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Inward investment and the development of Summit Therapeutics

When Summit Therapeutics began work with the Neidle group in 2007, the company was a small biotech based in Oxford, UK. By December 2019, Summit raised over USD150,000,000, of investment, with the major shareholder being billionaire entrepreneur Robert Duggan. Duggan, who is now acting CEO, himself invested USD75,000,000 [ S1] in order to support the companies Phase 3 Clinical Trials of ridinilazole. Summit is now an international Nasdaq-listed public company with three further pipeline streams and a proprietary discovery platform (Discuva) [ S2], all focused on the development of novel antibiotics based on the success of ridinilazole.

The inward investment that Summit has raised has allowed the company to grow in this way began with a Wellcome Trust Seeding Drug Discovery Grant (on which Neidle was a funded collaborator) to perform further chemistry, mode-of-action studies and pre-clinical work. The Wellcome Trust then supported Phase I studies (concluded 2012) followed by USD70,000,000 from BARDA (Biomedical Advanced Research and Development Authority) in the US to fund Phase 2 studies (completed in 2015). Robert Duggan invested USD25,000,000 in 2018 and USD50,000,000 in 2019; Phase 3 studies are currently underway and the results are expected to be available in 2021.

The success in securing investment and associated company growth is openly ascribed to the success of ridinilazole; The Chief Scientific Officer of Summit [ S3] has stated: “ The collaboration between Summit and UCL to drive the preclinical program is an excellent example of the type of industry-academia drug discovery collaboration that is now quite common across both biotech and big pharma. Ridinilazole has advanced directly through this collaboration but also indirectly through the foundation work of Professor Neidle at UCL over the previous nearly 20 years” and goes on to state that “ The origin of ridinilazole is indelibly linked with a research collaboration that started over a decade ago between Summit and the academic groups of Professors Stephen Neidle (UCL) and John Mann (University of Belfast).” There is a royalty agreement in place between UCL and Summit Therapeutics, reflecting the contribution made by Neidle and Taylor to the development of ridinilazole.

Successful patient outcomes in the Phase 2 ridinilazole study

The Phase 2 study for ridinilazole (initiated 2014) involved 100 patients in the US and Canada, and was performed as a double-blind comparison to the current standard of care, vancomycin. The outcomes showed not just equivalence but significant improvements in patient outcomes. In addition, where reoccurrence is a major issue for C. difficile infection (CDI), Ridinilazole showed significant advantages in terms of clinical cure (77.8% for ridinilazole vs. 68.7% for vancomycin), sustained clinical response (66.7% for ridinilazole vs. 42.4% for vancomycin) and prevention of reoccurrence (14.3% for ridinilazole vs. 34.8% for vancomycin) [ S4]. The trial also highlighted a sustained clinical response, indicating where patients were free from disease after ten days of treatment and remained free from disease for 30 days after treatment ended.

Phase 2 also reported alleviated symptoms related to quality of life index indicators such as mobility, self-care, pain/discomfort and mental health issues such as anxiety and depression [ S5]. The Chief Communications Officer of Summit stated, ‘ As early as Day five, patients treated with ridinilazole reported significant improvements in index scores (p=0.008), a measure which combines scores from the five domains, and visual analogue scale (VAS) scores (p=0.01), which is a self-reported score of overall health. As an example, by Day 40 of the trial, patients treated with ridinilazole had improved significantly more than vancomycin in anxiety and depression’. These results, along with the statistical superiority achieved in the primary clinical endpoint of sustained clinical response, supported the continued development of ridinilazole. As a consequence, the US FDA accorded the drug Fast Track Development and Qualified Infectious Disease Product status, which includes an extension of marketing exclusivity [ S5].

C. difficile gastric infection is an extremely serious condition with over 1 million cases in the US and Europe per annum and circa 29,000 annual deaths in the US. While the number of patients that have benefited from the drug thus far is limited by the regulatory status, this nevertheless represents a significant alleviation of suffering and risk of mortality for those involved in the trials to date. The current Phase 3 studies involve 1360 patients (two global studies of 680 patients) across North America, Australia, Asia, Europe and South America [ S6].

The strategic importance of ridinilazole

Over and above the success story of a small UK biotech company managing to bring a drug to Phase 3 (without the company or drug being sold to a more established concern), the ridinilazole narrative has several aspects that distinguish it from other development journeys. In the first instance, the need for new and novel classes of antibiotics, and the associated difficulties with bringing such molecules to market, is well established [ S7]. Furthermore, treatment of C. difficile is a major priority within this arena; the FDA has also designated C. difficile as one of three pathogens that pose an immediate public health threat requiring urgent action. Secondly, the drug is a first in class molecule. More specifically, the use of BBZ scaffolds as minor-groove binding compounds represents a new approach to treatment, opening possibilities not only of further analogues but also carrying implications for reduced resistance. Finally, the mechanism of action and the interaction with the gut microbiome are of themselves of great interest to the sector. The ‘microbiome friendly’ activity of ridinilazole in promoting the generation of secondary bile acids which in turn inhibit vegetative growth [ R6] presents the possibility to the sector of designing mechanism-targeted drugs that manipulate microbiome composition and activity, to the benefit of the patient and the sector.