- Results feature high-resolution elucidation of interaction
of ibezapolstat with its molecular target
- Mechanistic findings explain ibezapolstat's properties of
lacking cross resistance with other antibiotics and not fostering
the emergence of Enterococcus, including vancomycin-resistant
strains, a unique differentiation among anti-CDI
antibiotics
- Molecular structure data will be used to guide rational
design of new systemic therapeutic compounds with improved
inhibitory activity and PK characteristics
- Planning continues to prepare to advance ibezapolstat into
international Phase 3 clinical trials for treatment of C. difficile
Infection (CDI)
- Acurx is also preparing requests for regulatory guidance to
initiate clinical trials in the European Union, the United Kingdom, Japan and Canada
- Ibezapolstat has previously received FDA QIDP and Fast-Track
Designation from FDA
STATEN
ISLAND, N.Y., Sept. 24,
2024 /PRNewswire/ -- Acurx Pharmaceuticals, Inc.
(NASDAQ: ACXP) ("Acurx" or the "Company"), a late-stage
biopharmaceutical company developing a new class of small molecule
antibiotics for difficult-to-treat bacterial infections, today
announced results from its pioneering research with ibezapolstat in
collaboration with Leiden University Medical Center (LUMC). These
results were presented at the premier International C.
difficile Symposium (ICDS) held in Bled, Slovenia on September
17-19, 2024. Dr. Wiep Klaas Smits, PhD, Associate Professor,
LUMC, delivered a presentation entitled: Structure of the
Replicative Polymerase PolC Reveals Mode of Action and Mechanism of
Resistance of the Anti-CDI Agent Ibezapolstat and Related
Inhibitors.
According to Dr. Smits: "Our findings with ibezapolstat
regarding the structural biology of DNA pol IIIC inhibitors have
important implications for the development of a new family of
antibiotics to treat high priority, multi-drug resistant,
gram-positive infections". He further stated: "I believe that DNA
replication is a promising but underexplored target, and this novel
class of DNA pol IIIC inhibitors could be an important new tool to
address the pandemic of antimicrobial resistance"
Robert J. DeLuccia, Executive
Chairman of Acurx, stated: "We are very pleased with the outcome of
our collaboration with LUMC which has been exceptionally
productive." He added: "This detailed demonstration of the mode of
action of DNA pol IIIC inhibitors in general, and for ibezapolstat
specifically, is critically important to support our scientific
foundation and our regulatory filings as we advance into this
late-stage of ibezapolstat's development pathway toward
commercialization".
The presentation is available on the Acurx Pharmaceuticals
website www.acurxpharma.com.
Acurx has previously announced that it had a successful FDA
End-of-Phase 2 Meeting and Phase 3 Readiness for ibezapolstat for
the Treatment of C. difficile Infection. Agreement with
FDA was reached on key elements to move forward with its
international Phase 3 clinical trial program. Agreement was also
reached with FDA on the complete non-clinical and clinical
development plan for filing of a New Drug Application (NDA) for
marketing approval. Planning continues to advance ibezapolstat into
international Phase 3 clinical trials for treatment of C.
difficile Infection (CDI). Acurx is also now preparing to
submit requests for regulatory guidance to initiate clinical trials
in the European Union, the United
Kingdom, Japan and
Canada.
Key elements for the two Phase 3, non-inferiority, pivotal
trials were confirmed and included agreement with FDA on the
protocol design, patient population, primary and secondary
endpoints, and size of the registration safety database. Based on
FDA recommendations, and in anticipation of an EMA Scientific
Advice Meeting, the primary efficacy analysis will be performed
using a Modified Intent-To-Treat (mITT) population consistent with
EMA requirements. 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 Research Project, Leiden University Medical Center,
the Research Consortium
Health Holland awarded a grant
of approximately $500,000 USD to
Leiden University Medical Center which was co-funded by a PPP
(Public Private Partnership) allowance made available by
Health~Holland, Top Sector Life Sciences & Health, to stimulate
public-private partnerships and to further study the mechanism of
action of DNA pol IIIC inhibitors in scientific collaboration with
Acurx Pharmaceuticals. https://www.health-holland.com/
This innovative research included study of 3-dimensional
structures of DNA polymerases and their binding interactions with
Acurx inhibitors. The antibacterial action of Acurx's pipeline of
novel DNA pol IIIC inhibitors has been clinically validated by
ibezapolstat's completion of a Ph2 clinical trial for treatment of
C. difficile Infection
(CDI). https://www.lumc.nl/en/research/.
The research outcome is intended to accelerate lead product
candidate selection for Acurx's pre-clinical program for other WHO,
CDC and FDA high-priority, multi-drug resistant Gram-positive
pathogens where new classes of antibiotics are needed.
Together with Acurx Pharmaceuticals the PPP initiated 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."
About the C. difficile Symposium (ICDS)
The International C. difficile Symposium (ICDS)
is now established as the premier venue for the review of
Clostridium difficile research.
The 1st meeting was held in Kranjska
Gora in 2004, the 2nd in Maribor in 2007, while all earlier
meetings were in Bled in 2010, 2012, 2015 and in 2018. ICDS in 2020
was held virtually. The 2024 meeting will provide the ideal
opportunity to review progress in epidemiology, diagnostics,
clinical trials, basic research and in understanding C.
difficile pathogenesis and controlling the devastating
disease it causes.
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.
(see https://clinicaltrials.gov/ct2/show/NCT04247542). 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. and continue
to test for anti-recurrence microbiome properties seen in the Phase
2a trial, including the treatment-related changes in alpha
diversity and bacterial abundance and effects on bile acid
metabolism.
The completed Phase 2a segment of this trial was an open label
cohort of up to 20 subjects from study centers in the United States. In this cohort, 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). The
Trial Oversight Committee assessed the safety and tolerability and
made its recommendation regarding early termination of the
Phase 2a study and advancement to the Ph2b segment. The Company's
Scientific Advisory Board concurred with this recommendation.
In the now completed 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).
The Phase 2b clinical trial
segment was discontinued due to success. The Company made this
decision in consultation with its medical and scientific advisors
and statisticians based
on observed aggregate blinded data and other factors, including
the cost to maintain clinical trial sites and
slow enrollment due to COVID-19 and its aftermath. The Company had
determined that the trial performed as anticipated for both
treatments, ibezapolstat and the control antibiotic vancomycin (a
standard of care to treat patients with CDI), with high rates of
clinical cure observed across the trial.
The Phase 2b trial was originally
designed to be a non-inferiority (NI) trial and later amended to
include an interim efficacy analysis with review by an Independent
Data Monitoring Committee (IDMC). The decision to end the trial
early based on blinded clinical observations obviated the need for
an interim analysis, IDMC review, and NI assessment. The Company
determined, in consultation with its clinical
and statistical experts,
that presenting clinical cure rates for the primary
efficacy endpoint is the most appropriate representation for the
clinical activity of ibezapolstat in treating CDI.
In the Phase 2 clinical trial, 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.
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
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.
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).
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) and
drug-resistant Streptococcus pneumoniae (DRSP).
To learn more about Acurx Pharmaceuticals and its product
pipeline, please visit https://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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SOURCE Acurx Pharmaceuticals, Inc.