Impact case study database

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].