UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
WASHINGTON,
D.C. 20549
FORM
10-K
(Mark
One)
☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the fiscal year ended December 31, 2024
OR
☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the transition period from ________ to ________
Commission
file number: 001-41184
ZYVERSA
THERAPEUTICS, INC.
(Exact
name of registrant as specified in its charter)
(Address of registrant’s principal executive offices) (Zip Code)
(754)231-1688
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol Name of each exchange on which registered
Common Stock, $0.0001 par value per share ZVSA The Nasdaq Capital Market
Securities
registered pursuant to Section 12(g) of the Act: None
Indicate
by check if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes: ☐ No:
☒
Indicate
by check mark if the registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act
of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has
been subject to such filing requirements for the past 90 days. Yes: ☒ No: ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule
405 of Regulation S-T during the preceding 12 months (or for such shorter period that the registrant was required to submit such files).
Yes: ☒ No: ☐
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting
company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,”
“smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☒
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying
with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report. ☐
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to § 240.10D-1(b). ☐
Indicate
by check mark if the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes: ☐ No: ☒
As
of June 30, 2024, the last business day of the registrant’s most recently completed second fiscal quarter, the aggregate market
value of shares of the registrant’s common stock held by non-affiliates of the registrant (based upon the closing sales price of
$3.76 for such shares on the Nasdaq Capital Market on June 28, 2024) was approximately $3.1 million. For purposes of calculating the
aggregate market value of shares held by non-affiliates, we have assumed that all outstanding shares are held by non-affiliates, except
for shares held by each of our executive officers, directors, and 5% or greater stockholders. In the case of 5% or greater stockholders,
we have not deemed such stockholders to be affiliates unless there are facts and circumstances which would indicate that such stockholders
exercise any control over our company, or unless they hold 10% or more of our outstanding common stock. These assumptions should not
be deemed to constitute an admission that all executive officers, directors, and 5% or greater stockholders are, in fact, affiliates
of our company, or that there are not other persons who may be deemed to be affiliates of our company. Further information concerning
shareholdings of our officers, directors, and principal stockholders is included or incorporated by reference in Part III, Item 12 of
this Annual Report on Form 10-K.
As
of March 20, 2025, the number of shares outstanding of the registrant’s common stock, $0.0001 par value per share, was 2,568,191.
DOCUMENTS
INCORPORATED BY REFERENCE
None.
ZYVERSA
THERAPEUTICS, INC.
ANNUAL
REPORT ON FORM 10-K
FOR
THE FISCAL YEAR ENDED DECEMBER 31, 2024
TABLE
OF CONTENTS
Page
PART I 5
1. Business 5
1A. Risk Factors 39
1B. Unresolved Staff Comments 87
1C. Cybersecurity 88
2. Properties 88
3. Legal Proceedings 88
4. Mine Safety Disclosures 88
7A. Quantitative and Qualitative Disclosures About Market Risk 100
8. Financial Statements and Supplementary Data 100
9A. Controls and Procedures 100
9B. Other Information 100
9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 100
10. Directors, Executive Officers and Corporate Governance 101
11. Executive Compensation 104
14. Principal Accounting Fees and Services 114
15. Exhibits, Financial Statement Schedules 115
CAUTIONARY
NOTE REGARDING FORWARD-LOOKING STATEMENTS
This
Annual Report on Form 10-K (this “Annual Report”) contains forward-looking statements made pursuant to the safe harbor provisions
of the Private Securities Litigation Reform Act of 1995 under Section 27A of the Securities Act of 1933, as amended, and Section 21E
of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). Forward-looking statements include statements with
respect to our beliefs, plans, objectives, goals, expectations, anticipations, assumptions, estimates, intentions and future performance,
and involve known and unknown risks, uncertainties and other factors, which may be beyond our control, and which may cause our actual
results, performance or achievements to be materially different from future results, performance or achievements expressed or implied
by such forward-looking statements. All statements other than statements of historical fact are statements that could be forward-looking
statements. You can identify these forward-looking statements through our use of words such as “may,” “can,”
“anticipate,” “assume,” “should,” “indicate,” “would,” “believe,”
“contemplate,” “expect,” “seek,” “estimate,” “continue,” “plan,”
“point to,” “project,” “predict,” “could,” “intend,” “target,”
“potential” and other similar words and expressions of the future.
There
are a number of important factors that could cause the actual results to differ materially from those expressed in any forward-looking
statement made by us. These factors include, but are not limited to:
● our ability to continue as a going concern;
● the costs associated with our business;
● our ability to achieve and maintain profitability in the future
● our ability to effectively grow and expand operations;
● the risk of disruption to our current plans and operations;
● the impact of changes to applicable laws or regulations;
● our ability, assessment of, and strategies to compete with our competitors;
● our ability to prevent and guard against cybersecurity attacks;
● our ability to maintain and protect our brand and intellectual property; and
● other factors detailed under the section entitled “Risk Factors.”
The
foregoing does not represent an exhaustive list of matters that may be covered by the forward-looking statements contained herein or
risk factors that we are faced with that may cause our actual results to differ from those anticipated in such forward-looking statements.
Please see “Part I—Item 1A—Risk Factors” for additional risks which could adversely impact our business and financial
performance.
All
forward-looking statements are expressly qualified in their entirety by this cautionary notice. You are cautioned not to place undue
reliance on any forward-looking statements, which speak only as of the date of this report or the date of the document incorporated by
reference into this report. We have no obligation, and expressly disclaims any obligation, to update, revise or correct any of the forward-looking
statements, whether as a result of new information, future events or otherwise. We have expressed our expectations, beliefs and projections
in good faith and believe they have a reasonable basis. However, we cannot assure you that our expectations, beliefs or projections will
result or be achieved or accomplished.
PART
I
ITEM
1. BUSINESS
All
references in this report to “ZyVersa,” the “Company,” “we,” “us,” or “our”
mean ZyVersa Therapeutics, Inc. and its subsidiaries unless we state otherwise, or the context otherwise indicates.
Company
Overview
We
are a clinical stage biopharmaceutical company leveraging proprietary technologies to develop drugs for patients with chronic renal or
inflammatory diseases with high unmet medical needs. Our mission is to develop drugs that optimize health outcomes and improve patients’
quality of life.
We
have two proprietary globally licensed drug development platforms, each of which was discovered by research scientists at the University
of Miami, Miller School of Medicine (the “University of Miami” or “University”). These development platforms
are:
We
believe that each of our product candidates has the potential to treat numerous indications in their respective therapeutic areas. Our
strategy is to focus on indication expansion to maximize commercial potential.
Our
renal pipeline is initially focused on rare, chronic glomerular diseases. Our lead indication for VAR 200 is focal segmental glomerulosclerosis
(“FSGS”). On January 21, 2020, we filed an Investigational New Drug application (“IND”) for VAR 200, and the
United States Food and Drug Administration (“FDA”) has allowed our development plans to proceed to a Phase 2a trial in patients
with FSGS based on the risk/benefit profile of the active ingredient (2HPβCD). Prior to initiating a Phase 2a trial in patients
with FSGS, we are planning to initiate a small open-label Phase 2a trial in patients with diabetic kidney disease in H1-2025, in which
we expect to obtain patient proof-of-concept data more quickly than in an FSGS trial. This will enable assessment of drug effects as
patients proceed through treatment and will provide insights for developing a lager Phase 2a/b protocol in patients with FSGS. VAR 200
has pharmacologic proof-of-concept data in animal models representative of FSGS, Alport Syndrome, and diabetic kidney disease providing
opportunity for indication expansion.
Our
Inflammasome ASC Inhibitor IC 100 focuses on chronic inflammatory diseases. Our lead indication for IC 100 is obesity with metabolic
complications. IC 100’s preclinical development is nearing completion. Our focus is on advancing IC 100 toward a currently planned
IND submission in H2-2025, followed by initiation of a Phase 1 trial in healthy overweight patients with a BMU between 27 – 30.
IC 100 has preclinical data in animal models representing six different indications, each demonstrating that IC 100 attenuates pathogenic
inflammasome signaling pathways leading to reduced inflammation and improved histopathological and/or functional outcomes. Those indications
are stroke-related cardiovascular injury, retinopathy of prematurity (“ROP”), multiple sclerosis (“MS”), acute
respiratory distress syndrome (“ARDS”), spinal cord injury, and traumatic brain injury (TBI). Likewise, preclinical studies
are underway in Alzheimer’s and Parkinson’s diseases, and we are preparing to initiate IND-enabling preclinical studies in
animal models of diet-induced obesity.
About
Chronic Kidney Disease (CKD)
Chronic
kidney disease (“CKD”) is an increasing public health problem which affects over 75 million people worldwide, and approximately
37 million in the United States. The National Kidney Foundation estimates that approximately 80 million adults are at risk for kidney
disease in the United States. With no disease modifying drug therapies commercially available, a sizeable percentage of kidney patients
progress to end-stage renal disease (“ESRD”), requiring dialysis or transplant to survive. According to the Centers for Disease
Control and Prevention, in 2018, approximately 131,600 people in the United States started treatment for ESRD, and nearly 786,000 people
are currently living with ESRD in the United States (of those 786,000 people, approximately 71% are on dialysis, and 29% are living with
a kidney transplant). Further, the economic burden associated with chronic kidney disease is substantial, with Medicare Fee-for-Service
spending of $130 billion in 2018 according to the National Kidney Foundation. We believe the high incidence level and the steep monetary
burden caused by CKD create a need for effective, disease modifying drug therapies.
CKD
is associated with poor prognosis and in 2017, according to the National Vital Statistics Report, CKD was the ninth-leading cause of
death in the United States. To address this significant health problem, on July 10, 2019, the White House and Department of Health and
Human Services launched the Advancing American Kidney Health (“AAKH”) initiative to advance kidney disease prevention and
care in the United States, which has three goals: (1) to reduce the number of patients developing renal failure through better diagnosis,
treatment, and preventative care; (2) to maximize provision of home dialysis care; and (3) to expand the pool of kidneys available for
transplant. We believe that by mediating removal of excess renal intracellular cholesterol that contributes to kidney damage and dysfunction,
VAR 200 has the potential to help address the AAKH initiative’s first goal to reduce the number of patients developing renal failure.
Our
lead renal indication is FSGS, which is a progressive form of kidney disease with no approved drug therapies. Approximately 40-60% of
FSGS patients develop end stage kidney disease within 10-20 years, requiring dialysis and ultimately kidney transplant to survive. FSGS
is an orphan disease affecting approximately 40,000 people in the United States. It is characterized by injury to the kidneys’
filtration system or “glomerular podocytes” leading to scarring that is focal (i.e., affecting only some glomerulus) and
segmental (i.e., affecting only part of glomerulus). Accumulation of cholesterol and lipids in renal glomeruli, which has been associated
with structural damage and impaired kidney function, has been seen in FSGS patient biopsies and in representative FSGS animal models.
Damage to the glomeruli causes protein to leak into urine, a condition known as proteinuria. As the level of protein increases in the
urine, patients develop a specific set of symptoms known as nephrotic syndrome. Proteinuria is strongly associated with kidney disease
progression, and nephrotic syndrome is generally predictive of a poor prognosis. Approximately 70% of FSGS patients present with nephrotic
syndrome at diagnosis. By mediating removal of excess cholesterol from renal glomeruli, we believe that VAR 200 has the potential to
preserve renal structure and function and thereby reduce proteinuria that leads to FSGS progression.
About
Inflammatory Diseases
Chronic
inflammatory diseases have been recognized as one of the most significant causes of death in the world today, with more than 50% of all
deaths worldwide attributable to inflammation-related diseases such as ischemic heart disease, stroke, cancer, diabetes mellitus, chronic
kidney disease, non-alcoholic fatty liver disease (“NAFLD”), and autoimmune and neurodegenerative conditions. Excessive and
persistent activation of inflammasomes have been linked to the pathophysiology of these types of chronic diseases.
Inflammasomes
are comprised of 3 proteins: (i) one of several types of sensor molecules, (ii) an apoptosis-associated speck-like protein containing
a caspase recruitment domain (“ASC”), and (iii) proinflammatory caspase-1 (“pro-caspase-1”). There are multiple
types of inflammasomes that trigger inflammation. They are named based on their associated sensor molecule, such as NLRP1, NLRP2, NLRP3,
NLRC4, AIM2, and Pyrin. Numerous inflammatory diseases are often associated with activation of multiple types of inflammasomes. For example,
obesity is associated with activation of AIM2 and NLRP3, insulin resistance is associated with AIM2, NLRP1, NLRP3, NLRC4, and NLRP6,
and Parkinson’s disease is associated with activation of AIM2, NLRP1 and NLRP3. The ASC component of inflammasomes is a promising
drug target since it is a component of the six most common types of inflammasomes referenced above. We believe this is more advantageous
than targeting a specific sensor protein such as NLRP3, a component of only one type of inflammasome, which is the focus of several potential
competitors. In addition to its pivotal role in inflammasome formation and activation required for initiation of an inflammatory response,
ASC also plays a role in the perpetuation of inflammation associated with extracellular release of ASC specks. By targeting ASC, we believe
IC 100 has potential to effectively control inflammation in a multitude of inflammatory diseases.
Our
Pipeline
The
goal of our pipeline is to target renal and inflammatory indications with high unmet medical needs, which we believe can be addressed
by our mechanisms of action. We intend to further enhance and expand our product portfolio through the development of multiple indications
for VAR 200 and IC 100 each, and through potential in-licensing of promising renal and anti-inflammatory product candidates.
Our
current pipeline consists of the following:
Development
Phase: Phase in which a drug formulation is developed that ensures the proper drug delivery parameters are met
Preclinical
Phase: Phase in which in vitro (laboratory) and in vivo (animal) studies are conducted to gather evidence to justify
clinical trials in humans
Phase
1: First testing in healthy humans, primarily to test safety
Phase
2: Testing in a small number of patients to assess safety, monitor how a drug is metabolized, and gather initial data on efficacy
Phase
3: Large trial in patients to test efficacy and safety that are used for regulatory approval
Business
Strategy
We
seek to be recognized as a leading biopharmaceutical company at the forefront of innovation for patients with high unmet medical needs.
We are committed to restoring health and transforming the lives of patients through development of biopharmaceutical products. Our strategy
is to:
The
dates and events reflected in the foregoing are estimates only, and there can be no assurances that the events included will be completed
on the anticipated timeline presented, or at all. Further, there can be no assurances that we will be successful in the development of
any of our product candidates, or any other products or product candidates we may develop in the future, or that any product candidate
we may develop in the future, will receive FDA approval for any indication.
Our
Product Candidates
Cholesterol
Efflux Mediator TM VAR 200 (2-hydroxypropyl-beta-cyclodextrin, 2HPβCD)
Cholesterol
Efflux Mediator VAR 200 is an injectable drug in clinical development for treatment of chronic glomerular diseases, initially focusing
on FSGS as the lead. Prior to initiating a Phase 2a trial in patients with FSGS, we are planning to conduct a small Phase 2a trial in
patients with diabetic kidney disease, which we expect will provide patient proof-of-concept more quickly than an FSGS study. Alport
Syndrome and diabetic kidney disease indications may be pursued based on our indication expansion strategy.
VAR
200 was developed to mediate removal of excess cholesterol that damages renal glomeruli, with the intent to preserve renal structure
and function and reduce proteinuria that leads to glomerular disease progression. Although our lead renal indication is FSGS (VAR 200-01),
we are planning to initiate a small Phase 2a trial in patients with diabetic kidney disease in H1-2025, in which we expect to obtain
patient proof-of-concept data more quickly than in an FSGS trial. This will enable assessment of drug effects as patients proceed through
treatment and will provide insights for developing a larger Phase 2a/b protocol in patients with FSGS. Based on the anticipated data
and key learnings from these trials, we may progress development of VAR 200 for Alport Syndrome (VAR 200-02) and for diabetic kidney
disease (VAR 200-03) based on our indication expansion strategy.
Role
of Cholesterol and Lipid Accumulation in Glomerular Diseases (Including FSGS, Alport Syndrome, and Diabetic Kidney Disease)
In
chronic glomerular diseases, cholesterol accumulates in glomerular podocytes, due in part to impaired transport out of the cell, or “efflux,”
resulting from reduced expression of the cholesterol transporters ABCA1 and ABCG1. Glomerular lipid accumulation has been demonstrated
in in vitro podocyte studies, human biopsy data, and in animal models of various kidney diseases, including FSGS, Alport syndrome,
and diabetic kidney disease. As shown below, the lipid accumulation causes distorted podocyte structure, damaged podocyte foot processes,
and podocyte detachment and loss, which impairs kidney filtration resulting in proteinuria and disease progression. Preclinical animal
models with VAR 200 show that reduction in podocyte cholesterol and lipids protects against ongoing kidney damage and progression of
disease, which we hypothesize will translate to patients with kidney disease and potentially reduce or delay the need for dialysis and
ultimately transplant.
VAR
200 Mechanism of Action
VAR
200’s active ingredient, 2HβCD, is comprised of seven sugar molecules bound together in a 3-D ring with a hydrophobic core
and hydrophilic exterior. VAR 200 mediates cholesterol efflux both passively and actively by interacting with hydrophilic components
of the glomerular membrane.
Passive
Cholesterol Efflux
Passive
cholesterol efflux occurs with formation of 2HPβCD dimers, which bind to the cell membrane surface and incorporate cholesterol into
its hydrophobic core as an inclusion complex. Release of the 2HPβCD/cholesterol inclusion complex from the cell membrane surface
brings the cholesterol into solution for transfer to cholesterol acceptors, such as high-density lipoprotein (“HDL”).
Active
Cholesterol Efflux
Active
cholesterol efflux occurs through mediating metabolism of free cholesterol into oxysterols. Oxysterols activate the liver X receptor
(“LXR”)-transcription factors, resulting in induction of cellular cholesterol efflux pathways, including upregulation cholesterol
efflux transporters, ABCA1 and ABCG1, which transport free cholesterol outside the cell to cholesterol acceptors, such as HDL.
Preclinical
Support for VAR 200
We
believe that VAR 200 has an established benefit/risk profile supported by IND-enabling preclinical studies demonstrating safety and proof
of concept, which led to FDA clearance to progress into Phase 2 clinical trials. Data from animal models representing FSGS, Alport Syndrome,
and diabetic kidney disease demonstrate that VAR 200 promotes cholesterol removal from podocytes, protecting the kidney’s filtration
system from damage and reducing protein spillage into the urine or “proteinuria.” These types of outcomes are thought to
be key to delaying or preventing progression of kidney disease.
VAR
200 and FSGS
VAR
200 was evaluated in two FSGS mouse models, an experimental nuclear factor of activated T-cells (“NFAT”) FSGS model and an
Adriamycin (“ADR”)-induced FSGS model which is characterized by a milder, less progressive form of nephropathy than the NFAT
model.
Nuclear
Factor of Activated T-Cells (NFAT) Model
To
determine the role of altered podocyte cholesterol homeostasis in NFAT-mediated podocyte injury and the effects of treatment with VAR
200, researchers administered VAR 200 subcutaneously at 4,000 mg/kg to 6-week-old NFATc1nuc mice 24 hours prior to induction
with doxycycline, and then every other day for 4 days. Single transgenic (“ST”) mice served as a control.
VAR
200 (indicated by “CD” in the graphs below) significantly reduced cholesterol in the renal cortex of FSGS mice compared to
untreated double transgenic mice (indicated by “DT” in the graphs below). This was associated with a significant reduction
in proteinuria (albumin/creatine ratio) as shown below.
Adriamycin
(ADR)-induced Model
In
the second FSGS model, researchers injected 5-week-old BALB/c mice with one dose of Adriamycin at 11 mg/kg. Subsequently, VAR 200 was
administered 24 hours later at 40 mg/kg via subcutaneous osmotic pump for 10 weeks. Non-induced mice served as a control.
VAR
200 (indicated by “CD” in the graphs below) significantly reduced mesangial expansion, which is commonly associated with
lipid deposition, compared to untreated ADR-induced mice as shown below. This was associated with a significant reduction in proteinuria
(albumin/creatine) and blood urea nitrogen (“BUN”) in VAR 200-treated) ADR-induced mice compared to untreated ADR-induced
mice as shown below.
VAR
200 and Alport Syndrome
To
evaluate whether VAR 200 has a protective effect in Alport Syndrome, a genetic disease, researchers injected four-week-old female Col4a3
knockout (Col4a3−/−) mice with VAR 200 at 4000 mg/kg subcutaneously 3 times per week for 4 weeks. Wild type Col4a3 (“Col43+/+”)
mice served as controls.
VAR
200 (indicated by “CD” in the graphs below) significantly reduced renal neutral lipid, cholesterol ester, and cholesterol
crystal accumulation in Alport Syndrome mice when compared to untreated Alport Syndrome mice as shown below.
The
decreased intracellular lipids in VAR 200-treated Alport Syndrome mice were associated with a significant reduction in renal damage (reduced
mesangial expansion, fibrosis, and foot process effacement), and renal function was maintained when compared to untreated Alport Syndrome
mice, as evidenced by reduced proteinuria (albumin/creatinine), blood urea nitrogen, and serum creatinine when compared to untreated
Alport Syndrome mice as shown below.
VAR
200 and Diabetic Kidney Disease
To
determine if VAR 200 can sequester intracellular cholesterol and protect podocytes from cholesterol-dependent damage in diabetic kidney
disease, researchers treated 4-week old BTBR ob/ob homozygous mice, a diabetic model of progressive kidney disease, with 3 weekly subcutaneous
injections of VAR 200 at 4,000 mg/kg for 5 months. Heterozygous mice served as controls.
VAR
200 (indicated by “CD” in the graphs below) significantly reduced total cholesterol in the kidney cortex compared with untreated
diabetic mice. This was associated with a significant reduction in renal damage (mesangial expansion) and reduced proteinuria (albumin/creatinine)
compared to untreated diabetic mice starting at 2 months following treatment, with statistically significant reduced levels from 3 months
to end of study as shown below.
Based
on the results in animal models of 3 different renal diseases summarized above, we believe that VAR 200 has potential to induce and maintain
partial or complete remission of proteinuria in renal patients with nephrotic syndrome, thereby reducing the rate of renal disease progression.
Inflammasome
ASC Inhibitor IC 100
IC
100 is a humanized monoclonal antibody inflammasome ASC inhibitor in preclinical development for the treatment of numerous inflammatory
diseases, with obesity with certain metabolic complications as the lead. IC 100 was developed with the intent of attenuating chronic
aberrant inflammation that is pathogenic in a multitude of inflammatory diseases by blocking initiation and perpetuation of inflammation
to stop disease progression and improve quality of life.
Our
focus is on advancing IC 100 toward a planned submission of an IND application in H2-2025, following which we intend to initiate a Phase
1 trial in healthy subjects who are overweight (BMI 27 -30). Non-GLP toxicology data with IC 100 in mice and non-human primates (“NHP”)
demonstrate no adverse effects nor anti-drug antibodies at doses as high as 300 mg/kg. IC 100 has preclinical data in animal models representing
six different indications, each demonstrating that IC 100 attenuates pathogenic inflammasome signaling pathways leading to reduced inflammation
and improved histopathological and/or functional outcomes. Those indications are stroke-related cardiovascular injury, retinopathy of
prematurity (“ROP”), multiple sclerosis (“MS”), acute respiratory distress syndrome (“ARDS”), spinal
cord injury, and traumatic brain injury (TBI). Likewise, preclinical studies are underway in Alzheimer’s and Parkinson’s
diseases, and we are preparing to initiate two IND-enabling preclinical studies with IC 100 in DIO obesity models. One study will compare
the effects of IC 100 to semaglutide, and the other will compare the effects of IC 100 administered concurrently with semaglutide.
Role
of Inflammasomes in Inflammatory Diseases
Excessive
and persistent activation of inflammasomes have been linked to the pathophysiology of inflammatory diseases. Inflammasomes are multiprotein
complexes that initiate an immune response to pathogens or internal danger signals. They are comprised of three basic proteins: (i) one
of several types of sensor molecules (e.g., NLRP1, NLRP2, NLRP3, NLRC4, AIM2, and Pyrin), (ii) adaptor protein, ASC, and (iii) pro-caspase
1. Each sensor molecule responds to different pathogens or internal danger signals. Inflammasomes are named by their sensor molecule
(e.g., NLRP3 inflammasome).
As
depicted below, in the presence of harmful pathogens or cell damage, an intracellular sensor molecule (e.g., NLRP3) is triggered, stimulating
recruitment of adaptor ASC, which in turn recruits pro-caspase-1 to form an inflammasome. The inflammasome is the organizing center that
recruits additional ASC and polymerizes in a prion-like structure to form a large filamentous signaling platform, known as an ASC Speck.
ASC Specks provide a scaffold for pro-caspase-1 recruitment, which triggers conversion of pro-caspase-1 to active caspase-1, which in
turn converts the cytokine pro-IL-1ß to its active form IL-1ß, initiating the inflammatory response. Activated caspase-1
also drives cleavage of Gasdermin D, which triggers pyroptosis, a form of programmed cell death, releasing active cytokines and ASC Specks
into the extracellular space, with continued activation of pro-IL-1ß, heightening and perpetuating the inflammatory response in
neighboring cells and tissues. Although inflammasome triggering of the innate immune response is essential for protection against pathogens,
persistent overactivation of inflammasomes can lead to chronic inflammation underlying a multitude of inflammatory conditions and diseases.
Numerous inflammatory diseases are associated with activation of multiple types of inflammasomes. For example, obesity is triggered by
AIM2 and NLRP3 and Parkinson’s disease is triggered by NLRP1, NLRP3, and AIM2.
Inflammasome
ASC Inhibitor IC 100 Mechanism of Action
IC
100 was designed to bind to key amino acids in adaptor protein ASC that govern ASC recruitment into the inflammasome complex and ASC
Speck formation:
Inflammasome
Activation in One Condition Can Impact Another
A
recent paper published in Translational Research demonstrates that inflammasome activity and signaling proteins triggered by one unique
inflammatory condition can impact and potentially interact with another. The authors provided extensive evidence that traumatic brain
injury (TBI) and Alzheimer’s disease (AD) are linked by activation of multiple types of inflammasomes (NLRP3, NLRP1, and AIM2).
In each condition, inflammasome activation leads to cell death and release of active cytokines and ASC specks to neighboring cells allowing
for one condition to potentially exacerbate the other. For example, individuals with a history of moderate TBI have a 2.3 times greater
risk of developing AD. Likewise, AD pathology is potentially exacerbated by inflammasome activation in patients with TBI through IL-18
and pathological ASC speck interactions with amyloid beta and phosphorylated tau, hallmarks of AD. The authors reported that inflammasome
ASC represents a promising therapeutic target for TBI and AD because of ASC’s unique role in heightening and perpetuating inflammation
in neighboring cells, and its pathological interactions with amyloid beta and phosphorylated tau. In a subsequent study, also published
in Translational Research by several of the same authors, researchers evaluated if blocking inflammasome activity by inhibiting ASC with
IC 100 reduces the elevated inflammatory response in AD mice after TBI. Data demonstrated that 100 resulted in reduction of inflammasome-mediated
cytokine IL-1β in the injured cortex of AD mice at 1-week post-injury.
Preclinical
Support for IC 100
Non-GLP
toxicology studies in mice and non-human primates demonstrate that IC 100 has a good safety profile. There were no drug-related adverse
events at doses up to 300 mg/kg in either species. Likewise, epigenetic screening demonstrates a lower immunogenicity potential than
many biologics. Based on our preclinical study in an animal model representing MS, inflammation was attenuated without immunosuppression.
IC 100 has preclinical data in animal models representing six different indications, each demonstrating that IC 100 attenuates pathogenic
inflammasome signaling pathways leading to reduced inflammation and improved histopathological and/or functional outcomes. Those indications
are stroke-related cardiovascular injury, retinopathy of prematurity (“ROP”), multiple sclerosis (“MS”), acute
respiratory distress syndrome (“ARDS”), spinal cord injury, and traumatic brain injury (TBI). Following is a summary of preclinical
data in stroke-related cardiovascular injury, ROP, and MS. For an overview of preclinical data collected to date, refer to the IC
100 White Paper at https://investors.zyversa.com/static-files/64964310-ab95-4a06-bc47-dd44c63dc5c7.
IC
100 and Stroke-related Cardiovascular Injury
Cardiac
dysfunction occurs in 70% of patients following a stroke which is associated with a surge of catecholamines and inflammasome-induced
systemic and cardiac inflammation. To determine if IC 100 can attenuate post-stroke cardiac inflammation, IC 100 was administered IV
at 30 mg/kg in a mouse model of photothrombotic stroke (PTS) thirty minutes post-PTS. Additionally, catecholamine-treated zebrafish hearts
were used to determine if IC 100 can protect against post-stroke cardiac dysfunction. Action potential duration was evaluated in excised
zebrafish hearts with and without IC 100 (10 μg/ml) 20 seconds after catecholamine treatment.
IC
100 attenuated cardiac inflammation post-stroke based on significant reductions in IL-1β, and it improved cardiac function as evidenced
by attenuation of the shortened action potential duration depicted in the images below.
IL-1β
Levels in Mouse Atria and Ventricles
Ventricular
Action Potential Traces from Excised Zebra Fish Hearts Exposed to Epinephrine
These
data suggest that IC 100 has potential to attenuate stroke-related cardiovascular disease.
IC
100 and ROP
To
determine if IC 100 has potential to attenuate retinal microglial activation and inflammation leading to retinopathy and impaired vision,
IC 100 was administered immediately after 5 days of 75% O2 exposure by multiple IP injections of 10 or 20 μg/g or by single IVT
injection of 2.5 μg/0.5 μL per eye in an oxygen-induced mouse model of retinopathy (OIR models).
IC
100 attenuated retinal inflammation as evidenced by a 55% reduction in retinal ASC speck formation, and it reduced microglial density
and activation compared to the placebo-treated oxygen-exposed retina (02-PBS), as depicted below.
Retinal
ASC Speck Formation
Retinal
Microglial Density and Activation
IC
100 alleviated vaso-obliteration. Compared to the placebo-treated oxygen-exposed retina (02-PBS), IC 100 reduced the percentage
of avascular areas, the number of vascular tufts, and the percentage of intravitreal neovascularization, as depicted below.
Quantification
of Avascular Areas, Vascular Tufts, and Neovascular Areas
IC
100 restored retinal structure. With IC 100 the thickness of the inner nuclear layer (INL), outer nuclear layer (ONL), and total retinal
layer was comparable to the placebo control (RA-PBS). IC 100 also restored retinal function. With IC 100 there was a 70% increase in
amplitude compared to the placebo-treated oxygen-exposed retina (02-PBS). Results are depicted below.
Retinal Layer Thickness Amplitude
These
data demonstrate that inhibition of ASC speck formation by IC 100 in an animal model of retinopathy of prematurity reduced retinal inflammation
and its resulting structural damage and dysfunction.
IC
100 and MS
To
determine if IC 100 protects against MS progression, researchers induced active experimental autoimmune encephalomyelitis (“EAE”)
in C57BL/6 mice through immunization with myelin oligodendrocyte glycoprotein peptide 35 – 55 (“MOG35 – 55”).
IC 100 was administered via intraperitoneal (“IP”) injection at 10, 30, or 45 mg/kg on day 8 before appearance of clinical
symptoms, followed by treatment every 4 days for 32 days. Vehicle served as a control.
IC
100 penetrated the spinal cord and decreased the number of spinal cords activated microglial CD4+, CD8+, and myeloid cells. This was
associated with delayed onset and significantly improved functionality based on MS clinical scores as shown below.
ASC
as a Biomarker
Biomarkers
are valuable tools to predict, diagnose, and monitor disease progression. They can also be used to target patients who are likely to
respond to specific treatments, and to monitor ongoing efficacy of those treatments over time.
Researchers
at the University of Miami evaluated serum inflammasome proteins as potential biomarkers for inflammatory disorders and identified ASC
as a potential candidate. Serum ASC levels were elevated in patients with various inflammatory disorders when compared to healthy people.
Additionally, when compared to caspase-1 as a biomarker in patients with multiple sclerosis, ASC had a similar sensitivity to caspase-1,
but a significantly higher specificity than caspase-1.
ASC
levels have been demonstrated to correlate with disease outcomes and disease severity, for example:
Market
and Commercial Opportunity
We
believe that each of our product candidates has potential for treatment of numerous diseases with significant unmet medical needs.
VAR 200 has potential to treat Alport syndrome, diabetic nephropathy, and other glomerular diseases in addition to its lead
indication, focal segmental glomerulosclerosis (FSGS). IC 100 has potential to treat multiple and diverse inflammatory diseases,
including, but not limited to Parkinson’s and Alzheimer’s diseases, and multiple sclerosis in addition to its lead
indication, obesity with certain metabolic complications.
Cholesterol
Efflux MediatorTM VAR 200 Opportunity
According
to a report from Precedence Research, the global renal drug market was $17.71 billion in 2024 and projected to reach $30.3 billion by
2034. There are two key drivers of this growth. The first is the significant increase in obesity and diabetes which leads to renal disease.
The second is a resurgence in development of innovative new drug therapies resulting from the increasing economic and societal burdens
of chronic kidney disease, as well as advances in technology, such as creation of a kidney-on-a chip, which accurately mimics human kidney
filtration, and availability of genomic and multiomic data. Both of these technologies have facilitated a better understanding of the
molecular mechanisms underlying kidney disease. A more recent growth driver for the renal drug market is an expected regulatory change
that that will shorten the regulatory path for drugs in development for FSGS based on recommendations from the Parasol project. The Parasol
project, co-chaired by Dr. Aliza Thompson, Director of the Cardio-Renal Division at the FDA, was prompted by the urgent need to develop
safe and effective therapies for people with FSGS since there are no approved drug therapies. The goal of Parasol was to define a traditional
or reasonably likely surrogate endpoint for use in FSGS clinical trials to enable accelerated approval of novel therapies and expedite
access to effective treatments for this rare but devastating glomerular disorder. PARASOL was a partnership among NephCure, the National
Kidney Foundation, the International Society of Glomerular Disease, and the Kidney Health Initiative, who brought together all the
relevant parties - patients, clinical nephrologists, industry sponsors, basic scientists, biostatisticians, and regulatory authorities.
PARASOL’s analysis of 1600 FSGS patients found that a reduction in proteinuria over 24 months was strongly associated with a reduced
risk of kidney failure. Based on the data, Parasol recommended proteinuria as a surrogate endpoint for full regulatory approval of FSGS
drugs. It is believed that the FDA will adopt this recommendation based on Dr. Thompson’s statement that data supporting the recommendation
came from over 25 studies conducted all over the globe and involved more than 1,600 patients, providing a robust foundation for informed
regulatory decisions.
Following is a summary of the market for VAR 200’s current pipeline.
IC
100 Opportunity
Anti-Inflammatory
Biologics Market
According
to a report from Precedence Research, the global anti-inflammatory biologics market was valued at $104.81 billion in 2024, and it is projected
to reach $185.51 billion by 2034. This growth is driven by the rising incidence of chronic inflammatory diseases associated with population
aging, lifestyle changes, and environmental factors. The growth trajectory is expected to accelerate over time with R&D focus on
use of anti-inflammatory biologics, such as inflammasome inhibitors, as add-on to GLP-1 drugs to treat the inflammatory comorbidities
of obesity. According to Morgan Stanley, global sales of GLP-1 drugs were $6 billion in 2023. With the surging demand seen in 2024, they
project global sales to reach between $105 to $144 billion by 2030. Key drivers are the unsurpassed weight loss achieved and the broadening
evidence that these drugs have potential to improve outcomes in numerous obesity-related comorbidities. Following is a summary of the
market for IC 100’s current pipeline.
Other
Development Candidates
We
continue to seek to identify and acquire commercialization rights to other technologies relating to renal and inflammatory diseases.
Strategic
Alliances and Arrangements
Unless
otherwise specifically provided herein, all share and per share information (including information relating to warrants) reflect the
1-for-35 reverse stock split and the 1-for-10 reverse stock split that we effected on December 4, 2023, and April 25, 2024, respectively.
L&F
Research LLC License Agreement
We
entered into a License Agreement with L&F Research LLC (“L&F Research”) effective December 15, 2015, as amended (the
“L&F License Agreement”), pursuant to which L&F Research granted us an exclusive, royalty-bearing, worldwide, sublicensable
license under the patent and intellectual property rights and know-how specific to and for the development and commercialization of VAR
200, for the treatment, inhibition or prevention of kidney disease in humans and symptoms thereof, including FSGS. L&F Research was
founded by the VAR 200 inventors and researchers at the University of Miami Miller School of Medicine, who licensed the intellectual
property from the University of Miami. Pursuant to the L&F License Agreement, we (i) paid L&F Research an upfront license fee
of $200,000 upon signing; (ii) agreed to make additional payments to L&F Research upon the achievement of certain development milestones
up to an aggregate maximum of $21.5 million; and (iii) agreed to pay L&F Research royalty payments on net sales of any resulting
product upon the achievement of certain net sales milestones, ranging from 5% to 10% based on certain annual net sales thresholds. In
addition, upon the signing of and pursuant to the L&F License Agreement, we issued to L&F Research four (4) warrants (the “L&F
Warrants”), of which one (1) warrant was exercised for 200 shares of common stock and the remaining three (3) warrants are exercisable
in the aggregate for 300 shares of our common stock upon certain terms and conditions set forth in the L&F License Agreement and
the L&F Warrants.
On
December 23, 2022, we entered into a Second Amendment to Waiver of Certain Rights under License Agreement (the “Second Amendment”)
with L&F Research LLC (“L&F Research”), amending the previously disclosed Waiver of Certain Rights under License
Agreement, dated March 2, 2022, between ZyVersa Therapeutics, Inc., a Florida corporation (“Old ZyVersa”) and L&F Research,
as amended (the “Waiver Agreement”). The Second Amendment further extended to March 31, 2023, the period that L&F Research
waived its right to terminate the License Agreement and exercise any other remedies thereunder, with respect to $1,500,000 of aggregate
milestone payments due to L&F Research pursuant to the L&F License Agreement (the “Milestone Payments”).
On
February 28, 2023, we entered into an Amendment and Restatement Agreement (the “Restatement”) with L&F Research, amending
and restating the Waiver Agreement, as amended. The Restatement provides that, with respect to the Milestone Payments, L&F Research
waives its right to terminate the L&F License Agreement and exercise any other remedies thereunder, until (a) March 31, 2023, as
to $1,000,000 of such Milestone Payments (“Waiver A”), and (b) January 31, 2024, as to $500,000 of such Milestone Payments
(“Waiver B”). Waiver A is contingent upon (i) forgiveness by the Company of $351,579 in aggregate principal amount outstanding
under the previously disclosed Promissory Note, dated December 13, 2020, between L&F Research, as the borrower, and Old ZyVersa,
as the lender (the “Note”), and (ii) a cash payment by the Company to L&F Research in the amount of $648,421, in each
case, to be effectuated on or before March 31, 2023. Waiver B is contingent upon a cash payment by the Company to L&F Research in
the amount of $500,000 to be effectuated on or before the earlier of (x) January 31, 2024, and (y) ten business days from the date that
the Company receives net proceeds of at least $30,000,000 from the issuance of new equity capital. All other terms of the L&F License