ridinilazole (SMT 19969) / Summit Therapeutics, Eurofarma - LARVOL DELTA

In vitro susceptibility of clinical Clostridioides difficile isolates in Israel to metronidazole, vancomycin, fidaxomicin, ridinilazole and ibezapolstat. (PubMed, BMC Gastroenterol) - "RDZ and IBZ demonstrated potent in vitro activity against 313 C. difficile isolates belonging to different STs. These two antimicrobials may serve as effective agents for C. difficile infection."

Journal • Preclinical • Infectious Disease

Comparative effectiveness of different therapies for Clostridioides difficile infection in adults: a systematic review and network meta-analysis of randomized controlled trials. (PubMed, Lancet Reg Health Eur) - "In recurrent cases, fidaxomicin (P-score: 0.6734) showed significantly greater effectiveness than vancomycin (P-score: 0.3677) and tolevamer (P-score: 0.0365). For non-recurrent CDI treatments ridinilazole, fidaxomicin, FMT and nitazoxanide were equally effective...Our findings suggest that the preventive use of probiotics might be questioned. None."

HEOR • Journal • Retrospective data • Infectious Disease • Transplantation

Fighting against Clostridioides difficile infection: Current medications. (PubMed, Int J Antimicrob Agents) - "Recent guidelines recommend fidaxomicin and vancomycin as first-line drugs to treat CDI, bezlotoxumab to prevent recurrence, and fecal microbiota transplantation (FMT) for rescue treatment. Currently, researchers are investigating therapeutic antibacterial drugs (e.g., teicoplanin, ridinilazole, ibezapolstat, surotomycin, cadazolid, and LFF571), preventive medications against recurrence (e.g., Rebyota, Vowst, VP20621, VE303, RBX7455, and MET-2), primary prevention strategies (e.g., vaccine, ribaxamase, and DAV132) and other anti-CDI medications in the preclinical stage (e.g., Raja 42, Myxopyronin B, and bacteriophage). This narrative review summarizes current medications, including newly marketed drugs and products in development against CDI, to help clinicians treat CDI appropriately and to call for more research on innovation."

Journal • Review • Infectious Disease • Transplantation

A Randomized, Double-Blind, Phase 3 Safety and Efficacy Study of Ridinilazole Versus Vancomycin for Treatment of Clostridioides difficile Infection: Clinical Outcomes With Microbiome and Metabolome Correlates of Response. (PubMed, Clin Infect Dis) - P3 | "Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566."

Clinical • Clinical data • Journal • P3 data • Infectious Disease

Microbiome-preserving antibiotics for the treatment of Clostridioides difficile infection: a systematic review and meta-analysis. (PubMed, Tech Coloproctol) - "Fidaxomicin (in seven studies) demonstrated significant improvement in achieving sustained clinical cure. A limitation of this study may that more studies are needed to compare fidaxomicin with other antibiotics."

Clinical • Journal • Retrospective data • Review • Infectious Disease

A US-based national surveillance study for the susceptibility and epidemiology of Clostridioides difficile isolates with special reference to ridinilazole: 2020-2021. (PubMed, Antimicrob Agents Chemother) - "In comparison, fidaxomicin had an MIC 90 of 0.5 mcg/mL. The vancomycin MIC 90 was 2 mcg/mL with a 0.7% resistance rate [both CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria]...Ridinilazole maintained activity against all ribotypes and all strains resistant to any other agent tested. Ridinilazole showed excellent in vitro activity against C. difficile isolates collected between 2020 and 2021 in the United States, independent of ribotype."

Journal

Clostridioides difficile resistance to antibiotics, including post-COVID-19 data. (PubMed, Expert Rev Clin Pharmacol) - "The mean resistance to 2 mg/l vancomycin, 2 mg/l metronidazole, 4 mg/l moxifloxacin, and 4 mg/l clindamycin was 4.7% (0 to ≥ 26% in two studies), 2.6% (0 to ≥ 40% in 3 studies), 34.9% (6.6->80%), and 61.0% (30->90%), respectively. Resistance to erythromycin (>60-88%), rifampin (>23-55.0%), imipenem (0.6 to > 78% in a clone), tigecycline (0-<5.0%), and fidaxomicin (0-2%) was also found...New approaches, including biotherapeutics (Rebyota), strains, antibiotics (ridinilazole and ibezapolstat), and monoclonal antibodies/cocktails merit further evaluation...Post-COVID-19 resistance should be separately presented. Some discrepancies between vancomycin and metronidazole results need to be clarified."

Journal • Review • Infectious Disease • Novel Coronavirus Disease

Clostridioides difficile - New Insights and Therapy Recommendations (PubMed, Dtsch Med Wochenschr) - "The updated 2021 ESCMID guidelines recommend fidaxomicin instead of vancomycin as the antibiotic of choice for the treatment of CDI because of its lower recurrence rate...In the future, ridinilazole may be available as another therapeutic option that has a narrow spectrum of activity and low intestinal absorption. For the treatment of recurrent CDI, the new guidelines also include the use of the monoclonal antibody bezlotoxumab. In addition, a new oral microbiome therapy, SER-109 (capsules containing purified Firmicutes spores), which showed promising results in a phase 3 study, may provide an easy-to-administer alternative to fecal microbiota transplantation. Hopes for a well-performing toxoid vaccine for primary and secondary prevention of CDI have unfortunately not been fulfilled in the CLOVER trial."

Journal • Infectious Disease • Transplantation

The Novel DNA Binding Mechanism of Ridinilazole, a Precision Clostridiodes difficile Antibiotic. (PubMed, Antimicrob Agents Chemother) - "DNA binding and genomic localization was confirmed through confocal microscopy utilizing the intrinsic fluorescence of ridinilazole upon DNA binding. As such, ridinilazole has the potential to be the first antibiotic approved with a DNA minor groove binding mechanism of action."

Journal • Infectious Disease

The Urgent Threat of Clostridioides difficile Infection: A Glimpse of the Drugs of the Future, with Related Patents and Prospects. (PubMed, Biomedicines) - "Many possible drugs of the future for CDI, with diverse mechanisms of action, are in development in the form of microbiota-modulating agents (e.g., ADS024, CP101, RBX2660, RBX7455, SYN-004, SER-109, VE303, DAV132, MET-2, and BB128), small molecules (e.g., ridinilazole, ibezapolstat, CRS3123, DNV3837, MGB-BP-3, alanyl-L-glutamine, and TNP-2198), antibodies (e.g., IM-01 and LMN-201), and non-toxic strains of CD (e.g., NTCD-M3). The development of some therapeutic agents (e.g., DS-2969b, OPS-2071, cadazolid, misoprostol, ramoplanin, KB109, LFF571, and Ramizol) stopped due to failed clinical trials or unknown reasons...The current pipeline of anti-CDI medications appears promising. However, it will be fascinating to see how many of the cited are successful in gaining approval from drug regulators such as the US FDA and becoming medicines for CDI and r-CDI."

Journal • Review • Developmental Disorders • Infectious Disease

Ri-CoDIFy 1: Comparison of Ridinilazole Versus Vancomycin Treatment for Clostridium Difficile Infection (clinicaltrials.gov) - P3 | N=759 | Completed | Sponsor: Summit Therapeutics | N=355 ➔ 759

Enrollment change • Infectious Disease

Emerging Options for the Prevention and Management of Clostridioides difficile Infection. (PubMed, Drugs) - "These agents include one antibiotic (ridinilazole), three live biotherapeutic products (LBPs) (CP101, RBX2660, and SER109), and two toxoid vaccines (PF06425090 and a second toxoid vaccine). As new prevention and treatment strategies enter the market, clinicians and administrators will need knowledge of these products to make rational decisions on how best to adopt them into clinical practice."

Journal • Infectious Disease

Ri-CoDIFy 3: Safety, Tolerability and the Pharmacokinetics of Ridinilazole in Adolescent Subjects (clinicaltrials.gov) - P3 | N=2 | Terminated | Sponsor: Summit Therapeutics | N=40 ➔ 2 | Trial completion date: Dec 2023 ➔ Sep 2022 | Recruiting ➔ Terminated; SMT19969-C006 study was terminated in alignment with corporate decision to pursue further development of drug candidate with a partner.

Enrollment change • Trial completion date • Trial termination • Infectious Disease

A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Ridinilazole Compared with Vancomycin for the Treatment of Clostridioides difficile Infection (IDWeek 2022) - No abstract available

Clinical • P3 data • Infectious Disease

A US Based National Surveillance Study for the Susceptibility and Epidemiology of Clostridioides difficile Associated Diarrheal Isolates with Special Reference to Ridinilazole: 2020-2021 (IDWeek 2022) - No abstract available

Clinical • Infectious Disease

Transcriptomic analysis of the Clostridioides difficile-targeting antimicrobial ridinilazole implicates disruption of energy-generation pathways as its mechanism of action (ECCMID 2022) - No abstract available

Symmetric bis-benzimidazoles as DNA minor groove-binding agents with anti-tumour and antibacterial activity, and the evolution of the drug ridinilazole for the treatment of CLOSTRIDIUM difficile infections. (PubMed, Bioorg Med Chem) - "One of these BBZs has specific activity against Clostridium difficile and is currently in a phase 3 clinical evaluation as the drug ridinilazole. X-ray and computer modelling studies showed that BBZs typically exhibit high specificity for oligonucleotide sequences that occur in the minor groove of DNA."

Journal • Review • Infectious Disease • Oncology

Ridinilazole: a novel, narrow-spectrum antimicrobial agent targeting Clostridium (Clostridioides) difficile. (PubMed, Lett Appl Microbiol) - "One such agent, fidaxomicin, has been in therapeutic use for several years and is now recommended as a first-line treatment for CDI, as it is superior to vancomycin in reducing risk of recurrence. Phase I and II clinical trials have been completed, with ridinilazole showing high tolerability and efficacy in treatment of CDI, and superiority over vancomycin in reducing recurrence of CDI within 30 days of treatment completion. Phase III trials are currently underway, the results of which may prove its potential to reduce recurrent CDI and lessen the heavy health and financial burden C. difficile imposes on patients and healthcare systems."

Journal • Review • Infectious Disease

Ri-CoDIFy 2: To Compare Ridinilazole Versus Vancomycin Treatment for Clostridium Difficile Infection (clinicaltrials.gov) - P3; N=404; Completed; Sponsor: Summit Therapeutics; Active, not recruiting ➔ Completed

Clinical • Trial completion • Infectious Disease

Ri-CoDIFy 1: Comparison of Ridinilazole Versus Vancomycin Treatment for Clostridium Difficile Infection (clinicaltrials.gov) - P3; N=355; Completed; Sponsor: Summit Therapeutics; Active, not recruiting ➔ Completed

Clinical • Trial completion • Infectious Disease

[VIRTUAL] Characterisation of the DNA binding properties of ridinilazole, a selective antibiotic currently in phase III trials for the treatment of Clostridioides difficile (IDWeek 2021) - "In a phase II study, r idinilazole was shown to be effective at treating CDI and decreasing subsequent recurrence compared to vancomycin. Ridinilazole demonstrates tight binding with sequence specificity within the minor groove of DNA and co-localises with DNA in C. difficle . Further analysis is ongoing to fully understand this novel mechanism of action, the downstream consequences of these interactions and how they contribute to the bactericidal activity of ridinilazole."

P3 data • Infectious Disease

Ri-CoDIFy 2: To Compare Ridinilazole Versus Vancomycin Treatment for Clostridium Difficile Infection (clinicaltrials.gov) - P3; N=404; Active, not recruiting; Sponsor: Summit Therapeutics; Recruiting ➔ Active, not recruiting; N=680 ➔ 404; Trial primary completion date: Jun 2021 ➔ Sep 2021

Clinical • Enrollment change • Enrollment closed • Trial primary completion date • Infectious Disease

Ri-CoDIFy 1: Comparison of Ridinilazole Versus Vancomycin Treatment for Clostridium Difficile Infection (clinicaltrials.gov) - P3; N=355; Active, not recruiting; Sponsor: Summit Therapeutics; Recruiting ➔ Active, not recruiting; N=680 ➔ 355; Trial primary completion date: Jun 2021 ➔ Sep 2021

Clinical • Enrollment change • Enrollment closed • Trial primary completion date • Infectious Disease

"Check out ridinilazole from @Summitplc. I'm intrigued." (@SuperMal5)

Inhibition of spores to prevent the recurrence of Clostridioides difficile infection - A possibility or an improbability? (PubMed, J Microbiol Immunol Infect) - "Clostridioides difficile is one of the most common nosocomial gastrointestinal pathogens, and recurrence is a problematic issue because approximately 20-30% of patients experience at least one episode of recurrence, even after treatment with a therapeutic drug of choice for C. difficile infection (CDI), such as vancomycin...However, an antimicrobial agent, such as fidaxomicin, which has a good inhibitory effect on both C. difficile vegetative cells and spores is assumed to not only treat CDI but also prevent its recurrence...Some new antimicrobial agents in phase II clinical trials, including cadazolid and ridinilazole, have shown exceptional anti-C. difficile and spore-inhibiting effects that can be expected to not only treat CDI but also prevent its recurrence in the future."

Journal • Review • Gastrointestinal Disorder • Infectious Disease