuticals has focussed on the use of Halneuron® (TTX) for chemotherapy-induced neuropathic pain. Collaborating together since 2011, Neurosolutions/Cerebrasol were involved in the design and delivery of proof-of-concept studies for a chronic dosing regimen to treat persistent pain and inform phase II and III clinical trials – and Phase II trials for chemotherapy induced neuropathic pain (TTX-CINP-201) have been undertaken in the assessment period. This was a randomized, double-blind, placebo controlled, Phase II multicenter study of Tetrodotoxin in the treatment of chemotherapy induced neuropathic pain. The study determined that TTX is well tolerated, with promising efficacy. An unforeseen benefit for patients was prolonged pain relief and alleviation of spasticity associated with chemotherapy-induced neuropathy. Neurosolutions/Cerebrasol are currently engaged in identifying the mechanism of action underlying clinical benefits of this treatment, and Phase III trials have commenced. Wex Chief Operating Officer writes: “Cerebrasol has played an important role in helping Wex Pharmaceuticals advance the underlying science with Halneuron® and the support necessary to help advance our clinical programs.’’ [5.7]

Chemogenetic approaches for trigeminal neuralgia has been a focus of research and development undertaken since 2018 with Redpin Therapeutics, a venture capital-backed , preclinical-stage gene therapy company. Chemogenetics is a ground-breaking approach to selectively control cell function, including abnormal electrical activity in nerves, by using viruses to install engineered receptors sensitive to a chemical designed to target the receptor. By combining Neurosolutions technologies with Redpin’s ion channel based chemogenetic platform of designer targeted cell therapies, extensive pre-clinical proof-of-concept data for an FDA pre-submission supporting utility of this new technology for trigeminal neuralgia has been submitted. Initial studies are focused on trigeminal neuralgia but feasibility studies on epilepsy and Parkinson's are advancing. Redpin Chief Scientific Officer writes: “As a result of our collaboration we have been able to attract additional Series A investments and our positive interactions with regulatory bodies have been greatly facilitated by the contributions of NeuroSolutions to our research and development programs.’’ [5.8]

New therapeutics and novel molecular targets for neuropathic pain. Neurosolutions with PacificDiscoveryServices re-profiled a compound, originally indicated for obesity. Using the platform technologies, researchers identified a novel mechanism of action and proof-of-concept for a potential treatment specifically for neuropathic pain, currently in Phase II clinical trials. This work underpinned the development of a new privately-owned Australian biotech, Lateral Pharma, in 2015. In collaboration with Evotec, a global drug discovery and development company, the researchers identified a novel molecular target of this compound, lacking the side-effects seen with other pain killers and opioids. Based on the signal transduction pathway identified, the compound is now being assessed for anti-viral properties and a potential treatment for COVID 19 [5.9]

New treatments for schizophrenia

The researchers have been engaged in identifying the mechanism of action of SEP363856 with Sunovion pharmaceuticals. SEP363856 has a unique mechanism of action compared to current antipsychotic medications and was successful in Phase II. The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) for SEP-363856 in May 2019 and the DIAMOND (Developing Innovative Approaches for Mental Disorders) Phase 3 trials for SEP-363856, a novel agent for the treatment of adults and adolescents with schizophrenia in September 2019. Executive Director of Translational Medicine at

Sunovion writes: “This important collaboration enabled us to further delineate the mechanism of action that may underlie the pharmacological activities of novel compounds within Sunovion's drug discovery portfolio. The studies performed by Neurosolutions were instrumental in demonstrating that SEP-363856 inhibits dorsal raphe nucleus and ventral tegmental area neuronal firing via 5-HTlA and TAARl receptors. This was an extremely valuable contribution considering that SEP-363856 may represent a new class of psychotropic agent with a non-D2-receptor-binding mechanism of action for the treatment of psychosis in schizophrenia.’’ [5.10]

Enteric pathogens such as Escherichia coli and Salmonella enterica are important causes of human and animal infections and are a significant public health challenge. Salmonella is a key global cause of diarrhoeal diseases, and estimated to cause 93,000,000 enteric infections annually (Majowicz et al, 2010). National Reference Laboratories are responsible for investigating food-borne bacterial disease outbreaks to inform control and prevention measures and inform national surveillance. Public health scientists typically used methods such as serotyping using pulsed-field gel electrophoresis to identify strains. The methods were often time-consuming with additional challenges in the reliability of subtyping and the use of inconsistent nomenclature between regions and countries. Outbreaks are often multi-country and therefore require high-resolution, accessible, and replicable isolate typing schemes. Adopted by National Reference Laboratories, Achtman’s Enterobase has improved and accelerated the identification and tracking of outbreaks.

EnteroBase was first made publicly accessible in 2016 as a genotyping website for selected enteric pathogens. It enables rapid analysis of bacterial genomics using a common and stable nomenclature. Microbiologists with limited bioinformatic skills can use its user-friendly software platform to upload short reads, assemble and genotype genomes, and immediately investigate their genomic relationships and population structures. It now has more than 3,500 users in public health organisations and industrial and allied research laboratories globally. On average, 400 of them visit its web pages per month. Achtman has supported the adoption of EnteroBase by the provision of training and advice in its use.

In 2017, PulseNet International, the global network for laboratory-based surveillance for food-borne disease outbreaks confirmed the adoption of whole genome multilocus sequence typing (wgMLST) to standardise subtyping thanks to its higher resolution information. The scheme of genes selected for whole genome MLST in EnteroBase was selected as the global master scheme for Escherichia coli and Salmonella enterica [5.1]. The MLST schemes maintained by EnteroBase serve as the reference schemes for the public databases for molecular typing and microbial genome diversity (PubMLST), and used within the MLST module in CLC Genomics Workbench (Qiagen, Germany) and SeqSphere (Ridom, Germany)

The European Centre for Disease Prevention and Control’s (ECDC’s) 2018 external quality assessments for Salmonella typing (2018) and Shiga toxin-producing Escherichia coli (2019) state: “ For inter-laboratory comparability and communication about cluster definitions, cgMLST using a standard scheme (e.g. Enterobase) gives a very high degree of homogeneity in the results, whereas the use of non-standardised SNP analysis may be more challenging for comparison and communication between laboratories”, with participating labs using Enterobase for allele analysis [5.2]. Enterobase has been used globally by national reference laboratories including Public Health England; the Scottish Reference Microbiology Laboratories; the Irish National Reference Laboratory Services for Salmonella, Shigella, Listeria monocytogenes and Carbapenemase Producing Enterobacteriaceae; the French National Reference Centre for Escherichia coli- Shigella- Salmonella, Institut Pasteur; Statens Serum Institut, Denmark; the National Microbiology Laboratory, Canada; the China Center for Disease Control and Prevention and the Centre for Enteric Diseases, National Institute for Communicable Diseases South Africa [5.3-5.10].

Enterobase’s hierarchical clustering of core genome MLST sequence types facilitates immediate isolate characterisation and identification of close relatives of bacteria within those genera. Consistent nomenclature saves National Reference Laboratories valuable resources and time when liaising with the Epidemic Intelligence Information System, hosted by the European Centre for Disease Prevention and Control and improves communication between public health scientists, epidemiologists, medical and food safety officers, inspectors, and healthcare and environmental health professionals. The French National Reference Centre for Escherichia coli- Shigella- Salmonella (FNRC-ESSS) at Institut Pasteur has used EnteroBase to analyse more than 20,000 Escherichia coli, Shigella and Salmonella isolates since April 2017. The Head of the French National Reference Centre confirms “ the cgMLST hierarchical clustering tool has in particular revolutionized the typing of these pathogens and has now become the key information used when dealing with the epidemiologists from Public Health France and beyond” [5.5]. The Statens Serum Institut, Denmark has used EnteroBase since 2016 for all Salmonella, E. coli (STEC), and Clostridium isolates received and shares sequence types with their local hospitals: “the hierarchical clustering within EnteroBase is important to us because it gives us a means of fast communication which is crucial in outbreak investigations and further using cluster names makes our lives easier as no further analysis is required” [5.6].

EnteroBase’s tools such as GrapeTree enable users to help identify a possible source of the outbreak and perform genomic comparisons. Genomic comparisons are particularly helpful in the investigation of multi-national outbreaks and enable rapid exchange of harmonised data and reduce the hazardous exchange of isolates for comparison. Enterobase was used to confirm the close genetic relationship in the 2014-2018 multi-country S. Agona outbreak isolates, which along with seasonal peak timings indicated an intermittent common source (European Centre for Disease Prevention and Control/European Food Safety Authority. Multi-country outbreak of Salmonella Agona possibly linked to ready-to-eat food – 26 July 2018. Stockholm and Parma: ECDC/EFSA; 2018). The Director of the Irish National Reference Laboratory Services for Salmonella, Shigella, Listeria monocytogenes and Carbapenemase Producing Enterobacteriaceae (CPE) confirmed that in “ one recent outbreak of Salmonella enterica we were able to identify 3 closely related sequences in another jurisdiction which was relevant to the outbreak investigation. In the absence of EnteroBase we would not have been able to make that connection in such a rapid and convenient manner” [5.4]. The Head of the French National Reference Centre affirms that “ During several investigations here in France, EnteroBase has allowed us to identify within minutes several outbreak-related cases in other European countries” [5.5].

Genotyping and comparisons to earlier outbreak surveillance data increases resolution for epidemiological tracking of bacterial disease outbreaks and control. The Scottish Reference Microbiology Laboratories have used EnteroBase since 2017 for Salmonella and Shigella, using its hierarchical clustering function and SNP trees. The Principal Clinical Scientist confirms in 2019 they “ sequenced more than 1,400 isolates of Salmonella and Shigella from human and veterinary cases. Almost half of these cases were linked to new or previously identified clusters on the basis of cgMLST data provided by Enterobase. This constitutes a significant step forward in our ability to detect linked cases compared with traditional methods. The resolution obtained, particularly for the more common Salmonella enteritidis infections which have until now been extremely difficult to subtype, has greatly increased the statistical power essential to effective epidemiological investigation, by being able to forensically define an isolate as being part of, or being unrelated, to an outbreak. This allows more focus on confirmed cases, maximising the efficient use of investigative resources” [5.3].

The efficiency of EnteroBase is highlighted in the 2018-2019 investigation of a Salmonella enterica serotype Poona outbreak in infants in France. All isolates from children under 3 years of age underwent serotyping and whole genome sequencing by the French National Reference Centre for Escherichia coli, Shigella and Salmonella to rapidly identify the S. Poona genome cluster affiliation and inform the epidemiological investigation interviews. Initial epidemiological investigations identified consumption of the same brand of rice-based powdered infant formula and triggered a recall of the formula manufactured at the identified facility on 24 January 2019. An urgent enquiry in the European Centre for Disease Prevention and Control Epidemic Intelligence Information System for Food and Waterborne Diseases and Zoonoses identified two further confirmed cases in Belgium and Luxemburg. The rapid response was attributed to the routine whole genome sequencing of human isolates received at the French National Reference Centre. The genomic analysis using EnteroBase provided further advantages through the linking of isolates to an outbreak in in 2010–11 also connected to the identified infant formula facility. The 2010–11 and 2019 genetical relationship (EnteroBase cgMLST profile HC20-44730) has led to further investigations to identify the persistent source of contamination. [5.6, 5.10].

Brosens and Quenby’s research on the role of early embryo-endometrial interactions and RPL has had an impact on practitioners, patients and the public, in the UK and globally. It has addressed a previously unrecognised and unmet need for clinical care for many thousands of women by (i) establishing a dedicated research clinic, (ii) developing novel tests and treatment strategies, (iii) improving clinical guidelines and CPD, and (iv) through public engagement and patient advocacy.

Impact on practitioners: improving and guiding clinical management

(i) Specialised care in a dedicated facility: Since 2012 Brosens and Quenby have led a dedicated Implantation Research Clinic, a joint initiative between Warwick Medical School and University Hospitals Coventry and Warwickshire NHS Trust that provides a unique research-led service for women with complex reproductive histories. Between August 2013 and July 2020, 3,423 patients attended the clinic from across the UK and abroad including Ireland, Belgium, Germany, Sweden, France, Spain, Malta, Switzerland and the USA. Over 2,000 babies were born following research-led treatment to couples who had previously experienced multiple physically and emotionally difficult miscarriages. The clinic addressed, often for the first time, couples’ questions and fears, formulating a treatment plan and offering individualised support before and during pregnancy.

(ii) Developing and evaluating novel treatments and strategies: Brosens and Quenby have developed three tests to support better clinical diagnosis and treatment:

In 2016, Quenby optimised an accurate, rapid method of counting uNK cells using digital image analysis [5.1] that has informed the development of personalised approaches to guide clinical management for repeated miscarriage or failure of IVF. This has resulted in “many miracle babies” [5.2], not only in the Research Implantation Clinic but also specialist clinics around the world, including China, Denmark and Australia. Gavin Sacks, clinical director of IVF Australia, developed the Bondi Protocol, an inexpensive treatment for women who may have an immune problem causing either repeated IVF failure or repeated miscarriages. A combination of prednisolone and clexane, taken from the start of an IVF cycle or as soon as a pregnancy has been diagnosed, is continued until at least 12 weeks gestation. Dr Sacks states that Brosens and Quenby’s research has been “invaluable when developing, reviewing and updating the Bondi protocol. This has been used on approximately 700 couples… between August 2013 and July 2020.” [5.3]

In 19/08/2020, Brosens patented (UKIPO patent 1911947.8) a biomarker-based test to quantify decidual cells and senescent decidual cells [3.6]. This will be used to screen women for their risk of miscarriage and to guide pre-pregnancy sitagliptin treatment to reverse excessive decidual senescence. Sitagliptin, a DPP4 inhibitor that is already licensed as an oral antidiabetic drug, was found to be effective in enhancing endometrial plasticity during the implantation window in RPL patients in Warwick’s Sitagliptin for Implantation (SIMPLANT) study (2016-2019) - the first evidence that this is possible pharmacologically [5.4]. A large-scale follow-up RCT planned for 2021 is now expected to be delayed due to COVID-19.

In 2017-2018, Quenby optimised a chronic endometritis test based on immunohistochemical analysis of CD138+ cells followed by digital image analysis. The Chronic Endometritis and Recurrent Miscarriage (CERM) trial, a GBP1,800,000 multicentre NIHR/ MRC-funded RCT aimed at evaluating the efficacy of pre-pregnancy doxycycline in RPL patients who tested positive for chronic endometritis, was launched in December 2019.

(iii-a) Addressing gaps in clinical guidelines: As Coordinator of the European Society of Human Reproduction and Embryology (ESHRE) Early Pregnancy Special Interest Group from 2014 to 2018, Quenby co-authored the 2017 evidence-based ESHRE guidelines on RPL [5.5]. These draw on Warwick’s research and advocate the need for supportive, evidenced-based clinics in the context of a dearth of evidenced-based investigations and treatments for RPL. ESHRE has a significant influence on international clinical practice through its annual conference and training across Europe for over 10,000 embryologists, doctors, nurses, and scientists.

(iii-b) Contributing to training and continued professional development: As Executive Committee Member of the Association of Early Pregnancy Units (AEPU) (2014), Quenby supported the increased awareness of RPL and training for doctors, nurses, ultrasonographers, midwives and support staff from over 200 NHS Early Pregnancy Units, and presented Warwick’s research to 300-plus professionals at AEPU annual meetings. Quenby also lectures on the Royal College of Obstetricians and Gynaecologists (RCOG) educational and professional development courses; both Quenby and Brosens are mentors for academic trainees. As part of the Fetal Medicine Foundation’s educational programme for healthcare professionals and parents, Quenby reached over 12,000 doctors from 150 countries (July 2020) improving understanding of the role of endometrial stem cells.

Impact on patients and public: improving health and well-being, advancing knowledge

(iv-a) Establishing Tommy's National Miscarriage Research Centre: Tommy’s is the UK’s leading charity focused on premature birth, stillbirth and miscarriage. In 2016, Warwick was integral in launching Tommy's National Miscarriage Research Centre, a collaborative university/NHS model with the University of Birmingham, Imperial College London and their partner hospitals. The Centre enables women to access treatment and support, and participate in research studies; it has been instrumental in breaking the silence, stigma and lack of information around miscarriage. Tommy’s CEO Jane Brewin states that without Warwick’s research, “we would not have had the knowledge and understanding of recurrent miscarriage which has enabled the Tommy’s National Centre for Miscarriage Research to provide 24,000 women access to treatment via four associated clinics” [5.6]. The research has directly informed Tommy’s information and guidance to parents who have suffered from miscarriage via its website, social media platforms and phone line support, and Brosens and Quenby’s scientific evidence is “a significant factor for the 2,000,000 people who visit the [web] site each month” [5.6].

(iv-b) Support for donor events and other campaigns: During the assessment period, Brosens and Quenby presented their research to a wide range of organisations such as GSK, Johnson & Johnson, Betty Messenger Charitable Foundation and Tumble Tots, as well as potential individual donors and social media influencers, at 11 Downing St and other London locations. Tommy’s 2015 #misCOURAGE campaign encouraged sharing of experiences of miscarriage; it reached over 16,000,000 people on social media, with 7,000 women taking part in a survey and over 1,000 sharing their personal stories: “Our long journey started in 2008…I was referred to the research team at UHCW … our beautiful healthy little boy Hughie was born in Feb 2017. We can’t thank the research team enough as we believe that their study, which we took part in, helped us to conceive.” Tommy’s 2019 Tell Me Why? campaign uses Brosens’ research on role of the endometrium and early pregnancy checkpoints to help couples understand the causes of recurrent miscarriage providing a valuable coping mechanism when embarking on a future pregnancy; the animation and the video have had over 5,000 and 10,000 views respectively, as of 2 December 2019 [5.6].

(iv-c) Patient advocacy: Brosens and Quenby maintain a local (West Midlands) working group of patients who are/have been involved in pregnancy research and miscarriage trials. Amy Jackson, a former patient of the clinic and co-founder of Lily Mae Foundation, which supports parents who have lost a baby to miscarriage or stillbirth, says that “this group has been essential for bringing the patients’ voice to the forefront of research ideas from the beginning and shaping initial thinking” [5.7].

(iv-d) Engagement with the public: Brosens and Quenby increased understanding and changed attitudes to the causes of recurrent miscarriage through such vehicles as: the Fertility Show (2016 & 2017, attended by over 1,000 members of the general public); British Festival of Science 2019; webchats on Mumsnet (January 2016, [5.9]), Tommy’s Facebook live interview (February 2017, attended by 6,500 individuals) [5.6], Channel 4 News (October 2017), the Independent (3 March 2016) and many BBC national and regional radio programmes including Radio 4, Radio 5 Live, BBC Coventry and Warwickshire and Radio Scotland).