- Major finding provides mechanistic explanation for
ibezapolstat's (IBZ) selectivity in that the predicted bactericidal
interaction between IBZ and its target DNA pol IIIC is conserved
across most of the Bacillota phylum, including C. difficile, while
certain beneficial taxa are naturally resistant to IBZ, allowing
regrowth of resistant microbes known to confer health
benefits
- This study used in silico methods to better interpret the
narrower than expected ibezapolstat (IBZ) spectrum of activity
observed in human trials, which included increased proportion of
certain key gut microbiota of the Bacillota phylum
- IBZ susceptibility of human commensal (nonpathogenic)
microbiota was predicted using genomic analysis and a phylogenetic
tree construction of the IBZ target enzyme, pol IIIC
- Preparation continues to advance IBZ into international Ph3
clinical trials for treatment of CDI
- IBZ has previously been granted FDA QIDP and
Fast-Track Designation and has received SME (Small and Medium-sized
Enterprise) designation by the EMA
STATEN
ISLAND, N.Y., Feb. 24,
2025 /PRNewswire/ -- 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, with its
lead antibiotic candidate, ibezapolstat (IBZ), preparing to advance
to international Phase 3 clinical trials to treat patients with
C. difficile
Infection (CDI). The Company today announced
the results of a study and its publication in the Journal of
Antimicrobial Agents and Chemotherapeutics entitled: "The
Microbiome-restorative Potential of Ibezapolstat for the Treatment
of Clostridioides difficile Infection is Predicted Through
Variant PolC-type DNA Polymerase III in Lachnospiraceae and
Oscillospiraceae". The primary researcher and author is
Jacob K. McPherson, PharmD, a PhD
Pharmacology Candidate at the University of
Houston. This study was funded by the National Institute of
Allergy and Infectious Diseases at the National Institutes of
Health.
According to co-author Kevin
Garey, PharmD, MS, FIDSA, Professor and Chair, University of Houston College of Pharmacy,
Principal Investigator for microbiology and microbiome aspects of
the ibezapolstat clinical trial program, and Acurx Scientific
Advisory Board member: "These studies help to explain the narrower
than expected spectrum of activity of ibezapolstat in our ongoing
clinical trials that helps explain regrowth of beneficial gut
microbiota while patients are on ibezapolstat therapy." He added:
"Genomic differences in the PolC between these species affect the
binding of ibezapolstat allowing these beneficial microbes to be
resistant and confer health benefits. This is distinctly different
that the comparator vancomycin which kills these beneficial
microbes causing high rates of C. difficile recurrence."
Acurx's Executive Chairman, Bob
DeLuccia, stated: "This in silico genomic analysis
complements the structural biology data emerging from our
scientific collaboration with Leiden University Medical Center." He
further stated: "We're confident that these results can be
leveraged to advance not only the ibezapolstat program but also our
systemic Gram-positive antibiotic discovery program in lead
optimization for an oral pol IIIC inhibitor for
methicillin-resistant Staphylococcus aureus (MRSA) and in parallel
planning for our anti-anthrax bioterrorism program."
During clinical trials with IBZ, a narrower than expected
spectrum of activity was observed that included increased
proportion of certain key microbiota of the Bacillota phylum known
to confer health benefits, specifically Lachnospiraceae,
Oscillospiraceae (formerly Ruminococcaceae), and Coprobacillaceae
within Erysipelotrichales. The purpose of this study was to utilize
in silico approaches to better interpret the narrower than expected
IBZ spectrum of activity observed in human trials. IBZ
susceptibility to human commensal microbiota was predicted using
genomic analysis and PolC phylogenetic tree construction in
relation to C. difficile and commensal low G + C bacteria.
An amino acid phylogenetic tree identified certain residues that
were phylogenetically variant in Lachnospiraceae, Oscillospiraceae,
and Erysipelotrichales but conserved in C. difficile. The major
finding of this study was that the predicted interactions between
IBZ and pol IIIC is conserved across the majority of the Bacillota
phylum except for Lachnospiraceae and Oscillospiraceae, and
Erysipelotrichales (including Erysipelotrichaceae and
Coprobacillaceae), taxa that were not killed or regrown in
IBZ-treated subjects while on therapy.
THE PUBLICATION IS ON OUR WEBSITE: www.acurxpharma.com
About the AAC Journal:
Antimicrobial Agents and
Chemotherapy (AAC) is an interdisciplinary journal devoted
to the dissemination of knowledge relating to all aspects of
antimicrobial and antiparasitic agents and chemotherapy. Generally,
any report involving studies on or with antimicrobial, antiviral
(including antiretroviral), or antiparasitic agents is within the
purview of AAC. Studies involving animal models, pharmacological
characterization, and clinical trials are appropriate for
consideration.
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.
The primary efficacy analysis will be performed using a Modified
Intent-To-Treat (mITT) population. This will result in an estimated
450 subjects in the mITT population, randomized in a 1:1 ratio to
either ibezapolstat or standard- of-care vancomycin, enrolled into
the initial Phase 3 trial. The trial design not only allows
determination of ibezapolstat's ability to achieve Clinical Cure of
CDI as measured 2 days after 10 days of oral treatment but also
includes assessment of ibezapolstat's potential effect on reduction
of CDI recurrence in the target population. In the event
non-inferiority of ibezapolstat to vancomycin is demonstrated,
further analysis will be conducted to 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.
(Link to Clinicaltrials.gov/NCT042447542) 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).
In the Phase 2b trial segment,
which was discontinued due to success,
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.
The Company previously reported that the overall observed
Clinical Cure rate in the combined Phase 2 trials 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 was well-tolerated, with three patients each
experiencing one mild adverse event assessed by the blinded
investigator to be drug- related. All three events were
gastrointestinal in nature and resolved without treatment.
There were no drug-related treatment withdrawals or no
drug-related serious adverse events, or other safety findings of
concern. In the Phase 2b
vancomycin control arm, 14 out of 14 patients
experienced Clinical Cure. The Company is confident that based on
the pooled Phase 2 ibezapolstat Clinical
Cure rate of 96% and the historical vancomycin cure
rate of approximately 81% (Vancocin® Prescribing Information,
January 2021), we will demonstrate
non-inferiority of ibezapolstat to vancomycin in Phase 3 trials in
accordance with the applicable FDA Guidance for Industry
(October 2022).
In the Phase 2 clinical trial (both trial segments), the Company
also evaluated pharmacokinetics (PK) and microbiome changes and
test for anti-recurrence microbiome properties, including the
change from baseline in alpha diversity and bacterial abundance,
especially overgrowth of healthy gut microbiota Actinobacteria and Firmicute phylum species
during and after therapy. Phase 2a data demonstrated complete
eradication of colonic C. difficile by day three of
treatment with ibezapolstat as well as the observed overgrowth of
healthy gut microbiota, Actinobacteria and Firmicute phyla species,
during and after therapy. Very importantly, emerging data show an
increased concentration of secondary bile acids during and
following ibezapolstat therapy which is known to correlate with
colonization resistance against C. difficile. A
decrease in primary bile acids and the favorable increase in the
ratio of secondary-to-primary bile acids suggest that ibezapolstat
may reduce the likelihood of CDI recurrence when compared to
vancomycin. The company also recently reported positive extended
clinical cure (ECC) data for ibezapolstat (IBZ), its lead
antibiotic candidate, from the Company's recently completed Phase
2b clinical trial in patients with
CDI. This exploratory endpoint showed that 12 patients who agreed
to be followed up to three months following Clinical Cure of their
infection, 5 of 5 IBZ patients experienced no recurrence of
infection. In the
vancomycin control arm of the trial, 7 of 7 patients
experienced no recurrence of infection. ECC success is defined as a
clinical cure at the TOC visit (i.e., at least 48 hours post EOT)
and no recurrence of CDI within the 56 ± 2 days post EOT (ECC56)
and 84 ± 2 days post EOT (ECC84) in patients who consented to
extended observation. In the Phase 2b
trial, 100% (5 of 5) of ibezapolstat-treated patients who agreed to
observation for up to three months following Clinical Cure of CDI
experienced no recurrence of infection. Furthermore,
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 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 (CDI). 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 (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 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 (CDI)
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, 8, 200;
doi:10.3390/microorganisms8020200.) 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 (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, 2023, 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.
Investor Contact:
Acurx Pharmaceuticals, Inc.
David P. Luci, President & CEO
Tel: 917-533-1469
Email: davidluci@acurxpharma.com
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