Summit Announces Publication of Phase 2 Clinical Analyses of Gut Microbiome Health
July 13, 2020 – Summit Therapeutics plc announced the publication of data from the Phase 2 clinical trial of the company’s precision antibiotic, ridinilazole, in development for the treatment of C. difficile infection (‘CDI’) in the American Journal of Physiology – Gastrointestinal and Liver Physiology. The data published in collaboration with researchers at Tufts University and Tufts Medical Center demonstrated that ridinilazole’s microbiome preservation resulted in a gut environment expected to inhibit the growth of C. difficile. In contrast, vancomycin treatment resulted in a gut environment that may more highly favor the growth of C. difficile. The difference in gut environment could explain the approximately 60% relative reduction in recurrence observed in patients treated with ridinilazole over vancomycin in the Phase 2 trial.
“This is the first scientific article ever to show the effect of antibiotics treating CDI on the bile acid composition in the human gut. In addition, CoDIFy is the first clinical study to highlight the differential effects of antibiotics on bile acids, which are known to create environments that can either promote or protect against CDI,” said Dr. Ventzislav Stefanov, Executive Vice President and President of Discuva. “The protective gut environment observed after ridinilazole treatment, compared to vancomycin, provides a strong rationale for the higher sustained clinical response observed in patients taking ridinilazole in the CoDIFy clinical trial.”
The Phase 2 clinical trial enrolled 100 patients, half of whom received ridinilazole and the other half vancomycin. The publication, “Ridinilazole, a narrow spectrum antibiotic for treatment of Clostridioides difficile infection, enhances preservation of microbiota-dependent bile acids,” was authored by X. Qian, K. Yanagi, A. Kane, N. Alden, M. Lei, D. Snydman, R. Vickers, K. Lee and C. Thorpe. In the published data, there was a higher ratio of pro-C. difficile to anti C.-difficile bile acids at the start of treatment for both ridinilazole- and vancomycin-treated patients. This was expected, as patients who get CDI have perturbed microbiomes. However, during treatment, patients treated with vancomycin showed a further decrease in anti-C. difficile bile acids and had stools dominated by pro-C. difficile bile acids. In contrast, this did not occur in ridinilazole-treated patients. By the end of the study period, ridinilazole-treated patients’ bile acid ratios trended towards a healthy, non-CDI state. These results support the data from the Phase 2 clinical trial, in which patients receiving ridinilazole showed a statistically significant improvement in sustained clinical responses.
Summit Therapeutics Reports New Data from Phase 2 Clinical Trial Connecting Ridinilazole’s Microbiome Preservation to Improved Clinical Outcomes for Patients with C. difficile Infection
Summit Therapeutics announced the presentation of new data that explain the link between two key findings in the Company’s Phase 2 clinical trial of ridinilazole for C. difficile infection (‘CDI’):
Ridinilazole demonstrated superior efficacy compared to vancomycin, driven by a 60% lower recurrence rate.
Ridinilazole preserved the diversity of the gut microbiome.
Researchers at Tufts University, collaborating with Summit, showed that these findings are connected mechanistically by bile acids, part of the ‘metabolome’ of active chemicals made or modified by gut bacteria. Bile acids exist in different forms that can either favour or block the regrowth of C. difficile after treatment. Vancomycin kills bacteria that turn pro-C. difficile bile acids into anti-C. difficile bile acids – leaving an adverse ratio of pro- and anti-growth chemicals that favours the regrowth of C. difficile and the recurrence of C. difficile infection. By contrast, ridinilazole leaves these bacteria unharmed, allowing them to keep converting pro-C. difficile bile acids into anti-C. difficile bile acids, maintaining a positive chemical balance that prevents C. difficile recurrence.
“The damaging effect of broad-spectrum antibiotics in the treatment of CDI is far-reaching from the make-up and function of the gut microbiome through the poor clinical outcomes seen in one third of patients, driven by a high rate of disease recurrence,” said Dr David Roblin, President of R&D of Summit.“Ridinilazole has the potential to be a targeted CDI treatment that could result in significantly better patient outcomes for the over half million US patients per year who have an episode of CDI. These latest data help to put the science behind the function of a healthy microbiome into context and highlight its importance in sustaining CDI cures.”
The Phase 2 clinical trial enrolled 100 patients, half of whom received ridinilazole and the other half vancomycin. For both groups, there was a higher ratio of pro-C. difficile to anti C.-difficile bile acids at the start of treatment. This was expected, as patients who get CDI have perturbed microbiomes. However, during treatment, the proportion of anti-C. difficile bile acids increased in patients treated with ridinilazole, whereas patients treated with vancomycin initially showed decreases in anti-C. difficile bile acids and had stools dominated by pro-C. difficile bile acids. By the end of treatment, ridinilazole-treated patients’ bile acid ratios returned towards a healthy, non-CDI state. These results support the data from the Phase 2 clinical trial, in which patients receiving ridinilazole showed a statistically significant improvement in sustained clinical responses.
Copies of the two poster presentations are available in the Publications section of Summit’s website, www.summitplc.com.
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Summit Doses First Patient in Phase 3 Clinical Trials of Precision Antibiotic Ridinilazole for C. Difficile Infection
Trials Aim to Show Superiority of Ridinilazole Over Standard of Care Treatment Vancomycin
Health Economic Outcomes Included to Support Commercialisation
FROM PRESS RELEASE:
Oxford, UK, and Cambridge, MA, US, 13 February 2019 – Summit Therapeutics plc (NASDAQ: SMMT, AIM: SUMM), a leader in new mechanism antibiotic innovation, today announces it has dosed the first patient in the global Phase 3 clinical trials of its precision oral antibiotic, ridinilazole, for C. difficile infection (‘CDI’). The trials aim to show superiority of ridinilazole over the standard of care, vancomycin, in a measure that combines CDI cure and recurrence called sustained clinical response (‘SCR’). Ridinilazole achieved statistical superiority over vancomycin in SCR in a Phase 2 clinical trial.
“Starting our Phase 3 programme is an important milestone for Summit,” commented Mr Glyn Edwards, Chief Executive Officer of Summit. “With positive results, we believe ridinilazole could be positioned as the drug of choice in the front-line treatment of CDI, which potentially provides patients with sustained cures and hospitals with compelling cost savings.”
“Ridinilazole is the trail-blazer in our growing pipeline of innovative product candidates targeting serious infectious diseases,” added Dr David Roblin, President of R&D of Summit. “Our Phase 3 programme exemplifies our broader strategy of demonstrating significant advantages over current standards of care by gathering a carefully considered package of clinical and economic data to address the needs of physicians, regulators, healthcare providers, payors and, above all, patients.”
The Phase 3 clinical programme comprises two global, randomised, double-blind, active-controlled clinical trials called Ri-CoDIFy 1 and Ri-CoDIFy 2. The trials will be run concurrently with each expected to enrol approximately 680 patients at sites in North America, Latin America, Europe, Australia and Asia. Upon confirmation of a positive CDI toxin test, patients will be randomised to receive either ridinilazole (200mg twice a day) or vancomycin (125mg four times a day) for ten days. The primary endpoint of both clinical trials will test for superiority in SCR, defined as cure at the end of treatment and no recurrence of CDI within 30 days post-treatment. Secondary endpoints include cure at the end of treatment and SCR at 60 days and 90 days post-treatment. Additional endpoints will evaluate the impact of ridinilazole and vancomycin on the gut microbiome, which is known to protect against CDI. The Phase 3 clinical trials also include health economic outcome measures, such as readmission rates and length of hospital stay, to help support the commercialisation of ridinilazole, if approved.
Top-line data from the Phase 3 programme are expected to be reported in the second half of 2021.
The clinical and regulatory development of ridinilazole is being funded in part with Federal funds from the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (‘BARDA’), under Contract No. HHS0100201700014C. Summit is eligible to receive up to $62 million in funding from BARDA to support the clinical and regulatory development of ridinilazole.
Ridinilazole is an oral small molecule new mechanism antibiotic that is designed to selectively kill C. difficile, thereby preserving patients’ protective gut microbiome and leading to sustained CDI cures. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin. In that trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy. Ridinilazole was also shown to be highly preserving of the gut microbiome in the Phase 2 proof of concept trial, which was believed to be the reason for the improved clinical outcome for the ridinilazole-treated patients. In addition, ridinilazole preserved the gut microbiome to a greater extent than the marketed narrow-spectrum antibiotic fidaxomicin in an exploratory Phase 2 clinical trial. Ridinilazole has received Qualified Infectious Disease Product (‘QIDP’) designation and has been granted Fast Track designation by the US Food and Drug Administration. The QIDP incentives are provided through the US GAIN Act and include a potential extension of marketing exclusivity for an additional five years upon FDA approval.
About Summit Therapeutics
Summit Therapeutics is a leader in antibiotic innovation. Our new mechanism antibiotics are designed to become the new standards of care for the benefit of patients and create value for payors and healthcare providers. We are currently developing new mechanism antibiotics for infections caused by C. difficile,N. gonorrhoeae and ESKAPE pathogens and are using our proprietary Discuva Platform to expand our pipeline.
Summit Therapeutics — the drug discovery and development company advancing therapies for Duchenne muscular dystrophy and Clostridium difficile infection (‘CDI’), announces that it has entered into an exclusive license and commercialization agreement granting Eurofarma Laboratórios SA (‘Eurofarma’) rights in Latin America (the ‘Licensed Territory’) to Summit’s precision antibiotic ridinilazole in development for the treatment of CDI.
Summit retains commercialization rights in all other countries.
ridinilazole is a targeted antibiotic that has the potential as a frontline therapy to treat initial infection and preserve patients’ microbiomes to reduce the rate of recurrent CDI. In a Phase 2 proof of concept trial in CDI patients, ridinilazole demonstrated statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin.
ridinilazole is expected to enter Phase 3 clinical trials in the first half of 2018.
“Eurofarma’s established infrastructure and expertise in Latin America are ideally placed to commercialise our novel antibiotic, ridinilazole,”commented Glyn Edwards, Chief Executive Officer of Summit. “This agreement, combined with the recent contract award of up to $62 million from the US Government agency BARDA, will further support the Phase 3 clinical programme and regulatory development of ridinilazole. These partnerships endorse the potential of ridinilazole in the treatment of CDI, and move us a step closer to bringing this antibiotic to patients.”
Eurofarma is a multinational pharmaceutical company with headquarters in Brazil and operations in over 20 countries in South and Central America, the Caribbean and Africa. Eurofarma has a broad portfolio of products across multiple therapeutic areas including a focus in infectious diseases where it markets a number of antibiotics.
“CDI is a serious global healthcare threat including in Latin America,” added Martha Penna, P&D Vice-president of Eurofarma. “Through our interest in bringing innovative products to the region, we were impressed by the efficacy data from the ridinilazole Phase 2 programme and the differentiated profile of the drug. We believe it has the potential to address a major unmet need in CDI, and we look forward to working with Summit to bring ridinilazole to market for the benefit of patients.”
Under the terms of the licence and commercialisation agreement, Summit will receive an upfront payment of $2.5 million, and is entitled to receive a further $3.75 million in development milestones upon the achievement of staged patient enrolment targets in the planned Phase 3 clinical trials of ridinilazole. Summit is eligible to receive up to an additional $21.4 million through other development milestones, commercial milestones, and one-time sales milestones based on cumulative net sales up to $100 million in the Licensed Territory. Further, the agreement provides for product supply transfer payments expected to provide a return equivalent to a high single digit to low double-digit percentage of net sales. For each incremental $100 million in cumulative net sales achieved, Summit is entitled to a further milestone payment which, when combined with the aforementioned product supply transfer payments, is expected to provide a return equivalent to a mid- to high-teens percentage of net sales.
Eurofarma will be responsible for obtaining regulatory approval for ridinilazole in the Licensed Territory. Summit retains full responsibility for the clinical development of ridinilazole in all countries, and is responsible for obtaining regulatory approvals outside of the Eurofarma licensed territories.
A Form 6-K will be filed with the US Securities and Exchange Commission (‘SEC’) that contains additional information about the terms of the licence and commercialisation agreement with Eurofarma.
A copy of this Form 6-K will be available to download either from the Investors section of the Company website at www.summitplc.com or from the SEC website at www.sec.gov.
This announcement contains inside information for the purposes of Article 7 of EU Regulation 596/2014 (MAR).
Ridinilazole is a small molecule precision antibiotic that Summit is developing for the treatment of CDI. In preclinical efficacy studies, ridinilazole exhibited a targeted spectrum of activity that combined a potent bactericidal effect against all clinical isolates of C. difficile tested with minimal impact on other bacteria that are typically found in the gut microbiome. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin. In that trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy. Ridinilazole was also shown to be highly preserving of the gut microbiome in the Phase 2 proof of concept trial, which was believed to be the reason for the improved clinical outcome for the ridinilazole-treated patients. In addition, ridinilazole preserved the gut microbiome to a greater extent than the marketed narrow-spectrum antibiotic fidaxomicin in an exploratory Phase 2 clinical trial. Ridinilazole, an orally administered small molecule, has received Qualified Infectious Disease Product (‘QIDP’) designation and has been granted Fast Track designation by the US Food and Drug Administration. The QIDP incentives are provided through the US GAIN Act and include an extension of marketing exclusivity for an additional five years upon FDA approval.
About Summit Therapeutics
Summit is a biopharmaceutical company focused on the discovery, development and commercialisation of novel medicines for indications for which there are no existing or only inadequate therapies. Summit is conducting clinical programmes focused on the genetic disease Duchenne muscular dystrophy and the infectious disease C. difficile infection. Further information is available at www.summitplc.com and Summit can be followed on Twitter (@summitplc).
About the Eurofarma Group
As the first 100% Brazilian-owned multinational pharmaceutical company, Eurofarma has been in existence for 45 years, has 6,500 employees, and has operations in 20 Latin American countries. With 12 manufacturing plants in the region, the company has more than 280 products in its portfolio. In 2016, it produced more than 290 million units and reached revenues of R$3.3 billion, 15.7% higher than the previous year. The Group invests approximately 5.5% of its net sales in Research & Development and maintains a pipeline of more than 175 projects.
About Eurofarma Brazil
Considered one of the best companies to work for, Eurofarma Brazil is also considered the most sustainable pharmaceutical company in the country based on an analysis by the Exame Sustainability Guide. With operations in all main pharmaceutical segments including Medical Prescriptions, Generics, Hospital, Oncology, Veterinary, and Bids and Services to Third Parties, Eurofarma has the largest medical advertising salesforce in Brazil with more than 2,000 representatives that together perform 450,000 medical contacts per month. The company has the 4th largest pharmacy system in the country and has a portfolio of medicines that is the 2nd largest by prescription volume.
Raising global awareness with leading international topic experts have proven to be effective over the years with audiences attending our annual conferences.
The Global C. difficile Congress took place on November 11th, 2016 and broadened existing knowledge surrounding C. difficile infection (CDI) prevention, treatments, research, and environmental safety worldwide.
The drive and passion takes us forward in promoting the practical and technical advancements taking place across the globe. Healthcare Professionals from every area of expertise, discussed the control and treatment options, the healthcare perspectives, antibiotic-resistance stewardship programs, and much more to raise C. diff. awareness and share successful implementations and guidelines.
This free webinar is available to you and with the ease of learning without having to travel.
The Global C. difficile Congress — eight sessions presented by topic experts – in four hours – in one day – with goals to change the C. difficile world with a common focus; To
improve awareness of C. diff. infection prevention, treatments, research, and environmental safety in the healthcare communities worldwide.
Dr. Paul Feuerstadt; Native of Long Island, New York, Dr. Feuerstadt attended the University of Pennsylvania where he earned his Bachelor of Arts degree in Biology, with distinction in research and graduated Summa Cum Laude. Following completion of his undergraduate training, Dr. Feuerstadt attended the Weill Medical College of Cornell University in Manhattan, New York where he earned his Medical Doctor degree and stayed at New York Presbyterian Hospital/Weill Cornell medical center for his internship and residency in Internal Medicine. Following completion of his residency
Dr. Feuerstadt then moved on to the Montefiore Medical Center in the Bronx, NY for his clinical fellowship training.His areas of interest include ischemic diseases of the gut and chronic diarrheal syndromes with a specific focus on C.diff. infections.Dr. Feuerstadt is affiliated with St. Raphael campus of Yale-New Haven Hospital, Yale-New Haven Hospital and
Milford Hospital seeing outpatients in his offices in Hamden and Milford, CT Topic: Welcome – Introduction
8:15 – 8:45 a.m. 1:15 – 1:45 Jean de Gunzburg, PhD
Dr. de Gunzburg is Chief Scientific Officer of Da Volterra, an emerging biotechnology company, headquartered in Paris, France. Prior to this, Jean de Gunzburg led an academic research career in molecular and cell biology at the Institut Pasteur (Paris, France), the Whitehead Institute for Biomedical Research (Cambridge, MA, USA) and the Institut Curie (Paris, France). He is the author of over 70 publications in international peer reviewed scientific journals, and continues to serve on several grant review committees. Topic: “DAV132, A Novel Product Destined To Prevent Antibiotic-Induced
Clostridium difficile Infections.”
8:45 – 9:15 1:45 – 2:15 Arjun Srinivasan, MD
Dr. Arjun Srinivasan is the Associate Director for healthcare-associated infection (HAI) prevention programs in the Division of Healthcare Quality Promotion at the Center for Disease Control and Prevention’s National Center for Emerging and Zoonotic Infectious Diseases. Dr. Srinivasan is also a captain in the US Public Health Service. An infectious disease doctor, Dr. Srinivasan oversees several CDC programs aimed at eliminating healthcare-associated infections and improving antibiotic use. For much of his CDC career, Dr. Srinivasan ran the healthcare outbreak investigation unit, helping hospitals and other healthcare facilities track down bacteria and stop them from infecting other patients. Dr. Srinivasan leads the CDC’s work to improve antibiotic prescribing and works with a team of CDC experts researching new strategies. Topic: “Antibiotic Stewardship- Improving Antibiotic Use to Combat C diff.”
9:15 – 9:45 2:15 – 2:45 Clifford McDonald, MD
Dr. McDonald graduated from Northwestern University Medical School. He completed a medical microbiology fellowship at Duke University and is a former member of CDC’s Epidemic Intelligence Service. Dr. McDonald is currently the Associate Director for Science in the Division of Healthcare Quality Promotion at the CDC. He has first authored or co-authored over 100 peer reviewed publications on subjects related to healthcare and infectious disease epidemiology Dr. McDonald joins fellow world-renowned topic experts to discuss the burden of C. difficileinfections with the risk factors pertaining to current and emerging treatment options along with the importance of applying evidence-based clinical approaches to the prevention of a C. difficile infection (CDI), one of the leading community and healthcare-associated infections. Topic: “Challenges and Opportunities Posed by Current Diagnostics
for Clostridium difficile Infection”
Barley Chironda a Nurse, National Healthcare Sales Director and Infection Control Specialist Clorox Canada, Social Media Manager of IPAC Canada, and the current President of IPAC- GTA. Mr. Chironda is certified in Infection prevention and control (CIC) and has worked extensively in Infection Control. He is typically found engaged in motivating hospital staff, patients and the public on proper infection prevention practices. Mr. Chironda’s roles allow great participation in quality improvement interventions related to patient and public safety. Therefore Barley has been an integral to the successful decline in Clostridium difficile infections through implementing innovative technology and quality improvement behavioral change. Topic: “The C.diff.. Disinfection Debate: To Use
Or Not To Use Sporicidal Disinfectants Every-Time In Healthcare Facilities.”
10:15 -10:45 3:15 – 3:45 Dale Gerding, MD
Dr. Dale Gerding, Professor of Medicine at Loyola University Chicago Stritch School of Medicine in Maywod, Illinois and Research Physician at the Edward Hines Jr. VA Hospital. Prior to his present position Dr. Gerding was Chief of Medicine at VA Chicago, Lakeside Division, and Professor of Medicine at Northwestern University Feinberg School of Medicine. He is an infectious diseases specialist and hospital epidemiologist, past president of the Society for Healthcare Epidemiology of America and past chair the antibiotic resistance committee of SHEA. He is a fellow of the Infectious Diseases Society of America and past Chair of the National and Global Public Health Committee and the Antibiotic Resistance Subcommittee of IDSA. He served as a member of the Board of Directors of IDSA from 2005-2008. He is a Master of the American College of Physicians and the 2013 recipient of the William Middleton Award, the highest research award given by the Department of Veterans Affairs. He is a member of the American Society for Microbiology, and is board certified in Internal Medicine and Infectious Diseases. His research interests include the epidemiology and prevention of Clostridium difficile disease, antimicrobial resistance, and antimicrobial distribution and kinetics. He has been a Merit Review funded research investigator in the VA for over 40 years and is the author of over 400 peer-reviewed journal publications, book chapters, and review articles. He holds patents for the use of non-toxigenic C. difficile for the prevention and treatment of this disease. Topic: “Non-toxigenic Clostridium difficile for Prevention of CDI”
10:45 – 11:15 3:45 – 4:15 Richard Vickers, PhD
Dr. Richard Vickers is the Chief Scientific Officer, Antimicrobials and Programme Lead for CDI,
Summit Therapeutics. He joined Summit in 2003 and during his time has worked in a variety of roles involved in the development and management of various antibacterial therapeutic programs. This includes leading the discovery and development of ridinilazole, the investigational antibiotic for the treatment of C. difficile infection. Prior to joining Summit, Dr Vickers undertook postdoctoral research studies with Professor Stephen Davies at the University of Oxford and held a Stipendiary Lectureship in organic chemistry at St. Catherine’s College in Oxford. Dr Vickers received a Ph.D. in organic chemistry from the University of Reading and a B.Sc. in chemistry from King’s College London. Topic: “Ridinilazole; A Selective Therapy for the Treatment
of C. difficile Infections (CDI)”
11:15 – 11:45 4:15 – 4:45 Simon Cutting, PhD
Professor Cutting of Molecular Microbiology at Royal Holloway, University of London is a bacterial geneticist with over 25 years of experience with Bacillus since graduating from Oxford University with a D. Phil in 1986. His D.Phil was on understanding the genetic control of spore formation in Bacillus Clostridium difficile.. His other expertise is in the use of Bacillus spores as probiotics and has a number of contracts and consultancies with European and US companies in the food and feed sectors. Topic: “Thwarting the Opportunist: An Anti-adhesion
Vaccine That Prevents C.difficult Colonization.”
11:45 – 12:15 4:45 – 5:15 Hudson Garrett, Jr, PhD
Dr. Garrett is currently employed as the Global Chief Clinical Officer for Pentax Medical. He holds a dual Masters in Nursing and Public Health, Post-Masters Certificate as a Family Nurse Practitioner, a Post-Masters Certificate in Infection Prevention and Infection Control and a PhD in Healthcare Administration and Policy. He has completed the Johns Hopkins Fellows Program in Hospital Epidemiology and Infection Control, and the CDC Fundamentals of Healthcare Epidemiology program, and is board certified in family practice, critical care, vascular access, moderate sedation, infection prevention, legal nurse consulting, and a director of nursing in long term care. Dr. Garrett is also a Fellow in the Academy of National Associations of Directors of Nursing Administration in Long Term Care. Topic: “Improving Patient Safety and Reducing Clostridium difficile
through Collaboration with Clinical Nursing and Environmental Services Professionals”
For more information please visit the Global C. difficile Congress