UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
☒Annual
Report Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
For
the year ended December 31, 2021
☐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 001-39603
REVELATION
BIOSCIENCES, INC.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (zip code)
650-800-3717
(Issuer’s
Telephone Number, Including Area Code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of Each Class Trading Symbol(s) Name of Each Exchange on Which Registered
Common stock, par value $0.001 per share REVB The Nasdaq Stock Market LLC
Securities
registered pursuant to Section 12(g) of the Act: None
Indicate
by check mark 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 15(d) of the Exchange Act. Yes ☐ No ☒
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Exchange Act of 1934
during the past 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject
to such filing requirement 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 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 fi led 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 fi rm that prepared
or issued its audit report. ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No☒
As of June 30, 2021, the last day of the registrant’s
most recently completed second fiscal quarter, the aggregate market value of the common stock outstanding, other than shares held by
persons who may be deemed affiliates of the registrant, computed by reference to the closing sales price for common stock on June 30,
2021, as reported on The Nasdaq Stock Market LLC, was approximately $73,173,036.
As of April 13, 2022, 15,082,771 shares of common
stock, par value $0.001 per share, were issued and outstanding.
EXPLANATORY NOTE
On January 10, 2022 (the
“Closing Date”), Petra Acquisition, Inc., a Delaware corporation and our predecessor company (“Petra”), consummated
the business combination (the “Business Combination”), pursuant to the terms of the agreement and plan of merger, dated as
of August 29, 2021 (the “Business Combination Agreement”), by and among Petra, Petra Acquisition Merger, Inc., a Delaware
corporation and wholly-owned subsidiary of Petra (“Merger Sub”), and Revelation Biosciences, Inc. (“Old Revelation”).
Pursuant to the Business Combination Agreement, on the Closing Date, (i) Merger Sub merged with and into Old Revelation (the “Merger”),
with Old Revelation as the surviving company in the Merger, and, after giving effect to such Merger, Old Revelation was renamed Revelation
Biosciences Sub, Inc. and became a wholly-owned subsidiary of Petra and (ii) Petra changed its name to “Revelation Biosciences,
Inc.” (“Revelation” or the “Company” f/k/a Petra Acquisition, Inc.).
Because the Business Combination
occurred after the end of our most-recently completed fiscal year 2021, the financial information in this Annual Report reflects the operations
of Petra. The financial information for Old Revelation is presented in an Amendment to the Current Report of the Company reporting the
Business Combination which was filed with the Securities and Exchange Commission (the “SEC”) on April 15, 2022, which is incorporated herein by reference.
FREQUENTLY USED TERMS
Unless otherwise stated or
unless the context otherwise requires, the terms “we,” “us,” “our,” and “Revelation”
refer to Revelation Biosciences, Inc., and its subsidiaries.
In this document:
“BLA”
refers to the Biologics License Application.
“BPCIA”
means the Biologics Price Competition and Innovation Act of 2009.
“Business Combination”
means the business combination pursuant to the Business Combination Agreement.
“Business Combination
Agreement” means the Agreement and Plan of Merger, dated as of August 29, 2021, by and among Petra, Merger Sub and Old
Revelation.
“Charter”
means Revelation’s current third amended and restated certificate of incorporation as filed with the Secretary of State of the State
of Delaware on January 10, 2022.
“Common Stock”
means common stock of Revelation, $0.001 par value.
“Common Warrants”
means the common stock purchase warrants issued to the Selling Stockholder with an exercise price of $3.29 per share.
“cGCP”
or “GCP” means the current Good Clinical Practices.
“cGMP”
means the current Good Manufacturing Practices.
“CMO”
means contract manufacturing organization.
“Code”
means the Internal Revenue Code of 1986, as amended.
“CRO”
means contract research organization.
“DGCL”
means the Delaware General Corporation Law.
“EMA”
means the European Medicines Agency.
“EU” means
the European Union.
“Exchange Act”
means the Securities Exchange Act of 1934, as amended.
“FCA”
means the False Claims Act.
“FDA”
means the U.S. Food and Drug Administration.
“GAAP”
refers to the generally accepted accounting principles.
“HIPAA”
means the Health Insurance Portability and Accountability Act of 1996.
“IFN”
means interferon.
“IM” means
intramuscular.
“IND”
means Investigational New Drug Application.
“IRB”
means institutional review board.
“JOBS Act”
means the Jumpstart Our Business Startup Act of 2012, as amended.
“LPS”
means a major component of gram-negative bacterial cell membrane, lipopolysaccharide.
“Nasdaq”
means The Nasdaq Stock Market, LLC.
“Nasdaq Capital
Market” means The Nasdaq Stock Market, LLC’s Nasdaq Capital Market listing tier.
“NDA”
means New Drug Application.
“Petra”
means Petra Acquisition, Inc., our predecessor, prior to the Business Combination.
“Petra IPO”
means Petra’s initial public offering, which was consummated on October 13, 2020.
“Pre-Funded Warrants”
means the common stock purchase warrants issued to the Selling Stockholder with an exercise price of $0.00001 per share.
“PCR”
means polymerase chain reaction.
“PHAD®“ means
phosphorylated hexaacyl disaccharide.
“Private Warrants”
means the warrants sold by Petra in its IPO.
“Program Products”
refers to Revelation’s product candidates (REVTx-99 and REVTx-200) and Revelation’s diagnostic device program (REVDx-501).
“Public Warrants”
means the warrants underlying the Units sold in the Petra IPO.
“QSR”
means Quality System Regulation.
“REVDx-501”
means Revelation’s lead diagnostic device program.
“REVTx-99a”
means Revelation’s therapeutic product candidate being developed as a broad anti-viral nasal drop solution for the potential prevention
or potential treatment of respiratory viral infections.
“REVTx-99b”
means Revelation’s therapeutic product candidate being developed as a prevention or treatment for chronic nasal congestion and allergic
rhinitis.
“REVTx-200”
means Revelation’s intranasal adjunct vaccine product candidate.
“RSU”
means restricted stock unit.
“Sunshine Act”
means the Physician Payment Sunshine Act.
“TLR”
means Toll-like receptors.
“TLR-4”
means Toll-like receptor 4.
“Units”
means units of Petra issued in Petra’s IPO consisting of one share of Common Stock and one Public Warrant.
CAUTIONARY
NOTE REGARDING FORWARD-LOOKING STATEMENTS AND RISK FACTORS SUMMARY
This Annual Report contains
forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements
are statements that are not historical facts. These forward-looking statements are generally identified by the words “anticipate”,
“believe”, “expect”, “estimate”, “plan”, “outlook”, and “project”
and other similar expressions. We caution investors that forward-looking statements are based on management’s expectations and are
only predictions or statements of current expectations and involve known and unknown risks, uncertainties and other factors that may cause
actual results to be materially different from those anticipated by the forward-looking statements. Revelation cautions readers not to
place undue reliance on any such forward looking statements, which speak only as of the date they were made. The following factors, among
others, could cause actual results to differ materially from those described in these forward-looking statements: the ability of Revelation
to meet its financial and strategic goals, due to, among other things, competition; the ability of Revelation to grow and manage growth
profitability and retain its key employees; the possibility that the Revelation may be adversely affected by other economic, business,
and/or competitive factors; risks relating to the successful development of Revelation’s product candidates; the clinical utility
of an increase in intranasal cytokine levels as a biomarker of viral infections; the ability to successfully complete planned clinical
studies of REVTx-99a and REVTx-99b; risks relating to the successful completion of RVL-CLR01 and RVL-VRL01 clinical studies; the risk
that we may not fully enroll our clinical studies or enrollment will take longer than expected; risks relating to the occurrence of adverse
safety events and/or unexpected concerns that may arise from data or analysis from our clinical studies; changes in applicable laws or
regulations; expected initiation of the clinical studies, the timing of clinical data; the outcome of the clinical data, including whether
the results of such study is positive or whether it can be replicated; the outcome of data collected, including whether the results of
such data and/or correlation can be replicated; the timing, costs, conduct and outcome of our other clinical studies; the anticipated
treatment of future clinical data by the FDA, the EMA or other regulatory authorities, including whether such data will be sufficient
for approval; the success of future development activities for REVTx-99a, REVTx-99b, REVTx-200, REVDx-501, or any other product candidates;
potential indications for which product candidates may be developed; the potential impact that COVID-19 may have on Revelation’s
suppliers, vendors, regulatory agencies, employees and the global economy as a whole; the ability of Revelation to maintain the listing
of its securities on The Nasdaq Stock Market LLC (Nasdaq); investor sentiment relating to SPAC related going public transactions; the
expected duration over which Revelation’s balances will fund its operations; and other risks and uncertainties described in Item
1A. “Risk Factors” of this report and those described below.
Risks Related to Our Business
Risks Related to the Product Development, Regulatory Approval,
Manufacturing and Commercialization of Our Program Products and Product Candidates
i
Risks Related to COVID-19
Risks Related to our Reliance on Third
Parties
Risks Related to Our Intellectual Property
Risks Related to Our Business Operations
Risks Related to Commercialization of Our Program Products
and Product Candidates
General Risk Factors
We are subject to several
other risks of which other public companies are subject, including without limitation, the volatility of our Common Stock price; our
ability to comply with corporate governance laws and financial reporting standards; and our ability to maintain an effective system of
internal controls.
ii
TABLE
OF CONTENTS
PART I
Item 1. Business. 1
Item 1A. Risk Factors. 35
Item 1B. Unresolved Staff Comments. 72
Item 2. Properties. 72
Item 3. Legal Proceedings. 72
Item 4. Mine Safety Disclosures. 72
PART II
Item 6. [Reserved]. 73
Item 7A. Quantitative and Qualitative Disclosures About Market Risk. 73
Item 8. Financial Statements and Supplementary Data. 77
Item 9A. Controls and Procedures. 78
Item 9B. Other Information. 78
PART III
Item 10. Directors, Executive Officers and Corporate Governance. 79
Item 11. Executive Compensation. 84
Item 14. Principal Accounting Fees and Services. 93
PART IV
Item 15. Exhibits, Financial Statement Schedules. 94
iii
PART
I
References in this Annual
Report on Form 10-K, unless otherwise noted, “we,” “us,” “our,” “Revelation” and the
“Company” refer to Revelation Biosciences, Inc. and its subsidiary.
ITEM 1.
BUSINESS
Overview
Revelation
is a clinical-stage biopharmaceutical company founded in May 2020. We are focused on the development or commercialization of innate
immune system therapeutics and diagnostics.
During
the year ended December 31, 2021 and prior to the Business Combination, Petra was a blank check company incorporated under the laws of
Delaware for the purpose of effecting a merger, capital stock exchange, asset acquisition, stock purchase, reorganization, or similar
business combination with one or more businesses.
Recent
Developments
On
January 10, 2022, we consummated the previously announced Business Combination.
Immediately after giving
effect to the Business Combination, there were 12,944,213 shares of our Common Stock outstanding, 628,573 shares of our Common Stock
reserved for issuance upon vesting of Rollover RSUs and Rollover Warrants and 10,511,597 warrants outstanding.
In connection with the consummation
of the Business Combination, Petra changed its name to Revelation Biosciences, Inc. Our Common Stock is listed on Nasdaq under the ticker
symbol “REVB” and warrants to purchase the Common Stock at an exercise price of $11.50 per share are listed on Nasdaq under
the ticker symbol “REVBW.”
Business
Strategy after the Business Combination
Our current product candidates
were developed by Revelation to potentially prevent, treat and detect viral infections or allergies. Our therapeutic product candidates
consist of, REVTx-99a, which is being developed for the prevention or treatment of a wide array of viral infections, including SARS-CoV-2,
variants of SARS-CoV-2, Influenza A, Influenza B, parainfluenza, respiratory syncytial virus, rhinosinusitis, and others, REVTx-99b, which
is being developed for the prevention or treatment of nasal congestion due to allergies or chronic rhinosinusitis and REVTx-200 our nonclinical
stage product being developed as a potential intranasal therapy that will be administered concurrently with a commercially available intramuscular
(“IM”) vaccine. Our lead diagnostic, REVDx-501 (REVIDTM Rapid Test Kit), is being developed as a rapid point of
care diagnostic product that can potentially be used to detect various respiratory viral infections. The diagnostic is similar to a home
pregnancy test with a simple to read visual readout in less than 15 minutes without the need for specialized instrumentation or complicated
sample collection.
Our Pipeline
Revelation is leveraging
the human body’s innate immune system response to develop therapeutics and diagnostics to prevent, treat and detect respiratory
viral infections. Revelation’s pipeline is summarized in the table below:
1
The Therapeutic Platform
Our therapeutic platform
is based on the active ingredient PHAD®, a synthetic version of monophosphoryl lipid A or MPLA. Currently, as part of
the platform we have focused on the development of REVTx-99a REVTx-99b and REVTx-200. The current differences between REVTx-99a, REVTx-99b
and REVTx-200 (and as development progresses may) include indications, dosage, timing of dosing, formulations and delivery methods of
the drug product.
The therapeutic platform
focuses on the activation of protein receptors on the surface of cells exposed to the outside environment designed to recognize pathogen
molecules. These cell surface receptors are called pathogen pattern receptors, a subset of which are the Toll-like receptors (“TLR”).
One such TLR is TLR4 which is most well-known for recognition of lipopolysaccharide (“LPS”). The active ingredient PHAD®,
mimics LPS to potentially activate TLR4, without the adverse symptoms and toxicity related to LPS.
REVTX-99a
REVTx-99a is being developed as a broad anti-viral nasal drop solution
for the potential prevention or potential treatment of respiratory viral infections, including SARS-CoV-2 including variants, Influenza
A, Influenza B, parainfluenza, rhinovirus, respiratory syncytial virus, rhinovirus and others. The active ingredient in REVTx-99a may
stimulate the innate immune system via interaction with TLR4. The innate immune response which is a general first line of defense against
viral infections and is non-specific to the type of pathogen. The active ingredient in REVTx-99a, PHAD®, is thought to
interact with TLR4 to stimulate the TRIF pathway leading to the production of protective cytokines including interferons. The production
of protective cytokines is thought to help reduce viral load in respiratory viral infections.
We initiated a Phase 1
study in Australia in September 2020 and released top-line data in May 2021. The top-line data suggests REVTx-99a is well tolerated
and does elicit a response of protective cytokines in the nasal mucosa. Based on the data from the Phase 1 study, Revelation received
approval from the Federal Agency for Medicines and Health Products and the local Committee of Medical Ethics in Belgium to conduct our
Phase 2b viral challenge clinical study for the prevention of influenza infection in September of 2021.
The Phase 2b study began
enrollment in December 2021, dosing commenced in January 2022, in March of 2022 we announced that enrollment had completed and
on March 30, 2022 we announced that the primary endpoint of the Phase 2b study, area under the curve of viral load measured by RT-PCR
from nasopharyngeal swabs, did not meet statistical significance. We are waiting for the full data package which is expected by the end
of the second quarter of 2022 to help determine the future clinical development plan.
If we decide to pursue development
of REVTx-99a for the treatment of influenza infection, a separate Phase 2 study will be required. Separate Phase 3 studies
will be required for evaluating REVTx-99a as a prevention of respiratory viral infection and as a treatment of early respiratory viral
infection. In addition, each Phase 3 study will need to demonstrate activity for each individual virus (e.g., Influenza A, Influenza
B, parainfluenza, RSV, SARS-CoV-2) that will be claimed in the indication for use. To accomplish this, the Phase 3 studies may need
to be global and designed to enroll at times of the year and locations with a known, predominant viral pathogen such as influenza, SARS-CoV-2,
RSV, etc. to obtain data to support approval for multiple virus types.
REVTx-99b
REVTx-99b is being developed
as a prevention or treatment for chronic nasal congestion and allergic rhinitis. During the development of REVTx-99a we found that there
may be benefit for people that suffer from chronic nasal congestion and allergic rhinitis which lead to the early development of REVTx-99b.
There are three possible
mechanisms of action via the TLR4 pathway for REVTx-99b. They are (i) by the possible induction of a physical barrier to allergens, (ii)
by the possible reduction of IgE secretion as a result of IFN upregulation and (iii) possible because IP-10 competes for the native eotaxin
receptor.
We were granted ethics committee
approval from Bellberry Limited Human Research Ethics Committee in Australia to conduct our Phase 1b allergen challenge study in
October of 2021. The study began enrollment in December 2021 and dosing commenced in January 2022. Top-line data is expected
in the second half of 2022.
2
REVTx-200
REVTx-200 is our nonclinical
stage product being developed as a potential intranasal therapy that will be administered concurrently with a commercially available
intramuscular (“IM”) vaccine. We believe concurrent stimulation of the nasal mucosa with REVTx-200 upon IM vaccination may
provide a more complete immunization. REVTx-200 utilizes the same active ingredient (PHAD®) used in REVTx-99a/b. However,
based on feedback from the FDA, we believe REVTx-200 will be regulated as a biologic, and not as a therapeutic, since it is concurrently
administered with another vaccine. As such we believe the approval process will require its own unique development pathway to be approved
for this use.
We
hypothesize that optimal protection from a vaccine requires both a systemic immune response elicited by the IM vaccine injection and
a mucosal immune response elicited by the intranasal administration of REVTx-200 developed by recruiting immune cells into the mucosal
immune system. We believe that intranasal administration of REVTx-200 will result in improved recruitment of vaccine-specific activated
adaptive immune cells (e.g. T cells and B cells) into the nasal mucosa. Biomarker data from our Phase 1 therapeutic clinical study
(RVL-NHV01) supports this hypothesis. In particular, we were able to see increases in local (intranasal) IL-7 and MCP-1. IL-7 is a cytokine
that induces the differentiation of hematopoietic stem cells into T cells, B cells and NK cells. MCP-1 is a chemokine that attracts B
cells and T cells to a particular site. This data suggest, intranasal REVTx-200 will traffic antigen activated B cells and T cells to
the mucosal space. While this data is supportive of the theory, additional formulation development and preclinical testing will be necessary
for the development of REVTx-200.
We
plan to establish relationships with vaccine development companies with the intention of working with one or more of these companies
to develop REVTx-200 during 2022. Initial development will include studying REVTx-200 using commercially available IM vaccines in nonclinical
models unique to each potential partnering company during 2022.
REVDx-501
Our
lead diagnostic, REVDx-501 (REVIDTM Rapid Test Kit) is being developed as a rapid point of care in vitro diagnostic test (or
diagnostic device) that has the potential to detect respiratory viral infections including SARS-CoV-2, Influenza A, Influenza B, parainfluenza,
or respiratory syncytial virus. REVDx-501 is intended to be a user-friendly home test kit with a simple to read visual readout that provides
a result in less than 15 minutes without the need for specialized instrumentation. Preliminary evaluation of clinical samples demonstrated
good correlation between REVID and PCR for SARS-CoV-2 (100% positive agreement for replicating SARS-COV-2 virus, 86% negative agreement
for no replicating SARS-COV-2 virus). We plan to continue additional development during 2022 and once development is complete submit
for regulatory clearance to the FDA.
Our
Strategy
Our goal is to become a leading
biopharmaceutical company focused on the development of immune system therapeutics and diagnostics. The key components of our strategy
are to:
● Develop REVDx-501 for the detection of respiratory viral infections.
● Establish a commercial infrastructure or commercial partner for REVDx-501.
● Scale-up and optimize the manufacturing of REVDx-501.
Our
Corporate History and Team
Revelation Biosciences, Inc.
was formed on May 4, 2020 as a Delaware limited liability company named Revelation Therapeutics, LLC, and underwent a statutory
conversion to a Delaware corporation and changed our name to Revelation Biosciences, Inc. on August 27, 2020. We have assembled
a management team of biopharmaceutical experts with extensive experience in drug development, manufacturing and commercialization of
pharmaceutical products along with broad experience in building companies from inception, including La Jolla Pharmaceutical Company,
Pluromed, Inc., and Horizon Pharma, Inc. We are also supported by a group of directors and leading investors whose collective experience
will assist us in realizing our corporate strategy.
3
BACKGROUND
Influenza
Disease Overview
Influenza,
or the flu, is caused by the influenza virus. There are four strains of influenza virus: influenza A (Alphainfluenzavirus), B (Betainfluenzavirus),
C (Gammainfluenzavirus), and D (Deltainfluenzavirus). The influenza virus is a negative-sense, segmented, single-stranded RNA virus.
Through the hemagglutinin on the surface exterior, the influenza virus binds to sialic acid molecules attached to many proteins on the
cell surface. Sialic acid is expressed ubiquitously on cell surface receptors throughout the body, which allows the virus to infect many
different cell types.
Influenza
spreads through proximal transfer of respiratory droplets via coughing, sneezing, breathing, singing, or talking. These droplets can
be inhaled or land on the mouth, nose, or eyes of a nearby person. In some cases, influenza viral particles can remain suspended in airborne
droplets or aerosols for several minutes or hours, leading to airborne transmission.
Typically,
influenza infects 5-15% of the global population each year. The majority of influenza infections are mild to moderate. The symptoms
associated with influenza infection include runny nose, cough, headache, muscle aches, fever, and chills. However, approximately 5% of
all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of acute respiratory distress syndrome
(“ARDS”) in adults. In those suffering from seasonal influenza, caused by H1N1 and H3N2, mortality is concentrated in the
very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate.
There
are a number of comorbidities associated with increased severity of influenza. The most significant comorbidity for influenza prognosis
is age. Those older than 65 and those two years and younger are at greatest risk for severe influenza infection. Additional comorbidities
include coronary artery disease or cardiomyopathy, heart failure, diabetes, asthma, chronic obstructive pulmonary disease (“COPD”),
cystic or pulmonary fibrosis, obesity, smoking, chronic kidney disease, liver disease, sickle cell disease, and pregnancy. The primary
cause of death due to influenza infection is due to inflammation as part of the immune response (such as seen in macrophage activation
syndrome, or cytokine storm), which can lead to pneumonia or sepsis.
The
current prevalence of influenza worldwide was at 3 to 5 million cases per year, with 290,000 to 650,000 reported deaths (WHO, 2021).
According to the CDC, the burden of influenza disease in the United States can vary widely and is determined by a number of factors
including the characteristics of circulating viruses, the timing of the season, how well the vaccine is working to protect against illness,
and how many people got vaccinated. While the impact of flu varies, it places a substantial burden on the health of people in the United States
each year. CDC estimates that influenza has resulted in between 9 million–45 million illnesses, between 140,000 – 810,000
hospitalizations and between 12,000 – 61,000 deaths annually since 2010.
COVID-19
Disease Overview
COVID-19
is caused by the severe respiratory syndrome coronavirus 2 (“SARS-CoV-2”) virus. The SARS-CoV-2 virus is a positive sense,
single stranded RNA virus. Through the spike protein subunit on the surface exterior, the SARS-CoV-2 virus binds to the Angiotensin Converting
Enzyme II receptor, or ACEII. Although the ACEII receptor is expressed on a wide range of tissues throughout the body, it appears
the majority of the transmission of SARS-CoV-2 occurs in the nose, through the ciliated nasal goblet cells, and the nasal epithelial
cells, where expression levels of ACEII are most prevalent (Sungnak).
SARS-CoV-2
spreads through proximal transfer of respiratory droplets via coughing, sneezing, breathing, singing, or talking. These droplets can
be inhaled or land on the mouth, nose, or eyes of a nearby person. In some cases, SARS-CoV-2 viral particles can remain suspended in
airborne droplets or aerosols for several minutes or hours, leading to airborne transmission.
SARS-CoV-2
produces proteins that have a negative effect on the body’s natural interferon (“IFN”) response. These viral associated
proteins block a key enzyme in the STING pathway (stimulator of interferon genes) that results in a lack of IFN production. This disruption
in the IFN production have been shown to lead to more severe SARS-CoV-2 infection including the need for hospitalization and mechanical
ventilation.
4
The
majority of infections with SARS-CoV-2 are mild to moderate, and in some cases are completely asymptomatic. The symptoms associated with
SARS-CoV-2 infection include shortness of breath or difficulty breathing, runny nose, dry cough, headache, diarrhea, muscle aches, fever,
chills, and loss of smell and/or taste.
In
a small percentage (0.5-2%) of cases, serious illness occurs, leading to major complications including pneumonia and or trouble breathing,
organ failure in several organs, heart problems, acute respiratory distress syndrome, blood clots, acute kidney injury, and potential
further viral and bacterial infection.
There
are a number of comorbidities associated with increased severity of COVID-19. The most significant comorbidity for COVID-19 prognosis
is age. The greater in age, the more at risk a person is for severe SARS-CoV-2 infection. Additional comorbidities include coronary artery
disease or cardiomyopathy, heart failure, diabetes, asthma, COPD, cystic or pulmonary fibrosis, obesity, smoking, chronic kidney disease,
liver disease, sickle cell disease, and pregnancy.
As of April 13, 2022 there
have been over 79 million confirmed cases of COVID-19 and over 960,000 deaths in the United States according to the CDC and
there have been over 450 million confirmed cases of COVID-19 and over 6 million deaths worldwide according to the WHO.
Allergic
Rhinitis and Chronic Nasal Congestion Overview
Allergic
reactions are caused by the body’s overreaction to normally well-tolerated proteins called allergens. Allergy symptoms include
nasal congestion, sneezing, itchy watery eyes, and rash, each of which may be caused by pollen, grass, weeds, animal dander, or molds.
These symptoms are primarily caused by the release of histamine.
According
to the CDC, allergies are currently ranked as the 6th leading chronic disease according to the Asthma and Allergy Foundation
of America. Allergic rhinitis or “hay fever” is the most common allergy diagnosis and is a common cause of nasal congestion.
19.2 million adults were diagnosed with allergic rhinitis (7.7% of the general population) in the last 12 months (CDC). In
the same time frame, 7.1 million children have been diagnosed with respiratory allergies, and of those, 5.2 million children
(7.2% of the population of children age 18 or less) were diagnosed with allergic rhinitis (CDC). Over the past 20 to 30 years, allergic
rhinitis has increased worldwide. Over 400 million people suffer from allergic rhinitis around the world, and “direct medical
costs in the US increased from $6.1 billion in 2000 to $11.2 billion in 2005, with an estimated productivity decrease of $600
per employee yearly; this cost is greater than diabetes, coronary heart disease and asthma” combined (World Allergy Organization
Review of Rhinitis). Nasal congestion is typically due to swelling in the lining of the nose from inflamed blood vessels. Nasal congestion
can cause interference with hearing and speech, and more severe congestion may impact sleep and cause snoring.
In
a United States survey conducted in 61,655 adults, 14% had been diagnosed with nasal allergies and nasal congestion was the most
frequently reported symptom with 60% reporting a “stuffed-up nose” either every day (40%) or on most days (20%)
during the month when symptoms were most prevalent (Allergies in America).
Europeans
suffering from allergic rhinitis report nasal congestion as a problematic symptom. In a European survey, 59% report nasal congestion
with their allergic rhinitis and out of 562 people in Belgium suffering from allergic rhinitis, 53% reported nasal congestion (Bauchau)(Bachert).
The
apparent increase in the frequency of allergic rhinitis worldwide emphasizes the need for more treatment options including the problematic
symptoms of this disease, such as congestion, sneezing, itchy watery eyes, and rash (Stewart).
In
addition to allergic rhinitis, nasal congestion is a troublesome symptom of rhinosinusitis, which is inflammation of the paranasal sinuses
and adjacent nasal mucosa (Ferrand) (Pessey). Rhinosinusitis can be acute, with symptoms lasting less than a month, or chronic with symptoms
lasting 12 weeks or longer (Stewart). In clinical practice, rhinosinusitis is one of the most common diagnosis affecting 1 in 6
adults in the Unites States (Hickner). Internationally, several surveys have been conducted and the incidence of nasal congestion is
common (Leggett).
Nasal
congestion is caused by an array of environmental and medical conditions. Although not widely studied, the economic burden of nasal congestion
incurs costs from the diseases associated with congestion and are known to be substantial. Nasal congestion is reported as the most prevalent
and bothersome symptom of these diseases and more treatments are essential to the improving quality of life (Stewart).
5
Current
Prevention, Treatment and Detection Options
Prevention
of Respiratory Viral Infection
Current therapies for preventing
respiratory viral infections are limited. The main prophylaxis for preventing respiratory viral infections are vaccines. Each year, vaccines
are developed and administered to prevent influenza. The effectiveness of these vaccines can be quite variable due to the ability of
the influenza virus to mutate. According to the CDC, in some years, the influenza vaccine has been as low as 19% effective (https://
www.cdc.gov/flu/vaccines-work/effectiveness-studies.htm). Several vaccines have been developed and approved for emergency use for
the prevention of SARS-CoV-2. The main drawback to vaccines is their inability to offer broad protection against multiple or emerging
virus types.
Treatment
of Respiratory Viral Infection
Current
treatments for respiratory viral infections include rest, hydration, and treating fever and/or muscle soreness with over-the-counter
analgesics. For influenza, a few antiviral therapies exist. The most recognized is the antiviral Oseltamivir (Tamiflu), which works by
preventing replicated virus from exiting an infected cell. For COVID-19 the available options for treatment are limited. The current
treatments available include Dexamethasone, Remdesivir, and low dose heparin, to prevent the blood clots and microcoagulations that have
been commonly observed in COVID-19 patients. Currently, there are monoclonal antibody treatments available for treatment of SARS-CoV-2
infection, although these treatments have demonstrated improvement in symptoms associated with SARS-CoV-2 infection, none of these treatments
alone provides a significantly improved prognosis for patients with severe illness. In addition, the effectiveness of these treatments,
in particular the antibody treatments, may be diminished with the introduction of new SARS-CoV-2 variants.
Treatment
of Allergic Rhinitis and Chronic Nasal Congestion
There
are a number of medications currently available for allergies, including antihistamines, decongestants, and steroidal sprays. Over the
counter oral antihistamines include Benadryl (diphenhydramine), Claritin (loratadine), Allegra (fexofenadine), and Zyrtec (cetirizine),
and nasal sprays such as Nasahist B (brompheniramine). Prescription oral antihistamines include Clarinex (desloratadine), and nasal sprays
such as Astelin (azelastine nasal). Some of the decongestants available for treatment include Sudafed (pseudophedrine), Neo-Synephrine
(phenylephrine) and Afrin (oxymetazoline). Many decongestants are recommended to be taken with antihistamines for optimal relief of allergy
symptoms. Fluticasone is a steroidal spray also recommended to be taken in conjunction with decongestants. Many of these treatments have
well known side effects, including drowsiness (“medicine-head”) or increased blood pressure, and these side effects can be
more pronounced when treatments are combined.
Detection
Methods
While
multiple test methods exist for the detection of respiratory viral infections, they have many limitations. These limitations include
their inability to detect multiple virus types, turn-around time, sample collection and cost. The current gold-standard is the polymerase
chain reaction (“PCR”) test. PCR test can detect the genetic material of a specific organism, such as a virus, thus identifying
the specific virus types. However, PCR tests are expensive, time-consuming and can only detect virus types based on a “primer sequence”
used when running the test. Because the PCR test requires this primer sequence, its utility in detecting viral mutations may be limited.
These limitations make the PCR test non-ideal for at-home testing or as a screening tool for respiratory viral infections.
Other
methods for detecting viral infection include the so-called antibody and antigen tests. While these methods can be made relatively inexpensively
and in an at-home test format, they also suffer from the same limitation as PCR tests in that they are specific for the detection of
a single virus type.
This
limitation is illustrated in the following example: if you test a person infected with influenza using a SARS-CoV-2 test kit or a PCR
test, the result would be limited to solely showing the individual is not infected with SARS-CoV-2, even though they actually are infected
with a respiratory viral infection and should seek medical attention and/or self-quarantine.
6
REVELATION’S
PROGRAMS
REVTx-99a
Overview
REVTx-99a is a clinical stage
candidate being developed as a broad anti-viral nasal drop solution that may have the potential to be used to prevent and/or treat respiratory
viral infections, including SARS-CoV-2 including variants, Influenza A, Influenza B, parainfluenza, rhinovirus and respiratory syncytial
virus. REVTx-99a may work by boosting the body’s innate immune system, potentially preventing the user from becoming infected or
to combat early infections. If developed and approved as a prevention for respiratory viral infection, REVTx-99a would be taken prophylactically
(before exposure to a potential virus). If developed and approved as a treatment for respiratory viral infection, REVTx-99a would be
taken upon exposure to, or at the onset of symptoms.
The active ingredient in
REVTx-99a is Phosphorylated hexaacyl disaccharide PHAD® which is also known generically as glucopyranosyl lipid A (“GLA”).
REVTx-99a is formulated as a liquid for intranasal administration as drops.
We are currently developing
REVTx-99a as a broad anti-viral nasal drop for the potential prevention and/or treatment of respiratory viral infections. We anticipate
REVTx-99a will be regulated by FDA as a new chemical entity and will require filing of an NDA for approval. We have successfully completed
our Phase 1 clinical study in Australia. Top-line data showed REVTx-99a to be well tolerated and to have stimulated the production
of intranasal cytokines. We received approval from the Federal Agency for Medicines and Health Products and the local Committee of Medical
Ethics in Belgium to conduct our Phase 2b viral challenge study in Belgium for the prevention of influenza in September of 2021.
We began enrollment for the Phase 2b study in the December 2021, dosing commenced in January 2022 and in March of 2022
we announced that enrollment had completed. On March 30, 2022 we announced that the primary endpoint of the Phase 2b study, area under
the curve of viral load measured by RT-PCR from nasopharyngeal swabs, did not meet statistical significance.
We are waiting for the full
data package which is expected by the end of the second quarter of 2022 to help determine the future clinical development plan.
For FDA approval, it will
be necessary to show activity in preventing infection with each individual virus and therefore, any registration study will be designed
to focus on times of the year and locations with a known, predominant viral pathogen such as Influenza or SARS-CoV-2.
The regulatory approval pathway
would differ for a prophylactic treatment vs a therapeutic treatment, and as such if we decide to develop REVTx-99a as a prevention as
well as a treatment, we will need to initiate a separate Phase 3 study.
Scientific
Rationale/Mechanism of Action
The
innate immune system is our first line of defense against invading pathogens such as bacteria and viruses. The innate immune system is
the more primitive part of the human immune system and defends against infection by producing and releasing various types of cytokines.
Cytokines are proteins that direct different activities in cells to combat the invading pathogen, as well as stimulating recruitment
of the so called adaptive immune system which ultimately leads to the production of antibodies. TLRs serve a vital role in starting up
the innate immune system response by recognizing different molecular patterns associated with pathogens such as bacteria and viruses.
For example, TLRs are associated with cells (e.g., macrophage, dendritic) found in the nasal mucosal tissue and when a respiratory pathogen,
such as a virus, invades a person through the nose, TLRs recognize them as foreign and activate the innate immune response producing
cytokines.
The active ingredient in
REVTx-99a may stimulate the innate immune system via interaction with TLR4.
Figure 1. Interaction of
REVTx-99a with TLR4
The active ingredient in
REVTx-99a, PHAD®, may interact with TLR4 to stimulate the TRIF pathway leading to the production of protective cytokines
including interferons. Source: Revelation Biosciences
7
Stimulation
of TLR4 by an invading pathogen stimulates the production of numerous protective cytokines including interferons (e.g., IFN-α,
IFN-β, IFN-γ). Interferons are known to respond to early phases of viral infection and interfere with viral replication by