Impact case study database

The discovery and development of S-MGB anti-infective compounds by the Strathclyde researchers has led to:

• An effective new drug with novel mode of action for the treatment of serious C. difficile infections, to combat hospitalisations and mortality;

• Formation of a new biotechnology company ;

• Progress to successful international clinical trial programmes ;

• A new class of antibiotic .

Economic Impact

Following the discovery of several highly active anti-bacterial compounds [ R1] and the submission of patent applications with broad coverage of active compounds (US 8,012,967 [ R2] and cognate patents), the University of Strathclyde sought a commercial partner to discover and develop new anti-infective drugs, particularly antibacterial drugs, based on Strathclyde’s intellectual property of S-MGBs. A license was granted to Pharma Integra, a privately-owned drug development company, which was able to raise funds to establish a new, Scottish-based company, MGB Biopharma, for this purpose. MGB Biopharma began operations in 2009.

MGB Biopharma has established itself as a commercially successful company. Since its formation, the company’s researchers have worked closely with Strathclyde, undertaking the development of clinical candidate molecules selected from the range of compounds created at the University [ S1]. MGB Biopharma is the sole licensee of the patented S-MGBs for anti-infective applications world-wide.

Since August 2013 the company has raised GBP5,980,000 in equity funding from investment syndicates and over GBP4,100,000 from public funds [ S1], including a highly competitive GBP2,780,000 grant from Innovate UK in 2018 [ S2]. In 2019, funding to complete MGB-BP-3’s Phase-II trials was oversubscribed [ S1]. Companies House lists 110 shareholders, the majority having taken equity as a result of this crowdfunding initiative [ S3]. This demonstrates how MGB-BP-3, as a pre-clinical drug candidate, has caught the imagination of a broad range of investors – in a business area (often called the ‘Valley of Death’ for projects) that has been historically difficult to fund at this stage of development.

MGB Biopharma has also benefited from the Generating Ant ibiotics Incentives Now (GAIN) initiative in the USA [ S4], which extends commercial exclusivity of MGB-BP-3 by five years (to 2032), making it a much more attractive commercial investment. GAIN is applicable to a limited number of target pathogens including C. difficile, so treatment with MGB-BP-3 falls directly within the programme. As part of the GAIN initiative, MGB-BP-3 was granted Qualified Infectious Disease Product (QIDP) status by the US Food and Drug Administration in 2019, which accelerates its progress through subsequent clinical trials and simplifies its route to market [ S1, S4].

In 2020, the US Senate approved the ‘ Pioneering Antimicrobial Subscriptions To End Up-surging Resistance’ (PASTEUR) Act, which is an innovative financial model for development of antibiotics serving critical needs. It provides between USD750,000 and USD3,000,000,000 for each drug. MGB-BP-3 is eligible for development via PASTEUR [ S1] on commencement of a Phase-III trial. In the pipeline of US legislature, the ‘ Developing an Innovative Strategy for Antimicrobial Resistant Micro-organisms’ (DISARM) Act will improve critical Medicare reimbursement of new infection-fighting drugs. The CEO of MGB Biopharma has indicated the applicability of MGB-BP-3 to this initiative [ S1]. Taken together, it is clear that MGB-BP-3 addresses a critical market need for rapid development of a novel antibiotic that addresses antimicrobial resistance.

Health-care Impact

In 2019, the US Centre for Disease Control (CDC) cited Clostridioides (Clostridium) difficile (C.Diff) as the second biggest issue in antimicrobial resistance in the USA, with 223,900 people requiring hospital care and linked mortality of 12,800 per annum [ S5].

In clinical trial, MGB-BP-3 has shown outstanding activity against infections caused by C.Diff, which is the most prevalent causative pathogen of healthcare-associated diarrhoea worldwide. To date, an oral formulation of MGB-BP-3 has successfully completed an integrated Single Ascending Dose and Multiple Ascending Dose phase-I clinical trial [ S6] and Phase-II clinical trials [ S7]. In the Phase-I trial (2015 – 2016) carried out at Hammersmith Hospital, London, MGB-BP-3 caused no serious adverse effects and decreased/limited the proportion of Firmicutes (of which C. difficile is a member) in the gut microbiota, completely consistent with expectations from Strathclyde’s laboratory research. In the Phase-IIa trial (2019/2020), carried out at several locations in the USA and Canada where there are stable populations of C. difficile patients, MGB-BP-3 fully met the requirements for safety, efficacy, and dose selection, demonstrating better-than-expected efficacy at its lowest dosage level, with no serious adverse effects [ S7a].

The most significant benefit shown by MGB-BP-3 in the Phase-IIa trial was a complete absence of disease recurrence at the optimum dose, a unique advantage. In terms of its rapid and sustained action against C.Diff and its resilience to the generation of resistance, these trials have shown MGB-BP-3 to be superior to the current principal treatment for C. difficile, vancomycin. As reported by the CEO of MGB Biopharma:

‘In 2020 MGB-BP-3 completed its Phase IIa clinical study in which it showed efficacy of 91% - 100% in both initial and sustained cure. These results compare favourably with vancomycin, the current standard of care, which has published data showing sustained cure of between 42% - 75% across several studies. This efficacy, together with its novel mechanism of action, excellent safety profile and lack of observed resistance make MGB-BP-3 a distinctive and commercially attractive drug.’ [ S1]

The Clinical Lead and Principal Investigator of the Phase-II trial commented, ‘I am most pleased to have contributed to the success of the Phase 2 clinical study of MGB-BP-3. There is a real need for new agents to address CDI and it is gratifying to see this agent progressing onto its next phase of study’. [ S7b] With a plan for a Phase-III clinical trial approved by the United States FDA (January 2021) [ S7b], MGB Biopharma expects the drug to be fully licensed and commercialised in 2024/5 [ S1].

MGB Biopharma also reports that it is developing an intravenous formulation of MGB-BP-3 for the treatment of systemic Gram-positive infections such as MRSA, which is currently at the late pre-clinical stage. The Company is also conducting feasibility studies of topical applications of MGB-BP-3 for the treatment of serious Gram-positive skin infections [ S8a, b].

A new class of antibiotic

The combined work of the University of Strathclyde and MGB Biopharma has been acknowledged in the TV (2015) and print (2018) media as a significant step in the global fight against anti-microbial resistance [ S9a, b]. The ongoing success and importance of the MGB-BP-3 clinical trials have been stressed by the Clinical Lead and Principal Investigator of the Phase-II trial: ‘C. difficile infection represents a major burden to the Canadian and US healthcare systems. A novel antibiotic that is able to kill this deadly pathogen before it is able to sporulate offers hope to patients and their families who suffer the pain and misery caused by this disease’ [ S7a].

The World Health Organization (WHO) has defined criteria [ S10] to classify a novel antibiotic:

1. represents a new chemical class;

2. aims at a new target;

3. has a new mode of action; and

4. has an absence of cross-resistance to existing anti-microbials.

WHO cites only four compounds that satisfy their criteria; MGB-BP-3, delivered through the S-MGB project, is the fifth compound publicly recognised as entirely novel [ S10, p.47-48].

Antibiotic discovery and translation to the clinic has been the realm of ‘big pharma’. It is remarkable that this multi-disciplinary Strathclyde team has, in partnership with SME MGB Biopharma, taken its lead compound to the final phase of clinical trials during the assessment period.

The novel iridium catalysts emerging from the underpinning research (as detailed in Section 2) demonstrated a clear superiority over the industry-standard species. Further testing and refinement of the methodology at Strathclyde was followed by ready transfer of the technology into AstraZeneca, in the first instance, where the new catalysts were applied to a range of current drug candidates. As the research programme expanded, the links with AstraZeneca grew, and between 2012 and 2016 collaborations also developed with other pharmaceutical companies. Accordingly, the impacts achieved from the research during the current period have been:

• Appreciable uptake by global pharmaceutical companies, owing to the improved performance of the catalysts.

• More effective pharmacological assessment of a broader range of drug candidates, rapidly and directly labelled using the developed Kerr catalysts.

• Significant environmental, time and cost benefits to pharma companies.

• Enhanced availability of the catalysts, including new product ranges for Strem.

Process improvements, escalated pharmaceutical applications, and global uptake

In the period following their discovery, the new catalyst technology has significantly impacted the way pharmaceutical companies prosecute ADME studies on their pipeline of candidates. As described by the Head of Isotope Chemistry at Sanofi, ‘The catalysts developed by the Kerr group in Strathclyde are the gold standard in iridium-catalysed HIE reactions used in the pharma industry ’ [ S3].

The Global Head of Isotope Chemistry at AstraZeneca explicitly indicates [ S4] the quantitative difference that these catalysts have made and continue to make within their drug discovery and development programmes. For example, in the period since 2014 of all the drug candidates that were subjected to HIE within AstraZeneca laboratories globally, 72% were labelled using Kerr catalysts [ S4]. Since these labelling studies underpin the development and delivery of all AstraZeneca drug candidates, the new catalysts have a clear, pervasive and significant positive impact on the development of new medicines within this multinational company. The benefits of the Kerr catalysts for tritium labelling were also made clear by AstraZeneca’s Global Head of Isotope Chemistry: ‘[Alternative] routes would have been longer and/or would have generated more waste, with a negative impact on time, cost, and efficiency as a result’ [ S4]. The reduced environmental impact of the catalysts has also been demonstrated within AstraZeneca, who have made a commitment to the Swedish Nuclear Regulatory Agency to reduce gaseous emissions of tritium-labelled compounds. Including use of the Kerr catalysts, efforts to date towards this goal within AstraZeneca have resulted in a ~40% reduction in gaseous tritiated waste [ S4].

Global uptake of the Kerr catalysts has expanded significantly, with many of the world’s top pharmaceutical companies, including Merck, Sanofi, Research Triangle Institute (RTI), Roche, Janssen, and Bayer, now using the catalysts for more effective drug labelling. The broad applicability and impact of Kerr catalysts has been widely communicated by a number of these pharmaceutical companies, including within journal publications (e.g . Å. Lindelöf, et al., J. Label. Compd. Radiopharm., 2016, 59: 340-345; K. T. Neumann, et al., J. Label. Compd. Radiopharm., 2017, 60: 30–35; P. Allen, et al., J. Label. Compd. Radiopharm., 2017, 60: 124-129). At Roche, where around 50% of HIE-dependent tritium labelling now relies on Kerr catalysts, the Heads of Isotope Synthesis describe Kerr catalysts as ‘internationally leading in the way that they appreciably extend the toolbox for HIE’, and added that ‘Kerr catalysts are also notably employed in key screening campaigns with new substrates’ [ S5]. The improved solubility of the second-generation Kerr catalysts allows them to be used for a significantly greater number of ADME applications than previously, and Sanofi’s Head of Isotope Chemistry credits the catalysts with reducing the time needed to tritiate compounds from four weeks to just one [ S3]. This reduction in time for labelling studies also translates into significant financial savings. For example, the Director of Radiochemistry at RTI, and formerly of Merck and Schering-Plough, estimates that use of the Kerr catalysts ‘saved 3-8 weeks synthesis time for each compound accessed with the Kerr catalysts, alongside the removal of concomitant safety concerns with more lengthy routes involving radiolabelled materials. Such time savings equate to approximate average cost savings of around USD36,000 (07-2020) per compound, a figure which includes the labour hours, materials, instrumentation and projected waste costs ’ [ S6].

In addition to that detailed above, the catalysts have also been used specifically to label marketed pharmaceuticals. For example, at RTI a Kerr catalyst provided direct access to labelled drug molecules required as part of the National Institute on Drug Abuse (NIDA) programme [ S6]. Additionally, the catalysts were employed by Sanofi in the labelling of marketed Sanofi drug compounds, such as Zolpidem and Glibenclamide, in order to allow key pharmaceutical studies not previously performed on these products [ S3].

New catalyst product ranges via Strem Chemicals, Inc.

Commercial impact and significant worldwide uptake of the iridium catalysts have been driven through the adoption of the recently developed Kerr catalysts as commercial products by Strem Chemicals, Inc. Between October 2012 and October 2017, 3 NHC/phosphine iridium catalysts were commercialised by Strem Chemicals, Inc. As a result of Kerr’s further research, 2 of the new counter-ion complexes and 1 NHC/Cl catalyst were also commercialised by Strem Chemicals, Inc. in November 2017. Sales of the compounds have provided an economic benefit to this SME company [ S7], and the ready commercial availability of the catalysts has significantly lowered the barrier to adoption and widespread use of this new technology by international pharmaceutical companies, as described above.

Between August 2013 and July 2020, Strem made sales to more than 50 different customers in more than 10 countries. The purchasers of the Kerr catalysts include pharmaceutical companies, fine chemical companies, other industrial organisations and academic labs [ S7].

The Chief Executive Officer of Strem Chemicals, Inc. states that:

‘sales to pharmaceutical companies of the 3 catalysts first commercialised in 2012 have continued to grow and now represent a highly popular line of products within our portfolio. The addition of 3 of Kerr’s new complexes continues to expand this product line and have a positive impact on the pharmaceutical industry. These 3 new catalysts, added to our catalogue in 2017, have appreciably broadened the scope of the iridium(I)-catalysed hydrogen isotope exchange process, resulting in new users employing these catalysts, as well as existing users broadening the palette of catalysts they routinely employ.’ [ S7]

The impact of the suite of novel iridium catalysts developed by Kerr continues to expand. By shortening the time for pharmacological evaluation of a wider range of drug candidate molecules, those with a poor pharmacological profile are eliminated earlier, while more promising candidates can be accelerated through the drug discovery process. The increased efficiency and effectiveness of hydrogen isotope exchange afforded by the Kerr catalysts is making an important contribution to faster development of new drug products in the pharmaceutical industry.

Establishment of a Partnership between Strathclyde and GSK

The partnership with GSK was initiated in 2009 due to a distinct desire by the company to enhance the professional development and research-aligned capabilities of its drug discovery scientists as part of a sustained mission of continuous improvement. It was GSK’s intention to establish a unique research and training platform which ‘… would (i) provide GSK Chemists with an environment of continuous professional development that would equip them to achieve greater levels of scientific excellence, and (ii) enhance our scientific execution through direct collaboration’ [ S1]. The influence of the Strathclyde chemists in achieving GSK’s objectives was realised initially through GSK employees registering as Strathclyde MPhil/PhD students, and undertaking work-based research projects, with both GSK Industry and Strathclyde Academic supervision.

As the programme became established, senior GSK personnel commended the initiative for opening new pathways to research escalation, knowledge exchange, and staff advancement, noting that it was delivering business benefits well beyond the original aims [ S2, page 1]. As the Senior Vice-President and Chief Chemist, GSK, commented [ S3]: ‘This programme has led to enhanced levels of project-relevant scientific knowledge, advanced thinking, and overall scientific rigour … The established collaborative framework has had a positive impact on and is now contributing extensively to overall organisational learning within GSK.’

Buoyed by early successes of the scheme, GSK extended the collaborative programme with Strathclyde by additionally funding non-employee graduates to enrol as Strathclyde PhD students situated in GSK’s laboratories. Since August 2013, 115 employee and non-employee postgraduate researchers have been engaged directly in GSK-aligned discovery and development projects, with 79 students having graduated so far with higher degree awards (72 PhD and 7 MPhil) [ S1]. The collaborative programme is recognised within GSK as a landmark initiative for the development of early talent and is central to GSK’s strategy and policy. The direct funding committed to the programme by GSK, to date, has exceeded GBP7,700,000, reflecting the commitment of the approach across GSK. The success of the expanded scheme has resulted in a range of benefits to GSK and the wider UK and international healthcare sector:

• Enhanced the translation of innovative research approaches and methodologies into industry.

• Improved the performance, productivity, rigour and creativity of the researchers involved.

• Furthered GSK’s reputation, and associated GSK with distinct positive advancements in the pharmaceutical industry.

• Contributed to a highly skilled workforce in the wider healthcare sector.

Impact on GSK’s Scientific Operations and Innovation

The core impact has been on GSK’s operational practices and culture, and the influence this has had on specific projects in medicinal chemistry, chemical biology and process chemistry leading towards the discovery and development of new transformational medicines. The Strathclyde – GSK strategic relationship has enhanced the translation of new science into industry, allowing distinctive and ambitious initiatives to be more readily adopted [ S1].

In synthesis, preparative routes to previously less accessible molecular structures have been opened and new more sustainable bench and process-aligned methods established. In addition, advanced computational methods are guiding the understanding of biochemical systems within several drug discovery programmes. Projects have focussed on various diseases, including respiratory and inflammatory diseases, tuberculosis, and malaria. To date, 5 chemical entities associated with the Strathclyde partnership are progressing in GSK’s drug discovery pipeline with clinical trials targeted [ S1], 26 patents filed, and >95 GSK co-authored papers published [ S4].

Impact on GSK Staff, Standards of Training, and CPD

The scheme has led to enhanced researcher performance, productivity, rigour, and creativity from the scientists involved, as well as within the wider chemistry teams [ S2, S3]. To date, 50 GSK employees have benefitted from the continuous professional development programme and it is notable that 4 of the 5 newly appointed senior team leaders at GSK in 2015 were employee graduates of the PhD programme, with three others similarly promoted in 2016/17 [ S1]. Further to this, 11 non-employee scientists who graduated from the programme have now been appointed to leadership roles in permanent positions within GSK.

A further benefit has been a notable culture shift with regards to engagement of GSK scientists with the wider scientific community. In addition to a five-fold increase in scientific literature publications [ S1], GSK employees have contributed significantly to the over 100 national and international awards/prizes received by participants on the programme to date, which have included the 2015 Royal Society of Chemistry Young Industrialist of the Year, the 2017 Salters’ Centenary Award, the Society of Chemical Industry Young Chemist in Industry (2015, 2016, 2017, and 2020), and the Society of Chemical Industry Scholarship Award (2018, 2019, 2020). Additionally, since the start of the programme there has been a doubling of candidates receiving GSK Exceptional Science Awards further reflecting the impact of the framework’s training excellence [ S1].

Impact on GSK’s Reputation

Following significant accolades from the Scottish and UK Governments pre-2013 [ S5, S6], the programme has been highlighted as a case study of excellence in reports by Universities UK [ S7, page 39] (2014) and the Association of the British Pharmaceutical Industry [ S8, page 3] (2016). External awards received for the programme include winner of Best Business Partner category at the Prospects Postgraduate Awards (2013); the Excellence in Skills award at the Cogent Life Science Skills Awards (2014); the Best Commercial Programme at the Training Journal Awards (2014); and the Skills Award from the Chemical Industries Association (2017). One of the most significant accolades to date, has been the 2019 Princess Royal Training Award to GSK, with the Strathclyde programmes at the core of this award submission [ S1].

Furthermore, the philosophy adopted through the collaborative programmes is consistent with evolving thought-leadership within the pharma industry (e.g. Schultz and Campeau, Nature Chemistry, 2020, 12, 661-664), demonstrating that GSK is at the forefront of approaches to improve the efficiency and effectiveness of industrially based drug discovery and culture. The programmes have also had a positive and tangible impact on GSK’s reputation as an employer as evidenced by the 100% increase in applications to the company’s 2014 recruitment campaign in comparison to that held a few years earlier [ S1]. GSK’s enhanced reputation as an employer has been further exemplified by GSK Chemistry receiving the Learning and Development Award at the 2020 Personnel Today Awards.

Impact on the Wider Healthcare Sector

In addition to non-employee participants transitioning to permanent employment with GSK, several graduates from the programme have progressed to UK and international postdoctoral roles, with the remainder achieving competitively won positions within a broad array of national and international pharmaceutical organisations, such as AstraZeneca, Heptares, Charles River, Astex, Cancer Research UK, Evotec, Pharmaron, and Reckitt Benckiser. These individuals are having a significant influence on R&D programmes within these companies [ S9, S10]. The Head of Chemistry and DMPK, Charles River Laboratories reports:

‘… we are now reaping the benefits with a number of alumni now part of our company, including our Associate Director of Chemistry. … these colleagues are now delivering notably elevated levels of impact within our laboratories … [they] have, on several occasions, overcome significant synthetic chemistry challenges to deliver appreciably complex molecules for our client drug discovery programmes. Additionally, [they] have also contributed to the design of novel drug-like molecules, actively and strategically embedding their developed new skills, such as computational modelling, in order to do so. … I firmly believe that the established Strathclyde-GSK higher degree programmes … are delivering tangible impact across the sector.’ [ S9]

In summary, this initiative represents a synergistic and fresh approach that elevates the impact of academia-industry partnerships to a new level, developing and delivering a highly skilled cadre of industry-ready scientists. Complementary expertise from each partner has maximised innovation and research performance at GSK, which is catalysing the generation of new and essential healthcare products, has influenced the culture and creativity of individual scientists and collaborative teams, and extensively raised training standards, all leading to broader benefits to the wider healthcare sector with eventual downstream positive impacts on public health.