Impact case study database

A novel approach to tendinopathy: microRNA replacement therapy

The standard treatment for tendinopathy is physiotherapy for people and 6–9 months’ box rest for horses. Nonsteroidal anti-inflammatory drugs can be used but these agents are only palliative and do not target the underlying disease mechanism. Furthermore, the widespread uptake of biological therapies, such as platelet-rich plasma and autologous stem-cell injections, is limited by their ineffectiveness, restricted scalability and lack of understanding about their mode of action.

Replacement therapy with miRNA29a overcomes these hurdles. First, unlike other therapies, it directly targets the disease pathway and restores damaged tendon. Second, it can be chemically synthesised through an automated process and has a predicted shelf life of at least 2 years, thereby reducing manufacturing costs. Third, it can be delivered directly to the target tendon using ultrasonographic-guided injection, decreasing both systemic exposure and the dosage required for treatment.

UofG research on biological mechanisms underlying tendinopathy [3.1–3.3] and the proof-of-concept study of miRNA29a as a novel therapy [3.4] established commercial pathways for both equine and human indications. These pathways have progressed through:

(1) creation of a UofG spin-out company (CTL);

(2) securing funds from investors;

(3) obtaining patents for the miRNA29a replacement technology;

(4) forming a co-delivery partnership for development of EquiMiR™;

(5) securing UK, EU and US ethical and regulatory approvals for equine and human trials; and

(6) commencing trials for both EquiMiR™ (USA) and TenoMiR™ (UK).

CTL established to commercialise miRNA29a

CTL was co-founded by Millar and Gilchrist in 2015, with McInnes as the Lead Medical Advisor, to commercialise the miRNA29a replacement therapy for both equine and human indications [5.A].

During 2017–2020, CTL has attracted approximately GBP13 million in investment [5.B], with a current company valuation of GBP15 million. Initial seed investment of GBP1 million from Mediqventures and the Scottish Investment Bank provided a development runway to 2020 [5.B], enabling CTL to employ four full-time staff and develop EquiMiR™ and TenoMiR™ as its lead products. On announcing this funding, the Head of the Scottish Investment Bank stated: “ Scottish Enterprise, through the Scottish Investment Bank, is delighted to be co-investing with Mediqventures to help the company fully commercialise its technology. We have supported Causeway Therapeutics through our High Growth Ventures Programme to help with company formation, research and now investment to help it grow to the next stage. We look forward to working alongside Causeway to help it achieve its potential, both in Scotland and internationally” [5.B]. In 2020, CTL announced that a new round of venture capital investment opportunity would commence during January–March 2021 to raise GBP15 million in funding for the next phase of the company’s development [5.B].

CTL holds the intellectual property for miRNA29a replacement therapy, with Millar and Gilchrist named as the inventors on patents describing this technology as a novel method to improve tendon healing [5.C]. Patents have been granted in Europe (December 2017), the USA (April 2018), Canada (August 2018), Hong Kong (September 2018) and Russia (July 2019) [5.C]. Applications are pending in Australia, New Zealand, Saudi Arabia, United Arab Emirates, Japan and China.

Veterinary trials of EquiMiR™ as a treatment for tendinopathy

The equine indication for miRNA29a has a potential market of GBP120 million in the UK and over USD600 million in Europe and the USA [5.A]. EquiMiR™ is expected to dominate the treatment of equine lameness as no other pharmacotherapies currently exist within this disease area and none has been developed since the collagen-crosslinking inhibitor Bapten, which was removed from the market in 1998. Therefore, commercialisation of the UofG miRNA29a replacement therapy will benefit equine health and welfare, particularly in racing, as horses treated with EquiMiR™ are less prone to reinjury than are horses managed conventionally. Racehorses receiving EquiMiR™ are also less likely to be culled following premature termination of their competitive careers, providing substantial value to owners and trainers. Finally, use of EquiMiR™ would avoid lengthy periods of box rest for injured animals, thereby limiting lost days of training and racing.

In September 2014, EquiMiR™ received Minor-Use-Minor-Species recognition from the European Medicines Agency, which appreciably reduces the amount of data required to obtain a Marketing Authorisation from this regulatory body [5.D]. EquiMiR™ also received a fee waiver from the US Food and Drug Administration (FDA) under the Barrier-to-Innovation provision of the Animal Drug User Fee Act (July 2016) [5.E]. This waiver accelerates the development and regulatory process of EquiMiR™ towards marketing authorisation in the USA. These two regulatory approvals considerably decrease the cost of drug development and production, which will ultimately reduce the final price for end users of EquiMiR™.

Through the UofG research collaboration with Texas A&M University [3.4], CTL was introduced to [redacted], a mid-sized UK-based international veterinary pharmaceutical manufacturer with appreciable access to the equine market. In August 2017, CTL signed [redacted] as a co-delivery partner to share EquiMiR™ product development and be responsible for retail and distribution. [Redacted] has contributed GBP8 million to development costs to support safety studies, equine trials and regulatory approval, which includes GBP3 million in milestone payments to CTL. This partnership provides [redacted] with access to CTL’s cutting-edge research and development capability, and so will position it as the field leader in treating equine lameness.

In 2019, EquiMiR™ underwent a 6-month experimental dose-finding and efficacy trial at Texas A&M University using the equine collagenase-induced tendonitis model. Substantial improvements in structural parameters were demonstrated by ultrasonography among 36 horses treated with high doses of EquiMiR™ (findings not yet publicly available). An FDA-approved pivotal veterinary trial is scheduled to commence at several US sites in 2021 (originally due to start in 2020 but stalled owing to COVID-19).

Clinical trials of TenoMiR™ as a treatment for tendinopathy

The market for treating tendinopathy in humans is valued at USD5 billion worldwide [5.A]. Potential indications for TenoMiR™ include lateral epicondylitis (tennis elbow), which is predicted to be worth USD903 million in the USA, EU and Japan by 2020 [5.A]. As a first-in-class therapy, there is currently no competitor for TenoMiR™ in this clinical arena.

Recognising the success of CTL in developing EquiMiR™ [3.4], Mediqventures and the Scottish Investment Bank invested an additional GBP1 million in 2018 [5.B]. This funding—together with grants from Innovate UK of GBP1.4 million (2018) and GBP1.3 million (2019) [5.B]—accelerated the development of TenoMiR™ for human indications, particularly the preclinical packages required for filing an Investigational New Drug application. In 2020, CTL received a GBP230,986 Innovate UK COVID-19 Continuity Grant that enabled clinical work on TenoMiR™ to proceed during the pandemic [5.B].

Data from the equine studies of the miRNA29a replacement therapy supported regulatory filings by CTL to conduct first-in-human clinical trials of this approach. An NHS Research Ethics application was approved in September 2019, with TenoMiR™ designated as an Investigational New Drug by the UK Medicines and Healthcare Products Regulatory Agency in August 2020 [5.F]. In September 2020, a phase 1b clinical trial of TenoMiR™ commenced in Manchester among 24 patients with tennis elbow (8 patients enrolled as of November 2020) [5.F]. With a positive read-out from this trial expected to occur before May 2021, CTL will actively seek larger pharmaceutical partners either to sell or co-develop TenoMiR™. In addition, CTL has extended its preclinical development pipeline to other novel miRNA replacement therapies targeting conditions such as osteoarthritis and intravertebral disc disease (OsteoMiR™); skin ageing (DermaMiR™); and wound healing ( miRNA-148b) [5.F].

Context

GBS has an annual incidence of 1.1–1.8 cases per 100,000 people (equivalent to 600–1,000 cases in the UK each year). Although rare, this condition is associated with high healthcare costs, as approximately 20% of patients experience persistent and substantial morbidity that limits their mobility and quality of life, with an additional 15% reporting residual pain and tiredness. GBS is also the most frequent cause of acute flaccid paralysis worldwide; however, therapeutic options for affected individuals are limited.

Willison’s pioneering research on GBS has been widely recognised by his peers; for example, in 2015, he was awarded the Alan J Gebhart Prize by the Peripheral Nerve Society, the highest honour that this organisation can bestow [5.A]. Expertise in the immunopathogenesis of GBS has enabled Willison and his team to make major contributions to the field, including advances in targeted treatment options that provide commercial benefits for the pharmaceutical industry.

Development of targeted therapies for GBS

Rare disease is a difficult area of investment for pharmaceutical companies, with research and development of new treatments facing issues such as high level of complexity within disease groups; difficulty in recruiting sufficient numbers of patients for clinical trials; and low financial return. The UofG mouse model of GBS [3.1], which mimics human disease by recapitulating the relevant immunological pathways, has been pivotal in driving the development of targeted therapies for this rare condition.

Eculizumab

Alexion specialises in exploiting complement biology for the discovery, development and commercialisation of therapies for rare diseases. Willison first engaged with this company in 2003, when it agreed to supply eculizumab for his preclinical work in the UofG mouse model of GBS [5.A]. The positive response reported by the UofG team [3.2, 3.3] convinced Alexion to invest in further investigation of eculizumab as a treatment for GBS, with UofG researchers demonstrating a clinical benefit among patients with autoimmune neuropathy in two early phase clinical trials [3.4, 3.5]. This work led to a joint patent between UofG and Alexion ( Willison and Halstead listed as co-inventors), describing the methods and compositions for treatment with eculizumab repurposed for GBS [5.B]. The patent was granted novelty in Japan and Korea (2015), as well as in the USA and Europe (2016).

Demyelinating GBS is the predominant subtype detected in Europe and North America; by contrast, 30%–65% of GBS patients in East Asia, Central America and South America are diagnosed with the axonal subtype. Given this regional difference, a phase 2b randomised double-blind placebo-controlled trial was conducted in Japan during 2015–2016 (JET-GBS; NCT02493725) to inform Alexion’s global development plans for eculizumab as a treatment for GBS [5.C]. The design of JET-GBS was influenced by the ICA-GBS trial protocol [3.5, 5.A]. JET-GBS enrolled 35 patients who were unable to walk independently. An improvement in functional grade (ability to run) was recorded at 24 weeks post-intervention among 74% of patients in the eculizumab group versus 18% in the placebo group. These findings encouraged Alexion to seek regulatory approval for eculizumab in Japan. On 19 June 2020, the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) granted SAKIGAKE designation for eculizumab in GBS [5.C]. SAKIGAKE is analogous to the European Medicines Agency PRIME programme and the US Food and Drug Administration (FDA) Breakthrough Therapy designation. It provides enhanced support for companies developing innovative treatments for diseases with unmet clinical need, and confers several advantages, including prioritised consultation and expedited review. This was the first SAKIGAKE designation received by Alexion; consequently, the company focused its GBS development pipeline for eculizumab on the Japanese market, with plans to initiate a phase 3 study in 2021, pending regulatory feedback from the PMDA [5.C].

In December 2020, Alexion announced that it had been acquired by AstraZeneca. According to the press release [5.C], this deal benefits AstraZeneca through “ Greater scientific presence in immunology by adding Alexion's innovative complement-technology platforms and strong pipeline … the company will further globalise Alexion’s portfolio”. In addition, AstraZeneca will establish a dedicated rare disease unit, to be headquartered in Boston.

ANX005

Annexon develops disease-modifying therapies for patients with autoimmune diseases that involve the complement pathway. Given his expertise regarding the role of complement in GBS, Annexon reached out to Willison in 2012 and invited him to sit on the Scientific Advisory Board [5.D]. In this role, Willison has provided insight regarding the classical complement pathway in GBS; enabled preclinical research on Annexon’s anti-C1q antibody ANX005 using the UofG GBS mouse model [3.6]; advised on the design of proof-of-concept clinical trials for ANX005; and brokered introductions between Annexon and physicians around the world who have contributed to both preclinical and clinical studies by providing samples from patients with GBS [5.D]. Annexon’s Chief Scientific Officer highlighted that the preclinical findings [3.6] have “proven to be critical for obtaining both financial investor and clinical investigator interest in our clinical studies. As a result, we have initiated GBS clinical studies in Bangladesh, have obtained Fast Track and Orphan Drug Status designations for our studies in GBS by the US FDA and will begin early phase clinical studies in the EU and USA” [5.D]. This approach to GBS treatment led to a joint UofG–Annexon patent, with Willison and McGonigal listed as co-inventors (2016) [5.B].

Annexon conducted the first clinical trial of ANX005 for GBS at the National Institute of Neurosciences and Hospital in Dhaka, Bangladesh, primarily on the advice of Willison owing to the increased incidence of GBS in this country (3.25 cases per 100,000 people). He was also able to broker introductions to key staff; for example, at the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) [5.E]. This phase 1b placebo-controlled dose-escalation trial was conducted during 2017–2019. It was the first clinical trial of a novel interventional drug of this nature to take place in Bangladesh, providing a valuable developmental opportunity such as the employment of more than 40 study personnel (physicians, laboratory staff, support staff) [5.E]. The preliminary data were released by Annexon in September 2019 [5.E]. ANX005 was well-tolerated at all dose levels among 31 patients with GBS, and no drug-related serious adverse events or discontinuations were recorded. Patients treated with ANX005 had reduced levels of a biomarker for nerve damage in neurodegenerative disease and exhibited positive trends across key GBS outcome measures such as muscle strength. These findings were sufficiently promising to warrant additional clinical trials for this indication.

In September 2019, ANX005 received FDA Fast Track designation for the treatment of GBS [5.E]. This designation expedites the development, review and approval of investigational product candidates that are intended to treat serious conditions with unmet medical need. A phase 1b multicentre study to evaluate the safety, tolerability and drug–drug interactions of ANX005 and intravenous immunoglobulin ( NCT04035135) started recruitment in February 2020. Recruiting centres are located in Bangladesh, Denmark, the Netherlands, the UK (UofG Biomedical Research Centre) and the USA. Study completion is expected by September 2021. In addition, patient dosing has started in a phase 2/3 clinical study of ANX-005. On announcing this development in December 2020, the President and Chief Executive Officer of Annexon stated: “ We are pleased to advance our GBS program into later-stage clinical development, bringing us closer to potentially delivering a much-needed treatment option to patients combatting this debilitating disease. The advancement of ANX005 also continues to inform our ongoing clinical development across a host of additional complement-mediated autoimmune and neurodegenerative diseases” [5.E].

Imlifidase

The International GBS Outcome Study (IGOS) Consortium aims to identify clinical and biological determinants and predictors of disease course in a large international cohort (>1,500 patients). Willison is a member of the IGOS Consortium Steering Committee; he also runs the UK arm of this programme, and chairs the Biomarkers Subgroup. UofG involvement is instrumental for the development of GBS clinical trial platforms, where it provides a means for recruitment and assessment of cases. One example of IGOS-supported research is a phase 2 study of imlifidase conducted by Hansa Biopharma (Lund, Sweden). This potential intervention for GBS is a bacterial immunoglobulin G-degrading enzyme derived from Streptococcus pyogenes. The clinical trial ( NCT03943589) will assess the safety, tolerability, efficacy, pharmacodynamics and pharmacokinetics of imlifidase among 30 patients with GBS. Recruitment began in June 2019, with study completion expected by December 2022. Recruiting centres are based in France, the Netherlands and the UK (Queen Elizabeth University Hospital, Glasgow; Goodfellow).

Supporting preclinical drug development

In August 2019, Willison signed research agreements with argenx (Breda, the Netherlands) and Polyneuron Pharmaceuticals (Basel, Switzerland) to conduct preclinical work using the UofG mouse model of GBS [3.1]. Argenx takes a strategic academic–industry collaborative approach to developing antibody-based therapies for autoimmune diseases. Willison is supporting development of the argenx complement factor c2 inhibitor (ARGX-117) [5.F], which has already entered a phase 1 trial to test route of administration among healthy volunteers (data expected by mid-2021) [5.F]. Polyneuron Pharmaceuticals is a biotechnology start-up company focussing on rare autoimmune diseases of the nervous system with unmet clinical need. Willison is investigating a molecule (PN-1018) developed by this company to target a novel therapeutic pathway in GBS [5.F].

Research at the UofG has provided key insights, direction and proofs of principle towards the synthesis and assessment of novel molecules that selectively target Free Fatty Acid receptors FFAR1 and FFAR4. In doing so, UofG research has provided a platform for the design of novel therapeutic molecules with the potential to treat type-2 diabetes, obesity and other aspects of ‘metabolic syndrome’ such as the fatty liver disease non-alcoholic steatohepatitis (NASH).

To help realise this potential, a spin-out company has been founded with significant financial investment, creating new jobs; money invested in the spin-out has funded research and development, with 80% spent within UK scientific services—benefitting the operations of partner contract research organisations; the spin-out has generated new patented intellectual property and identified late stage drug candidates for progression (impact 1). The UofG research has also influenced the wider thinking and direction of independent pharmaceutical research and development (impact 2).

Impact 1: Caldan established to exploit FFAR agonists

On the basis of this research and collaboration between Professor Graeme Milligan (UofG) and Professor Trond Ulven (USD), in 2015 the UofG and USD spun out Caldan Therapeutics Ltd. (Caldan, https://www.caldantherapeutics.com/). Caldan’s core business is developing novel, small molecule therapeutic agents to treat type-2 diabetes as well as NASH by targeting either FFAR4 selectively or activating both this receptor and FFAR1.

Caldan has attracted GBP8.15 million in funding. This comprises an initial GBP4.45 million in Series A funding (2015) from Epidarex Capital (a leading international early-stage life science venture capital fund) and the Scottish Investment Bank [5.A]. It has gone on to receive two further rounds of funding, of GBP2.1 million (2019) and GBP1.5 million (2020), reflecting their progress and investor belief in Caldan’s potential. “ Epidarex had identified Professor Graeme Milligan as an eminent researcher working in an area of high strategic interest. Subsequent discussions between Epidarex and Professor Milligan, his collaborator Professor Ulven, and the commercialisation offices at UoG and USD, led to the initiation of the Caldan investment” – Partner, Epidarex [5.A]. The initial investment package was supported specifically by:

• a portfolio of patented FFAR1-activating molecules developed through a multidisciplinary collaboration between USD and UofG [3.1, 3.2]—validating the therapeutic potential of these ligands;

• a portfolio of selective FFAR4-activating molecules, which together with the underpinning portfolio of UofG research on FFAR4 [3.3–3.5], has established know-how to identify molecules and dosing regimens that will not desensitise FFAR4—making them suitable for long-term conditions;

• establishing know-how on molecules that can dually target both FFAR1 and FFAR4—offering added value as potential therapeutics [3.6].

“The research collaboration between UofG and USD offered compelling preclinical evidence that Caldan’s FFAR programmes could address unmet needs in treatments for type-2 diabetes and NASH” [5.A]. The investment decision also followed successful independent due diligence with consultants in type-2 diabetes drug discovery and medicinal chemistry validating the strength and rationale of the UofG/USD technology and IP, and pharmaceutical interest in targeting FFARs [5.A].

Caldan has created new jobs with this investment and 80% of funds are spent directly on scientific efforts within the UK [5.B]. The company employs a highly experienced management team: Chief Executive Officer, Chief Operating Officer, Chief Financial Officer and a Vice-President Drug Discovery, with an office based in Nottingham. Caldan operates a lean in-house model using a variety of contract research organisations to go through Lead Generation and Lead Optimisation phases to compete with the large Pharma groups also investigating FFA4 agonists [5.B]. The workforce has largely been employed at three companies (Sygnature Discovery, RenaSci and XenoGesis) based at BioCity in Nottingham and varies from 8–13 according to whether the research is in a ‘discovery chemistry’ mode, or a ‘deep in vivo biological testing’ phase but has included: 4–6 medicinal chemists, 1–2 computational chemists, 1–2 biological screening, 1–2 in vivo testing and 1 drug metabolism pharmokineticist [5.B]. Following his research characterising FFAR, Dr Brian Hudson has, since 2019, also acted as a consultant to Caldan and previously was bought out by Caldan at a 20% level [5.B].

Building on the multidisciplinary partnership between USD and UofG, Caldan made rapid progress on a selective FFAR4 agonist programme, which is now supported by a patent ‘Tetrahydro-benzo[d]azepine derivatives as GPR120 [FFAR4] modulators’ ( WO/2018/172727, international publication date 27.09.2018) [5.C]. Caldan has developed several series of molecules which have shown activity in animal models of metabolic dysfunction, notably type-2 diabetes and NASH. In particular, these have shown excellent efficacy in models of diet-induced obesity using a novel dosing regimen that was predicted by understanding the mechanisms of regulation of FFAR4, uncovered by Milligan and Hudson [3.5], and were integral to Caldan’s foundation. The company now has late-stage compounds with appropriate properties to be candidates for progression into development as novel treatments for these diseases.

In August 2019, Caldan secured a further GBP2.2 million in Series A investment, primarily from LifeArc Seed Funds [5.A, 5.D]. “ Attracting LifeArc as new investors into Caldan is a reflection of the great progress that Caldan has made and the company’s potential to become the leading company developing GPR120 [FFAR4] agonists for metabolic disease” – Partner, Epidarex [5.A]. This funding has allowed the company to identify preclinical candidates from late stage FFAR4 agonist compounds and demonstrate efficacy in models of NASH. NASH is a severe form of fatty liver disease that causes inflammation of the liver, affecting 5% of the UK population, and can lead to liver damage and is associated with increased risk of diabetes and high blood pressure. With no drugs to treat the underlying condition, current treatment is through lifestyle change and palliative care. Takeda Pharmaceutical Company (Japan) has estimated (p.13) that clinically useful treatments for NASH is a market expected to be worth USD3.8 billion. In October 2020, Caldan’s investors provided additional funding of GBP1.5 million; Epidarex stated that this will “ equip the company with a clear runway for the company to declare a clinical candidate molecule for NASH, a key milestone for the company” [5.A].

Impact 2: wider influence on pharmaceutical drug discovery research

The phenyl-propionic acid backbone of the TUG-891 ligand, identified through the UofG-USD collaboration [3.3, 3.4] has been instrumental to the chemistry and design of chemical series to target FFAR4 in the pharmaceutical industry. This molecule was the first potent and selective agonist of FFAR4 and has been used as a probe compound by almost all groups involved in the free fatty acid biological and drug discovery arena.

“The structure of TUG-891 has had a huge influence on the chemistry of FFAR4 agonists. … As evidenced by literature publications and patents several large and small pharma groups have taken the phenylpropionic acid group as the basis for their drug discovery programs. These include BMS [Bristol Myers Squibb] , Cymabay, Janssen and Piramal who elaborate the appendage in their individual, novel way. Others such as LG Life Sciences and Merck start with a phenylpropionic acid but introduce novelty by adding ring constraints or scaffold-hopping to related but rearranged frameworks. It is fair to say that the phenylpropionic acid grouping underlies a great deal of the current medicinal chemistry research looking for drug-like agonists of FFA4” – VP Drug Discovery, Caldan [5.B].

Several academic and industry-published reviews and research articles have similarly highlighted the broad stimulus to industrial drug discovery derived from TUG-891 chemistry and biological characterisation within the REF2021 period. For example, a team at Janssen Research & Development LLC cite Shimpukade et al., 2012 [3.3], describing TUG-891 and its biological properties, and state that they ‘ sought ways to modify the structure to improve pharmaceutical properties’ [5.E1]. In a 2020 review of the FFAR4 patent literature the same author identified how Janssen lead compounds are structurally related to TUG-891 [5.E2]. They also state, “ TUG-891 has been an important tool compound, as a selective GPR120 [FFAR4] agonist, for validating the effects of GPR120 activation on insulin sensitization, dietary fat intake and obesity. The ortho-biphenyl of the [1,1ʹ-biphenyl]-2-yl-methoxyphenyl core, which is a distinguishing structural feature of TUG-891, has been applied to other chemical scaffolds in the patent literature.” They go on to highlight screening activities at Piramal Enterprises Ltd (Mumbai, India) that has also used this chemistry as a driver [5.E2].

Between 2017–2019, both Janssen [5.F] and Piramal [5.G] were granted patents that cite Shimpukade et al. [3.3]. These were also reported by Li et al. (2016) in a review of FFAR drug development: with regard to Janssen they stated: “ patent applications by Janssen claimed a series of heterocyclic compounds as FFAR4 agonists which are bioisosteres of TUG-891 series”. With regard to Piramal they stated, “ based on the structure of TUG-891, Piramal has disclosed a series of substituted phenyl alkanoic acid as FFAR4 agonists in 2016” [5.H].

In 2016, the company was named ‘Early Stage/Risk Capital Deal of the Year’ at the 2016 ‘Scottish Business Insider Deals and Dealmakers’ awards [5.I]. Prof. Milligan was also named one of nine finalists, from 50 entries, in the BBSRC’s 2016 Innovator of the Year awards for his work linked to Caldan [5.J].