Impact case study database

Impacts on commerce and the economy: NTU’s spin-out company Intelligent OMICS Ltd. has commercialised NTU IP and has generated significant revenue and finance investment.**

Successful business Intelligent OMICS Ltd has been built through the commercial exploitation of the ANN methods and ANNi machine learning algorithms developed at NTU for in silico biomarker and drug target discovery. The company was rebranded as Intelligent OMICS Ltd in 2019 (see Section 2) to better reflect the key technological breakthrough that its Intuitive Informed Intelligence (I3) machine learning platform, built around the NTU research, could now process 50 million models to a given dataset per hour. This innovation has shortened analysis, that would have previously taken six to seven months, down to two to three weeks. The IP assigned to Intelligent OMICS from NTU includes the patent “Data analysis method and system” (US8788444 B2, and equivalents) covering Ball’s machine learning methodologies. The company has attracted £148,000 from Innovate UK (total grant £873,000, grant reference 101555, Nov 2013 to Jan 2017). Over the current REF2021 impact period, the company “ has generated over £230,000 of revenue from third parties – pharma and biotech companies, and UK healthcare-related institutions” ( S1), created 4 jobs, and the company has “ financed and completed over £5,070,000 of research and clinical trials in China” ( S1). This latter figure, of which £2m pro-rata has been invested during the period 1 August 2013 to 31 July 2020 (latest information available within REF2021), includes investment over 5 years from Hubei provincial government, China.

Impacts on commerce and the economy: NTU and Intelligent OMICS’ research has stimulated foreign direct investment of £4.5m from United States DTRA for UK Dstl-led consortia.**

Defence Science and Technology Laboratory (Dstl, an executive agency, sponsored by the UK Ministry of Defence), its military stakeholders, and NTU/Intelligent OMICS Ltd. have received contracts from the US Defence Threat Reduction Agency (DTRA) based on the application of NTU and Intelligent OMICS Ltd. machine learning algorithms. The arising IP is being jointly exploited for a civilian context by Ploughshare Innovations, Dstl’s commercial arm, and Intelligent OMICS. The letter of corroboration from a Senior Principal Statistician in the Cyber and Information Division of Dstl states, “ The research collaboration is focussed on bringing better health care to the military and Prof Graham Ball’s research output is having impact on the defence community through rapid diagnosis of infection, particularly trauma induced sepsis” ( S2), and furthermore, “ *the civilian applications could really assist with the fight against antimicrobial resistance (AMR). The methods that have come from the collaboration have identified previously unseen patterns in gene behaviour in the presence of infection and have helped secure international contracts totalling £4.5m in US funding. Contract references DSTLX 1000896368 AM 2, HDTRA1-14-24-FRCWMD-BAA. A further project PREDICTS HDTRA118-CBA-01-1-0044 is being negotiated (Value £2.1M)*” ( S2).

Impacts on commerce and the economy: commercial adoption of NTU spin-out Intelligent OMICS’ algorithms have provided Cumulus Oncology with a significantly more cost-effective method to target drugs for development, and facilitated their successful £1.7m fund raise.**

Using public and private molecular data Ball through Intelligent OMICS has brought about change in practice and generated commercial income through a pathway-based data mining approach based on Artificial Neural Network Inference ANNi ( R4) algorithmic process that identifies disease/pathway-specific molecular drivers. This approach replaces the expensive and time-consuming drug screening process with the modelling of biological pathways in a disease. These highly influential molecules operating in a pathway make excellent biological targets for drugs. As a result, Intelligent OMICS has entered into a strategic partnership with Cumulus Oncology. Work with Cumulus has provided insights into key pathways of interest to the company around DNA repair (DDR and CHEK1) in lung cancer. This has enabled Cumulus to define further druggable targets of interest and develop biomarker hypotheses for the drug assets under development, facilitating a recent investment into Cumulus from Private Investors and Scottish Enterprise. A key requirement of this investment was the incorporation of AI methods into the drug discovery process. The CEO of Cumulus Oncology stated, “ Through our collaboration with Intelligent OMICS, the application of the AI based methods developed by the company has provided Cumulus with insights into key pathways of interest for current and future assets. In turn, this has facilitated a recent successful fund raise of £1.7m by Cumulus Oncology” ( S3).

Impacts on commerce and the economy: commercial adoption of NTU spin-out Intelligent OMICS’ algorithms within Mologic’s new low cost rapid diagnostic tests.**

The ANN algorithms developed by Ball have been offered as a service to diagnostics companies, where they are used to rapidly discover optimised panels of biomarkers, incorporate the biomarker panel into a diagnostic model and deliver that model as a piece of software for incorporation onto a diagnostic device. The Chief Scientific Officer of Mologic Ltd, which employs 70 people, stated that, “ With the help of the machine learning based techniques of Prof Graham Ball and the spin out company Intelligent OMICS Ltd, our company is now able to identify and develop optimised biomarker panels incorporated into point of care diagnostic devices” ( S4), and furthermore, that “ The methods and diagnostic interpretation principles coming from Professor Ball’s research have greatly improved the efficiency, sensitivity and specificity of the ground-breaking diagnostic tests we are developing” ( S4). In November 2019, Mologic announced it had started a clinical trial (COPE-WEL; 263 patients) to validate its patented, urine-based, multi-biomarker self-test Headstart^® for the early detection of exacerbations in patients living with moderate to severe Chronic Obstructive Pulmonary Disease (COPD) ( S4, S5). Clinical decisions are being made within the COPE-WEL trial based on the early detection of COPD exacerbation, benefiting patients by providing timely and appropriate interventions. The test can predict the early onset of a COPD exacerbation up to six days before symptom onset, or up to nine days before clinical diagnosis by a healthcare provider. It “ depends on an associated algorithm developed by Professor Ball” ( S4). Following proven success from the validation trials, this urine test will be available for launch in 2021. Another complex biomarker test “ made simple by Prof Ball’s technology” ( S4) has been developed for sepsis, and in September 2019 Mologic announced it had finished recruiting 550 people to a clinical trial being carried out at University College London Hospitals ( S6). Clinical decisions separating bacterial infections from inflammatory responses where there is no bacterial cause have help managed the way patients are treated leading to patient benefit.

Impact on human health: trial of a new clinical test for latent tuberculosis in collaboration between NTU spin-out Intelligent OMICS and Wuhan Pulmonary Hospital (China), successfully detected latent cases of the disease enabling patients to be treated, and led to phase 2A trials which have been completed.**

Ball, through Intelligent OMICS Ltd., has developed and applied algorithms to generate a panel of diagnostic biomarkers which identify the presence of Latent Tuberculosis in otherwise healthy individuals. These inventive methods were developed by Ball and patent protected (GB201211158A, priority date 22 June 2012, equivalents EP2864499 B1, US2015197806 A1, WO2013190321 A1, “Biomarkers for determining the M. tuberculosis infection status”, Inventor G.R. Ball). In 2017 Intelligent OMICS Ltd. embarked on clinical evaluation trials in collaboration with Wuhan Pulmonary Hospital (WPH) in Hubei Province, China to exploit the predictive capability of Ball’s patented technology ( S7). Initial investment to run the trial was received from the Hubei provincial government, followed within the current REF period by a further 3551 Foreign talent programme grant of £112k (¥1.0m) from Wuhan City and Wuhan Biolake development fund ( S8), plus additional match funding investment from Wuhan Pulmonary Hospital. This project received the backing of Wuhan’s Vice Mayor and the province Consul, who were present at a contract signing ceremony ( S9). The phase 1 trial revealed 6 asymptomatic cases of Latent Tuberculosis, and the phase 2A revealed 50 latent cases, via simple blood test, enabling these patients to receive early treatment. The results of the completed phase 2A Clinical trial are currently being decoded. Wuhan City £224k (¥2.0m) funding is already in place to commence a Phase 2B trial that will examine 250 patients.

NTU research has shaped the design of immunotherapy clinical trials for the treatment, and benefit, of adult patients with aggressive AML. Primary refractory AML, a subtype of the disease, is extremely challenging to treat; the current median survival rate is just four months. To date, no specific treatments have been identified for this patient subset and there is a clear, unmet medical need. Working with MacroGenics, a Nasdaq-listed biopharmaceutical company with annual revenues averaging around $100 million, NTU has carried out an international, multi-centre phase I/II clinical trial (NCT02152956) to determine the maximum tolerated dose level of an immunotherapy drug flotetuzumab in patients with AML, whose disease is not expected to benefit from cytotoxic chemotherapy. The trial has also studied how the drug acts in the body and evaluated its potential anti-tumour activity. MacroGenics’ Senior Director of Clinical and Translational Sciences ( S1) said: “ ln my capacity as clinical lead of flotetuzumab development, I can confirm that Sergio’s work has been directly applied to our clinical development pipeline. Specifically, Sergio’s research has led to modifications in patient selection in clinical trial #NCT02152956 enabling us to identify and include individuals with the ‘hot’ or inflamed AML immune subtype who are the most likely (45.5%) to benefit from immunotherapy drug flotetuzumab.” More specifically, he said: “ *These individuals, who have an immune-infiltrated tumor microenvironment, have chemotherapy-refractory AML (primary induction failure, PIF). Hence, the further benefit of identifying and including these individuals in the trial is that they will avoid overtreatment from cytotoxic chemotherapy that is debilitating and from which they are not likely to derive benefit and be shifted instead to immune based therapies with likely improved responses.*”

Reporting its 2018 end-of-year results to investors, MacroGenics highlighted the presentation of clinical trial data and Rutella’s gene signature data at the 2018 American Society of Hematology (ASH) Annual Meeting. Its news release in February 2019 ( S2) said: “ In the study, flotetuzumab demonstrated anti-leukemic activity and acceptable tolerability in patients with relapsed/refractory AML, with a higher response rate observed in primary refractory patients, an extremely challenging population to treat.” Historically, patients who do not respond to chemotherapy have remission rates to subsequent interventions in the range of only 5-12%, with a median overall survival of 3.5 months. As shown by the updated clinical data presented at the 2020 ASH Annual Meeting ( S3), “ a remission rate of 32% with good duration and a manageable safety profile observed in the ongoing registrational study of flotetuzumab is very encouraging”. MacroGenics plans to define a potential registration path for flotetuzumab in patients with primary induction failure and early relapsed AML. In August 2019 MacroGenics submitted a briefing document to the US FDA to seek approval for flotetuzumab under the Biologics Licensure Pathway and to seek guidance on other registrational components. The company’s Senior Director of Clinical and Translational Sciences confirmed the impact of Rutella’s work ( S1, S4): “ Professor Rutella’s seminal work has guided and informed o ur interactions with health regulatory agencies, the Federal Drug Agency of the United States of America. We are currently planning a single-arm, registration-enabling clinical study to evaluate flotetuzumab in up to 200 patients with primary induction failure or early relapse AML. The study will be conducted as a continuation of the ongoing phase I/II study NCT02152956. This is key as it shows a recognition by regulatory agencies of an immune-based classification of AML”.

Rutella’s group has also shown that flotetuzumab modulates the immune TME of individuals who are sensitive to its therapeutic effects by inducing the upregulation of PD-L1, a negative immune checkpoint. This observation has impacted on the development of the next generation of combination immunotherapy clinical trials sponsored by MacroGenics by providing a sound rationale for the administration of flotetuzumab in combination with PD-1-blocking antibodies ( S5). The company confirmed ( S1): “ Sergio’s research identified upregulation of checkpoint inhibitory molecules in a selection of AML patients; this finding helped inform a study of combinatorial immunotherapy in AML, i.e., a new immunotherapy clinical trial that combines flotetuzumab with MGA012, a proprietary anti-PD-1 antibody (clinical protocol #CP-MGD006-03). First patient was dosed on 28 October 2019.” This also supports MacroGenics’ collaboration with US pharmaceutical company Incyte; a licensing agreement announced in October 2017, expected to be worth up to $900 million for MacroGenics, gave Incyte exclusive rights to develop and commercialise MGA012, while allowing MacroGenics to develop its own pipeline candidates (in this case flotetuzumab) in combination with the anti-PD-1 checkpoint inhibitor ( S6).

Development expense for flotetuzumab in 2019 was $15.1 million, which was approximately 8% of total annual research and development expense for MacroGenics, and $4.4 million in the quarter ended March 31, 2020, an increase of 26% compared to the first quarter of 2019 ( S7). MacroGenics’ VP of Investor Relations & Corporate Communications says: “ Professor Rutella’s work has contributed positively to the perception of flotetuzumab by investors and biotech equity analysts who follow MacroGenics […]. Professor Rutella’s oral presentations at major scientific conferences, the recent high-impact scientific publication, and his participation in a key webcast event hosted by MacroGenics for analysts and investors during the American Society of Hematology Meeting in December 2019, have all contributed to a heightened profile for flotetuzumab, as evidenced by inclusion in a number of analysts’ proprietary financial models for the Company”.

NTU research has informed the correlative biology studies for the first in-child trial of flotetuzumab in patients with relapsed/refractory AML

The first-in-child PEPN1812 phase 1 trial studying flotetuzumab in pediatric patients with relapsed/refractory AML opened in January 2020 (NCT04158739, S8). This is sponsored by the US Children's Oncology Group under the auspices of the US Pediatric Early Phase-Clinical Trial Network. According to the clinical trial description, “ Giving flotetuzumab may stop the leukemia from growing or shrink for a period of time, as well as possibly lessening symptoms, such as pain, that are caused by the leukemia” ( S8). The vice-chair of the trial at the Centre for Childhood Cancer Research at the Children’s Hospital of Philadelphia wrote, “PEPN1812 correlative biology studies have benefitted deeply from Sergio’s expertise and demonstrated track record of success in the analogous adult patient studies, including his expertise from the adult phase 1/2 flotetuzumab trial (NCT02152956), and Sergio’s impactful discoveries of novel immune signature predictors” ( S9).

NTU’s protocols have delivered commercial benefits to NanoString Technologies through the expansion of their product portfolio for molecular profiling of haematological tumours

NanoString (Seattle, more than 500 employees), develops and commercialises tools for biological research. Its GeoMx Digital Spatial Profiler (DSP) generates whole tissue images at single cell resolution and digital profiling data for DNA, RNA and proteins, enabling researchers to rapidly assess the biological implications of the heterogeneity within tissue samples. NanoString’s Chief Scientific Officer ( S10) confirms that Rutella’s research has enabled the company to integrate bone marrow profiling into the platform. He said: “Dr. Rutella has served as an alpha tester and trusted advisor in the development of a number of our products, including our GeoMx platform, on which he was among the first users to apply the technology to characterizing bone marrow biopsies, a clinically meaningful yet notoriously difficult sample type to work with. Through the expert guidance of Dr. Rutella, NanoString was able to develop protocols that allow us to successfully profile these samples and enable fundamental research in both hematological malignancies and bone metastases of solid tumors.” He also said: “Dr. Rutella has given multiple seminars and webinars at national meetings and company-sponsored scientific events describing his work and how our technologies enabled it, and these events draw an average attendance of over 300 people. These new contacts are materially important for the company because they represent new users to the platform who will help grow and expand our customer base. […] Dr. Rutella’s impact on NanoString extends far beyond the field of AML. As a key early and enthusiastic adopter of nCounter and GeoMx, he has given investigators across a wide range of disciplines the confidence to incorporate NanoString technologies into their work”.

Rutella’s work with NanoString’s GeoMx DSP platform has benefitted NanoString’s marketing efforts for a platform that costs around £250,000. NanoString’s Chief Scientific Officer also said ( S10): “In the 5 years that we have been working together, the NanoString market capitalization has grown from $242 million to $1.14 billion. I can’t say that it’s all due to the work of Dr. Rutella, but without doubt a big element of our success is our ability to do great science with great collaborations such as him.

Impacts on commerce and the economy: spin-out company Pharm2Farm Ltd. has commercialised NTU’s patented technologies, created jobs, attracted investment, and significant growth led to the company’s £2.37 million acquisition

Pharm2Farm Ltd. was incorporated as an NTU spin-out company in August 2015. It has licenced Gareth Cave’s granted patents ( R3, R4) and is commercialising Cave’s ground-breaking research innovations in nanoparticle biofortification and virucides, including nanoparticle fabrication techniques that reduced the cost of nano particle production from over £1000 per kilogram to [text removed for publication] per kilogram, making volume production possible. Pharm2Farm Ltd. adopted, further developed, and scaled up Cave’s novel coated nanoparticle manufacture techniques ( R3, R4) and brought to market a range of commercial ‘nano plant fertiliser’ plant feed products based on this technology. These plant feed products, which have been sold and supplied globally, include own brands Seasons™ and Spectrum^TM, and nanoparticles supplied as active ingredients into third party manufacturers ( S1).

Braveheart Investment Group PLC., a fund management and strategic investment group, acquired a 33% holding in Pharm2Farm Ltd. on 8 July 2019. Braveheart invested a further £200k into Pharm2Farm Ltd. on 2 December 2019, to increase its holding from 33.33% to 51.72% ( S2). Braveheart’s Chief Executive Officer said, “ The interest shown in P2F products and technology since we acquired our original investment has significantly exceeded our expectations” ( S2).

AIM-listed Remote Monitored Systems PLC. acquired Pharm2Farm Ltd. from Braveheart Investment Group and Cave in August 2020 through the issue of 600 million new shares ( S3). The Director of Remote Monitored Systems PLC wrote, “ *Acquisition was satisfied by the issue of 600,000,000 new ordinary shares of 0.01 pence each in RMS, equating to approximately £2,370,000 based on RMS's closing share price on 20 August 2020 (0.38p; £5.4 million market capital)*” , and added, “The market valuation of P2F was based primarily on Dr Cave's knowledge and know-how and the underpinning patented process, licenced from Nottingham Trent University, for producing and functionalising nanoparticles” (S4). The Director of Remote Monitored Systems PLC added that the share price had risen from to 0.38p on 20 August 2020 to 3.00p by the date of their testimonial letter, the close of trading day 15 Jan 2021, and “ This rapid and dramatic increase in the current market valuation of RMS is widely attributed to the step changes that Dr Cave and his team have achieved in implementing their platform nano technology into real work applications” ( S4).

The Director of Innovation, Pharm2Farm Ltd. commented that, “ *the licensing of Dr Cave’s nanoparticle manufacturing scale-up technology from NTU has led to significant investment from both the Braveheart Investment Group plc and new investors, Remote Monitored Systems plc,*” ( S1). This funding facilitated Pharm2Farm’s move into a new 400 m² commercial clean room manufacturing and distribution facility that employed 10 full time staff, in addition to contracted support staff. In January 2021, the Director of Innovation at Pharm2Farm Ltd. attributes, “ Dr Cave’s research and technology breakthroughs, support, drive and commitment has been instrumental for Pharm2Farm’s rapid expiation from a company valued at £75,000 in August 2019 to a current valuation (31 December 2020) of over £40,000,000” ( S1).

Impacts on commerce and the economy: Pharm2Farm Ltd. created a new a product range, incorporating NTU’s patented technologies, which has achieved global sales, and have provided increases in turnover for suppliers and retailers and yield and income for farmers

The product range created by Pharm2Farm Ltd. includes their home and garden plant foods, Seasons™ “ that incorporates Dr Cave’s advanced nanoparticle plant feed” ( S1), and their hydroponic feeds range, Spectrum^TM, “ designed with Dr Cave and incorporate his plant feed nanotechnology” ( S1). Seasons™ is sold throughout the UK, at nurseries, national garden centre chains and at Asda supermarkets and Spectrum™ products are sold in around [text removed for publication] shops in the UK ( S1).

Pharm2Farm Ltd. also supply directly to commercial growers , including supermarket suppliers of tomato, chilli and strawberries, and supply the nanoparticles as active ingredients into third party agrochemical manufacturers with the UK and EU, including [text removed for publication]., [text removed for publication]., [text removed for publication]. and [text removed for publication]. (S1). The Director of Innovation at Parm2Farm Ltd. confirmed that, “ Dr Cave’s technology and the corresponding global license agreement has opened new markets and territories to Pham2farm, examples include South Korea, India, Canada, and USA” ( S1).

ÔpennLabs Europe Ltd., a nanotechnology firm based in the UK and France, has created a new line of plant nutrient and growth stimulant products as a direct result of adapting bespoke nanoparticles supplied by Pharm2Farm, with direct support from Cave. This has allowed the company to “ disrupt existing markets for silicon-based nutrient products and compete in sectors, including North America and Australia” ( S5). It has resulted in a “ 3,500% increase in turnover since 2018 and the creation of three new full-time employment positions” ( S5).

End retailer Liverpool-based hydroponic shop NPK Technology Ltd. took on nanoparticle Iron and Silicon products in 2015 for their business, and reported that “Since then we have sold over 12,500 units of nano particle material to our customers who have had excellent results and are now repeat customers for that product. Financially, the product has helped our business increase its nutrition turnover [text removed for publication] , which we believe having this novel product allowed us to gain more customers for other products as well” ( S6).

South Korean urban basil farmers, Griin Co Ltd., [text removed for publication] utilise nano silica and iron, supplied by Pharm2Farm Ltd. They report that the nanoparticle plant food has increased their average harvest yield [text removed for publication] ( S7).

Srirama Raithu Sangham, a co-operative agricultural organisation in India, have been using nano fertiliser formulations, supplied by Pharm2Farm Ltd. to grow their chilli crops over a land area of over 750 hectares since 2017. This has “… reduced the time for fruit ripening and harvesting time from 155 days to 118 days” with the impact that “ *on average each farmer has secured annual agricultural income of Rs.250000/Hectare (£2500 GBP)*” ( S8)