Clinical Development Program
Acurx is currently enrolling patients in its Phase 2b clinical trial of ibezapolstat compared to vancomycin, a standard of care to treat C. difficile infection or CDI. The Phase 2b clinical trial consists of 64-patients, randomized (1-to-1), non-inferiority, double-blind trial of oral ibezapolstat compared to oral vancomycin, a standard of care to treat CDI.
The Company successfully completed Phase 1 and Phase 2a clinical trials of ibezapolstat. The Phase 2a trial demonstrated 100% clinical cure at end of treatment and 100% sustained clinical cure in patients with C. difficile Infection (CDI), along with beneficial microbiome changes during treatment including overgrowth of Actinobacteria and Firmicutes phylum species while on therapy and new findings which demonstrate potentially beneficial effects on bile acid metabolism.
The Phase 1 clinical trial included a head-to-head comparison of oral ibezapolstat to oral vancomycin for impact on the microbiome and the results were exceptional, leading to the creation of a new exploratory endpoint in the Phase 2b clinical trial to continue to compare the impact on the microbiome between ibezapolstat and standard of care oral vancomycin.
We intend to meet with the FDA after completing the Phase 2b clinical trial to finalize the size and scope of the Phase 3 clinical trial program. Regulatory precedent indicates that two Phase 3 trials of approximately 400 patients each would need to be conducted.
Additional information about the trial can be found in our press release, dated November 5, 2020, and at www.clinicaltrials.gov (Study identifier: NCT04247542).
In June 2018, ibezapolstat was designated by the U.S. Food and Drug Administration (FDA) as a Qualified Infectious Disease Product (QIDP) for the treatment of patients with CDI and will be eligible to benefit from the incentives for the development of new antibiotics established under the Generating New Antibiotic Incentives Now (GAIN) Act. In January 2019, FDA granted "Fast Track" designation to ibezapolstat for the treatment of patients with CDI. The CDC has designated C. difficile as an urgent threat highlighting the need for new antibiotics to treat CDI.
A New Approach to Treating CDI
Ibezapolstat (formerly named ACX-362E) is our lead antibiotic candidate. Ibezapolstat is a first-in-class of a new class of Pol IIIC inhibitors which is in clinical development to treat C. difficile infections or CDI. Current treatments for CDI infections utilize other mechanisms of action while ibezapolstat is the first antibiotic candidate intended to work by blocking the Pol IIIC enzyme in C. difficile. This enzyme is necessary for replication of the DNA of the DNA of the bacterial cell.
Acurx has worked closely with the FDA to obtain FDA “Fast track” designation as well as designation of ibezapolstat as a qualified infectious disease product, or QIDP, which provides incentives through the GAIN Act including priority review by the FDA, “fast-track” eligibility and extension of statutory exclusivity periods in the U.S. for an additional 5 years upon FDA marketing approval of the product to treat patients with CDI.
Acurx acquired the worldwide rights to ibezapolstat from GLSynthesis Inc. in February 2018.
Ibezapolstat is active against the GAIN Pathogen Clostridium difficile
C. difficile, or CDI, is a pathogen listed in the GAIN Act as a pathogen that causes serious or life-threatening infections and the CDC identifies CDI as an urgent need in terms of generating new antibiotics to treat these infections.
The GAIN Act, Title VIII (Sections 801 through 806) of the FDA Safety and Innovation Act, seeks to provide pharmaceutical and biotechnology companies with incentives to encourage the development of new drugs to treat, prevent, detect and diagnose antibiotic-resistant infections. Qualifying pathogens are defined by the GAIN Act to include multi-drug resistant Gram-negative bacteria, including Pseudomonas, Acinetobacter, Klebsiella, and Escherichia coli species; resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE); multi-drug resistant tuberculosis; and Clostridium difficile. It extends the length of time an approved drug is free from competition and clarifies the regulatory pathway for new antibiotics.
Mechanism of Action
DNA polymerase IIIC (pol IIIC) has been shown to be essential for replicative DNA synthesis in aerobic, low G-C Gram-positive bacteria, i.e. those with a low guanine-cytosine (G-C) ratio relative to their adenine-thymine (A-T) ratio. Pol IIIC-specific genes of several such Gram-positive bacteria have been cloned and expressed, and these enzymes share a unique capacity to be inhibited by 6-anilinouracils (AU), 2-phenylguanines (PG) and related compounds which are analogs of 2'-deoxyguanosine 5'-triphosphate (dGTP). Ibezapolstat is a recent example of this class of compounds and is being advanced to clinical trials.
Ibezapolstat has been demonstrated to inhibit purified C. difficile pol IIIC with a Ki of 0.325 µM, confirming the ternary complex hypothesis. In addition, a whole cell study involving the measurement of chromosomal DNA replication demonstrated the expected gene dosage results that suggest inhibition of DNA replication by ibezapolstat.
About Clostridioides Difficile Infection (CDI)
According to the 2017 Update (published February 2018) of the Clinical Practice Guidelines for C. difficile Infection by the Infectious Diseases Society of America (IDSA) and Society or Healthcare Epidemiology of America (SHEA), CDI remains a significant medical problem in hospitals, in long-term care facilities and in the community. C. difficile is one of the most common causes of health care associated infections in U.S. hospitals (Lessa, et al, 2015, New England Journal of Medicine). Recent estimates suggest C. difficile approaches 500,000 infections annually in the U.S. and is associated with approximately 20,000 deaths annually. (Guh, 2020, New England Journal of Medicine). Based on internal estimates, the recurrence rate of two of the three antibiotics currently used to treat CDI is between 20% and 40% among approximately 150,000 patients treated. We believe the annual incidence of CDI in the U.S. approaches 600,000 infections and a mortality rate of approximately 9.3%.