Impact case study database

Beneficiaries:

1. Pharmaceutical industry

2. Patients

3. Biotech reagent companies

Impacts:

1. Focussing and enabling commercial drug discovery on LRRK2 inhibitors

The robust evidence that a common LRRK2 pathogenic mutation in Parkinson’s increased its kinase activity, and the development of a synthetic LRRK2 substrate, had critical impact in directly stimulating the development of LRRK2 inhibitor therapeutics by industry [E1]. The Vice President of MJFF and former Merck LRRK2 Inhibitor Program Biology Lead confirms Alessi’s contribution:

“During the early days of LRRK2 kinase inhibitor programs, all pharmaceutical companies relied on his published work to establish primary assays to screen for LRRK2 kinase inhibitors…[and used his]… synthetic LRRK2 substrate…to screen their compound libraries…These discoveries…had a major impact on the field since they stimulated the pharmaceutical industry to embark on LRRK2 kinase inhibitor drug discovery and development…[His tools] …directly facilitated the entry of the first LRRK2 kinase inhibitors into the clinic in 2017. People with Parkinson’s are now testing these potential therapies thanks to Dr. Alessi’s efforts” [E1].

1. Underpinning investment in LRRK2 inhibitors and their entry into the clinic

As a result of the progress facilitated by Alessi’s research, biopharma company Denali Therapeutics developed two brain-penetrant LRRK2 inhibitors that have generated positive results in Phase 1 and Phase 1b clinical trials in healthy volunteers and Parkinson’s patients [E2]. One Denali inhibitor is now in preparation for late-phase clinical trials. This success stimulated significant investment in the company in 2020, with Biogen announcing a USD1billion deal to co-develop and co-commercialise Denali’s LRRK2 inhibitors [E3]. Denali document many direct impacts of the research in enabling their trials [E3] which led to economic and patient benefits.

Global pharmaceutical company GlaxoSmithKline (GSK) has directly collaborated with Alessi on LRRK2 since 2008. GSK published nine World Intellectual Property Organization LRRK2 inhibitor patents 2015-2019 that cite Alessi’s 2007 research [R1]; six also cite the 2016 paper [R3] which they had involvement with [E4]. In 2018, GSK announced a $300M partnership with DNA testing company 23andMe to expedite recruitment to their LRRK2 inhibitor clinical trials by targeting individuals with LRRK2 mutations [E4]. Worldwide, more than 43 patents were published 2014-2019 on small molecule LRRK2 inhibitors [E5]. Many belong to global pharmaceutical companies such as GSK, Pfizer, Merck, Roche and Genentech who all cite Alessi’s work [E5].

1. Adoption of LRRK2 biomarkers with direct impact in enabling clinical trials

Alessi’s research discoveries provided the two blood biomarkers that are essential to evaluating the effectiveness of treatments for LRRK2-mutation Parkinson’s in clinical trials. Monitoring, via Alessi’s UDD2 antibody, phosphorylation at a key site in LRRK2 became “ a gold standard measure of target engagement for LRRK2 kinase inhibitors” according to MJFF [E1]. MJFF’s precompetitive alliance with Denali, Pfizer, Merck and Biogen, the ‘LRRK2 Detection in PBMC Consortium’, depended on UDD2 to develop a biomarker for their therapeutic trials [E6]. Similarly, referring to Alessi’s identification of Rab GTPases as LRRK2 substrates, Denali say they “ immediately recognized the importance of this published insight and applied this to…[develop] high throughput clinical grade assays to measure Rabs as a pathway engagement biomarker” [E3]. Both types of biomarker were measured in participant/patient blood during the Denali clinical trials to evaluate LRRK2 inhibitor effectiveness [E2]. Alessi’s research also enabled Denali to find the correct inhibitor dose for the trials [E3]. MJFF and others are sponsoring clinical studies in the USA and Europe measuring the same blood biomarkers to see if they can identify people with enhanced LRRK2 pathway activity whether or not they have LRRK2 mutations or Parkinson’s symptoms [E7]. The Vice President MJFF states:

“All of the target engagement work being conducted by pharmaceutical companies to measure LRRK2 and Rabs in…[blood] cells is due to Dr. Alessi’s efforts and collaboration with MJFF to generate and make available at cost, crucial monoclonal antibodies” [E1].

1. Marketing of LRRK2 products by laboratory reagent supply companies

LRRK2-related reagents from the Alessi lab are marketed to industry and academia by Abcam, NeuroMab, and the Dundee MRC-PPU Reagents and Services facility [E8]. Revenue from sales to industry by MRC-PPU was approximately GBP200,000 over the REF period [E8] and is likely to have been higher for the commercial vendors. These reagents are used extensively by Pharma, including Pfizer, Boehringer Ingelheim and Merck, for Parkinson’s preclinical research [E9].

1. Bringing hope and encouraging people with Parkinson’s to participate in research

In 2017, Parkinson’s UK established the Dundee Parkinson’s Research Interest Group (DRIG). Researchers from the University of Dundee regularly interact with DRIG, enabling people affected by Parkinson’s to input to the research. The Chairperson of DRIG comments: “ DRIG has benefitted greatly from our association with the MRC PPU…[We contribute] …through occasionally commenting on research proposals…as well as by funding some small research projects.” [E10]. The group keeps up-to-date with Sammler’s genetic testing for early-onset or inherited Parkinson’s patients diagnosed in Scotland. People identified as having LRRK2 mutations become eligible to join clinical studies she leads for Dundee/UK such as the industry-led Rostock International Parkinson’s Disease Study enrolling participants worldwide [E7], and the LRRK2 International Parkinson’s Disease Study [E7]. Informed involvement in such research benefits people with Parkinson’s:

“…working with the MRC-PPU gives us not just hope, but also knowledge and a little bit of control over our future, which strengthens our determination to carry on and ultimately beat Parkinson’s” – Chair of DRIG [E10].

Impacts:

• Partnership with FIND and Abbott to accelerate HAT diagnostic test deployment

• Development of improved, more cost-effective diagnostic, BIOLINE HAT 2.0

• Successful clinical study of diagnostic BIOLINE HAT 2.0

• Adoption and implementation of the new, supply chain-resilient HAT diagnostic

• Commissioning of a combined RDT prototype for both HAT and malaria

1. Partnership with FIND and Abbott (SD Inc) to accelerate HAT test deployment

Ferguson identified FIND as the ideal partner to help translate his research into a product for clinical use. In 2014, FIND and the University of Dundee entered a formal partnership, signing a

License and Material Transfer Agreement under which reagents developed by Ferguson were made available free of charge for the development of an improved RDT for HAT [E1]. FIND provided the bridge to the private sector and commissioned Abbott (SD Inc) to produce BIOLINE HAT 2.0 using Dundee’s recombinant ISG65. Dundee provided the ISG65 expression clone, optimised protocols, and consultancy advice to enable scale-up of rISG65 production by Abbott [E2]. Both FIND and Abbott benefited from the partnership with Dundee. Abbott benefit through for-profit production of the RDT, while FIND Senior Project Manager says [E2]:

“FIND is grateful for Professor Ferguson's continued engagement and assistance in technology transfer to Standard Diagnostics and Abbott… we acknowledge the University of Dundee's significant research contributions to achieving FIND's goals in supporting the elimination of HAT. ”

1. Development of improved, more cost-effective rapid diagnostic test BIOLINE HAT 2.0

By providing antigen ISG65 and prototype technology, Dundee initiated a workflow at FIND that included evaluations on affordability, performance, market analysis, and risk assessment [E2]. FIND Senior Project Manager describes their conclusions and confirms that Dundee research:

“had a significant impact, prompting FIND’s development of their second-generation ‘all- recombinant’ RDT for HAT… The removal of reliance on the supply of native antigens, which can be laborious and dangerous to produce, provided the opportunity for a step change in the robustness of HAT screening…The all-recombinant nature of this second-generation device is critical to RDT production resilience, quality and cost control. The Bioline HAT 2.0 is affordable at US$ 0.50/test and stable for up to 2 years at temperatures up to 40°C… Packaging of HAT 2.0 will be smaller… giving distribution cost savings. The RDT format also provides several advantages over the traditional CATT test, including no requirements for electrical supply, ancillary equipment, a cold-chain or highly-trained operators. All of these factors are important for deploying HAT screening programmes in sub-Saharan Africa” [E2].

1. Successful clinical study of rapid diagnostic test BIOLINE HAT 2.0

In 2015, FIND began a multi-centre clinical study in the Democratic Republic of the Congo to compare the performances, under field conditions, of the all-recombinant BIOLINE HAT 2.0, the native antigen SD BIOLINE HAT, and the traditional ‘standard of care’ CATT test [E3]. A total of 57,632 people were screened, and 260 HAT cases were confirmed by microscopy with benefit to the individuals involved who received treatment. The outcome was that the new BIOLINE HAT

2.0 device was more sensitive than SD BIOLINE HAT and CATT (71.2% versus 59.0% and 62.5%, respectively) while all three tests had a specificity above 98% [E3].

1. Adoption and implementation of the new, supply chain-resilient HAT diagnostic

As a result of the definitive outcome of the clinical study, FIND officially adopted BIOLINE HAT

2.0 (Figure 1) as their preferred test for HAT screening and surveillance and launched the commercial product with Alere in September 2017 (Alere subsequently acquired by Abbott), acknowledging the contribution of the University of Dundee [E4]. The General Manager of SD Inc. said at the time:

“This test is the fruit of several years of joint efforts, and a major achievement resulting from the successful partnership that has been established with FIND to support the development of rapid tests for diseases associated with poverty” [E4].

The Chief Executive Officer of FIND said the test:

“will facilitate diagnosis of sleeping sickness patients in even the most remote corners of affected countries and enhance the prospects of achieving and sustaining elimination of the disease” [E4].

Figure 1. BIOLINE™ 2.0 Rapid diagnostic test (C = control; 2,1 = test antigens).

Full commercial roll out was anticipated to complete in spring 2020 but has been delayed due to FIND’s need to develop and market RDTs for COVID-19. The test is now planned to complete roll out in February 2021 [E2].

1. Commissioning of a combined RDT prototype for both HAT and malaria

Patients with malaria or the early stage of HAT have similar symptoms. A diagnostic test that differentiates between them could inform treatment and control transmission. The success of BIOLINE HAT 2.0 led FIND to commission Abbott to develop a combined RDT incorporating Ferguson’s rISG65 recombinant antigen and an antigen from the malaria parasite. The new combined RDT is as accurate as the individual HAT and malaria RDTs under laboratory conditions [E5]. FIND has sponsored a new clinical observational study to evaluate the dual RTD in the field to screen for HAT and diagnose malaria [E6].

FIND has declared the transformational impact of the availability of BIOLINE HAT 2.0 and the development of the HAT/malaria combined RDT in their diagnostic strategy pipeline for HAT [E7]. The tests are FIND’s two prioritized activities for HAT in “ addressing the most critical gaps in the diagnostic landscape” for screening interventions (the other two tests are for case confirmation) [E7]. FIND’s HAT screening programme was supported by investment from the Bill & Melinda Gates Foundation, UK aid from the UK Government, and the Swiss Government [E4].

Phase II clinical trial of fexinidazole for treatment of human VL, and application in dogs

The discovery by Fairlamb, Read and Wyllie that oral fexinidazole had anti-leishmania activity in mouse models prompted a re-evaluation by DND i that ultimately resulted in a Phase II clinical trial to determine the efficacy and safety of fexinidazole to treat VL patients [E1]. All patients benefited from clinical improvement during treatment and the trial delivered conclusive knowledge to DND i that fexinidazole reduces parasite burden. However, not all patients remained cured due to insufficient exposure to fexinidazole (requiring higher or longer dosing) and the trial terminated [E1]. Since anti-leishmanial drugs are subject to resistance, DND i’s goal is for two safe, orally administered drugs to be used in combination. Fexinidazole is one of only two orally-available therapies and it’s superior safety profile compared to the other oral drug, miltefosine, means it could be a partner candidate for combination treatments with new oral drugs in development.

Leishmania infantum is the causative agent of infantile VL in the Mediterranean region and Latin America, with expanding geographical incidence. Dogs are the primary reservoir for infection of humans and up to 10% of dogs in endemic areas develop disease. Existing treatments do not produce a reliable cure and have significant side effects. In 2014, Merial (now Boehringer Ingelheim Animal Health) filed a patent on fexinidazole as a treatment and cure for leishmaniasis in dogs, evidenced by trials they had undertaken [E2]. Their trials and patent are a clear direct consequence of the earlier published DDU research [R1] which they cite.

Delivery and clinical trial of new oral candidates for VL treatment in collaboration with GSK

There is an urgent need for new oral treatments for VL that work through novel modes of action. This enables combination therapies that will improve efficacy and reduce the risk of resistance. In April 2017, DND i and GlaxoSmithKline, in collaboration with the DDU, entered into a formal agreement for the preclinical development of two such compounds [R4, R5] discovered in Dundee for treatment of leishmaniasis [E3]. The most advanced compound was declared as a preclinical candidate by GlaxoSmithKline in July 2018 [E4] and human Phase 1 clinical trials began in May 2019 [E5]. The second compound was approved for Phase 1 clinical trials in June 2020 [E6] and the first subjects were dosed in October that year.

These clinical candidates represent step-changes in the development of treatments for VL since both are orally bioavailable in humans. Globally, only three other oral VL candidates are currently being clinically assessed [E7]. Dundee has therefore contributed 40% of the global new compounds in the pipeline for combination clinical testing. Addressing the impact of these new drug treatments, the Discovery Director at DND i said:

“To have a new compound with a novel mode of action against VL is a huge advance for the field as it enables testing and development of multiple new combination therapies with other new and existing drugs. For the DDU to identify not one, but two such new drug candidates in just a few years, is an outstanding achievement for an academic drug discovery unit” [E8].

Adoption of gold-standard screening assays for leishmaniasis drug development

An important impact of Dundee’s research has been adoption by industry of a suite of screening and assay platforms developed by the DDU for VL drug discovery. These were transferred to GlaxoSmithKline (following training of GSK staff in Dundee) and are now widely used by industry and Product Development Partnerships [E9]. In total, DNDi and GlaxoSmithKline have screened >500,000 and 1.8 million compounds respectively using DDU assays [E9], a feat previously impossible with earlier, laborious assays. DDU Mode of Action screening cascades also provided DND i, GlaxoSmithKline and others with knowledge that saved resources by enabling decisions not to proceed with compounds that might have negative outcomes [E10]. Overall, the DDU’s drug discovery expertise has enhanced the productivity of the global VL drug discovery portfolio. DND i comment on DDU’s gold standard screening assays thus:

“…continued development of high capacity, physiologically relevant assays using Leishmania by the Dundee DDU has been transformational for visceral leishmaniasis (VL) drug discovery. The high throughput [parasite-killing] assay and high content imaging platform for intracellular assays have revolutionized the capacity and efficiency of screening, enabling many millions of compounds to be screened for new chemical starting points…The Dundee L.donvani screening platform allowed rapid identification of hit series of molecules for both Dundee and other groups around the world, including major Pharma companies.” [E8].

a) Raising multi-million investment in, and revenue from, AI-guided drug design

Exscientia has rapidly-grown into a leading pharmatech company at the forefront of AI drug discovery. Since 2017, Exscientia has raised a total of GBP84 million, comprising:

• Series A EUR15 million in 2017 [E1]

• Series B USD26 million in 2019 [E2]

• Series C USD70 million in 2020 [E3]

(including USD10 million raised after the announcement).

Evotec, one of four investors, said of Series A in 2017:

“Our investment in Exscientia represents Evotec’s single biggest equity placement to date and in, what we feel, is the world leading AI technology company” [E1].

Exscientia’s revenue rose from GBP1.5 million in 2018 to GBP9.8 million in 2020, with GBP23.0 million total revenue since 2016 [E4]. This enabled Exscientia to expand from its initial space in Dundee, to a second office in Oxford (2017), then into larger premises on the Oxford Science Park (2018). Recently (2019/2020), offices opened in Osaka (Japan) and Miami (USA). In the REF period, expansion increased the workforce from 3 to 91 staff [E4] by creating 88 highly-skilled new jobs (headcount: 88; FTEs: 88) with staff numbers doubling each year for the past 3 years (Figure).

b) Innovation and partnership with Pharma to accelerate drug discovery using AI

In addition to its own pipeline, Exscientia provides services to pharmaceutical companies where its automated AI drug design process can accelerate development of candidates for clinical trial.

These services have attracted 18 partnerships on 28 separate projects, developing drugs or technology for a range of diseases, including cancer, COVID-19, psychiatric disease, bone disease, fibrosis and others [E4]. Many collaborations are with global Pharma companies with revenue generated through initial upfront and research payments, near-term and clinical milestone payments, and royalties on final products. Examples of such deals include: Bayer (2019; EUR240 million), Roche (2019; CHF67 million), Celgene/Bristol Myers Squibb (2019; USD25 million upfront, with undisclosed milestones), GlaxoSmithKline (2017; GBP33 million), Sanofi (2017, EUR250 million), Sunovion (2014; total USD4.8 million) [E4]. Partnerships also exist with GT Apeiron, Evotec, SRI, RallyBio, Blue Oak, Huadong Medicine, IMI CARE, Diamond Light Source/Calibr, Sumitomo Dainippon Pharma, and the Gates Foundation [E4]. Twelve patents were filed or published on Exscientia molecules/methods in the REF period [E4].

c) Significant efficiency and cost savings compared to conventional drug discovery

Published industry benchmarks estimate it takes 4.5 years and USD63 million to get to pre-clinical testing of a drug candidate. In 2014, Exscientia signed a partnership with Sumitomo Dainippon Pharma Ltd and one year later delivered a molecule meeting Sumitomo criteria [E5]. Fewer than 400 compounds needed to be synthesized to identify the final compound using Exscientia’s automated system, saving over 80% costs in these drug discovery stages, or 30% of the total drug development cost [E4, E6]. The Director of Sumitomo’s chemistry team said:

“Working with Exscientia has been transformative, enabling us to progress projects far faster than had previously been possible”, and their Director of Drug Development added, “... projects by ex scientia are providing exciting productivity and efficiency gains…” [E5].

In 2019, Exscientia provided GlaxoSmithKline with a first selective, potent in vivo, lead molecule, discovered in 5 iterative cycles with only 85 compounds tested [E7] in comparison with industry benchmarks of 2,500 per project. Also in 2019, Sanofi exercised its option to advance a compound from their 2017 partnership where Exscientia designed bispecific-binding molecules after triaging >1,000 disease-relevant target combinations and designing nearly 100 billion novel compounds. The first-in-class bispecific molecule being progressed by Sanofi interacts with two drug targets related to inflammation and fibrosis - normally needing two separate drugs [E8].

These achievements highlight the efficiency and productivity gains made possible through Exscientia’s algorithms. Their current pipeline has 12 drug discovery projects [E4], and 5 new drug candidates have been delivered in under 14 months, far quicker than the 4.5 to 5-year industry benchmark and with associated cost savings [E7]. Evotec confirm:

“Through our partnership with Exscientia we have seen first-hand evidence that they can deliver the most productive drug discovery engine in the industry” [E2].

d) Fastest AI-designed drugs to accelerated IP filing and first-in-human clinical trials

Exscientia has been the fastest AI-design drug developer in the world to reach the clinic, enabling accelerated IP filing. In January 2020, though partnership with Sumitomo Dainippon Pharma Ltd, Exscientia delivered into Phase 1 clinical trials the first AI-designed drug ever to be tested in humans [E9]. The drug, in trial in Japan, treats patients with obsessive-compulsive disorder, enabling Sumitomo to expand its pipeline to treat key unmet needs in psychiatry/neurology. Sumitomo’s Senior Executive Officer said:

“We are very excited with the results of the joint research that resulted in the development of candidate compounds in a very short time…” [E9].

An Exscientia-proprietary AI-designed drug targeting cancer is also in Phase I first-in-human clinical trial, enrolling its first participant in December 2020 [E9]. Exscientia and Hopkins have received numerous accolades (collated in E10) and their leading position in the sector is confirmed by many:

GSK say “ Exscientia has… proven innovation in drug discovery technologies…their industry-leading approach will accelerate the discovery of new molecules” [E4];

Forbes list Exscientia as a “ leading AI drug discovery startup” for possible acquisition by Big Pharma for over USD2 billion in the near future [E10];

Evotec say “[Exscientia’s] AI approaches…can positively and radically impact drug discovery” [E1].

Single dose cure molecule targeting multiple lifecycle stages adopted by MMV

DDU research led to invention of DDD107498 that can treat malaria with a single dose. Crucially, it is effective against parasites resistant to current drugs at a dose within MMV’s goal of ~1USD per treatment, affordable in lower-income countries. In 2014, MMV formally declared DDD107498 as a candidate for preclinical development [E1]. The discovery won MMV’s Project of the Year 2014 [E2]. At the time MMV said:

“This molecule has caused a stir…. DDD498 has potent activity against multiple stages of the malaria parasite’s lifecycle, giving it the potential to cure and stop the spread of the disease as well as protect people, all in a single-exposure” [E2].

Incentivising Pharma by de-risking drug discovery

Developing a new drug costs over GBP1billion. For diseases like malaria, with high prevalence in developing countries, this investment is too high for Pharma, since it cannot be recouped from low-income patients or aid budgets. The DDU’s research to invent and characterize DDD107498 incentivized MMV to take it forward through a formal licensing partnership [E4]. In 2015 MMV explained the impact on them:

“Thanks to these attractive properties, MMV was able to successfully partner this compound with Merck KGaA…it was licensed their flagship anti-malarial for pre-clinical and clinical development and renamed M5717” [E3].

Similarly, the Head of Merck Global Health Institute explains the impact on the company:

“The DDU’s work to identify DDD107498 and characterise it and its safety profile meant that Merck were provided with a highly effective drug candidate ready for clinical trial…The DDU de-risked the process and provided the incentive for us to proceed to clinical development in 2017 with a new drug for malaria that we would have been very unlikely to develop independently. This also allowed Merck to develop our malaria portfolio” [E5].

Both MMV and Merck benefited by progressing their objective of defeating malaria, thereby encouraging sustained investment. People in malaria-endemic countries benefit from survival of such R&D partnerships working toward malaria treatments and eradication.

Malaria complete cure in clinical trial with first ever Phase 1 Volunteer Infection Study

Merck wished to fully understand M5717 (formerly called DDD107498) efficacy earlier than previously possible, due to its promise, and to minimise costs. In 2017, they began novel first-in-human Phase I trials that included volunteer infection studies (VIS) where healthy volunteers received a small inoculum of malaria to investigate M5717 as a clinical cure [E6]. This was the first time VIS were conducted by a pharmaceutical company as part of Phase I trials. The Head of Merck Global Health Institute confirmed the benefits of this unique study design, prompted by M5717’s promise/properties, saying that it “allowed us to reduce timelines, manage resources and minimize the number of patients needed in Phase II” [E5].

Merck reported M5717 as a single dose cure for malaria at the ASTMH Annual Meeting in 2019, following completion of the Phase I VIS trial. Their abstract confirms that “Administration of 800 mg M5717 resulted in complete clearance of parasitemia” [E7, abstract 1] . In a recent testimonial [E5] Merck confirm the trial demonstrated that M5717:

“…could cure subjects with a single dose, which marks a key milestone in its development…The phase I study demonstrated that M5717 has a positive benefit/risk profile and supports its further clinical development as a single dose for the treatment of malaria. M5717 is also active against the liver-stage of the parasite, making it a unique candidate for the prophylaxis and prevention of malaria.”

To this end, a second human challenge Phase 1b trial, initially delayed by COVID-19, has begun to assess the potential not just for cure but for prevention of malaria [E8]. The first subject was dosed in September 2020 [E9] (trial completes May 2021).

Unblocking the pipeline of new malaria combination treatments

WHO recommends combination antimalarial therapy, where each drug has a different mode of action to mitigate against the emergence of resistance. M5717’s completely novel mode of action opens up a pipeline towards new malaria combination treatments that partner it with existing or new drugs, and also identifies protein translation/eEF2 as targets for new drug development. Consequent impacts are the sale of DDD107498 to global customers by several international companies to facilitate drug discovery research [E10], and pursuit of combination clinical trials as confirmed by the Head of Merck Global Health Institute:

”*M5717 is identified as a key asset of the global malaria portfolio and is a central element of the next generation of malaria combinations that are managed by MMV. We are now in the process of identifying a potential partner drug to take M5717 further into Phase IIa.*” [E5].

The Chief Scientific Officer of MMV also explains:

“The fact that no-one had previously proposed EF2 as a target for malaria underlines the ground-breaking nature of this discovery…The compounds inhibiting EF2…are the only series we have seen so far…to hit all three [parasite] stages equally. This means that any drug will have potential not only for treating malaria, but for protecting against infection, and also to impact transmission… MMV are pleased to acknowledge the significant contribution and impact of the University of Dundee’s Drug Discovery Unit in delivering next-generation anti-malarial therapies. The combination of scientific rigour, the entrepreneurial spirit and the deep expertise… has made DDU a triumph of UK science over the last decade…” [E3].

Reshaping drug discovery programmes and investment within Pharma

Ciulli’s research helped transform a niche area of chemical biology into one of the most exciting new fields of drug discovery. An expert opinion piece in Nature [E1] cites his 2015 publication [R3] and work of two other groups as achieving the spectacular leap in performance that enabled PROTAC technology, which had not gained traction in a decade, to become the focus of a “ gold rush”. By 2019, PROTACs were “ driving billions of US dollars in investment from pharmaceutical companies such as Roche, Pfizer, Merck, Novartis and GlaxoSmithKline” [E1]. Intellectual property underpins investments; Ciulli has filed 3 patents since 2015 and 34 other unique patent families from 15 companies cite his research (including Arvinas, C4 Therapeutics, AstaZeneca, GlaxoSmithKline and Boehringer Ingelheim) [E2]. A 2020 global market report by Roots Analysis indicates over USD3.5billion investment in targeted protein degrader drugs since 2014, with PROTACs accounting for over 30% of pipeline drugs in this class.

Enabling development and successful clinical trial of PROTAC drugs for cancer patients

These research advances and investments directly resulted in a first wave of PROTAC drugs entering clinical trials. Arvinas Inc. has PROTACs in expedited Phase 1/2 clinical trials for highly refractory metastatic castration-resistant prostate cancer (>250,000 new patients a year in the USA alone) and metastatic breast cancer (half a million global deaths annually) respectively. In their December 2020 Clinical Program Update, Arvinas report continued patient benefit and clear signs of efficacy. The development of these drugs was significantly dependent on the research contribution of Ciulli, with R1-R6 variously cited in 11 patent families filed by Arvinas [E2].

Creation of spin-out company Amphista Therapeutics

The 2017 publication of the ligase-PROTAC-target crystal structure [R4] generated enormous investor interest. Amphista Therapeutics was consequently spun-out in December 2017 from the University of Dundee with co-founding venture capital investor Advent Life Sciences. In 2020, Amphista raised GBP6million Series A financing from co-investors Advent, the Scottish Investment Bank, the European Investment Fund and US-based BioMotiv [E3]. Amphista has created jobs for 15 employees (headcount: 15, FTEs:15) and is expected to grow to 25-30 in 2021. A General Partner of Advent Life Sciences explains:

”Advent invests in companies with first or best in class approaches…Amphista is an ideal example of the UK emulating some of the best US academic–industry partnerships. A world leading scientist who has pioneered an important new approach to the discovery of new medicines, working with an experienced Venture Firm to form a University spinout which then raises international finance to build an internationally recognised independent company operating within the UK. While there are some such companies in the UK, they are all too few compared to the US.” [E3].

Partnerships with Boehringer Ingelheim and others

In July 2016 Boehringer Ingelheim (BI) announced a significant (non-disclosed) investment in a collaboration to develop new classes of therapeutics based on PROTAC technology [E4]. The partnership, extended in 2018, created 12 (headcount: 12; FTEs: 12) research jobs in Dundee and approximately 30 (headcount 30: FTEs 30) at BI as part of a novel joint research team [E4, E5]. With an initial focus on oncology, the team progresses PROTACs against human targets suggested by BI, such as the BAF complex that is mutated in 20% of human cancers [E5]. Of the partnership, a Senior Vice President at BI said:

“Dundee University share our vision to transform cancer medicines with PROTACs. We extended our multi-million-pound investment in our alliance with Prof Ciulli to progress new PROTAC therapeutics and bring previously deemed undruggable targets within reach. Alessio Ciulli’s ground-breaking work in defining one of the first ever non-peptidic PROTAC degrader and mechanistic insights into how PROTACs work was instrumental in BI’s decision to collaborate with the University of Dundee” [E4].

The research has continued to attract interest, leading to GBP18million of collective investment since 2016 into Dundee from pharmaceutical companies BI, Nurix, Ono Pharma, Eisai and Almirall, and a total commercialisation income (royalties plus milestones) of GBP1,020,858 [E6].

Sale and open-access use of tools/reagents enabling PROTAC research and innovation

In 2018, Boehringer released Ciulli’s MZ1 on their Open Innovation OpnMe portal, as the first PROTAC freely-available to researchers [E7], with five Ciulli PROTACs now offered [E4]. Of 133 orders in 2019/2020, 45% came from private companies, with orders going to 25 countries [E4]. Two Dundee PROTACs are in the top 5 requested OPnMe molecules [E4]. Several biotech companies, including Tocris, ProbeChem, Medchemexpress and Cayman, market larger quantities of Ciulli’s PROTACs under license from the University of Dundee [E8] with current royalty income to the university of GBP200,000 [E6]. Life Sciences company Promega has also significantly benefited, as explained by their Group Leader of Research & Development:

“The early sharing with us by Alessio Ciulli of key PROTACs discovered in his lab, including but not limited to MZ1, was truly enabling to Promega. He provided fundamental tools to develop novel technologies to study targeted protein degradation and benchmark our efforts in this space, which is today one of the fastest-growing commercial areas for Promega” [E9].