Acurx Pharma Presents DNA pol IIIC Inhibitor Findings at FASEB Conference

Overview

Acurx Pharmaceuticals, Inc. (NASDAQ: ACXP) (""Acurx"" or the ""Company"") is a late-stage biopharmaceutical company developing a new class of small molecule antibiotics for difficult-to-treat bacterial infections. Its lead antibiotic candidate, ibezapolstat (IBZ), is ready to advance to international pivotal Phase 3 clinical trials for treatment of patients with C. difficile infection (CDI).

Acurx Showcases DNA pol IIIC Inhibitor Research at FASEB Conference

• The Company today announced that a presentation of a poster and an oral presentation regarding Acurx's overall DNA pol IIIC inhibitor platform was presented at a scientific conference on May 21 by Mia Urem, PhD, from Leiden University Medical Center in the Netherlands entitled: ""A Unique Inhibitor Conformation Selectively Targets the DNA Polymerase PolC of Gram-Positive Priority Pathogens"".  
• This scientific conference is sponsored by the Federation of American Societies for Experimental Biology and is the premier venue for the newest research and technological trends in molecular ""machines"" inside the human body that ensure DNA replication and expression of genes to create proteins that make up a cell.
• The distinctive non-planar conformation of ACX-801 and IBZ, together with high conservation of the induced binding pocket in PolC, suggests that this is a general mechanism for this class of inhibitor and is conserved in Gram-positive bacteria.

Words from the principal investigator

According to Dr. Wiep Klaas Smits, Associate Professor/Principal Investigator, Leiden University Medical Center: ""Our findings with regards to the structural biology of DNA pol IIIC in complex with inhibitors have important implications for the development of this novel class of antibiotics to treat high priority, multi-drug resistant, gram-positive infections.""

Statement from the Acurx's Executive Chairman

Acurx's Executive Chairman, Bob DeLuccia, stated: ""This research outcome provides a deeper understanding of the mechanism of action and selectivity of ibezapolstat in the gut. These data will guide the rational design of new compounds with improved inhibitory activity and drug-like characteristics that will be crucial in addressing the pandemic of antimicrobial resistance.""
POSTER AND PRESENTATION ARE ON ACURX WEBSITE www.acurxpharma.com

The Federation of American Societies for Experimental Biology

• Since its inception 20 years ago, this conference has been the premier venue for the newest research and technological trends that aid in studying the molecular ""machines"" inside the human body. 
• These biological elements ensure faithful DNA replication and expression of genes to create the many proteins that make up a cell. 
• The Machines on Genes scientific conference covers all aspects that govern the central building blocks of life, DNA replication, transcription, and translation, as well as activities that impact these processes such as DNA repair, DNA editing, and RNA editing. 
• There is special emphasis on how they work, how they interact with one another, and how they may be used as diagnostic tools or as targets for novel therapies.

About Leiden University Medical Center

• Antimicrobial resistant microorganisms are a major threat to global health and pose a significant economic burden. 
• Increasing resistance to multiple agents and resistance to so called last-resort antibiotics underscore the necessity to develop therapeutics that have a novel mode of action. 
• DNA replication is a process that can be successfully targeted by small molecules. 
• Ibezapolstat, an inhibitor of the replicative DNA polymerase pol IIIC from Gram-positive bacteria identified by screening library of dGTP analogues, has shown promising results for the treatment of Clostridioides difficile Infection in a recent Phase 2a clinical trial, but the molecular basis of selective inhibition is not fully characterized as no structural information is available on pol IIIC proteins from pathogens. 
• Ongoing research project will determine the structure of pol IIIC from the multidrug-resistant organism’s methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococci (VRE) and/or penicillin resistant Streptococcus pneumoniae (PRSP) in the absence and presence of lead compounds. 
• These results will reveal the structural space of inhibitor-binding and guide the rational design of inhibitors with optimal pharmacological properties and organism-specificity that will be demonstrated by in vitro polymerase inhibition assays and in vivo minimal inhibitory concentration determination.
• Leiden University was the first university to be established in the Netherlands. Its motto is praesidium libertatis – bastion of freedom.  
• The University wishes to create an increasingly attractive and challenging working climate for top academics and young researchers that is guided by quality and excellence. 
• Leiden University Medical Center (LUMC) research aims to meet the highest international standards of quality and academic integrity. 
• LUMC promotes excellent research through greater collaboration, both disciplinary and interdisciplinary; stronger positioning and greater scope for top talent; and better supervision and more support for young researchers.

Dutch Public-Private Partnership Supports Life Sciences Innovation

• The presented research was performed in part as a public-private partnership that includes the Dutch Top Sector Life Sciences and Health ('Topconsortium voor Kennis en Innovatie' or 'TKI' Life Sciences and Health) and is represented by Stichting Life Sciences Health – TKI (aka, Health~Holland). 
• This foundation is tasked by the Dutch government to promote and stimulate public-private partnerships (PPPs) to undertake R&D projects in the life sciences. 
• To promote such partnerships, the Minister of Economic Affairs and Climate Policy has allocated certain funds to Stichting LSH-TKI, to grant allowances to projects under the TKI-programme Life Sciences & Health. 
• Stichting LSH-TKI has designated the Board of Directors of LUMC as delegated grantor for the PPP allowance allocated to the LUMC.

The combined project

• Together with Acurx Pharmaceuticals the PPP has led to the research project entitled ""Bad bugs, new drugs: elucidation of the structure of DNA polymerase C of multidrug resistant bacteria in complex with novel classes of antimicrobials."" 
• The collaboration project was co-funded by the PPS Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships.

Acurx Receives EMA Guidance for Advancing Phase 3 Trials

• Acurx previously announced that it had received positive regulatory guidance from the EMA during its Scientific Advice Procedure which confirmed that the clinical, non-clinical and CMC (Chemistry Manufacturing and Controls) information package submitted to EMA supports advancement of the ibezapolstat Phase 3 program and if the Phase 3 program is successful, supports the submission of a Marketing Authorization Application (MAA) for regulatory approval in Europe.  
• The information package submitted to EMA by the Company to which agreement has been reached with EMA included details on Acurx's two planned international Phase 3 clinical trials, 1:1 randomized (designed as non-inferiority vs vancomycin), primary and secondary endpoints, sample size, statistical analysis plan and the overall registration safety database. 
• With mutually consistent feedback from both EMA and FDA, Acurx is well positioned to commence our international Phase 3 registration program.

Phase 3 Trial Design for Ibezapolstat Efficacy Analysis

• Modified Intent-To-Treat (mITT) population will be used for the primary efficacy analysis
• An estimated 450 subjects will be enrolled, randomized 1:1 to either ibezapolstat or vancomycin.
• The trial assesses ibezapolstat’s ability to achieve Clinical Cure of CDI after 10 days of treatment, measured 2 days post-treatment.
• The study also evaluates ibezapolstat’s effect on CDI recurrence in the target population.
• If ibezapolstat shows non-inferiority to vancomycin, further analysis will test for superiority.

About the Ibezapolstat Phase 2 Clinical Trial

• The completed multicenter, open-label single-arm segment (Phase 2a) study was followed by a double-blind, randomized, active-controlled, non-inferiority, segment (Phase 2b) at 28 US clinical trial sites which together comprise the Phase 2 clinical trial. 
• This Phase 2 clinical trial was designed to evaluate the clinical efficacy of ibezapolstat in the treatment of CDI including pharmacokinetics and microbiome changes from baseline.
• From study centers in the United States. In the Phase 2a trial segment,10 patients with diarrhea caused by C. difficile were treated with ibezapolstat 450 mg orally, twice daily for 10 days.
• All patients were followed for recurrence for 28± 2 days. Per protocol, after 10 patients of the projected 20 Phase 2a patients completed treatment (100% cured infection at End of Treatment (10 of 10).

During phase 2b

• In the Phase 2b trial segment, 32 patients with CDI were enrolled and randomized in a 1:1 ratio to either ibezapolstat 450 mg every 12 hours or vancomycin 125 mg orally every 6 hours, in each case, for 10 days and followed for 28 ± 2 days following the end of treatment for recurrence of CDI. 
• The two treatments were identical in appearance, dosing times, and number of capsules administered to maintain the blind.
• In the Phase 2b trial, the Clinical Cure rate in patients with CDI was 96% (25 out of 26 patients), based on 10 out of 10 patients (100%) in Phase 2a in the Modified Intent to Treat Population, plus 15 out of 16 (94%) patients in Phase 2b in the Per Protocol Population, who experienced Clinical Cure during treatment with ibezapolstat. 

Ibezapolstat's Phase 2 Trial Results & Microbiome Insights

Clinical Cure & Tolerability

• 100% (25 of 25) ibezapolstat-treated patients remained cured one month post-treatment vs 86% (12 of 14) in the vancomycin group.
• No serious adverse events were deemed drug-related.
• Clinical Cure Rate: Ibezapolstat 96% vs vancomycin's historical range of 70%-92%.
• Sustained Clinical Cure Rate: Ibezapolstat 100% vs vancomycin’s historical range of 42%-74%.
• Confidence in ibezapolstat's non-inferiority in Phase 3, aligning with FDA Guidance (October 2022).

Microbiome & Anti-Recurrence Properties

• Phase 2 trial assessed pharmacokinetics (PK), microbiome shifts, and anti-recurrence potential.
• Complete eradication of colonic C. difficile observed by day 3 of treatment.
• Overgrowth of healthy gut microbiota (Actinobacteria & Firmicute phyla) during & post-therapy.
• Increase in secondary bile acids (linked to colonization resistance against C. difficile).
• Decrease in primary bile acids, improving secondary-to-primary bile acid ratio, reducing CDI recurrence risk vs vancomycin.

Extended Clinical Cure (ECC) Data

• Phase 2b exploratory endpoint: 5 of 5 IBZ patients remained infection-free for 3 months post-Cure.
• Ibezapolstat-treated patients had lower primary bile acids and a higher beneficial secondary-to-primary bile acid ratio than vancomycin-treated patients.

About Ibezapolstat

• Ibezapolstat is the Company's lead antibiotic candidate planning to advance to international Phase 3 clinical trials to treat patients with C. difficile infection. 
• Ibezapolstat is a novel, orally administered antibiotic, being developed as a Gram-Positive Selective Spectrum (GPSS®) antibacterial. 
• It is the first of a new class of DNA polymerase IIIC inhibitors under development by Acurx to treat bacterial infections. 
• Ibezapolstat's unique spectrum of activity, which includes C. difficile but spares other Firmicutes and the important Actinobacteria phyla, appears to contribute to the maintenance of a healthy gut microbiome.
• 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 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.

About Clostridioides difficile Infection

• 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, 2015, NEJM).
• 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, NEJM). 
• Based on internal estimates, the recurrence rate for the 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%.

About the Microbiome in C. difficile Infection and Bile Acid Metabolism

• C. difficile can be a normal component of the healthy gut microbiome, but when the microbiome is thrown out of balance, the C. difficile can thrive and cause an infection. 
• After colonization with C. difficile, the organism produces and releases the main virulence factors, the two large clostridial toxins A (TcdA) and B (TcdB). (Kachrimanidou, Microorganisms 2020.) 
• TcdA and TcdB are exotoxins that bind to human intestinal epithelial cells and are responsible for inflammation, fluid and mucous secretion, as well as damage to the intestinal mucosa. 
• Bile acids perform many functional roles in the GI tract, with one of the most important being maintenance of a healthy microbiome by inhibiting C. difficile growth. 
• Primary bile acids, which are secreted by the liver into the intestines, promote germination of C. difficile spores and thereby increase the risk of recurrent CDI after successful treatment of an initial episode. 
• On the other hand, secondary bile acids, which are produced by normal gut microbiota through metabolism of primary bile acids, do not induce C. difficile sporulation and therefore protect against recurrent disease. 
• Since ibezapolstat treatment leads to minimal disruption of the gut microbiome, bacterial production of secondary bile acids continues which may contribute to an anti-recurrence effect. 
• Beneficial effects of bile acids include a decrease in primary bile acids and an increase in secondary bile acids in patients with CDI, which was observed in the Company's Ph2a trial results and previously reported (Garey, CID, 2022). 
• In the Ph2b trial, ibezapolstat-treated patients showed lower concentrations of fecal primary bile acids, and higher beneficial ratio of secondary to primary bile acids than vancomycin-treated patients.

About Acurx Pharmaceuticals, Inc.

• Acurx Pharmaceuticals is a late-stage biopharmaceutical company focused on developing a new class of small molecule antibiotics for difficult-to-treat bacterial infections. 
• The Company's approach is to develop antibiotic candidates with a Gram-positive selective spectrum (GPSS®) that blocks the active site of the Gram-positive specific bacterial enzyme DNA polymerase IIIC (pol IIIC), inhibiting DNA replication and leading to Gram-positive bacterial cell death. 
• Its R&D pipeline includes antibiotic product candidates that target Gram-positive bacteria, including Clostridioides difficile, methicillin- resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE), drug- resistant Streptococcus pneumoniae (DRSP) and B. anthracis (anthrax; a Bioterrorism Category A Threat-Level pathogen).
• Acurx's lead product candidate, ibezapolstat, for the treatment of C. difficile Infection is Phase 3 ready with plans in progress to begin international clinical trials next year. 
• The Company's preclinical pipeline includes development of an oral product candidate for treatment of ABSSSI (Acute Bacterial Skin and Skin Structure Infections), upon which a development program for treatment of inhaled anthrax is being planned in parallel.

To learn more about Acurx Pharmaceuticals and its product pipeline, please visit www.acurxpharma.com.

Forward-Looking Statements

• Any statements in this press release about our future expectations, plans and prospects, including statements regarding our strategy, future operations, prospects, plans and objectives, and other statements containing the words ""believes,"" ""anticipates,"" ""plans,"" ""expects,"" and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. 
• Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: whether ibezapolstat will benefit from the QIDP designation; whether ibezapolstat will advance through the clinical trial process on a timely basis; whether the results of the clinical trials of ibezapolstat will warrant the submission of applications for marketing approval, and if so, whether ibezapolstat will receive approval from the FDA or equivalent foreign regulatory agencies where approval is sought; whether, if ibezapolstat obtains approval, it will be successfully distributed and marketed; and other risks and uncertainties described in the Company's annual report filed with the Securities and Exchange Commission on Form 10-K for the year ended December 31, 2024, and in the Company's subsequent filings with the Securities and Exchange Commission. 
• Such forward- looking statements speak only as of the date of this press release, and Acurx disclaims any intent or obligation to update these forward-looking statements to reflect events or circumstances after the date of such statements, except as may be required by law.

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