- First ever head-to-head comparison of gut microbiome changes
associated with ibezapolstat (IBZ) to other anti-CDI antibiotics in
a germ-free mouse model
- Changes in alpha and beta microbiome diversities following
IBZ treatment were less pronounced compared to those observed in
vancomycin (VAN)-or metronidazole (MET)-treated groups,
complementing prior Phase 2 clinical findings showing IBZ's more
selective antibacterial activity
- Notable differences were observed between the microbiome of
IBZ- and fidaxomicin (FDX)-treated groups, which may allow for
differentiation of these two anti-CDI antibiotics in future
studies
- Results establish IBZ differentiating effects on the gut
microbiome, indicating a more selective spectrum of microbiome
alteration compared to broader-spectrum antibiotics like VAN and
MET and a narrower spectrum of microbiome alteration compared to
FDX
- 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., March 3,
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, 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 in a humanized mouse model and its
publication in the Journal of Antimicrobial Agents and
Chemotherapeutics entitled: "Microbiome impact of ibezapolstat
and other Clostridioides difficile infection-relevant antibiotics
using humanized mice". The primary author is Trenton Wolfe, a PhD student at the University of Montana. This study was funded by the
National Institute of Allergy and Infectious Diseases (NIAID), the
National Cancer Institute (NCI), National Center for Advancing
Translational Sciences (NCATS), and the Company.
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: "This study provides critical evidence to
begin to distinguish ibezapolstat from other C. difficile directed
antibiotics, especially fidaxomicin. Although both ibezapolstat and
fidaxomicin were narrower spectrum than vancomycin or
metronidazole, ibezapolstat's effect on the microbiome was
distinctly different than fidaxomicin. How this translates into
beneficial health effects or emergence of antimicrobial resistance
will be an area of further study."
Acurx's Executive Chairman, Bob
DeLuccia, stated: "These results of this first ever direct
comparison of the gut microbiome effects of ibezapolstat in a
validated humanized mouse model set the stage for potential
competitive advantage of IBZ over all commonly used anti-CDI
antibiotics, including fidaxomicin". He added: "These data also
serve as a foundation upon which to build future planned
preclinical and clinical studies at the appropriate time to further
clarify ibezapolstat's favorable effect on the microbiome known to
confer health benefits to patients with CDI."
This study was a head-to-head comparison of intestinal
microbiome effects of IBZ with other CDI antibiotics and has not
been done previously in non-clinical, in vivo models. The purpose
of this study was to compare gut microbiome changes associated with
IBZ to other anti-CDI antibiotics in groups of germ-free mice.
Changes in alpha and beta microbiome diversities following IBZ
treatment were less pronounced compared to those observed in VAN-
or MET-treated groups. By the end of therapy, IBZ increased the
relative abundance of Bacteroidota and Actinomycetota
phyla. In microbiome-humanized mice, IBZ and FDX had smaller
effects on gut microbiome diversity, a positive outcome, compared
to VAN and MET. This analysis places IBZ in a similar category of
microbiome disruption as FDX with notable favorable differences of
IBZ over FDX and indicating a narrower spectrum of microbiome
alteration compared to broader-spectrum agents like VAN and MET.
However, notable differences were observed between the microbiome
of IBZ- and FDX-treated groups, which may allow for differentiation
of these two antibiotics in future studies, such as increased
proportion of Actinomycetota bacteria which include
Bifidobacteria and other species known to confer human
health benefits.
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.
100% (25 of 25) ibezapolstat-treated patients in Phase 2 (Phase
2a and 2b) who had Clinical Cure at
EOT) (End of Treatment) remained cured through one month after EOT,
as compared to 86% (12 of 14) for the vancomycin patient
group.
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
importantActinobacteria 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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