ITEM 1A. RISK FACTORS 29
ITEM 1B. UNRESOLVED STAFF COMMENTS 77
ITEM 2. PROPERTIES 77
ITEM 3. LEGAL PROCEEDINGS 77
ITEM 4. MINE SAFETY DISCLOSURES 77
PART II
ITEM 6. RESERVED 78
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 91
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 91
ITEM 9A. CONTROLS AND PROCEDURES 92
ITEM 9B. OTHER INFORMATION 94
ITEM 9C. DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 94
PART III
ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 95
ITEM 11. EXECUTIVE COMPENSATION 99
ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 115
PART IV
ITEM 15. EXHIBITS AND FINANCIAL STATEMENT SCHEDULES 116
REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM F-2
CONSOLIDATED BALANCE SHEETS F-3
CONSOLIDATED STATEMENTS OF OPERATIONS F-4
CONSOLIDATED STATEMENTS OF CHANGES IN SHAREHOLDERS’ EQUITY F-5
CONSOLIDATED STATEMENTS OF CASH FLOWS F-6
CONSOLIDATED NOTES TO FINANCIAL STATEMENTS F-7
FORWARD
LOOKING STATEMENTS AND CERTAIN CONSIDERATIONS
This
report, along with other documents that are publicly disseminated by us, contains or might contain forward-looking statements within
the meaning of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). All statements included in this report
and in any subsequent filings made by us with the Securities and Exchange Commission (the “SEC”) other than statements of
historical fact, that address activities, events or developments that we or our management expect, believe or anticipate will or may
occur in the future are forward-looking statements. These statements represent our reasonable judgment on the future based on various
factors and using numerous assumptions and are subject to known and unknown risks, uncertainties and other factors that could cause our
actual results and financial position to differ materially. We claim the protection of the safe harbor for forward-looking statements
provided in the Private Securities Litigation Reform Act of 1995, Section 27A of the Securities Act and Section 21E of the Exchange Act.
Examples of forward-looking statements include: (i) projections of revenue, earnings, capital structure and other financial items, (ii)
statements of our plans and objectives, (iii) statements of expected future economic performance, and (iv) assumptions underlying statements
regarding us or our business. Forward-looking statements can be identified by, among other things, the use of forward-looking language,
such as “believes,” “expects,” “estimates,” “may,” “will,” “should,”
“could,” “seeks,” “plans,” “intends,” “anticipates” or “scheduled to”
or the negatives of those terms, or other variations of those terms or comparable language, or by discussions of strategy or other intentions.
Forward-looking
statements are subject to known and unknown risks, uncertainties and other factors that could cause the actual results to differ materially
from those contemplated by the statements. The forward-looking information is based on various factors and was derived using numerous
assumptions. Important factors that could cause our actual results to be materially different from the forward-looking statements include
the following risks and other factors discussed under the Item 1A “Risk Factors” in this Annual Report on Form 10-K. These
factors include:
● Our ability to successfully commercialize our product candidates;
i
● Our ability to identify, recruit and retain key personnel and consultants;
● The safety, efficacy and benefits of our product candidates;
● The impact of laws and regulations, including those that may not yet exist.
We
caution investors that actual results or business conditions may differ materially from those projected or suggested in forward-looking
statements as a result of various factors including, but not limited to, those described above and in the Risk Factors section of this
report. We cannot assure you that we have identified all the factors that create uncertainties. Moreover, new risks emerge from time
to time and it is not possible for our management to predict all risks, nor can we assess the impact of all risks on our business or
the extent to which any risk, or combination of risks, may cause actual results to differ from those contained in any forward-looking
statements. Readers should not place undue reliance on forward-looking statements. Except as required by applicable law, we undertake
no obligation to publicly release the result of any revision of these forward-looking statements to reflect events or circumstances after
the date they are made or to reflect the occurrence of unanticipated events.
ii
PART
I
ITEM 1.BUSINESS.
This
description contains certain forward-looking statements that involve risks and uncertainties. Our actual results could differ materially
from the results discussed in the forward-looking statements as a result of certain of the risks set forth herein. We assume no obligation
to update any forward-looking statements contained herein.
Overview
We
are a development-stage company dedicated to the research and development of potential therapies to fight infectious diseases including
coronaviruses and multidrug-resistant organisms. Our lead product (NT-CoV2-1) is an intranasal vaccine candidate to prevent coronavirus
disease (“COVID-19”) from the SARS-CoV-2 virus and variants thereof. The NT-CoV2-1 program leverages coronavirus spike protein
research licensed from the National Institutes of Health and the National Research Council of Canada with a focus on reducing viral transmission
and offering a more patient-friendly intranasal administration. Our proprietary lantibiotics program features a novel class of antibiotics
against bacteria our research has shown may be applicable to multiple antibiotic-resistant organisms.
Our
SARS-CoV-2 Vaccine Product Candidate – NT-CoV2-1
Following
our May 2020 acquisition of one hundred percent (100%) of the total issued and outstanding common stock of Noachis Terra, Inc. (“Noachis
Terra”) we are focused on the development and commercialization of a vaccine product candidate to provide long-lasting immunity
from SARS-CoV-2, which causes COVID-19. Noachis Terra is a party to a worldwide, nonexclusive intellectual property and biological materials
license agreement with the National Institute of Allergy and Infectious Diseases (“NIAID”), an institute within the National
Institutes of Health (“NIH”), relating to certain research, patent applications and biological materials involving pre-fusion
stabilized coronavirus spike proteins and their use in the development and commercialization of a vaccine to provide specific, long lasting
immunity from SARS-CoV-2. Since the acquisition we have conducted testing in animal models, including SARS-CoV-2 challenge studies in
hamsters, using specific formulations for intramuscular administration (our Terra CoV-2 vaccine candidate) and intranasal administration
(our NT-CoV2-1 vaccine candidate), both based on the NIAID pre-fusion stabilized spike protein antigens. Following consideration of a
number of factors, including but not limited to the competitive landscape, we determined to bring the intranasal vaccine candidate NT-CoV2-1
into further development due to the greater differentiation versus current COVID-19 vaccines and the potential benefits of intranasal
over intramuscular administration. We believe these benefits could include a higher reduction of transmission of SARS-CoV-2 and would
offer a needle-free delivery option. We therefore are currently focusing our development efforts on our more highly differentiated NT-CoV2-1
vaccine candidate.
On
July 26, 2021, we entered into a licensing agreement with the National Research Council of Canada (“NRC”) that enables us
to pursue the development of next-generation vaccines against the SARS-CoV-2 virus and its variants. The license was subsequently amended
to include the Omicron variant, broaden the non-exclusive field of use to include all diseases caused by coronaviruses and any genetic
variants thereof, add research protocol developed by the NRC, and add reagents as part of the NRC technologies licensed by us. We extended
the license in April 2022. The NRC technologies, in combination with the licensed technologies from the U.S. NIH used in our NT-CoV2-1
vaccine candidate, provide us with a platform that can generate cell lines for high-yield production of spike protein antigens for existing
and emerging variants of concern. This platform should allow production of cell lines within six to eight weeks of spike gene sequence
availability, compared with six to nine months for traditional production of such cell lines. The NRC technologies, developed with support
from the NRC’s Pandemic Response Challenge Program, are expected to enable expedited evaluation of SARS-CoV-2 antigen candidates
in pre-clinical and clinical studies.
Coronaviruses
are a family of viruses that can lead to upper-respiratory infections in humans. Recent clinical reports also suggest that the SARS-CoV-2
virus can affect other body-systems, including the nervous, cardiovascular, gastrointestinal and renal systems. Among the recent iterations
of coronaviruses to move from animal to human carriers is SARS-CoV-2, which, beginning in Wuhan, China, in late 2019, caused a global
pandemic due to its rapid spread and the relatively high mortality rate (as compared to the seasonal influenza). Pfizer-BioNTech received
approval from the U.S. Food and Drug Administration (“FDA”) for their COVID-19 vaccines in August of 2021 and the Moderna
vaccine in January 2022. The Janssen vaccine is currently available in the United States under Emergency Use Authorizations (“EUA”)
by the FDA. In July 2022, the FDA granted EUA for the Novavax COVID-19 vaccine as well. Current vaccines have reduced the rates of hospitalization
and death due to COVID-19 in vaccinated individuals, but the transmission levels, even in vaccinated individuals, has allowed SARS-CoV-2
variants to continue to circulate. We believe, given the size of the worldwide spread of COVID-19, that even with additional vaccines
available, there will be demand for the highly differentiated NT-CoV2-1 vaccine once development is successfully completed. We intend
to combine the research, patent applications and biological materials covered by our NIAID license with our NRC license and our existing
clinical research and manufacturing capabilities to respond to this ongoing, global, public health issue. We believe our NT-CoV2-1 vaccine
holds the possibility of playing an important role in addressing this issue.
Coronaviruses,
such as SARS-CoV-2, possess signature protein spikes on their outer capsule. Our NIAID license covers patents and data on a vaccine candidate
that were created based on a stabilized pre-fusion spike trimeric protein. By stabilizing the spike protein in the pre-fusion state,
the number of immunogenic centers is increased thereby allowing for a greater likelihood of successful antibody binding, resulting in
an improved immunogenic response. Spike protein antigens stabilized in the pre-fusion state have been used successfully in the leading
COVID-19 vaccines from Pfizer-BioNTech and Moderna, which we believe reduces the risk of using the same approach in our NT-CoV2-1 vaccine
candidate. The genetic code, acquired from the NIH, for the stabilized pre-fusion spike protein was provided to Aragen Bioscience, Inc.
(“Aragen”) for the purpose of insertion of the spike protein gene sequence into a Chinese Hamster Ovary (“CHO”)
cell line. Aragen is a leading contract research organization focused on accelerating pre-clinical biologics product development, has
extensive experience building CHO cell lines for recombinant proteins, such as monoclonal antibodies. Aragen successfully inserted the
NIH pre-fusion spike protein gene sequence into a CHO cell line and we are currently producing Phase 1 clinical material based upon this
cell line.
We
entered into both a material transfer agreement and a non-exclusive research license agreement with Inspirevax Inc. for the use of intranasal
mucosal adjuvants in our NT-CoV2-1 vaccine candidates. Regarding the intranasal mucosal adjuvants of interest, BDX300 and BDX301 are
proteosome-based adjuvants comprised of proteins and lipopolysaccharides with improved attributes including enhanced immune response,
manufacturing efficiency and the benefits of intranasal vaccine administration. More recently, we entered an exclusive global license
agreement with Inspirevax for its BDX301 adjuvant. These agreements allow for collaboration and research regarding the intranasal delivery
of the vaccine during clinical development with the opportunity to enter into a commercial agreement upon regulatory approval of the
intranasal vaccine. In particular, under the exclusive license agreement, we will be forming a joint committee with Inspirevax to oversee
the clinical development efforts collaboratively. The NT-CoV2-1 vaccine containing Inspirevax’s intranasal mucosal adjuvant BDX301
has been studied in pre-clinical animal studies, including hamster viral challenge studies and mouse immunogenicity studies. A rabbit
toxicology study has been initiated and is required for regulatory approval prior to the Phase 1 clinical study.
We
began pre-clinical studies in June of 2021 through our collaboration and material transfer agreement with the NRC. We initiated an immunogenicity
study in mice to evaluate several adjuvant candidates. On August 30, 2021, we announced the successful completion of these mouse immunogenicity
studies that supported further development using either the intramuscular or intranasal routes of administration. A hamster challenge
study was initiated in September of 2021 to assess inhibition of viral replication using adjuvants specific for intramuscular and intranasal
administration. In December of 2021, we announced that both formulations generated robust immune responses and reduced the SARS-CoV-2
viral loads to undetectable levels in the nasal passages and lungs five days following a viral challenge. By contrast, hamsters in the
control groups that had received saline or adjuvants alone had no detectable immune response and substantial viral loads. The vaccines
delivered by intranasal and intramuscular routes generated immune responses as measured by multiple assays. On June 14, 2022, we announced
that the results of these studies were published in Scientific Reports, a Nature journal.
In
March 2022, following a positive assessment of a rabbit-based pilot study, we initiated a Good Laboratory Practice (GLP) toxicology study
to evaluate the safety profile and immunogenicity of NT-CoV2-1 in rabbits. This important preclinical study is designed to provide data
required to advance our intranasal vaccine candidate into human clinical studies. We announced favorable preliminary results in August
2022 and, as of December 2022, the study has concluded and we completed the full set of toxicology data, which is needed to support the
filing of an Investigational New Drug (“IND”) application for NT-CoV2-1. Based on the findings of the final toxicology report,
including a full histopathology evaluation, we were able to confirm a safety and immunogenicity profile that further support our plan
to submit regulatory filings required to progress to a Phase 1 clinical study.
While
we previously had a Type B Pre-IND Meeting with the FDA on our intramuscular vaccine product candidate, we again met with the FDA in
a Type B Pre-IND Meeting request to discuss our intranasal vaccine product candidate. As a result of this meeting, the FDA indicated
that we could file an IND application for NT-CoV2-1 following the availability of the final GLP toxicology report for inclusion in the
IND.
We
believe the benefits of our NT-CoV2-1 vaccine product candidate through its intranasal delivery mechanism to be:
Through
assessment of a variety of factors, including our pre-clinical testing to date, the expected benefits noted above, and evolving variants
and available vaccines in use, we determined to focus our development efforts on the intranasal delivery of our vaccine product candidate,
NT-CoV2-1, which we believe is more highly differentiated than the currently available and late-stage COVID-19 vaccines. We are currently
evaluating formulation options and considering regulatory pathways to advance the program. In connection therewith, we are strategically
assessing multiple opportunities inclusive of further regulatory guidance and requirements, and the potential implications thereof. As
a result, we now anticipate being in a position to file an IND application in the United States and/or a Clinical Trial Application in
Canada and to thereafter commence a Phase 1 clinical study with NT-CoV2-1 in the back half of 2023.
We
expect to use our currently available cash resources to continue to advance the development of NT-CoV2-1 through IND-enabling studies
and commencement of a Phase 1 clinical trial with further clinical development being contingent upon the receipt of additional funding,
including non-dilutive government grant funding which we continue to pursue or partnering or out-licensing opportunities.
Our
Antibiotic Product Candidate – Oragenics Derived Compound (ODC-x)
Members
of our scientific team discovered that a certain bacterial strain of Streptococcus mutans, produces Mutacin 1140 (MU1140), a molecule
belonging to the novel class of antibiotics known as lantibiotics. Lantibiotics, such as MU1140, are highly modified peptide antibiotics
made by a small group of Gram-positive bacterial species. Over 60 lantibiotics have been discovered, to date. We believe lantibiotics
are generally recognized by the scientific community to be potent antibiotic agents.
In
nonclinical testing, MU1140 has shown activity against all Gram-positive bacteria against which it has been tested, including those responsible
for a number of healthcare associated infections, or HAIs. A high percentage of hospital-acquired infections are caused by highly antibiotic-resistant
bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) or multidrug-resistant Gram-negative bacteria. We believe
the need for novel antibiotics is increasing as a result of the growing resistance of target pathogens to existing FDA approved antibiotics
on the market.
Lantibiotics
have been difficult to investigate for their clinical usefulness as therapeutic agents in the treatment of infectious diseases due to
a general inability to produce or synthesize sufficient quantities of pure amounts of these molecules. Traditional fermentation methods
can only produce minute amounts of the lantibiotic.
The
timing of the filing of an IND regarding any future lantibiotic candidate is subject to our having sufficient available human, material
and financing capital, which includes research subjects, both animal and human, given all of our anticipated needs and expected requirements
in connection with our ongoing research and development initiatives. We expect to seek to continue to advance our lantibiotics program
to an IND filing subject to the availability of both human and financial capital. Based upon the current funding, we expect to reduce
our focus on the identification of new potential product lantibiotic product candidates, efficient and cost-effective improvements in
the manufacturing processes and pre-clinical studies required to support a first in human Phase 1 clinical study until such time as we
raise additional capital.
In
October 2021, we were awarded a small business innovation research grant in the amount of $250,000 (“Computer-aided Design for
Improved Lantibiotics” R41GM136034) for the Company’s continued research and development of lantibiotics, including its collaborative
program with the Biomolecular Sciences Institute at Florida International University (FIU). The grant provides the Company with funding
to develop novel lantibiotics for the treatment of ESKAPE pathogens (defined as Enterococcus faecium, Staphylococcus aureus, Klebsiella
pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.).
In
March 2023, we reported favorable findings from third party laboratory testing of several compounds in our lantibiotics platform to combat
multiple pathogens despite the resistance of those pathogens to standard-of-care antibiotics. Lantibiotics are a novel class of antibiotics
with the potential to treat serious, life-threatening infections. Through our platform, we have created more than 700 potential lantibiotic
structures.
Our
lantibiotics platform is focused on the development of new antibiotics effective against certain pathogens including Enterococcus
faecium (VRE) and Staphylococcus aureus (MRSA). This preclinical testing was conducted through our collaboration
with Linnaeus Bioscience Inc.
Product
Candidates.
Through
our wholly-owned subsidiary, Noachis Terra, we began the research and development stage for our new Terra CoV-2 and NT-CoV2-1 vaccine
product candidates. We hold a non-exclusive, worldwide intellectual property license agreement for certain research, patent applications
and biological materials relating to the use of pre-fusion coronavirus spike proteins for the development and commercialization of a
vaccine against SARS-CoV-2. We also hold a non-exclusive license with the NRC that enables us to pursue the rapid development of next-generation
vaccines against SARS-CoV-2 (the “NIH License”) and its variants (the “NRC License”) and an exclusive global
license with Inspirevax (the “Inspirevax License” and, together with the NIH License and NRC License, the “License
Agreements”).
Additionally,
we are developing semi-synthetic lantibiotic analogs that may be effective against systemic Gram-positive multidrug infections, and analogs
that may be effective in treating Gram-negative infections. We seek to protect our product candidates through patents and patent applications,
pursuant to the terms of the License Agreements.
Product/Candidate Description Application Status
Our
Business Development Strategy
Success
in the biopharmaceutical and product development industry relies on the continuous development of novel product candidates. Most product
candidates do not make it past the clinical development stage, which forces companies to look externally for innovation. Accordingly,
we expect, from time to time, to seek strategic opportunities through various forms of business development, which can include strategic
alliances, licensing deals, joint ventures, collaborations, equity or debt-based investments, dispositions, mergers and acquisitions.
We view these business development activities as a necessary component of our strategies, and we seek to enhance shareholder value by
evaluating business development opportunities both within and complementary to our current business, as well as opportunities that may
be new and separate from the development of our existing product candidates.
Our
SARS-CoV-2 Vaccine Product Candidate-NT-CoV2-1
Market
Opportunity
The
worldwide revenues for the Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines in 2022 were $37.8 billion and $18.4 billion, respectively.
In January 2023, the World Health Organization’s estimates indicated that, as of January 8, 2023, the number of worldwide COVID-19
infections exceeded 659,000,000 and the number of deaths directly attributed to COVID-19 have exceeded 6,600,000.
The
overall disease burden has continued to increase in the US despite 91% of those 65 years of older being fully vaccinated and 71% of those
5 years of age or older. Current vaccines have reduced the rates of hospitalization and death due to COVID-19 in vaccinated individuals,
but the transmission levels even in vaccinated individuals has allowed the SARS-CoV-2 variants to continue to circulate. We believe an
intranasally-administered vaccine against COVID-19 has the potential to reduce transmission more effectively than those delivered intramuscularly
because the intranasal is expected to induce mucosal immunity in the nose and throat, which are the early entry points for SARS-CoV-2.
The inclusion of COVID-19 vaccines in the routine childhood immunization schedule may be anticipated assuming COVID-19 enters an endemic
phase. Intranasal COVID-19 vaccines could play an important role in routine pediatric immunization since they create less anxiety in
needle-phobic children and can more easily fit into an increasingly crowded schedule of injected vaccines.
COVID-19
disease epidemiology is closely monitored and, as such, recommendations as to vaccinations and treatments have been evolving accordingly.
The possibility of new COVID-19 variants, and the potential spread of such variants have altered the dynamics of disease spread and led
to the requirement of booster shots in the US and other countries to help facilitate control of the newer viral strains.
Our
Strategy
We
seek to continue developing the NT-CoV2-1 vaccine candidate to the point of entering into a licensing deal or strategic partnership.
In connection with the development of our NT-CoV2-1 vaccine candidate, we expect to focus on differentiation of our vaccine product candidate
by using intranasal administration, which none of the currently available intramuscular vaccines can offer. We believe that development
of a vaccine that has differentiated attributes to those currently being used will be beneficial in helping to control the spread of
SARS–CoV-2. We anticipate that the main use of NT-CoV2-1 will be as a booster dose for those already vaccinated with a different
COVID-19 vaccine, since the vaccination coverage rates in developed countries is already very high. A potential longer-term objective
would be to offer NT-CoV2-1 as an intranasal vaccine for the primary immunization of infants or children in the routine childhood immunization
schedule.
Should
the spread of SARS-CoV-2 be controlled to such extent that it would potentially impact our efforts to commercialize our NT-CoV2-1 as
a vaccine candidate, we believe we could identify and pursue other vaccines to develop that are capable of preventing new infectious
disease threats.
Regulatory
We
held a pre-IND meeting with the FDA on our Terra CoV-2 vaccine candidate. The broad support for our approach by the FDA included a number
of activities, including: (i) use of the Research Cell Bank in the early manufacturing process development; (ii) Use of early pilot batch
manufacture under Good Manufacturing Processes (GMP) for the anticipated Phase 1 clinical trials; and, (iii) submission of draft toxicology
reports during IND filing. We have conducted the pre-clinical studies including the Syrian Hamster virus challenge study, the mouse immunogenicity
study with positive results for both the intramuscular formulation (Terra CoV-2) and the intranasal formulation (NT-CoV2-1). Due to the
potential for greater differentiation with the intranasal vaccine NT-Cov2-1, we are moving that candidate forward into a rabbit toxicology
study. Data from the hamster and mouse studies and the rabbit toxicology study will be submitted as part of the IND filing prior to initiation
of the Phase 1 human clinical trial for NT-CoV2-1.
Manufacturing
The
creation of a stable pool Master Cell Bank is complete and GMP manufacturing of the bulk drug substance has been completed by our Phase
1 biologics contract development and manufacturing organization, Biodextris, Inc. Creation of the clonal Research Cell Bank, required
for later stage manufacturing, is completed and will be followed by manufacturing of the clonal Master Cell Bank prior to Phase 2 GMP
manufacturing. We use third-party suppliers for the development of our vaccine product candidate, including with respect to the manufacturing
of our vaccine candidate for use in pre-clinical studies and expected clinical trials. We enter into agreements with these third-party
suppliers as part of, and in connection with, our product development plans and timing. In order to have sufficient product available
for anticipated future clinical trials we need to enter into agreements with GMP certified manufactures that have the capability and
capacity to meet our expected product needs and timing in advance of when our actual needs will arise in order for us to be positioned
to continue development without delays due to the manufacturing process and capabilities of qualified manufacturers.
In
March 2022 we entered into an agreement with KBI Biopharma, Inc. for the process transfer, process optimization and cGMP manufacturing
of our vaccine candidate in anticipation of a future Phase 2 clinical trial. This agreement obligates us to make certain payments to
KBI in connection with the manufacture of our vaccine product candidate based upon our current expected timing. If the timing of our
current development plans changes, we could be required to make additional payments to KBI associated with such delays and/or associated
with the cancellation of the agreement without achieving the benefits anticipated from the agreement. Additionally, a fill/finish, packaging
and labeling company has been identified to support the Phase 1 program and is scheduled for GMP manufacturing of clinical material in
2Q22.
Homologs
of MU1140 and Other Lantibiotics
In
the course of research and development, MU1140 was found to be a potent antibiotic that is naturally produced by the parent of the SMaRT
strain. MU1140 shows antibacterial activity against all Gram-positive bacteria against which it has been tested, including those responsible
for a variety of multi-drug resistant organisms and healthcare-associated infections, or HAIs.
We
intend to develop lantibiotics, a novel class of antibiotics, as active pharmaceutical ingredients toward the goal of commercialization
for the treatment of infectious diseases in humans, focusing on infections caused by the most dangerous bacteria identified by the WHO
and CDC priority list. Antibiotic resistance is spurred by overuse and misuse of antibiotics and worsened by the lack of scientific innovation.
The timing of the filing of an IND regarding homologs of MU1140 is subject to our having sufficient available capital given all of our
anticipated needs and expected requirements in connection with our ongoing research and development initiatives. We expect to seek to
continue to advance our lantibiotics program to an IND filing subject to the availability of both human and financial capital. Based
upon the current funding, we expect to reduce our focus on the identification of new potential product lantibiotic candidates, efficient
and cost-effective improvements in the manufacturing processes and pre-clinical studies required to support a first in human Phase 1
clinical study until such time as we raise additional capital. In addition, we have undertaken research programs to expand
our capabilities to improve the physical chemical characteristics (i.e., solubility and stability) of lantibiotics for use to treat systemic
Gram-positive infections and also exploring lantibiotics that may be efficient against Gram negative bacteria.
Market
Opportunity
Many
Gram-positive related HAIs are caused by drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, or MRSA;
vancomycin-resistant Enterococcus faecalis, or VRE; and Clostridium difficile, or C. diff. According to the most
recent Centers for Disease Control and Prevention, (“CDC”) report on Antibiotic Resistance Threats in the US (2019), the
number of people facing antibiotic resistance in the United States is too high. More than 2.8 million antibiotic-resistant infections
occur in the United States each year, and more than 35,000 people die as a result. In addition, nearly 223,900 people in the United States
required hospital care for C. difficile and at least 12,800 people died in 2017.
Antimicrobial
resistance is one of the greatest threats to global health. Without innovation, we risk falling into a post-antimicrobial era in which
minor infections will become life threatening, and routine medical procedures will be nearly impossible to perform. The World Health
Organization predicts that by 2050, antimicrobial resistance could cause 10 million deaths each year, surpassing the projected number
of deaths due to cancer. Notably, antimicrobials have a prominent role in the treatment of secondary bacterial infection complications
of viral respiratory infections, such as the novel coronavirus.
The
literature review findings indicate that the cost of AMR across the globe is extremely high. The CDC estimated that the cost of antimicrobial
resistance is $55 billion every year in the United States, $20 billion for health care and about $35 billion for loss of productivity.
Recent research by the World Bank indicates that antimicrobial resistance would elevate the rate of poverty and impact low-income countries
compared to the rest of the world. Studies show that annual global GDP could decrease by approximately 1% and there would be a 5–7%
loss in developing countries by 2050. This percentage ultimately translates into $100-210 trillion.
The
need for novel antibiotics is increasing but unfortunately, the worldwide rise of bacterial pathogens resistant to antibacterial agents
cannot be counteracted by the current low development pace of therapeutics with new mode(s) of action. While there are nearly 4,000 immuno-oncology
agents in development, only about 30–40 new antibacterial compounds are currently in the clinical trial phases of development,
and, notably, those candidates targeting World Health Organization (WHO) priority pathogens are derivatives of existing classes. Less
than 25% of current drugs in the clinical development pipeline represent a novel class or act through a novel mechanism, and none of
these are potentially active against Gram-negative ESKAPE or WHO critical threat pathogens. Only a small fraction of the antibiotics
approved over the past 40 years represents new compound classes, while the majority were derived from already known chemical structures,
and the most recent new class of antibiotics was discovered during the 1980s. According to Nature.com, no new class of Gram-negative
antibiotics has been launched for more than 50 years.
Lantibiotics
such as MU1140 are highly modified peptide antibiotics made by a small group of Gram-positive bacterial species. Over 60 lantibiotics
have been discovered since the first lantibiotic, nisin, was discovered. Lantibiotics are generally known to be potent antibiotic agents;
however, attempts to investigate their clinical usefulness have generally met with failure due to the inability to produce sufficient
pure amounts of any of these molecules to be able to test them as a therapeutic agent for the treatment of infectious diseases. Standard
fermentation methods, such as those used to make a variety of other antibiotics, have historically resulted in the production of only
minute amounts of the lantibiotic.
Our
Solution
To
develop homologs of MU1140 and, engineered in parallel, high producing strains to the point of partnership, and to develop additional
lantibiotics in connection with our work on MU1140. MU1140 has demonstrated activity against a wide variety of disease-causing Gram-positive
bacteria, including MRSA, VRE, and C. difficile.
To
develop homologs of MU1140 paired with high producing strains to the point of partnership, and to develop additional lantibiotics in
connection with our work on MU1140. MU1140 has demonstrated activity against a wide variety of disease-causing Gram-positive bacteria,
including MRSA, VRE, C. difficile, Mycobacterium tuberculosis and Bacillus anthracis.
To
develop new antibiotics effective against certain pathogens including Enterococcus faecium (VRE) and Staphylococcus aureus
(MRSA).
Our
Strategy
We
are developing and testing recombinantly derived homologs of the native MU1140 molecule and its chemical derivative with improved therapeutic
profiles and physical-chemical characteristics. The data generated over the past few years enabled us to engineer hundreds of homologs
of MU1140, and select those homolog candidates with improved profiles, including homologs of higher activity and stability, lower toxicity
and with a scalable manufacturability. The best homolog candidates were further developed internally and through the use of several Contract
Research Organizations (“CROs”). We believe that this strategy represented the best and most efficient path to produce sufficient
quantities of MU1140 homologs, to support continued research, selection of a lead candidate, nonclinical studies, clinical studies and
ultimately commercialization. We intend to continue to follow this proven discovery path to identify novel MU1140 derivatives to treat
other multi-drug resistant infections and HAIs.
Regulatory
Status
We
have performed nonclinical testing on MU1140 and several of its homologs, which has demonstrated the molecule’s novel mechanism
of action. We expect to continue our research and pre-clinical development activities on derivatives of MU1140 subject to the availability
of adequate financing as we move towards the filing of an IND.
Manufacturing
While
we have been able to produce a significant increase in the fermentation titer of homologs of MU1140, we continue to work to improve on
the manufacturing through collaborations with fermentation and purification experts and third party CROs. We will need to further optimize
and scale up the production/purification scheme internally and through third party vendors. The need to examine many new homologs of
MU1140 has resulted in the need to reproduce the fermentation and purification steps on each individual homolog candidate being studied.
Each homolog requires different optimizations for both the fermentation, purification and chemical derivatization steps and in some cases
requires a new approach. As such, our work on the research and development of new lantibiotic homologs using genetically modified bacteria
continues. We believe these developments represent progress toward our goal of commercial production of sufficient quantities of our
MU1140 homologs and deliver a step in validating the lantibiotics platform targeting infectious diseases.
We
are working with a third-party manufacturer to produce additional quantities of designated homologs, based upon the developments achieved
from our work with our outside contractors. The production of additional quantities of designated homologs, that are needed for the consummation
and pursuit of our nonclinical testing activities supporting the IND filing, are ongoing. We will continue to explore improved methods
of manufacturing and synthesis to improve our yields and ultimately, potentially reduce our cost of manufacture.
Our
License Agreements
Our
NIH License Agreement
Through
our wholly-owned subsidiary, Noachis Terra, we are party to a Patent License and Biological Materials License Agreement (the “License
Agreement” or “NIH License”), dated March 23, 2020, with the United States Department of Health and Human Services
(the “HHS”), as represented by the NIAID, an Institute of the NIH. Under the terms of the License Agreement, we hold a nonexclusive,
worldwide license to certain specified patent rights (including patent applications, provisional patent applications and Patent Cooperation
Treaty (“PCT”) patent applications) and biological materials relating to the use of prefusion coronavirus spike proteins
to exploit products (“Licensed Products”) and practice processes (“Licensed Processes”) that are covered by the
licensed patent rights and biological materials for the purpose of developing and commercializing a vaccine product candidate for SARS-CoV-2.
The License Agreement is subject to certain statutory limits and reserved rights, as required under federal law and NIH requirements,
including the requirement to provide reasonable quantities of Licensed Products or materials made through the Licensed Processes for
NIH research and to manufacture Licensed Products or materials made through the Licensed Processes substantially in the United States.
We may not sublicense the intellectual property or biological materials licensed to us under the License Agreement.
Pursuant
to the License Agreement, we must use reasonable commercial efforts to manufacture, practice or operate the Licensed Products and the
Licensed Processes, including adhering to a commercial development plan and achieving certain benchmarks. Additionally, following the
first commercial sale of any Licensed Products or the practice of any Licensed Processes, we must use reasonable commercial efforts to
make the Licensed Products and the Licensed Processes reasonably accessible to the United States public and reasonable quantities of
the Licensed Products and the Licensed Processes available to patient assistance program, among other educational support activities.
The NIAID has agreed to assume responsibility for the preparation, filing, prosecution and maintenance of all patent applications and
patents covered by the licensed patent rights.
Under
the terms of the License Agreement, the NIAID is entitled to receive a non-creditable, nonrefundable upfront license issue royalty (which
has already been paid), as well as reimbursement for our pro rata share of the NIAID’s past and future patent prosecution-related
expenses. Additionally, the NIAID is entitled to receive nonrefundable minimum annual royalties, which increase each year after the first
commercial sale of any Licensed Products or the practice of any Licensed Processes, as well as benchmark royalties following our completion
of certain commercial development and sales-related benchmarks. The NIH is entitled to receive earned royalties on the annual net sales
of Licensed Products and the practice of any Licensed Processes (subject to certain reductions), at certain low- to mid-single digit
royalty rates, which rates vary based on the total amount of annual net sales and the geographic market in which those sales occur. We
must provide regular written reports to the NIAID on the development status of and royalty payments relating to the Licensed Products
and the Licensed Processes.
We
must indemnify and hold the NIAID and its associates harmless from and against all liability and damages in connection with or arising
out of (a) the use or beneficial use of the Licensed Patent rights by us, our Directors, employees or third parties and (b) the design,
manufacture, distribution or use of any Licensed Products or Licensed Processes, including other products or processes developed in connection
with the Licensed Patent Rights.
Unless
terminated earlier, the License Agreement will terminate upon the earlier of (a) twenty (20) years from the first commercial sale where
no licensed patent rights exist or have ceased to exist or (b) the expiration of the last to expire of any licensed patent rights. At
this time, no patents covered by the licensed patent rights have been issued. We may terminate the License Agreement at any time, subject
to advance notice. Subject to certain cure and appeal rights, the NIAID may terminate or modify the License Agreement in the event of
a material breach or default, including, among others, the following:
(i) We become insolvent or the subject of a bankruptcy petition;
(iv) We cannot reasonably satisfy public health and safety needs; or
Our
NRC License Agreement
On
July 26, 2021, we entered into a non-exclusive Technology License Agreement (the “License Agreement”) with the NRC pursuant
to which the NRC granted us a license to use NRC’s inventions, patents, trade secrets, know-how, copyright, biological material,
designs, and/or technical information created by or on behalf of the NRC (the “NRC Technologies”) relating to the derivatives
of CHO 2353 TM Cell Line listed in the License Agreement (the “Stable Cells”) to: (i) make, research, and develop SARS-CoV-2
spike protein manufactured by a Stable Cell (the “Drug Substance”) within Canada, Australia, the United Kingdom, the European
Union and the United States (U.S.) (collectively the “Territory”); (ii) file regulatory approval, export and sell the final
formulation of the Drug Substance (“Products”) and (iii) engage contractors to use the Stable Cells to make Drug Substance
or Products on our behalf to be used and sold, worldwide, by us. The License Agreement was subsequently amended to include the Delta
and Omicron variants. In addition, we subsequently amended the License Agreement to broaden the non-exclusive field of use to include
all diseases caused by coronaviruses and any genetic variants thereof.
As
consideration for the grant of the license, we will pay to the NRC an annual (low five digits) license fee, with the initial portion
of the fee covering the first three years of the license. Additionally, we will pay certain milestone payments (a) upon transfer of each
Stable Cell listed in the Agreement and (b) with regard to each of the first three Products, (i) upon submission of the IND application
related thereto, (ii) upon dosing the first patient in a Phase 1 or Phase 2 clinical trial, (iii) upon dosing the first patient in a
Phase 3 clinical trial and (iv) upon first regulatory approval. Milestone payments range from the low five digits to high six digits.
In addition, Oragenics will pay a low single-digit royalty to the NRC for the sale of Products, based on sales revenue, commencing after
the first commercial sale.
Pursuant
to the License Agreement, the NRC is required to bear the responsibility and pay the costs to obtain and maintain patents related to
the NRC Technologies in the U.S., Canada, Brazil, European Union, Japan, South Korea, Singapore, Australia, China, and India, and the
NRC shall use reasonable efforts to obtain and maintain those patents. Additional countries may be requested by us, in which event, the
NRC will file and maintain such patents, at our expense.
Pursuant
to the License Agreement, we are required to indemnify and hold the NRC and its employees and agents harmless from and against all liability
and damages in connection with or arising out of all claims, demands, losses, damages, costs including solicitor and client costs, actions,
suits or proceedings brought by any third party that are in any manner based upon, arising out of, related to, occasioned by, or attributable
to the manufacturing, distribution, shipment, offering for sale, sale, or use of Products, services based on the NRC Technologies and
product liability and infringement of intellectual property rights other than copyright, if any, licensed under the License Agreement.
Unless
terminated earlier, the License Agreement will terminate twenty (20) years from the effective date of the License Agreement. Either party
may terminate the License Agreement, by giving written notice to the other party, if the other party defaults or is in breach of the
License Agreement, provided that if the defaulting party cures the breach within 60 days after the notice is given, the License Agreement
shall continue in full force and effect. The NRC may terminate the License Agreement if we become bankrupt, or insolvent, or has a receiver
appointed to continue its operations, or passes a resolution for winding up. The License Agreement contains customary confidentiality
obligations.
Our
Inspirevax License Agreement
On
February 23, 2023, we entered into a Commercial License Agreement (the “License Agreement”) with Inspirevax Inc. (“Inspirevax”)
pursuant to which Inspirevax granted us an exclusive worldwide license to use Inspirevax’s inventions, patents, trade secrets,
know-how, copyright, biological material, designs, and/or technical information created by or on behalf of Inspirevax (the “Inspirevax
Technologies”) relating to its novel lipid-protein based intranasal adjuvants, to make, research, and develop an intra-nasal vaccine
in combination with an antigen (“Combination Product”) to be used in an intranasal vaccine for use against diseases caused
by coronaviruses and any genetic variants thereof to be sold by us.
As
consideration for the grant of the license, we will pay an upfront signing fee of $50,000. We will be subject to certain milestone payments
as follows: (a) $75,000 upon our decision on an appropriate nasal spray device, (b) $100,000 upon a first patient being dosed in a phase
2a clinical trial, (c) $200,000 upon a first patient being dosed in a Phase 2b/3 clinical trial, (d) $800,000 upon a biologics License
Application being submitted to the FDA, (e) $400,000 upon first filing of marketing authorization outside of the United States, and $200,000
for each such additional filing up to five filings, (f) $2,000,000 upon first commercial sale in the United States, (g) $1,000,000 upon
first commercial sale in Europe, (h) $500,000 upon first commercial sale outside of United States and Europe and $250,000 for each other
country or region up to five. Additionally, during the term we will pay to Inspirevax a 7% royalty on net sales subject to certain gross
revenue limitations at which time the royalty will decrease to 4%.
We
will be required to use our best efforts to develop a product using the Inspirevax technology including the following: (a) first subject
enrollment in first clinical study by December 31, 2023, (b) the first subject enrolled in a Phase 2a study by September 30, 2024, (c)
first subject enrolled in a phase 3 registration trial by December 31, 2026, and (d) first marketing approval application submitted by
June 30, 2028.
Pursuant
to the License Agreement, Inspirevax is required to bear the responsibility and pay the costs to obtain and maintain patents related
to the Inspirevax Technologies.
Pursuant
to the License Agreement, any and all intellectual property rights in any invention conceived, reduced to practice, or developed during
the Term of the License Agreement solely arising from or solely related to the Combination Product or the antigen will be owned by us,
and we will bear the responsibility and pay the costs to obtain and maintain patents related to these inventions.
Pursuant
to the License Agreement, we are required to indemnify and hold Inspirevax and its employees and agents harmless from and against all
liability and damages in connection with or arising out of all claims, demands, losses, damages, costs including solicitor and client
costs, actions, suits or proceedings brought by any third party that are in any manner based upon, arising out of, related to, occasioned
by, or attributable to the manufacturing, distribution, shipment, offering for sale, sale, or use of Products, services based on the
Inspirevax Technologies and product liability and infringement of intellectual property rights other than copyright, if any, licensed
under the License Agreement.
Unless
terminated earlier, the License Agreement will terminate the later of (i) twenty (20) years from the first commercial sale of a product,
(ii) the last date a product is covered by a valid patent claim, or (iii) the expiration of regulatory exclusivity. We may terminate
the License Agreement, by giving thirty (30) days written notice to Inspirevax. Either party may terminate, if the other party defaults
or is in breach of the License Agreement, provided that if the defaulting party cures the breach within sixty (60) days after the notice
is given, the License Agreement shall continue in full force and effect. The License Agreement contains customary confidentiality obligations.
The
companies formed a Joint Development Committee (JDC) comprising representatives of both companies to oversee the development efforts
collaboratively. Additionally, the agreement provides a certain period of time for the companies to expand their collaboration to pursue
the development of additional intranasal vaccine candidates using Inspirevax’s adjuvants.
Other
Product Candidates and Technologies
We
have historically developed other product candidates and potential product candidates. For example, we developed a weight loss candidate,
LPT3-04, and a topical treatment to prevent dental carries which we refer to as SMaRT Replacement Therapy. We out licensed LPT3-04 to
a third party and continue to monitor our licensee’s performance under the license. We do not expect the LPT3-04 license to have
a material effect on our business or operations. While we retain certain intellectual property rights with respect to homologs through
our (i) prior relationship with Texas A&M University Systems and (ii) ILH Holdings (as assignee of Precigen) that could allow for
the continued research and development of compounds for the SMaRT replacement Therapy, we do not intend to pursue further development
of SMaRT Replacement Therapy and as such we do not consider these rights to be a material part of our business and operations.
Government
Regulations
In
the United States, foods (including dietary supplements), drugs (including biological products), medical devices, cosmetics, tobacco
products and radiation-emitting products are subject to extensive regulation by the FDA. The FDC Act and other federal and state statutes
and regulations govern, among other things, the manufacture, distribution and sale of these products. These laws and regulations prescribe
criminal and civil penalties that can be assessed, and violation of these laws and regulations can result in enforcement action by the
FDA and other regulatory agencies.
FDA
Regulation of Drugs-New Drug Approval Process
Pharmaceutical
products are subject to extensive regulation by the FDA. The FDC Act, and other federal and state statutes and regulations, govern, among
other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution,
post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products. Failure to comply with applicable
U.S. requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA refusal to approve pending
NDAs or Biologics License Applications (“BLA “)s, warning or untitled letters, product recalls, product seizures, total or
partial suspension of production or distribution, injunctions, fines, civil penalties and criminal prosecution.
Pharmaceutical
product development for a new product or certain changes to an approved product in the United States typically involves the following
steps before a biological product or new drug may be marketed in the United States:
● submission of an NDA or BLA to the FDA for review;
● FDA approval of the NDA or BLA; and
● payment of user and establishment fees, if applicable.
Satisfaction
of FDA pre-market approval requirements typically takes many years and the actual time required may vary substantially based upon the
type, complexity and novelty of the product or disease.
Pre-clinical
tests include laboratory evaluation of product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics
and potential safety and efficacy of the product. The conduct of the pre-clinical tests must comply with federal regulations and requirements,
including good laboratory practices. The results of pre-clinical testing are submitted to the FDA as part of an IND along with other
information, including information about product chemistry, manufacturing and controls, and a proposed clinical trial protocol. Long
term pre-clinical tests, such as animal tests of reproductive toxicity and carcinogenicity, may continue after the IND is submitted.
A
30-day waiting period after the submission of each IND is required prior to the commencement of clinical testing in humans. If the FDA
has neither commented on nor questioned the IND within this 30-day period, the clinical trial proposed in the IND may begin.
Clinical
trials involve the administration of the IND to healthy volunteers or patients under the supervision of a qualified investigator. Clinical
trials must be conducted: (i) in compliance with federal regulations; (ii) in compliance with good clinical practice, or GCP, an international
standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators, and monitors;
as well as (iii) under protocols detailing the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness
criteria to be evaluated. Each protocol involving testing on U.S. patients and subsequent protocol amendments must be submitted to the
FDA as part of the IND.
The
FDA may order the temporary, or permanent, discontinuation of a clinical trial at any time, or impose other sanctions, if it believes
that the clinical trial is not being conducted in accordance with FDA requirements or presents an unacceptable risk to the clinical trial
patients. The trial protocol and informed consent information for patients in clinical trials must also be submitted to an institutional
review board or IRB for approval. An IRB may also require the clinical trial at the site to be halted, either temporarily or permanently,