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%.

Clinical Development Program

Ph2A efficacy trial is now completed. The Ph2A segment of the Ph2 clinical trial, provided for the treatment of up to 20 patients with CDI per protocol, was terminated early due to success as provided for in the study protocol. All 10 patients enrolled in Ph2A met the primary endpoint of Clinical Cure at the end of treatment (48 hours post Day 10 dosing). In addition, all 10 patients enrolled met the secondary endpoint of no recurrence of infection (Sustained Clinical Cure) at the 30-day follow up following end of treatment.

Based on the recommendation of our Scientific Advisory Board (SAB), we terminated enrollment in Phase 2a early and will advance to Phase 2b. The SAB unanimously supported the early termination of the Phase 2a trial after 10 patients were enrolled in the trial instead of 20 patients as originally planned. The early termination was further based on the evidence of meeting the treatment goals of eliminating the infection with an acceptable adverse event profile.

The Phase 2b portion of the Phase 2 clinical trial is designed as a 64-patient vancomycin-controlled efficacy study. 32 of the patients will receive 450mg of ibezapolstat twice per day, and 32 of the patients will receive 125mg of vancomycin four times per day. Both groups of patients will receive this treatment for 10 days. Phase 2b is expected to begin in the second half of 2021.

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).