What changed in this filing

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Item 1. Business

2023-03-15 compared with 2022-03-16 · 120 added, 94 removed, 606 unchanged (26% of the section changed)

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According to the WHO, the current clinical development pipeline remains insufficient to tackle the challenge of the increasing emergence and spread of antimicrobial resistance.

Our approach is to develop antibiotic candidates that block the DNA polymerase IIIC (“Pol IIIC”).

We believe we are developing the first Pol IIIC inhibitor to enter clinical trials.

Our approach is to develop a new class of antibiotic candidates that block the DNA polymerase IIIC enzyme (“Pol IIIC”).

We believe we are developing the first Pol IIIC inhibitor to enter clinical trials and have clinically validated the efficacy of our lead Pol IIIC antibiotic candidate in a Phase 2a clinical trial.

Pol IIIC is the primary catalyst for DNA replication of several Gram-positive bacterial cells.

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Pol IIIC is required for the replication of DNA in certain Gram-positive bacterial species.

By blocking this enzyme, our antibiotic candidates are believed to be bactericidal and inhibit proliferation of several common bacterial pathogens, including both sensitive and resistant C.

By blocking this enzyme, our antibiotic candidates are believed to be bactericidal and inhibit proliferation of several common Gram-positive bacterial pathogens, including both sensitive and resistant C.

difficile, MRSA, vancomycin-resistant Enterococcus, penicillin-resistant Streptococcus pneumonia (“PRSP”) and other resistant bacteria.

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Our lead antibiotic candidate, ibezapolstat (formerly named ACX-362E), has a novel mechanism of action that targets the Pol IIIC enzyme, a previously unexploited scientific target.

On December 3, 2021, we commenced enrollment in a double-blind, active controlled clinical trial of ibezapolstat versus vancomycin, the standard of care to treat C.

difficile infections (“CDI”), pursuant to the trial design provided below.

Phase 2a clinical data validate the efficacy of our lead antibiotic candidate as well as Pol IIIC as an appropriate bacterial target.

On December 3, 2021, we commenced enrollment in a Phase 2b 64-patient, randomized (1-to1), non-inferiority, double-blind trial of oral ibezapolstat compared to oral vancomycin, a standard of care to treat C.

difficile infections (“CDI”).

Prior to that, we completed our Phase 2a clinical trial of ibezapolstat to treat patients with CDI and reported the top-line data in November 2020.

The Phase 2a clinical trial was terminated early based upon the recommendation of our Scientific Advisory Board (the “SAB”).

The SAB reviewed the study data presented by management, including adverse events and efficacy outcomes, and discussed their clinical impressions.

The SAB reviewed the study data presented by management, including adverse events and efficacy outcomes, and discussed its clinical impressions.

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.

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This constitutes a 100% response rate for the primary and secondary endpoints of the trial.

All 10 patients enrolled in the Phase 2a trial met the study’s primary and secondary efficacy endpoints, namely, Clinical Cure at end of treatment and Sustained Clinical Cure of no recurrence of CDI at the 28-day follow-up visit.

follow-up visit.

No treatment-related serious adverse events (“SAEs”) were reported by the investigators who enrolled patients in the trial.

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Additionally, data obtained to date demonstrate that ibezapolstat enhances actinobacteria in the microbiome and suppresses regrowth of proteobacteria;

potentially lessening the likelihood of CDI recurrence or new infection by MDR Gram-negative bacteria (Garey, et.

al., Late-Breaker Presentation, Ibezapolstat Clinical Update, 8th Annual International C.

Virtual Conference, November 14, 2020).

potentially lessening the likelihood of CDI recurrence or new infection by MDR Gram-negative bacteria.

Additionally, the unexpected finding from further analysis of the Phase 2a study is that the beneficial Firmicutes were shown to regrow while patients were receiving ibezapolstat therapy.

Several follow-up experiments have demonstrated that many of these beneficial Firmicutes have heterogeneous susceptibility to ibezapolstat allowing them to continue to perform their beneficial biologic functions even while a patient is receiving ibezapolstat for their C.

difficile infection.

(Garey, Oral Presentation, IDSA, IDWeek 2022 Conference, Oct 19-23, 2022).

Prior to conducting the Phase 2a clinical trial, we successfully completed a Phase 1 clinical trial of ibezapolstat for the oral treatment of CDI (the “Phase 1 Trial”).

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In addition, the laboratory of Dr.

Kevin Garey at the University of Houston performed state-of-the-art microbiomic testing of gastrointestinal flora in trial subjects as compared with vancomycin, the standard of care for the treatment of patients with CDI, which testing was the first of its kind in Phase 1 clinical trials for CDI.

Kevin Garey at the University of Houston performed state-

of-the-art microbiomic testing of gastrointestinal flora in trial subjects as compared with vancomycin, the standard of care for the treatment of patients with CDI, which testing was the first of its kind in Phase 1 clinical trials for CDI.

Data from the case report forms completed by the principal investigators of the Phase I Trial showed that single and multiple ascending doses of ibezapolstat demonstrated a safety signal similar to placebo according to the principal investigators as evidenced by the case report forms.

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No significant abnormalities developed in the 12-lead electrocardiogram traces for any subject at any dose given according to the data reported by the principal investigators in the case report forms.

No changes were observed in serum

biochemistry or hematological blood evaluations.

No changes were observed in serum biochemistry or hematological blood evaluations.

No dose-dependent increase in adverse events, (each, an “AE”) was reported, and no serious AEs were observed.

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The GAIN Act amended the federal Food, Drug, and Cosmetic Act to add a designation for QIDPs.

A QIDP is defined as “an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections, including those caused by (1) an antibacterial or antifungal resistant pathogen, including novel or infectious pathogens, or (2) qualifying pathogens listed under” 21 C.F.R.

A QIDP is defined as “an antibacterial or antifungal drug for human use intended to treat serious

or life-threatening infections, including those caused by (1) an antibacterial or antifungal resistant pathogen, including novel or infectious pathogens, or (2) qualifying pathogens listed under” 21 C.F.R.

The primary incentive for developing a QIDP is a five-year exclusivity extension for the relevant antibiotic or antifungal indications of the QIDP, but the designation also offers FDA priority review for the first application submitted for the QIDP and eligibility for fast track designation.

FDA’s fast track designation is a process designed to facilitate the development and expedite the regulatory pathway of new drugs to treat serious or life-threatening conditions and that fill a high unmet medical need.

To be eligible for a fast track designation, the FDA must determine, based on the request of a sponsor, that a product is intended to treat a

serious or life-threatening disease or condition and demonstrates the potential to address an unmet medical need by providing a therapy where none exists or a therapy that may be potentially superior to existing therapy based on efficacy or safety factors.

To be eligible for a fast track designation, the FDA must determine, based on the request of a sponsor, that a product is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address an unmet medical need by providing a therapy where none exists or a therapy that may be potentially superior to existing therapy based on efficacy or safety factors.

Fast track designation provides opportunities for more frequent interactions with the FDA review team to expedite development and review of the product.

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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 of Healthcare Epidemiology of America (SHEA) provides a recommendation for clinicians to prescribe either vancomycin or fidaxomicin over metronidazole for an initial episode of CDI.

Fidaxomicin (Dificid ® ) is an antibiotic approved to treat patients with CDI in the U.S.

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Fidaxomicin was the first antibacterial drug the FDA approved in more than 30 years to treat CDI.

Summit Therapeutics has a clinical stage antibiotic, ridinilazole, and in January 2019 had opened enrollment of two Phase 3 clinical trials to treat patients with CDI.

In December 2021, Summit Therapeutics announced that ridinilazole had failed to achieve the primary endpoint in the Phase 3 clinical trials and is considering its strategy forward, if any, for ridinilazole based upon the entirety of the trial data when it becomes available.

The ridinilazole Phase 3 program included two randomized trials testing efficacy in CDI versus vancomycin as the positive control.

The trials appeared to be identical in design and plan to enroll 680 patients each.

Cubist Pharmaceuticals was acquired by Merck in 2015 for approximately $8.4 billion.

continues to market fidaxomicin (Dificid ® ) and is expected to continue through the patent life which is expected to expire in mid-2027.

Summit Therapeutics had a clinical stage antibiotic, ridinilazole, and in January 2019 had opened enrollment of two Phase 3 clinical trials to treat patients with CDI.

In December 2021, Summit Therapeutics announced that ridinilazole had failed to achieve the primary endpoint in the Phase 3 clinical trials and has since announced a plan to partner ridinalazole and has moved strategically into oncology drug development.

The ridinilazole Phase 3 program included two randomized trials testing efficacy in CDI versus oral vancomycin, the standard of care, as the positive control.

The trials appeared to be identical in design and planned to enroll 680 patients each.

Prior to failing to achieve the primary endpoint in its Phase 3 clinical trials, in the fourth quarter of 2021, Summit Therapeutics announced that the FDA had rejected Summit’s request to change the endpoint in the then ongoing Phase 3 clinical trials.

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Prior to failing in its Phase 3 clinical trial, ridinilazole completed two Phase 2 clinical trials successfully meeting or exceeding its primary efficacy endpoints.

Despite the approval of fidaxomicin to treat CDI, the CDC continues to cite it as an urgent need for new antibiotics.

Despite the approval of fidaxomicin to treat CDI, the CDC continues to cite C.

difficile bacteria as an urgent need for new antibiotics to treat CDI.

Clinical Strategy

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We successfully completed the Phase 1 clinical trial in August 2019 and the data supported advancing to Phase 2 according to our medical and scientific advisors.

Blood levels of ibezapolstat show low systemic exposure, as predicted by previously conducted animal studies and are desirable in treating CDI, and fecal concentrations of ibezapolstat were 2 to 3 orders of magnitude above the level required to kill CDI bacteria at the site of the infection.

of ibezapolstat show low systemic exposure, as predicted by previously conducted animal studies and are desirable in treating CDI, and fecal concentrations of ibezapolstat were 2 to 3 orders of magnitude above the level required to kill CDI bacteria at the site of the infection.

Phase 2 Clinical Trial.

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Government Regulation

The research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, marketing, among other things, of drug products are extensively regulated

by governmental authorities in the U.S.

and other countries.

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For an all new molecular entity (“NME”), NDAs, the ten and six-month time periods run from the filing date;

for all other

original applications, the ten and six-month time periods run from the submission date.

for all other original applications, the ten and six-month time periods run from the submission date.

Despite these review goals, it is not uncommon for FDA review of an NDA to extend beyond the goal date.

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No material issues were noted in the manufacture of either the 1 kg or 9 kg batches of ibezapolstat to date with 36-month stability very good and well within acceptable FDA standards.

Additionally, we can extrapolate to 48-months stability per FDA Manufacturing Guidance in advance of a 48-month pull point to occur in the second half of 2022.

Ibezapolstat drug product (DP), 150mg capsules, have been manufactured and used in the Phase 1 and Phase 2a clinical trial and will be used in the Phase 2b clinical trial.

Additionally, we can extrapolate to 48-months stability per FDA Manufacturing Guidance in advance of a 48-month pull point to occur in the first half of 2023.

Ibezapolstat drug product (DP), 150mg capsules, have been manufactured and used in the Phase 1 and Phase 2a clinical trial and are being used in the Phase 2b clinical trial.

Thirty-six months stability data on capsules show no significant changes in the key quality attributes and no discernable data trends at any of the storage conditions.

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difficile bacteria that produce toxins causing inflammation of the colon, severe diarrhea and, in the most serious cases, death.

Patients typically develop CDI from the use of broad-spectrum antibiotics that disrupt normal gastrointestinal (gut) flora, thus allowing C.

Patients typically develop CDI from the use of broad-

spectrum antibiotics that disrupt normal gastrointestinal (gut) flora, thus allowing C.

difficile bacteria to flourish and produce toxins.

difficile is a spore forming bacterium, creating spores excreted in the environment of the patients that can survive for months on dry surfaces in hospital rooms such as beds and doors, and can contaminate other patients by fecal-oral transmission through the hands of healthcare workers.

We estimate that, if approved, ibezapolstat could capture over 20% of the CDI market in peak year sales based on the incidence rates noted above.

At a preliminary price estimate of $3,000 to $3,500 per full course of treatment, this projects out to estimated peak year sales of approximately $500 million.

The peak market penetration of 20% assumes that there will be at least three treatment options available to treat CDI in addition to ibezapolstat even though only two antibiotics are currently recommended for the treatment of CDI and only ridinilazole is in late-stage development and may or may not succeed in Phase 3 clinical trials and/or obtain FDA approval.

The selling price estimate of $3,000 to $3,500 is considered by management to be conservative as it is well below the price point of fidaxomicin, the most- recent approval in treating CDI.

We estimate that, if approved with clinical data consistent with current data generated to date, ibezapolstat could capture over 40% of the CDI market in peak year sales based on the incidence rates noted above.

At a preliminary price estimate of $3,000 to $3,500 per full course of treatment, this projects out to estimated peak year sales of over $1 billion per year in the U.S.

The peak market penetration of 40% assumes that there will be at least two treatment options available to treat CDI in addition to ibezapolstat even though only two antibiotics are currently recommended for the treatment of CDI and oral vancomycin has vulnerabilities with its 20%-40% reinfection rate and poor impact on patients’ microbiome.

The selling price estimate of $3,000 to $3,500 is considered by management to be conservative as it is well below the price point of fidaxomicin, the most- recent approval in treating CDI which we believe is between $4,500 and $5,000 for a full course of treatment.

Management believes that this market opportunity is substantial and provides significant upside potential for those investing at this early stage of development.

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Many of our competitors may have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do.

These competitors also compete with us in recruiting and retaining qualified scientific advisors and consultants as well as management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Other small or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any

products that we may develop.

Our competitors also may obtain marketing approvals for their products more rapidly than we obtain approval for ours.

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We expect these products, if approved, will compete with ibezapolstat;

● Current antibiotic treatments for patients with CDI include broad spectrum antibiotics like vancomycin and metronidazole, both of which are available in generic form in the U.S.

Generic antibiotics typically are sold at lower prices than branded antibiotics and generally are preferred by managed care providers of health services;

● Current antibiotic treatments used for patients with CDI include broad spectrum antibiotics like vancomycin and metronidazole, both of which are available in generic form in the U.S.

Generic antibiotics typically are sold at lower prices than branded and currently marketed antibiotics and generally are preferred by managed care providers of health services although we believe we price competitively compared to any currently marketed branded or generic antibiotic to treat patients with CDI based on low cost of goods to manufacture ibezapolstat.

Further pricing strategy will follow completion of our clinical development program;

● Fidaxomicin (Dificid® in the U.S., Dificlir™ in Europe) is approved for the treatment of CDI in the U.S.

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Cubist was then acquired by Merck & Co., Inc.

● Ridinilazole is a new antibiotic candidate (Summit Therapeutics) and, in January 2020, its sponsor opened enrollment in a Phase 3 clinical trial program for the treatment of CDI.

The ridinilazole Phase 3 program included two randomized trials testing efficacy in CDI versus vancomycin as the positive control.

The trials appeared to be identical in design and planned to enroll 680 patients each.

Ridinilazole is an orally administered small molecule antibiotic designed to selectively target C.

difficile bacteria without causing collateral damage to the gut flora and thereby reduce CDI recurrence rates.

Prior to failing in its Phase 3 clinical trial, ridinilazole completed two Phase 2 clinical trials successfully meeting or exceeding its primary efficacy end points ;

(“Merck”) in 2015;

● A number of other approaches for the treatment of CDI are in development or have been approved as follows:

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Difficile bacteria and would be an adjunctive therapy to antibiotics.

● Pfizer is developing PF-06425090, a three-dose recombinant vaccine designed to stimulate an antibody against the two main toxins (A and B) produced by C.

difficile which cause the characteristic diarrhea and colitis.

● Fecal biotherapy aims to recolonize the bacteria that comprise the natural gut flora and, according to the 2017 IDSA Guidelines would be used for patients with multiple recurrences of CDI who have failed to resolve their infection despite treatment attempts with antibiotic agents targeting CDI.

Finch Therapeutics recently failed with CP101, its lead therapeutic targeting patients with multiple recurrences of CDI using donor derived stool samples in an oral formulation, to our understanding, and in January 2023 discontinued its Ph3 clinical trial in this area.

● Fecal biotherapy approaches in development include SER-109, being developed by Seres Therapeutics, Inc., which is an investigational oral microbiome therapeutic for the prevention of recurrent C.

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The FDA has granted SER-109 both Breakthrough Therapy and Orphan Drug designations and has recently initiated a Phase 3 clinical trial.

● RBX2660 which is being developed by Rebiotix, Inc.

is a microbiome-based technology and is currently being evaluated in a Phase 3 clinical trial for the prevention of recurrent C.

difficile infection.

● Rebiota™(fecal microbiota, live-jslm) was recently approved by FDA as a fecal microbiota product which is prepared from stool donated by qualified individuals and delivered via enema for the prevention of recurrent Clostridioides difficile infection (CDI) in adults.

● CRS3123 (Crestone Inc) is a novel small molecule that selectively inhibits methionyl-tRNA synthetase of C.

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● MGB-BP-3 (MGB Biopharma) is a novel synthetic polyamide active against Gram- positive pathogens and binds to the minor groove of DNA.

MGB announced that it has completed a dose-ranging Phase 2 clinical trial.

MGB announced that it has completed a dose-ranging Phase 2 clinical trial in 2020 but there are no indications publicly that MGB BioPharma has commenced Ph3.

● No new antibiotics in clinical development have shown improvement in either initial clinical cure (“ICR”) or sustained clinical response (“SCR”) in comparison to currently marketed antibiotics.

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difficile infection and preventing recurrence as well as simultaneous promotion of microbiome health.

We filed a non-

provisional patent application and an international patent application in 2022 covering methods of treating C.

difficile infection and preventing recurrence while simultaneously promoting microbiome health.

We also filed a new provisional patent application in 2022 covering compositions and methods to promote gut microbiome health.

We believe the commercial opportunity for ibezapolstat is best protected by regulatory exclusivity in the U.S.

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We have obtained three U.S.

patents on ACX-375C, our second antibiotic program, and have a fourth U.S.

patent application and foreign applications pending for ACX-375C.

patents and one Israeli patent on ACX-375C, our second antibiotic program, and has a fourth U.S.

patent application and multiple foreign applications pending for ACX-375C.

Our three U.S.

patents on ACX-375C include composition-of-matter, surface coating, and method of use claims and, absent any patent extensions, will expire in December 2039 worldwide.

We anticipate that the patent protection will be further supported by regulatory exclusivity available to new classes of antibiotics treating life-threatening infections under the GAIN Act.

Management believes that ACX-375C series lead product candidate will be QIDP and Fast-Track eligible as it is a new chemical entity and its antibacterial spectrum of activity covers bacterial pathogens included in the FD&C GAIN Act as “qualifying pathogens” for QIDP status.

Accordingly, management anticipates 10 years of regulatory exclusivity from FDA approval to further secure the commercial potential of ACX-375C.

We intend to file for QIDP and Fast-Track designations with the FDA at the appropriate time in the drug development process as was done in 2018 with ibezapolstat.

patents and Israeli patent on ACX-375C include composition-of-matter, surface coating, and method of use claims.

Absent any patent extensions, these patents will expire in December 2039.

We anticipate that the patent protection will be further supported by regulatory exclusivity available to new classes of antibiotics treating life-threatening infections (QIDP Designation by FDA – 5 years) and New Chemical Entity Designation (5 years).

We anticipate filing for and receiving QIDP Designation as well as “Fast Track” with FDA in the next 24 months for ACX-375C, both of which designations have been granted by FDA for ibezapolstat, our lead antibiotic program.

GAIN Exclusivity for Antibiotics

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Congress passed the GAIN Act as part of FDASIA in 2012 to encourage the development of antibacterial and antifungal drug products that treat pathogens that cause serious and life-threatening infections.

Potential External Positive Drivers in 2022 for Sector

Potential External Positive Drivers for Sector

Future external funding opportunities change over time but include the following:

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Congress which would remove the financial disincentives now in place for prescribers of antibiotics to use novel agents possibly more efficacious than older, less effective antibiotics that are prescribed at a lower cost.

Accordingly, treating physicians would have the opportunity to treat patients with infectious disease with the most effective agents thereby enhancing patient outcomes as well as reducing the cost burden on public health.

Accordingly, treating physicians would have the opportunity to

treat patients with infectious disease with the most effective agents thereby enhancing patient outcomes as well as reducing the cost burden on public health.

EU Pull Incentives .

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Further characterization and testing in animal models are ongoing.

We had previously synthesized >435 novel analogs targeting Pol IIIC, which have been screened for potency (MIC) against a panel of pathogens.

The table below shows the number of compounds with strong potency vs.

MRSA, VRE, and both MRSA and VRE.

These potential lead compounds have met the first criteria, MIC potency ≤4 µg/mL vs.

key pathogens.

The Lead Optimization goal is to identify and synthesize compounds with this potency while demonstrating improvements in (1) aqueous solubility, (2) plasma protein binding and (3) cytotoxicity.

Number of Pol IIIC inhibitor compounds with potent MICs vs.

MRSA and/or VRE:

Acurx has pioneered the clinical development of a pol IIIC inhibitor as a clinically valid bacterial target.

Ibezapolstat cured 10 of 10 (100%) patients after 10-days treatment with no recurrences during the 30-day follow up period in a Phase 2a trial for C.

difficile infection (CDI).

Gut microbiome analyses further showed that potentially beneficial bacterial species are selectively preserved in CDI patients during treatment with ibezapolstat;

the pol IIIC Mechanism-of-Action (MOA) suggests that this is a class effect.

Acurx is also developing a systemic pol IIIC Gram-positive selective spectrum (GPSS) oral and IV antibiotic.

The initial hit ACX 375C is pan-active against wild-type and drug-resistant Gram-positive bacteria (e.g., MRSA, VRE

Acurx has synthesized and tested >600 novel analogs targeting pol IIIC.

To date, 20 novel compounds with MIC values ≤1 μg/mL for both MRSA and VRE have been identified (see Table below).

>1 to < 2 µg/mL

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>2 to < 4 µg/mL

Analogs with good MIC are tested for cytotoxicity (CC50;

mammalian cell lines Hep G2 (liver) and HEK 293t (kidney), and against primary human hepatocytes.

Several compounds show significant reduction of

cytotoxicity (CC50 >128 µg/mL for both cell lines) as compared to ACX-375C (CC50 =35 µg/mL).

The thermodynamic solubility has been improved for numerous compounds as well.

As of the date of this Form 10-K, a number of potential lead compounds have been tested in a lethal systemic MRSA-infection mouse model vs.

vancomycin and vehicle control.

These data show that some of our novel compounds show superior efficacy vs.

low-dose vancomycin, as demonstrated by an increase in survival rate and duration, including one new lead compound dosed orally.

Additional preliminary work demonstrated good bactericidal activity for several compounds vs.

MRSA and VRE, as well as significant post-antibiotic effect (“PAE”), or the suppression of bacterial growth that persists after brief exposure of organisms to antimicrobials, (PAE >5 hours) vs.

VRE, but not vs.

Early lead compounds show oral bioavailability from 33 – 59% in the absence of any absorption enhancing agents.

An MIC screen of a few Acurx compounds vs.

recent clinical isolates demonstrates potent activity against daptomycin-, vancomycin- and linezolid resistant strains of MRSA, E.

faecalis and E.

Based on the novel MOA for these Pol IIIC inhibitors, we anticipate strong antibacterial activity vs.

all currently resistant isolates.

We continued our efforts to further enhance the physicochemical properties and have screened an additional 38 new compounds identifying many with improved antibacterial potency.

We expect that these will advance to PK/PD, safety and solubility testing in 2022.

Our goal is to select a lead compound with back-ups by mid-year 2022, to be followed by key microbiology studies, manufacturing development and to enter IND enabling toxicology studies in the first half of 2023.

Taken as a whole, the nonclinical microbiology results indicate that our new antimicrobial potential lead product candidates (a) show potent in vitro inhibitory and killing activity against MRSA, vancomycin resistant Enterococcus, PRSP and other resistant bacteria, (b) are likewise effective in protecting and treating animals from induced life-threatening infections, and (c) therefore show promise in being able to treat Gram-positive infections in patients.

The Hit-to-Lead program produced improvements in solubility, cytotoxicity, and protein binding with a comprehensive SAR understanding.

Pol IIIC inhibitors have a novel MOA and activity of ACX-375 against MRSA and VRE bacteria was not impacted by vancomycin-, daptomycin-, or linezolid-resistance.

Pol IIIC is absent in Gram-negative bacteria and mammalian cells.

New analogs show improved characteristics directly related to clinical therapeutic utility:

improved solubility for IV formulation, improved safety vs.

HepG2, as an initial predictor of pharmacologic safety, and decreased plasma protein binding, to further improve in vivo efficacy.

These analogs have maintained potent MICs against MRSA, MSSA, PRSP, E.

faecalis and VRE.

In vivo pharmacology studies have been encouraging but are not yet determinative.

PK studies in mice demonstrate oral and IV exposures sufficient for efficacy testing in infection models.

Oral bioavailability of 31-59% was demonstrated by 10 different analogs when administered as a simple liquid formulation.

Oral bioavailability will improve further through formulation optimization.

The solubility of pol IIIC inhibitors has been improved by prodrug efforts, which support the viability of an IV formulation.

Phosphate prodrugs for two compounds showed rapid conversion from inactive prodrug to active parent drug with good exposures following IV and PO dosing in mice.

Solubility was improved to the range of 1 mg/mL, which is viable for IV formulation.

Efficacy has been demonstrated in 4 different mouse models involving different body sites including the critically important lung and thigh.

The models were:

MRSA peritonitis (3 analogs >60% protection, median survival >7 days);

MRSA thigh (neutropenic;

1 analog 1.28 log10 CFU reduction);

VRE thigh (neutropenic;

4 analogs 1.21-1.94 log10 CFU reduction);

and PRSP lung (neutropenic;

5 analogs 1.03-1.69 log10 CFU reduction).

Oral efficacy was demonstrated in 3 models.

Lead optimization will seek to further improve efficacy, especially in the thigh model which is a simulation of the initial clinical indication.

One analog tested in a battery of safety screens (Eurofins 44 panel, CiPA panel, and CYP inhibition assays) showed no liabilities.

As a pilot study, two analogs were tested in 5-day repeat dose studies in mice at 50 mg/kg TID (150 mg/day).

One analog showed no HepG2 cytotoxicity (IC50 >128 µg/mL) in vitro, while the 2nd showed effects (IC50 30 µg/mL).

There were no adverse effects observed in life, no changes in body weight, and no significant gross necropsy findings for either compound.

Serum chemistry showed no effects (treated vs.

n=5/group) for the 1st compound (IC50 >128 µg/mL) while the 2nd (IC50 30 µg/mL) showed elevated liver enzymes for one analog in several mice dosed IV and PO.

These results were encouraging since the HepG2 in vitro assay is used as a marker for potential in vivo toxicity.

Spontaneous resistance frequency is low (<3.17x10-9 and <1.30x10-9 for MRSA and VRE, respectively, at 4xMIC), and there is no cross-resistance with other antibiotics.

Acurx is studying potential MOR (Mechanism of Resistance) to pol IIIC inhibitors using whole genome sequencing.

In collaboration with two laboratories at Leiden University Medical Center under a Dutch government grant, the 3-D structure of pol IIIC from MRSA, VRE and PRSP alone and bound to Acurx inhibitors will be studied using cryo-EM/X-ray crystallography.

Using this, novel analogs with improved binding will be tested.

The Acurx Lead Optimization program is modifying existing leads to develop compounds with improved potency, less plasma protein binding, and increased exposures.

The Lead Optimization Program includes developing an improved rapid assay of pol IIIC inhibitor activity (Ki) for MRSA, VRE, and PRSP;

determining the 3 D structure of Acurx compounds bound to pol IIIC enzymes for improved SAR;

developing/testing novel oral formulations to improve bioavailability;

and testing prodrug compounds in animal infection/safety models.

Oral and IV candidates from Lead Optimization will then advance to preclinical testing and Phase 1 SAD (Single Ascending Dose) / MAD (Multiple Ascending Dose) trials.

The initial clinical indication is targeting gram-positive acute bacterial skin and skin structure infections (ABSSSI);

subsequent trials may target confirmed Gram-positive infections for hospital-acquired bacterial pneumonia (HABP), bloodstream infections/endocarditis, diabetic foot infections, and/or osteomyelitis.

ABSSSI is an ideal clinical indication for a pan active gram-positive drug since the clinical end points, comparators, and execution are well established.

These bacterial targets (MRSA, VRE and PRSP) involve an incidence of approximately six million patients per year in the U.S.

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Employees and Human Capital Resources

As of March 15, 2022, we had three full-time employees.

Of these employees, none were engaged in research and development activities.

As of March 15, 2023, we had four full-time employees.

Of these employees, one was engaged in research and development activities for a portion of his time.

Substantially all of our employees are based in Staten Island, New York.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business