What changed in this filing

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Item 1. Business

2024-03-22 compared with 2023-03-30 · 284 added, 557 removed, 358 unchanged (70% of the section changed)

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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 Public Warrants are listed on Nasdaq under the ticker symbol “REVBW.”

Our common stock and Public Warrants are listed on Nasdaq under the ticker symbol “REVB” and “REVBW,” respectively.

Recent Developments

2024 Reverse Stock Split

On January 17, 2024, at a special meeting of stockholders, our stockholders approved a Certificate of Amendment to our Third Amended and Restated Certificate of Incorporation to effect a reverse stock split of our outstanding shares of common stock at a specific ratio within a range of one-for-two (1-for-2) to a maximum of a one-for-fifty (1-for-50) split.

On January 22, 2024, we filed the Certificate of Amendment which effected a 1-for-30 reverse stock split of our outstanding shares of common stock as of 12:01 a.m.

Eastern Standard Time on January 25, 2024.

2023 Change in Authorized Shares and Reverse Stock Split

On January 30, 2023, at a special meeting of stockholders, our stockholders approved a Certificate of Amendment to our Third Amended and Restated Certificate of Incorporation to change the authorized common stock from 100,000,000 to 500,000,000 shares and effect a reverse stock split of our outstanding shares of common stock at a specific ratio within a range of one-for-twenty (1-for-20) to a maximum of a one-for-one hundred (1-for-100) split.

Additionally, on January 30, 2023, we filed the Certificate of Amendment which set the authorized common stock to 500,000,000 and effected a 1-for-35 reverse stock split of our outstanding shares of common stock as of 12:01 a.m.

On January 30, 2023, we filed the Certificate of Amendment which set the authorized common stock to 500,000,000 and effected a 1-for-35 reverse stock split of our outstanding shares of common stock as of 12:01 a.m.

Eastern Standard Time on February 1, 2023.

Business Strategy

Our current product candidates are being developed by Revelation to potentially modulate the activity of the immune system through stimulation of TLR-4.

Our current programs consist of:

REVTx-300, which is being developed as a potential therapy for the prevention and treatment of acute organ injury (e.g.

AKI, MI) and chronic organ disease including CKD;

REVTx-100, which is being developed for the prevention and treatment of infections including healthcare-associated bacterial infection resulting from surgery, severe burns, and antibiotic resistance;

REVTx-200, which is being developed as a potential intranasal therapy that will be administered concurrently with a traditional commercially available IM vaccine and REVTx-99b, which is being developed as a potential treatment for food allergies.

REVTx-99a was being developed for the prevention or treatment of a wide array of viral infections and REVTx-99b was being developed as a prevention or treatment for chronic nasal congestion and allergic rhinitis until July of 2022.

Our diagnostic, REVDx-501 (REVID TM Rapid Test Kit), was being developed as a rapid point of care diagnostic that can be used to detect IP-10 as a surrogate biomarker for any type of respiratory infection, without the need for specialized instrumentation.

Revelation is currently leveraging the human body’s innate immune response to develop therapeutics to prevent and treat disease.

Revelation’s pipeline is summarized in the table below:

Business Strategy and Pipeline

Revelation is developing a pipeline of potential high-value products based on Gemini.

Gemini is Revelation’s proprietary formulation of phosphorylated hexaacyl disaccharide (PHAD ® ) an established TLR4 agonist that can stimulate the human body’s innate immune response to prevent and treat disease.

The product candidates being developed by Revelation are based on our proprietary Gemini formulation of PHAD.

Our current Gemini based programs consist of:

Gemini-SSI, which is being developed for the prevention of surgical site infection (SSI);

Gemini-AKI, which is being developed for the prevention of acute kidney injury (AKI);

and Gemini-CKD for the treatment of chronic kidney disease (CKD).

Revelation’s pipeline is summarized in the figure below:

Preclinical and Phase 1 data will be used to support SSI and AKI indications.

The Therapeutic Platform

Our current therapeutic candidates are all based on the active ingredient PHAD ® , a synthetic version of MPLA, that is known to stimulate TLR-4.

Stimulation of TLR-4 leads to the production of multiple types of cytokines and chemokines which modulate the activity of the innate and adaptive immune response.

Modulated activities may include stimulation and recruitment of infection fighting immune cells, down-regulation of inflammation, and/or upregulation of inflammation depending on the degree and nature of the stimulation which enables the multiple potential product candidates in development.

REVTx-300 is being developed as a potential therapy for the prevention of acute organ injury such as AKI and as a treatment of chronic organ disease including CKD.

Acute organ injury may be caused by many different events, including blood or fluid loss (such as with bleeding or severe diarrhea), low blood pressure or shock leading to hypotension, heart failure or heart attack, overuse of certain pain medications including NSAIDs, ibuprofen, etc., toxicity due to chemotherapy, contrast agents, etc., burns, or major surgery.

During surgery, ischemia or deprivation of blood supply to a tissue followed by the reperfusion or re-introduction of blood to prevent tissue necrosis can result in further damage and/or dysfunction to the organ.

Chronic disease of an organ, due to chronic inflammation and subsequent fibrosis, follows a pattern of perpetual and ongoing destruction of living functional cells and subsequent replacement by the non-functional protein, collagen, resulting in fibrosis (scar tissue) (Wilson 2015).

The establishment of fibrosis and subsequent death of the organ is driven by ongoing inflammatory processes and reactive oxygen species associated with the innate immune response.

We believe redirection of the innate immune response with REVTx-300 from a pro-inflammatory state to an anti-inflammatory (protective) state may rebalance the innate immune response to slow down or halt the progressive destruction and scarring of organ tissue, allowing the healing process to take place.

Revelation conducted a nonclinical study to evaluate the anti-fibrotic activity of REVTx-300.

Specifically, a range of daily systemic dosing levels of REVTx-300 were tested in a rat Unilateral Ureteral Obstruction model.

The unilateral ureteral obstruction (UUO) model is appropriate for studying the anti-inflammatory and anti-fibrotic effects of potential new therapies for acute and chronic kidney disease as complete ureteral obstruction of one kidney results in significant inflammation and subsequent fibrosis of the affected kidney over a 7-day period.

The present study consisted of 6 groups with the following outcomes on renal cortical fibrosis as measured by detection of collagen deposition using picosirius red stained histology sections assessed at three different sampling depths.

Group 1 animals had no UUO surgery and received vehicle only (collagen deposition:

Group 2 animals had UUO surgery and received vehicle only (collagen deposition:

Group 3 animals had UUO surgery and received SB-525334, a known TGF-β

inhibitor of fibrosis (collagen deposition:

0.37%, 75% reduction vs Group 2 minus background from group 1, p < 0.05).

Group 4 animals had UUO surgery and received 0.1 mg/kg REVTx-300 (collagen deposition:

0.95 %, 1% reduction vs Group 2 minus background from group 1).

Group 5 animals had UUO surgery and received 0.3 mg/kg REVTx-300 (collagen deposition:

0.91%, 44% reduction vs Group 2 minus background from group 1, p < 0.05).

Group 6 animals had UUO surgery and received 0.9 mg/kg REVTx-300 (collagen deposition:

0.54%, 58% reduction vs Group 2 minus background from group 1, p < 0.05).

Revelation will continue evaluating the potential of REVTx-300 in additional preclinical models including AKI, CKD, nonalcoholic steatohepatitis (NASH) and myocarditis to identify optimal dosing conditions required for prevention and resolution of inflammation and fibrosis.

Revelation plans to initiate a Phase 1a clinical study in the second half of 2023 in healthy volunteers to evaluate the safety of systemically delivered REVTx-300, and investigate biomarkers to elucidate the pharmacokinetic/pharmacodynamic relationship.

For efficiency, this phase 1a clinical study will be the same one conducted for REVTx-100.

This study will be followed by a Phase 1b study in patients to further evaluate the safety and activity of REVTx-300 in preparation for Phase 2.

REVTx-100 is being developed, through a license agreement with Vanderbilt University, as a potential therapy for the prevention or treatment of healthcare-associated bacterial infection including post-surgical infection, post-burn infection, urinary tract infection (e.g.

as a result of hospital-based or outpatient catheterization), sepsis, antibiotic-resistant infection, etc.

We hypothesize controlled stimulation of TLR-4 will selectively prime the body’s immune system to be able to better respond to subsequent pathogen exposure.

Multiple preclinical studies have shown that systemic pretreatment with PHAD results in significantly increased immune response leading to significantly reduced duration and severity of infection following bacterial challenge with either gram-positive or gram-negative bacteria.

Revelation plans to initiate a Phase 1a clinical study in the second half of 2023 in healthy volunteers to evaluate the safety of systemically delivered REVTx-100 and investigate biomarkers to elucidate the pharmacokinetic/pharmacodynamic relationship.

The Phase 1a study will be followed by a phase 1b study in patients undergoing colorectal surgery to establish proof-of-concept in preparation for phase 2.

REVTx-200 is being developed as a potential intranasal therapy that will be administered concurrently with a commercially available traditional IM vaccine.

We believe concurrent stimulation of the nasal mucosa with REVTx-200 upon IM vaccination may provide a more complete immunization.

We believe 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.

We hypothesize 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 clinical study (RVL-NHV01) and Phase 2 virus challenge study (RVL-VRL01) supports this hypothesis.

In particular, we were able to see increases in local (intranasal) IL-7 and MCP-1, as well as increased titers of antibodies specific to the viral challenge pathogen.

The adjuvant activity attributed to REVTx-200 will likely benefit a number of vaccines by increasing mucosal immunity.

For this reason, it can be paired with a variety of potential vaccine products.

We plan to establish relationships with vaccine product development companies with the intention of working with one or more of these companies to develop REVTx-200.

Initial development will include studying REVTx-200 using commercially available IM vaccines in nonclinical models unique to each potential partnering company.

Initial clinical studies will likely evaluate the potential of REVTx-200 to improve the performance of influenza or SARS-CoV-2 vaccinations.

Since REVTx-200 will be used in combination with a traditional vaccine, and based on feedback from the FDA, we believe REVTx-200 will be regulated as a biologic, and the approval process will require its own unique development pathway.

REVTx-99b for Food Allergies

REVTx-99b is being developed as a treatment for food allergies.

Most food allergies are diagnosed early in life and sometimes resolve over time, while other allergies develop later in life.

As a Type I hypersensitivity, food allergies induce a Th2-biased response, resulting in allergen-specific IgE antibodies, which bind to mast cell and basophil receptors upon challenge with antigen, resulting in degranulation and release of inflammatory mediators (e.g., histamine, leukotrienes, tryptase) (Bousquet 2020).

Systemic responses, e.g., anaphylaxis, may also occur within minutes or hours post-challenge.

Accordingly, there remains a significant need for effective therapies for treating and preventing allergic disease.

REVTx-99b potentially engages three different aspects of the allergic response via stimulation of the TLR-4 pathway.

These include (i) the possible induction of a physical barrier to allergens, (ii) the possible reduction of IgE secretion as a result of IFN upregulation and (iii) by secretion of IP-10 which competes for the native eotaxin receptor.

Revelation intends to explore the potential for treatment of food allergies with REVTx-99b in several preclinical models, minimally including an anaphylaxis model, in which administration of allergen will be followed by treatment with multiple dose levels of intranasal REVTx-99b.

Resolution of symptoms will be assessed through the evaluation of local and systemic allergic endpoints including IgE and/or IgG4 titers, tryptase, histamine, and eotaxin levels.

REVTx-99a for Prevention of Viral infection and REVTx-99b for Allergic Rhinitis

REVTx-99a was being developed as a broad anti-viral nasal drop solution for the potential prevention or treatment of respiratory viral infection until June of 2022.

We conducted a Phase 1 study in 2020 and Phase 2b study, on March 30, 2022 we announced that the primary endpoint of the Phase 2b study, reduction in AUC of viral load measured by RT-PCR from nasopharyngeal swabs, did not meet statistical significance.

We received the full data package during the second quarter of 2022 and have determined to stop all future clinical development of REVTx-99a.

REVTx-99b was being developed as a prevention or treatment for chronic nasal congestion and allergic rhinitis until July of 2022.

We conducted a Phase 1b allergen challenge study and on July 22, 2022 we announced that the primary endpoint to evaluate the effects of REVTx-99b versus placebo on safety and tolerability was met but exploratory endpoints for efficacy were not met.

This includes no reduction in allergy symptoms (Total Nasal Symptom Score) and no increase in peak nasal inspiratory flow versus placebo.

We have determined to stop all future clinical development of REVTx-99b for this indication.

Our diagnostic, REVDx-501 (REVID TM 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 IP-10 as a surrogate marker of respiratory viral infections including SARS-CoV-2, Influenza A, Influenza B, Parainfluenza, or Respiratory syncytial virus.

REVDx-501 is currently being developed as a point of care test kit with a simple to read visual readout which 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 non-replicating or inactive SARS-CoV-2 virus).

We have suspended development of REVTx-501 at this time to focus our resources on development of our therapeutic candidates.

Our goal is to become a leading biopharmaceutical company focused on the development of therapeutics that modulate the immune system to prevent and treat conditions with significant unmet.

Our current therapeutic candidates are all based on our proprietary Gemini formulation of PHAD ® , a synthetic version of MPLA, that is known to stimulate TLR4.

Stimulation of TLR4 via Gemini leads to a more controlled production of varied cytokines and chemokines which modulate the activity of the innate and adaptive immune response, relative to LPS, a traditional TLR4 agonist.

This “Immunostimulatory Preconditioning” with Gemini prepares the body to better guard against a rapid upregulation of multiple pro-inflammatory and microbial gene products and proteins, such as PAMPS (pathogen-associated molecular patterns) and DAMPS (damage-associated molecular proteins) (Zwirner 2017, Hernandez 2019, Ismaeli 2002).

Modulated activities may include stimulation and recruitment of infection fighting immune cells, reduction of inflammation, and/or regulation of inflammation depending on the degree and nature of the stimulation, which enables the multiple potential product candidates in development.

Interaction of PHAD with TLR4

The Gemini-SSI program is being developed, through a license agreement with Vanderbilt University, as a potential therapy for the prevention or treatment of surgical site infection.

We believe immunologic preconditioning with Gemini prepares the body to resist infection by priming the body’s immune system to better and more rapidly respond to pathogen exposure.

Multiple preclinical studies have shown that systemic pretreatment with PHAD results in a significantly augmented immune response leading to significantly reduced duration and severity of infection following bacterial challenge with either gram-positive or gram-negative bacteria.

Phase 1 safety and biomarker activity data is expected in the summer of 2024.

The Gemini-AKI program is being developed as a potential therapy for the prevention of acute kidney injury (AKI) due to external stress or insult (e.g.

surgical procedure, chemotherapy toxicity).

We believe immunologic preconditioning with Gemini prepares the body to handle biologic stress by redirecting the body’s immune system to have an attenuated response to the stress.

Nonclinical studies have demonstrated that preconditioning with PHAD significantly reduces the severity and duration of AKI following an ischemia of the kidney.

Additional data from these nonclinical studies have been accepted for presentation at The International Conference on Advances in Critical Care Nephrology on March 12, 2024.

Phase 1 safety and biomarker activity data is expected in the summer of 2024.

The Gemini-CKD program is being developed as a potential therapy for preventing the progression of chronic kidney disease (CKD).

We believe Gemini may modulate the immune response from a pro-inflammatory state to an anti-inflammatory (protective) state to rebalance the innate immune response and slow down or halt the progressive destruction and scarring of organ tissue, allowing the healing process to take place.

Nonclinical studies have demonstrated that Gemini significantly reduces the degree of scar tissue formation in a hyperinflammatory kidney injury model.

Revelation plans to conduct additional nonclinical CKD studies in 2024 to optimize the dose and dosing regimen for Gemini in this indication.

Our goal is to become a leading biopharmaceutical company focused on the development of therapeutics that modulate the immune system to prevent and treat conditions with significant unmet needs.

The key components of our strategy are to:

Advance the development of REVTx-300 for the prevention of acute organ injury (including AKI) an treatment of chronic organ disease (including CKD).

Advance the development of REVTx-100 for the prevention and treatment of healthcare associated infection.

Advance the development of our intranasal product candidate, REVTx-200 for improving the immunity and durability of traditional IM vaccinations.

Advance the development of our intranasal product candidate, REVTx-99b for the treatment of food allergies.

• Advance the development of Gemini for the prevention and treatment of surgical site infection

• Advance the development of Gemini for the prevention of acute kidney injury

• Advance the development of Gemini for the treatment of chronic kidney disease

Our Corporate History and Team

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We are also supported by a group of directors and leading investors whose collective experience will assist us in realizing our corporate strategy.

Infection Overview

Acute Organ Injury Overview

During surgery, ischemia or deprivation of blood supply to a tissue followed by the reperfusion or reintroduction of blood to prevent tissue necrosis can result in further damage and/or dysfunction to the organ.

AKI, also known as acute renal failure, is rapid loss of kidney function that onsets within a few hours or a few days.

AKI causes a build-up of waste products in your blood and makes it hard for your kidneys to keep the right balance of fluid in your body.

AKI can also affect other organs such as the brain, heart, and lungs.

Due its severe nature, AKI an important contributor to increased hospital stay duration and patient morbidity as well as significantly increased healthcare costs.

AKI is a significant health problem that continues to grow especially in patients with co-existing conditions such as diabetes.

Approximately 1% of all hospitalized patients having AKI upon admission.

During all hospitalization, the approximate incidence rate of acute kidney injury is 2 to 5%.

Development of AKI is even worse for patients admitted to the intensive care unit occurring in up to 67% of patients admitted.

AKI can have many different causes including decreased blood flow to the kidneys, direct damage to the kidneys or blockage of the kidney.

AKI inducing events may include shock (low blood pressure), blood or fluid loss (such as bleeding, severe diarrhea), heart attack, heart failure, and other conditions leading to decreased heart function, organ failure (e.g., heart, liver), overuse of pain medicines such as NSAIDs, severe allergic reactions, burns, injury, infection (sepsis), cancer, toxicity (e.g.

chemotherapies), hereditary factors or major surgery.

AKI is of particular concern after cardiac surgery and published evidence suggests that even slight postoperative increases in serum creatinine levels are associated with a significant increase in the risk of death.

Surgical Site Infection Overview

Despite efforts to monitor and prevent infection in hospital care settings, Infections arise from a range of different causes including surgery, burn wounds, central line catheters or urinary catheters, and sepsis, as well as long courses of antibiotic treatment, which may lead to the development of MRSA.

According to the most recent prevalence study data published by the Center for Disease Control and Prevention in 2015, approximately 3% of hospital patients suffered at least one infection, and there were approximately 687,000 infection cases in acute care settings resulting in approximately 72,000 deaths.

According to the CDC, on any given day about 31 hospital patients has at least one healthcare-associated infection.

A World Health Organization cooperative study which included 55 hospitals in 14 countries from four regions, approximately 8.7% of hospitalized patients developed infection within 48 hours of hospitalization (Tikhomirov 1987).

The most common healthcare-associated infections are bloodstream infection, pneumonia, urinary tract infections, and surgical site infections.

Acute Kidney Injury Overview

AKI, also known as acute renal failure, is defined as a rapid loss of kidney function.

AKI causes a build-up of waste products in blood and makes it more difficult for kidneys to maintain the correct balance of fluid in the body.

AKI can also have a significant impact on other organs such as the brain, heart, and lungs.

Due to its severe nature, AKI represents a significant and increasingly frequent health problem, especially in patients with co-morbidities such as diabetes.

Approximately 1% of all hospitalized patients present with AKI upon admission.

Of these hospitalizations, rates of AKI increased 165% and 114% for diabetic men and women, respectively from the years 2000 to 2014 (Goyal 2023, Pavkov 2018).

During all hospitalizations, the approximate incidence of AKI is 2 to 5%.

Development of AKI is even more prevalent in patients admitted to the intensive care unit, occurring in up to 67% of patients admitted (Pavkov 2018, Workeneh 2022).

AKI can develop as a result of many different causes including decreased blood flow to the kidneys, direct damage to the kidneys, or blockage of urine flow through the kidney.

AKI is of particular concern after cardiac surgery.

Published evidence suggests that even slight postoperative increases in serum creatinine levels are associated with a significant increase in the risk of death.

Up to 31% of patients undergoing cardiac surgery with no prior CKD develop post operative AKI with a high mortality rate.

The average cost to treat AKI is about $46,000 and results in about a 4-7 day increase in hospitalization time.

Chronic Organ Disease Overview

The average cost to treat AKI is about $42,600 and results in an approximate 4-7 day increase in hospitalization duration (Lysak 2017).

In this surgical setting, ischemia may be initiated intentionally, such as during a procedure that requires cardiopulmonary bypass.

Alternatively, ischemia may be the unintentional result of an untoward complication such as intraoperative hypotension.

Regardless of etiology, the ischemic event initially leaves the affected area(s) deprived of blood, oxygen, and other nutrients which then can exacerbate to injury when the blood supply returns to the site along with reactive oxygen species (ROS) and other constituents that cause oxidative stress to the tissues.

There are no approved therapies for preventing AKI, including AKI due to cardiac surgery.

Chronic Kidney Disease Overview

Organ damage, due to chronic disease, is a pervasive problem in the United States and world-wide.

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Examples of chronic organ and tissue disease include CKD through end-stage renal disease, liver diseases such as NASH, osteoarthritis, rheumatoid arthritis, pulmonary fibrotic disease, heart disease, pancreatitis, cancer, and irritable bowel syndrome.

In addition, acute organ stress may lead to reduced functionality and eventual decline, contributing to a chronic organ disease.

One example of this is acute kidney toxicity (the stress) associated with platinum-based chemotherapy which could lead to the development of chronic kidney disease.

Kidney disease is a major public health problem, affecting ~10% of populations in industrialized countries.

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Other risk factors include heart disease, obesity family history of CKD or older age.

Other causes for CKD include:

Glomerulonephritis (inflammation in the glomerulus), polycystic kidney disease, autoimmune diseases (such as systemic lupus erythematosus), vesicoureteral reflux (a condition where urine flows back up to the kidneys, pyelonephritis, interstitial nephritis (inflammation of the tubules), kidney stones, obstruction in kidney or cancer can lead to kidney failure over a period of time, overuse of certain medications, drug (heroin or cocaine) abuse, chemotherapy (such as cisplatin).

Every day more than 360 people begin treatment for kidney failure (dialysis or transplant).

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The CDC estimates Medicare costs in excess of $87 billion and continues to promote reduced costs including better management of CKD.

Other causes for CKD include:

Healthcare Associated Infection Overview

Despite efforts to monitor and prevent infection in hospital care settings, HAI arise from a range of different causes including surgery, burn wounds, central line catheters or urinary catheters, and sepsis, as well as long courses of antibiotic treatment, which may lead to the development of MRSA.

According to the most recent prevalence study data published by the Center for Disease Control and Prevention in 2015, approximately 3% of hospital patients suffered at least one HAI, and there were approximately 687,000 HAI cases in acute care settings resulting in approximately 72,000 deaths.

According to the CDC, on any given day about 31 hospital patients has at least one healthcare-associated infection.

A World Health Organization cooperative study which included 55 hospitals in 14

countries from four regions, approximately 8.7% of hospitalized patients developed infection within 48 hours of hospitalization (Tikhomirov 1987).

The most common healthcare-associated infection are bloodstream infection, pneumonia, urinary tract infections, and surgical site infections.

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).

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.

Typically, influenza infects 5-15% of the global population each year.

The majority of influenza infections are mild to moderate and symptoms 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 ARDS in adults.

The current prevalence of influenza worldwide is at 3 to 5 million cases per year, with 290,000 to 650,000 reported deaths according to the World Health Organization.

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 9 to 45 million illnesses, 140,000 –

810,000 hospitalizations, and 12,000 –

61,000 deaths annually since 2010.

COVID-19 Disease Overview

COVID-19 is caused by the severe respiratory syndrome coronavirus 2, or 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 ACEII receptor.

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 2020).

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, ARDS, blood clots, acute kidney injury, and potential further viral and bacterial infection.

As of October 2022 there have been over 96 million confirmed cases of COVID-19 and over one million deaths in the United States according to the CDC and there have been over 623 million confirmed cases of COVID-19 and over 6.5 million deaths worldwide according to the World Health Organization.

Food Allergy Overview

According to research performed by the Food Allergy Research & Education group, approximately 11% of adults in the United States have one or more food allergies with different levels of severity, which equates to approximately 32 million Americans, including 5.6 million children under age 18, and these numbers are increasing (FARE 2020).

Each year in the US, 200,000 people require emergency medical care for allergic reactions to food.

Most food allergies are diagnosed early in life and sometimes resolve over time, while other allergies develop later in life.

It is estimated that caring for children with food allergies costs US families nearly $25 billion annually (FARE 2022).

As a Type I hypersensitivity, food allergies result in activation of a Th2-biased response to an antigen, resulting in allergen-specific IgE antibody production (Bousquet 2020).

Allergen-specific IgE antibodies bind to mast cell and basophil receptors upon subsequent challenge with antigen, resulting in degranulation and release of inflammatory mediators (e.g., histamine, leukotrienes, tryptase).

These mediators cause mobilization of basophils,

eosinophils, and T lymphocytes to the site of insult, as well as activation of T cells, which compound symptomology and enhance inflammation.

Systemic responses, e.g., anaphylaxis, may also occur within minutes or hours post-challenge.

Accordingly, there remains a significant need for effective therapies for treating and preventing allergic disease.

Current Prevention, Treatment, and Detection Options

Prevention of Surgical Site Infection

There are no approved therapies currently available for the prevention of infection outside of pre- and post-surgical administration of antibiotics and commonly recommended procedures for the preventing the transmission of bacteria including hand washing, mask wearing, and cleaning the surgical site pre- and post-surgery.

In the case of antibiotic pretreatment, the typical course of treatment may require an initial empiric broad-spectrum antibiotic, later targeted to an organism if detected, with consideration for the presence of multidrug resistant pathogens, specifically MRSA.

Antibiotic resistance has become a major consideration in the need for pretreatment of yet-to-be diagnosed infections, as the number of antibiotic resistant strains have increased, and the over prescription of antibiotics further contributes to resistance.

Prevention and Treatment of AKI

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Treatment for AKI requires hospitalization and intensive supportive care until kidney function recovers.

In more serious cases, dialysis may be needed to help replace kidney function until your kidneys recover.

The main treatment is to address what is causing your acute kidney injury.

Prevention and Treatment of Chronic Organ Disease

There are currently no effective therapies for treating chronic organ disease or therapies for preventing loss of function due to acute organ dysfunction, outside of steroidal treatment or organ transplantation.

There is no cure for CKD but treatments may help manage symptoms or stop it from progressing.

These treatments include life style changes to control health and weight, medications to control associated diseases such as high blood pressure or high cholesterol and for later stages, filtering the blood with a machine known as dialysis.

Avoiding conditions or exposures that can harm the kidneys like certain medications or kidney infections is also beneficial.

In more serious cases, dialysis may be needed to help replace kidney function until kidneys can recover.

The main treatment is to address what is causing the acute kidney injury.

Prevention and Treatment of Chronic Kidney Disease

In April 2021, The FDA approved the use of Farxiga (Dapagliflozin) to reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults who are at risk of disease progression.

Farxiga was originally approved in 2014 for diabetic control in adults in addition to diet and exercise.

In addition to the approved drug, other treatments include lifestyle changes to control health and weight, medications to control associated diseases such as high blood pressure or high cholesterol and for later stages, filtering the blood with a machine known as dialysis.

Avoiding conditions or exposures that can harm the kidneys like certain medications or kidney infections is also beneficial.

Still, at this time, there is a significant unmet need for therapies that slow disease progression and improve outcomes of patients with chronic kidney disease.

Prevention of Bacterial Infection

There are no recommended anti-bacterial prescriptions currently available for the prevention of infection.

Measures commonly recommended for the prevention of bacterial infection are typically focused on the prevention of transmission, including regular hand washing, mask wearing, social distancing and/or self-isolation/self-quarantine, and cleaning potentially contaminated surfaces.

Treatment and Management of Bacterial Infection

Because the presence of bacteria in humans is ubiquitous, not all bacterial growth is considered pathogenic.

Therefore, interpretation of patient bacterial cultures needs to take into account clinical presentation, patient immune status, reason for performing patient culture test, the testing procedure, and any alternate evidence of infection.

Based on the source of infection and patient results, medical care may include administration of antibiotics, administration of anti-fungal or anti-viral medication, line removal, or surgical debridement as necessary.

In the case of antibiotic treatment, the typical course of treatment may require an initial empiric broad-spectrum antibiotic, later targeted to the organism detected, with consideration for the presence of multidrug resistant pathogens, specifically MRSA.

Antibiotic resistance has become a major consideration in the treatment of yet-to-be diagnosed infections, as the number of antibiotic resistant strains have increased, and the over prescription of antibiotics further contributes to resistance.

Prevention and Treatment 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.

Several vaccines have been developed

and approved for emergency use for the prevention of SARS-CoV-2.

The main drawback to intramuscular vaccines is the durability of their imparted protection and their poor ability to provide a strong mucosal immunity.

Prevention or Treatment of Food Allergies

Prevention of food allergies is currently limited to the practice of active avoidance of known allergens.

This can have a highly negative impact on patient’s quality of life, especially in the case of severe food allergies, in which avoidance may dictate declining normal social activities in which foods with knows allergens may be present.

Although several therapies are being developed, there is no cure for food allergies.

The current standard of care for food allergies is allergen immunotherapy, which involves the progressive increase in exposure to allergens under controlled clinical conditions, which is time consuming and has as yet provided unpredictable efficacy.

Palforzia is the only approved medication for food allergy, which has varied degrees of efficacy, dependent on age (Perkin, 2022), and peanut avoidance is recommended during treatment with Palforzia.

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 PCR assay.

PCR testing is highly sensitive and can detect extremely low levels of genetic material of a specific organism, such as a virus, thus identifying the specific virus type.

However, PCR tests are expensive, time-consuming, and can only detect virus types based on a specific “primer sequence”

used when running the test.

Because the PCR test requires this primer sequence, its utility in detecting new viral variants may be limited.

PCR tests may also detect inactive, non-proliferating virus, leading to false positive results, in some cases several weeks after resolution of active infection.

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 rapid antigen test kits.

While these methods can be performed 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.

REVELATION’S PROGRAMS

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 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 adaptive immune system which ultimately leads to the production of antibodies.

Cytokines can be inflammatory or protective, meaning they may be able to modulate certain established cellular activities.

TLRs serve a vital role in initiating 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 cells) found in the nasal mucosal tissue, and when a pathogen, such as a bacteria, invades through the nose, TLRs recognize the pathogen as foreign and activate the innate immune response, producing cytokines.

Stimulation of TLR-4 by PHAD may modulate the cellular response, leading to the production of protective (non-inflammatory and regulatory) cytokines that have multiple therapeutic applications as illustrated in the following Figure.

REVELATION’S PROGRAMS

Gemini Platform

Our current therapeutic candidates are all based on Gemini, our proprietary formulation of PHAD ® , a synthetic version of MPLA, that is known to stimulate the innate immune response via TLR-4.

The innate immune system is our first line of defense against stress such as trauma, infection and acute and chronic disorders.

The innate immune system responds to stress (e.g.

infection) by producing and releasing various types of cytokines.

Cytokines are proteins that direct different activities in cells and can be inflammatory or protective, meaning they may be able to modulate certain established cellular activities.

TLRs serve a vital role in initiating the innate immune system response by recognizing different molecular patterns associated with pathogens such as bacteria and viruses (e.g.

pathogen associated molecular patterns) as well as tissue damage (e.g.

damage associated molecular patterns).

Revelation believes immunostimulatory preconditioning with Gemini prepares the body to respond better to stress due to infection, trauma, or other acute and chronic disorders.

Modulated activities may include stimulation and recruitment of infection fighting immune cells, reduction of inflammation, and/or regulation of inflammation depending on the degree and nature of the stimulation which enables the multiple potential product indications in development.

Interaction of PHAD with TLR4

The active ingredient PHAD ® , may interact with TLR-4 to stimulate the TRIF pathway leading to the production of protective and regulatory cytokines, including IP-10, IL-7, MCP-1, and TGF- b .

Revelation Biosciences

REVTx-300 is being developed as a potential therapy for the prevention of acute organ injury such as AKI and as a treatment of chronic organ disease including CKD.

REVTx-300 utilizes the active ingredient PHAD ® and is formulated as a liquid for intravenous administration.

The establishment of fibrosis and subsequent death of the organ is driven by ongoing inflammatory processes and reactive oxygen species associated with the innate immune response.

Revelation conducted a nonclinical study to evaluate the anti-fibrotic activity of REVTx-300.

Specifically, a range of daily systemic dosing levels of REVTx-300 were tested in a rat Unilateral Ureteral Obstruction (UUO) model.

Revelation will continue evaluating the potential of REVTx-300 in additional preclinical models including CKD and myocarditis to identify optimal dosing conditions required for prevention and resolution of inflammation and fibrosis.

Clinical Development Plan

Revelation plans to initiate a Phase 1a clinical study in the second half of 2023 in healthy volunteers to evaluate the safety of systemically delivered REVTx-300 and investigate biomarkers to elucidate the pharmacokinetic/pharmacodynamic relationship.

The proposed study will consist of cohorts of single ascending doses of REVTx-300.

The primary readout will be safety with exploratory endpoints evaluating biomarkers.

The Phase 1a study will be followed by a phase 1b study in 2024 in patients undergoing cardiac surgery to establish proof-of-concept in preparation for phase 2.

The proposed Phase 1b study will consist of a placebo group and low and high dose REVTx-300 groups.

The primary readout will be safety with exploratory endpoints to evaluate biomarkers and rate, duration and severity of AKI.

as a result of hospital-based or outpatient catheterization), sepsis, antibiotic-resistant infection, etc.

We hypothesize controlled stimulation of TLR-4 will selectively prime the body’s immune system to be able to better respond to subsequent pathogen exposure.

As illustrated in the following figure, we hypothesize REVTx-100 will prime the body’s immune response to be able to better respond upon exposure to a pathogen.

Gemini-SSI Program

Gemini is being evaluated as a potential therapy for the prevention or treatment of surgical site infection.

We believe immunologic preconditioning with Gemini prepares the body to resist infection by priming the body’s immune system to respond to pathogen exposure more rapidly.

In addition to surgical site infection, we believe Gemini may also have utility for post-burn infection, urinary tract infection (e.g.

as a result of hospital-based or outpatient catheterization), sepsis, and antibiotic-resistant infection.

Revelation is developing Gemini for the prevention of infection through a license agreement with Vanderbilt University.

Nonclinical studies

Multiple preclinical studies have shown that systemic pretreatment with PHAD results in significantly increased immune response with significantly reduced duration and severity of infection following bacterial challenge with either gram-positive or gram-negative bacteria as indicated in the following figures.

Multiple preclinical studies have shown that pretreatment with PHAD results in significantly augmented immune response with significantly reduced duration and severity of infection following bacterial challenge with either gram-positive or gram-negative bacteria as indicated in the following figures.

Pretreatment with PHAD Impart Protection from Gram Negative Bacterial Infection

Pretreatment with PHAD Impart Protection from Gram Positive Bacterial Infection

Pretreatment with PHADs Impart Protection from Gram Positive Bacterial Infection

Clinical Development Plan

The proposed study will consist of cohorts of single ascending doses of REVTx-100.

The primary readout will be safety with exploratory endpoints evaluating biomarkers.

The Phase 1a study will be followed by a phase 1b study in 2024 in patients undergoing colorectal surgery to establish proof-of-concept in preparation for phase 2.

The proposed Phase 1b study will consist of a placebo group

and low and high dose REVTx-100 groups.

The primary readout will be safety with exploratory endpoints to evaluate biomarkers, infection rate, duration and severity.

REVTx-200 is being developed as a potential intranasal therapy that will be administered concurrently with a commercially available IM vaccine.

We believe concurrent stimulation of the nasal mucosa with REVTx-200 upon IM vaccination will provide a more complete immunization.

REVTx-200 utilizes the active ingredient PHAD ® .

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.

Most vaccinations for respiratory viruses (influenza, SARS-CoV-2) are being developed or have been developed for IM administration.

It has been shown that IM vaccination results in a strong systemic immune response, but a weak mucosal immune response.

Contrary to this, intranasal vaccination (e.g., FluMist ® ) has been shown to elicit a strong mucosal response and a moderate systemic response.

We hypothesize that optimal protection from a vaccine requires both a systemic immune response elicited by the IM injection and a mucosal immune response developed by recruiting immune cells into the mucosal immune system.

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.

We hypothesize 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 clinical study (RVL-NHV01) and Phase 2 virus challenge study (RVL-VRL01) supports this hypothesis.

In particular, we were able to see increases in local (intranasal) IL-7 and MCP-1 as well as increased titers of antibodies specific to the viral challenge pathogen.

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 recruits B cells and T cells to the site of application.

In addition, MPLA has been reported to improve expression of T cell stimulatory co-factors such as CD80 to improve the engagement of the adaptive immune system.

This data suggest intranasal REVTx-200 will traffic antigen activated B cells and T cells to the intranasal space.

Nonclinical studies

Revelation is currently conducting a preclinical study to evaluate improved mucosal immunity against a SARS-CoV-2 trimeric peptide vaccination administered intranasally or IM.

Vaccine administered in conjunction with REVTx-200 will be evaluated relative to vaccination alone, through improved systemic and mucosal antibody titers, including the detection of an antigen specific antibody response.

Additional endpoints will be evaluated to provide additional clarity on the impact of REVTx-200 on immune cell recruitment and activation.

Additional nonclinical studies will be necessary to optimize the formulation and dosing regimen for REVTx-200.

REVTx-99b potentially engages three different aspects of the allergic response via stimulation of the TLR-4 pathway.

Stimulation of TLR-4 results in mobilization of exosomes from epithelia which can release antimicrobial peptides and nitric oxide that can destroy invading pathogens/antigens (Nocera 2018).

TLR-4 stimulation also leads to generation of Type I interferons which block activation of Th2 cellular activity, resulting in reduced IgE secretion and reduction in allergic symptoms (Gonzalez-van Horn 2015).

Type I IFN response results in the generation of IP-10, which is capable of binding to CCR3, the native receptor for eotaxin and is present on cells involved in the allergic

response, including eosinophils, basophils, and mast cells (Loetscher 2001).

IP-10 binding to CCR3 prevents eotaxin from binding and recruiting immune cells, thereby reducing recruitment of Th2 cells and attenuating the allergic response.

Future development activities will include formulation development and optimization which is a key aspect for intranasal delivery.

This formulation development will be done in conjunction with preclinical models (including an anaphylaxis model, in which administration of allergen will be followed by treatment with multiple dose levels of intranasal REVTx-99b.

Resolution of symptoms will be assessed through the evaluation of local and systemic allergic endpoints, likely including IgE and IgG4 titers, tryptase, histamine, and eotaxin levels.

REVDx-501 (Diagnostic) Overview

REVDx-501 (REVID TM 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 IP-10 as a surrogate marker of respiratory viral infections including SARS-CoV-2, Influenza A, Influenza B, parainfluenza, or respiratory syncytial virus.

REVDx-501 is currently being developed as a point of care test kit with a simple to read visual readout which provides a result in less than 15 minutes without the need for specialized instrumentation.

Sample collection is simply a swab of the anterior nares (nostrils) making sample collection easy.

If approval is obtained, we anticipate the commercial version of the kit to be a self-contained, portable kit that can be shipped anywhere.

The instructions will direct users with a positive result to seek confirmatory testing and/or medical treatment.

While the kit could potentially be used universally at home as a self-screening method a more practical and potential early use would be as a screening tool in healthcare facilities (e.g.

hospitals and nursing homes) to allow for rapid triage and appropriate isolation of patients with potential respiratory infection.

In addition, the diagnostic can be used to increase the efficiency of PCR testing by eliminating wasted testing on subjects who are not infected with a viral infection.

The figure below explains the concept of increasing the efficiency of PCR testing.

The left panel shows the current state of PCR testing with most patients (>80%) being PCR negative for infection.

The right panel shows the effect of the addition of the REVID screening test to rule out virus negative patients resulting in better utilization of the PCR test.

The diagnostic is based on the knowledge that respiratory viral infection results in elevated nasal mucosal secretions containing specific cytokines (e.g., IP-10, IFN), which can be detected rapidly after exposure.

One or more of these cytokines can be detected using a lateral flow assay format (e.g., home pregnancy kit) from a mucosal sample collected from the anterior nares.

Device Testing and Data supporting the potential utility of REVDx-501

Clinical samples were collected under protocol and with consent from volunteers presenting at a COVID-19 testing center.

Participants included those presenting with symptoms including fever, cough, loss of taste or loss of smell as well as asymptomatic (no symptoms) subjects.

For each subject, a sample was collected using the nasopharyngeal method and tested by PCR for SARS-CoV-2 and a second sample of the lower nose was collected using the REVDx-501 swab and tested using the REVDx-501 test method.

The results shown below from this testing

showed REVDx-501 to have excellent correlation with PCR for replicating SARS-CoV-2 virus (100% positive agreement for replicating SARS-CoV-2 virus, 86% negative agreement for no replicating SARS-CoV-2 virus).

REVDx-501 Test Kit

Test Kit POSITIVE

Test Kit NEGATIVE

TOTAL SAMPLES

Patients who reported symptoms of fever, cough, loss of taste or loss of smell were tested by REVDx-501 and PCR.

REVDx-501 had a 0% false negative rate for replicating SARS-CoV-2.

These results include patients who reported onset of symptoms within 24 hours of the test, which may make the diagnostic an earlier detection method than even PCR.

In addition, the positive REVDx-501 results that were PCR negative for COVID-19 were likely caused by other viral infections.

In addition to the clinical evaluation described above, the FDA recommends a series of validation studies for IVD devices prior to submission for approval.

These studies are planned and ongoing and include limit of detection, inclusivity, cross-reactivity, flex, usability, and clinical evaluation studies.

The LOD, inclusivity, cross-reactivity, and flex test studies are generally analytical laboratory-based (“bench”) studies to test how well the diagnostic device can detect the chemical or pathogen the device is intended to measure, as well as under different conditions.

Usability (human factors) studies are investigations that enable a device design team to improve the usability of their device to meet acceptable standards of risk —

it informs the development team if the device kit and instructions for use are appropriate for typical users.

Generally, the final study is the clinical evaluation study, which is the largest study (at least 100 users).

This study is considered the “real-world”

testing of the product.

Study participants will use the test kit as recommended in a clinical setting or a simulated clinical environment.

The device test kit results are compared to a PCR assay, as the reference standard test.

Overall, in order to be considered for marketing approval by FDA, users should have minimal issues using the test and the device test results should align very closely with the reference test.

We have suspended development of REVDx-501 to focus our resources on development of our therapeutic candidates.

Phase 1 safety and biomarker activity data is expected in the summer of 2024.

The Phase 1 study will be followed by a Phase 1b study in patients undergoing colorectal surgery to evaluate safety and efficacy in this patient population.

Gemini-AKI Program

Gemini is being evaluated as a potential therapy for the prevention of acute kidney injury (AKI) due to external stress (e.g.

surgical procedure, chemotherapy toxicity).

We believe immunologic preconditioning with Gemini prepares the body to handle biologic stress by directing the body’s immune system to have an attenuated response to the stress.

Gemini is being evaluated as a potential therapy for the prevention of acute kidney injury (AKI).

Preclinical studies have shown that pretreatment with PHAD results in significantly decreased severity and duration of acute kidney injury due to ischemia.

PHAD Pretreatment Reduces AKI in a Unilateral Ischemia/Reperfusion Model 1

1 Mice pretreated with intravenous PHAD at 2, 20, and 200 µg/mouse or vehicle control, 48 and 24 hours prior to undergoing right nephrectomy followed by clamping of the left renal pedicle for 28 minutes.

A) Blood was analyzed for BUN and creatinine at baseline (D0), and post-injury day 1 and 3.

Results expressed as means +/-SEM with N = 8.

Two-way ANOVA was used to compare differences between PHAD- and vehicle-treated mice over time, with p values indicated;

B) Representative images of periodic acid-Schiff staining (PAS) sections of the outer medulla at Day 3 after injury in sham, vehicle- and PHAD-treated mice.

Arrows point to casts within the collecting tubules.

Scale bar, 100 µm.

C) Pretreatment with PHAD reduced tubular injury in a dose dependent manner as visualized (PAS).

Hernandez A, Patil N, et.

Pretreatment with a novel Toll-like receptor 4 agonist attenuates renal ischemia-reperfusion injury.

American Journal of Physiology-Renal Physiology 2023 324:5, F472 – F482

PHAD Pretreatment Reduces AKI in a Bilateral Ischemia/Reperfusion Model

Mice were pretreated with intravenous PHAD at 200 µg/mouse or vehicle control, 48 and 24 hours prior to undergoing bilateral renal pedicle clamping for 24 minutes.

A) Blood was analyzed for BUN and creatinine at baseline (0), and post-injury day 1 and 3.

Results expressed as means +/-SEM with N = 10.

Two-way ANOVA was used to evaluate between group differences over time (p <0.05 for both BUN and serum creatinine), with p values shown after Sidak’s correction for multiple post hoc between group comparisons at each time point;

B) Tubular injury scores in the outer stripe of the outer medulla from PAS-stained sections Day 3 after injury;

C) Apoptosis in the outer stripe of the outer medulla from TUNEL stained sections Day 3 after injury.

Hernandez A, Patil N, et.

Pretreatment with a novel Toll-like receptor 4 agonist attenuates renal ischemia-reperfusion injury.

American Journal of Physiology-Renal Physiology 2023 324:5, F472 – F482.

Clinical Development Plan

Phase 1 safety and biomarker activity data is expected in the summer of 2024.

The Phase 1 study will be followed by a Phase 1b study in patients undergoing cardiac surgery to establish dose and dosing regimen in preparation for Phase 2.

The proposed Phase 1b study will consist of a placebo group and low and high dose Gemini groups.

The primary readout will be safety with exploratory endpoints to evaluate biomarkers and rate, duration, and severity of AKI.

Gemini-CKD Program

Gemini is being evaluated as a potential therapy for preventing the progression of chronic kidney disease (CKD).

Revelation conducted a nonclinical study to evaluate the potential of Gemini to prevent kidney fibrosis due to excess inflammation.

Specifically, a range of daily systemic dosing levels of Gemini were tested in a rat Unilateral Ureteral Obstruction (UUO) model.

Gemini Treatment Reduces Fibrosis in Acute and Chronic Kidney Model (UUO in Rats)

Rats (n=11-12 per treatment group) were subjected to the UUO surgical procedure.

Animals were administered either vehicle (Sham, UUO, and Positive control) or Gemini (doses listed are for active ingredient) on days 1-7 post surgery.

Kidneys were harvested and analyzed at the end of the treatment period.

Composite data represents the average of 3 anatomically distinct depths (10 images/depth/rat/group = ~60-65% of renal cortical area).

Treatment with Gemini resulted in a significant dose-dependent reduction in fibrosis.

The high dose group (0.9 mg/kg) reduced new collagen deposition (fibrosis) by 58% vs new collagen deposition observed in the no treatment UUO group (normalized to sham group, n=6).

Gemini Antifibrotic Effects Likely Mediated by Validated Target Cytokines

Gemini reduced TGF-β and increased IL-10 and NGAL in a dose dependent manner.

TGF-β is pro-fibrotic and is directly linked to the propagation of fibrosis.

The positive control (PC) is an established TGF-β blocker.

IL-10 is a key driver for the reduction and resolution of inflammation, and NGAL is an important defense for preventing excessive oxidative damage resulting from injury/ongoing inflammation.

Development Plan

During 2024, Revelation will continue evaluating the potential of Gemini in additional preclinical models of CKD to identify optimal dosing conditions and conduct the nonclinical testing required for chronic dosing in patients.

The biopharmaceutical industry is intensely competitive and subject to rapid innovation and significant technological advancements.

We believe the key competitive factors that will affect the development and commercial success of REVTx-300, REVTx-100, REVTx-200, REVTx-99b, and any future Program Product candidates are efficacy, safety and tolerability profile, reliability, convenience of dosing, price, the level of generic competition and reimbursement.

We believe the key competitive factors that will affect the development and commercial success of REVDx-501 and any future product candidates are reliability, convenience, and price.

We believe the key competitive factors that will affect the development and commercial success of our Gemini based programs and any future Program Product candidates are efficacy, safety and tolerability profile, reliability, convenience of dosing, price, the level of generic competition, and reimbursement.

Our competitors include multinational pharmaceutical companies, specialized biotechnology companies, universities, and other research institutions.

A number of biotechnology and pharmaceutical companies are pursuing the development or marketing of pharmaceuticals that target the same diseases that we are targeting.

A number of device companies are pursuing the development or marketing of devices in the same or similar space.

Smaller or earlier-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large, established companies.

Given the high incidence of respiratory viral infections, it is likely that the number of companies seeking to develop products and therapies for the prevention or treatment of viral infection, will increase.

If REVTx-300 is approved is approved for prevention or treatment for chronic kidney disease, we would face competition from currently approved and marketed products including Farxiga®.

We would also have future competition that could arise from products currently in development.

If REVTx-100 is approved for prevention or treatment of infection, we would face competition from currently approved and marketed products including many antibiotics that are effective against non-resistant strains of bacteria.

We would also have future competition that could arise from products currently in development.

If REVTx-200 is approved is approved as an intranasal adjunct for intramuscular vaccination, we would face competition from currently approved and marketed products including most intramuscular vaccine adjuvants, such as CpG 1018 (Dynavax).

Given the high incidence of AKI and CKD, and the rate of surgical site infections, it is likely that the number of companies seeking to develop products and therapies for the prevention or treatment of such, will increase.

If Gemini-SSI is approved for prevention of surgical site infection, we would face competition from currently approved and marketed products including many antibiotics that are effective against non-resistant strains of bacteria.

We would also have future competition that could arise from products currently in development.

If REVTx-99b is approved is approved is approved for prevention or treatment of food allergies, we would face competition from currently approved and marketed products including Palforzia® for prophylactic desensitization and epinephrine for acute anaphylactic shock due to exposure to a peanut allergen.

If Gemini-AKI is approved for prevention of acute kidney injury, we would face competition that could arise from products currently in development.

If Gemini-CKD is approved for treatment of chronic kidney disease, we would face competition from currently approved and marketed products including Farxiga®.

We would also have future competition that could arise from products currently in development.

If REVDx-501 is approved, it will need to be a stand alone test and will not be able to be combined with other diagnostic test and competition would arise from various companies and partnerships currently engaged in clinical studies with competing device concepts including:

Quest Diagnostics, Inc., Laboratory Corporation of America Holdings, and Eurofins Advantar Laboratories.

As well as from currently approved COVID-19 home test from Ellume Limited, MeMed, Abbot Laboratories, and Lucira Health.

Many of our competitors have substantially greater financial, technical, human, and other resources than we do and may be better equipped to develop, manufacture, and market technologically superior products.

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We do not own or operate manufacturing facilities for the production of our Program Products or any other product candidates, nor do we have plans to develop our own manufacturing operations in the foreseeable future.

We currently rely, and expect to continue to rely, on third parties for the manufacturing of our Program Products or any other product candidates for preclinical and clinical testing, as well as for commercial manufacturing if REVTx-300, REVTx-100, REVTx-200 or any future product candidate receives marketing approval.

Also, we currently rely and continue to rely on third parties for the manufacturing and development of our diagnostic devices for clinical testing, as well as for commercial manufacturing if REVDx-501 gets marketing approval.

We currently rely, and expect to continue to rely, on third parties for the manufacturing of our Program Products or any other product candidates for preclinical and clinical testing, as well as for commercial manufacturing if Gemini or any future product candidate receives marketing approval.

Also, there is only one supplier for PHAD ® , Avanti Polar Lipids, Inc., with whom we do not have a long-term supply agreement.

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We are working to deepen the pipeline of Revelation through both internal organic development of new technologies along with portfolio additions from acquisitions, strategic partnerships and in-licensing of new therapeutic product candidates.

From time to time we enter into discussions regarding potential transactions;

our focus is on development of our existing pipeline and discussions with third parties to date have not progressed beyond the preliminary stage.

Vanderbilt License

From time to time we may enter into discussions regarding potential transactions;

however, our focus is on development of our existing pipeline and discussions with third parties to date have not progressed beyond the preliminary stage.

On September 29, 2022, we entered into an exclusive worldwide license agreement with Vanderbilt University to develop and commercialize PHAD, for treating or preventing infections.

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Vanderbilt has the right to terminate the license agreement if the development milestones are not made, subject to a six-month grace period.

Global Health

We entered into a Global Health Agreement (“GHA”) with AXA IM Prime Impact Fund on December 31, 2020.

As part of the GHA for six years from December 31, 2020 (the “Term”) we will (i) provide REVTx-99a/b and REVDx-501 (the “GHA Program Products”), if approved by the FDA and/or the EMA, to non-profit organizations and public-sector purchasers (“Global Health Purchasers”) in certain low and middle income countries (as defined by the World Bank) (“Target Countries”), to be determined by the Global Access Committee (the “GAC”), at a price of no more than 30% above the cost of goods sold, (ii) make available up to 20% of the annual unit sales volume, (iii) allocate $50,000 per year to the GAC to work on training programs, and (iv) work with global health authorities to have the products added to protocols and treatment guidelines.

In the event that the GHA Program Products are acquired directly or through an acquisition of the Company by a third party the GHA shall continue to survive for the Term and shall be assumed by the acquirer.

In the event that the Company (i) fails to use commercially reasonable efforts to obtain regulatory approvals as agreed by the GAC, (ii) fails to cure a non-compliance within the GHA, (iii) if we transfer the intellectual property and the successor fails to assume the GHA, or (iv) if the Company institutes any bankruptcy, reorganization, dissolution, liquidation, or similar proceeding, the Company will grant a nonexclusive, perpetual, irrevocable, non-terminable, fully paid up, royalty free license in the Target Countries for Global Health Purchasers.

Sales and Marketing

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We plan to seek third-party support from established pharmaceutical and biotechnology companies for those products that would benefit from the promotional support of a large sales and marketing force.

In these cases, we

might seek to promote our products in collaboration with marketing partners or rely on relationships with one or more companies with large established sales forces and distribution systems.

In these cases, we might seek to promote our products in collaboration with marketing partners or rely on relationships with one or more companies with large established sales forces and distribution systems.

Intellectual Property

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We also rely on trade secret protection of our confidential information and know-how relating to our proprietary technology, platforms, and product candidates.

As of March 21, 2023 , our patent portfolio includes three U.S.

provisional patent applications –

one for REVTx-300, one for REVTx-99b and one for a new drug program.

These provisional patent applications will be converted to utility patent applications prior to their respective 1-year anniversaries.

Our portfolio includes three international PCT patent applications, two for REVTx-99b, and one for REVDx-501.

In regard to our REVTx-99b program, one PCT patent application is directed to MPLA formulations including REVTx-99b and one PCT patent application is directed to the use of REVTx-99b for the treatment of allergic rhinitis and chronic nasal congestion.

In regard to our REVDx-501 program, the PCT patent application has claims directed to the rapid detection kit and methods for detecting a signal of viral infection of the respiratory tract.

The provisional application for REVTx-300 is directed to the use of MPLA formulations for the prevention of loss of function associated with chronic organ disease.

The provisional application for REVTx-99b is directed to nasal administration of MPLA formulations as an adjuvant to traditional allergy immunotherapy, such as oral allergy immunotherapy.

As of March 18, 2024, our patent portfolio includes one U.S.

provisional patent application directed to methods of treating cancer using MPLA formulations, including GEMINI.

We expect to convert this provisional application to a utility patent application prior to its 1-year anniversary.

Our portfolio also includes two patent families, each of which has been filed in the U.S., Canada, and Europe.

One of these patent families is directed to MPLA formulations, including GEMINI;

the other patent family is directed to the use of GEMINI for the treatment of allergic rhinitis and chronic nasal congestion.

Regarding our GEMINI AKI and GEMINI CKD programs, our portfolio also includes a PCT application directed to the use of MPLA formulations for the prevention of loss of function associated with acute organ disease and chronic organ disease.

Our portfolio additionally includes a PCT application directed to methods of using MPLA formulations, including GEMINI, as an adjuvant to traditional allergy immunotherapy, such as oral allergy immunotherapy.

Finally, we have licensed from Vanderbilt University a patent directed to methods of using phosphorylated hexaacyl disaccharides (PHADs) for treating or preventing infections.

We expect to file a non-provisional patent application prior to the twelve-month convention date for each provisional patent application.

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We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.

As of March 21, 2023 , we had 6 full-time employees, 2 of whom are engaged in research and development activities or operations and 4 of whom are engaged in general and administrative activities or operations.

employees are represented by a labor union or covered by a collective bargaining agreement.

As of March 18, 2024, we had 9 full-time employees and one part-time employee, 5 of whom are engaged in research and development activities or operations and 5 of whom are engaged in general and administrative activities or operations.

None of our employees are represented by a labor union or covered by a collective bargaining agreement.

We consider our relationship with our employees to be good.

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On February 18, 2022, LifeSci Capital LLC filed an action against the Company in the U.S.

District Court for the Southern District of New York seeking damages in the amount of approximately $2.7 million in cash and $2.6 million in equity for unpaid banking and advisory fees.

These fees arise under contracts which were entered into prior to the Business Combination and the Company is disputing the amount owed under those contracts and has asserted affirmative defenses including the defense that the amount of the fees sought exceeded the $8.5 million cap on transaction expenses in the Business Combination Agreement.

District Court for the Southern District of New York seeking damages in the amount of approximately $5.3 million plus interest for unpaid banking and advisory fees.

These fees arise under contracts which were entered into prior to the Business Combination and the Company has asserted that LifeSci Capital LLC is not entitled to the fee because it violated its responsibilities by misrepresenting to Petra the funds that would be available following the Business Combination, absent which Petra would not have entered into the Business Combination Agreement.

This action remains pending as of the date of this report.

On March 2, 2023, the court denied the plaintiff’s motion for summary judgment.

As of the date of this report, the court has not set any schedule for discovery or a timetable for any trial.

Of the LifeSci Capital LLC claim, $1.5 million relates to deferred underwriting fees from the Petra initial public offering.

In addition, but separate from the claim, one of the underwriters in the Petra initial public offering who is not a participant in the litigation with LifeSci Capital LLC recently issued a demand letter seeking repayment for $655 thousand in fees owed from the Petra initial public offering that remain unpaid.

Both of these amounts are recorded as a current liability in the financial statements as of December 31, 2022 under deferred underwriting commissions.

No other liabilities are reflected in the financial statements as the amount of any additional liability cannot be determined at this time.

$1.5 million of the claim relates to deferred underwriting commissions from the Petra initial public offering, which are recorded as a current liability in the financial statements as of September 30, 2022 under deferred underwriting commissions.

On December 1, 2023 a Magistrate Judge issued a report recommending summary judgment in favor of LifeSci Capital LLC.

On December 15, 2023, the Company filed objections to the Magistrate’s report asserting that the Magistrate Judge made factual determinations not appropriate for summary judgment and misapplied the law.

The Magistrate’s report is a recommendation to the trial judge who is responsible for reviewing the case de novo.

Other than the deferred underwriting commissions, no liabilities are reflected in the financial statements as the amount of any additional liability cannot be determined at this time.

On September 27, 2022, A-IR Clinical Research Ltd.

(“A-IR”) filed a claim against the Company in the High Court of Justice, in the Business and Property Courts of England and Wales, seeking £1.6 million in unpaid invoices, plus interest and costs, relating to the Company’s viral challenge study.

The Company is disputing the claim because many of the invoices relate to work that was not performed and A-IR had misrepresented its qualifications to perform the contracted work.

Since this proceeding is at a very early stage, no liability is reflected in the financial statements as the amount of any liability cannot be determined at this time.

On January 30, 2023, Marwood Advisory Group, LLC filed an action in the Supreme Court of New York for the County of New York seeking damages in the amount of $150,000 plus interest in respect of a contract agreed by the sponsors of Petra allegedly relating to a due diligence report with another target considered by Petra prior to the Business Combination.

The Company believes it has defenses to this claim and as of the date of this report no answer is due.

Since this proceeding is at a very early stage, no liability is reflected in the financial statements as the amount of any liability cannot be determined at this time.

Government Regulation

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If we fail to comply with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other regulatory requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale, we may become subject to administrative or judicial sanctions or other legal consequences.

These sanctions or consequences could include, among other things, the FDA’s refusal to approve

pending applications, issuance of clinical holds for ongoing studies, suspension or revocation of approved applications, warning or untitled letters, product withdrawals or recalls, product seizures, relabeling or repackaging, total or partial suspensions of manufacturing or distribution, injunctions, fines, civil penalties or criminal prosecution.

These sanctions or consequences could include, among other things, the FDA’s refusal to approve pending applications, issuance of clinical holds for ongoing studies, suspension or revocation of approved applications, warning or untitled letters, product withdrawals or recalls, product seizures, relabeling or repackaging, total or partial suspensions of manufacturing or distribution, injunctions, fines, civil penalties or criminal prosecution.

Our product candidates must be approved for therapeutic indications by the FDA before they may be marketed in the United States.

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• completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice, or GLP, requirements;

completion of the manufacture, under current Good Manufacturing Practices (“cGMP”), conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing;

• completion of the manufacture, under current Good Manufacturing Practices (“cGMP”), conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing;

• submission to the FDA of an investigational new drug application, or IND, which must become effective before clinical trials may begin and must be updated annually and when certain changes are made;

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• a determination by the FDA within 60 days of its receipt of an NDA to file the application for review;

satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

• satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

• satisfactory completion of FDA audit of the clinical trial sites that generated the data in support of the NDA;

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• FDA review and approval of the NDA, including, where applicable, consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the United States.

Preclinical studies and the IND process —

Preclinical studies and the IND process

Preclinical studies include laboratory evaluation of product chemistry and formulation, as well as in vitro and animal studies to assess the potential for adverse events and in some cases to establish a rationale for therapeutic use.

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Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.

An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical studies and places the study on clinical

In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical study can begin.

As a result, submission of an IND may not necessarily result in the FDA allowing clinical studies to commence.

Clinical studies —

Clinical studies involve the administration of the investigational new drug to human subjects —

healthy volunteers or patients —

under the supervision of qualified investigators in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical study.

Clinical studies

Clinical studies involve the administration of the investigational new drug to human subjects — healthy volunteers or patients — under the supervision of qualified investigators in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical study.

Clinical studies are conducted under written study protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

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The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects.

An IRB may also require the clinical study at the site to be halted, either temporarily or permanently, for failure to comply with the IRB’s requirements, or may impose other conditions.

For clinical studies involving an IND, an IRB must operate in compliance with FDA regulations.

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Furthermore, the FDA or the sponsor may suspend or terminate a clinical study at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical study at its institution if the clinical study is not being conducted in accordance with the IRB’s requirements or if the drug or biologic product has been associated with unexpected serious harm to patients.

Concurrent with clinical studies, the company usually complete additional animal studies, develop additional information about chemistry and physical characteristics of the product candidate, and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements.

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Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

In some cases, the FDA may approve an application for a product candidate but require the sponsor to conduct additional clinical studies to further assess the product candidate’s safety and effectiveness after approval.

Such post-approval studies are typically referred to as Phase 4 clinical studies.

These studies are used to gain additional experience from the treatment of a larger number of patients in the intended treatment group and to further document a clinical benefit in the case of drugs approved under accelerated approval regulations.

Clinical studies —

Clinical studies are almost always required to support pre-market approval and are sometimes required for 510(k) clearance or de novo clearance.

In the United States, for significant risk devices, these studies require submission of an application for an IDE to the FDA.

The IDE application must be supported by appropriate data, such as animal and laboratory testing results, showing it is safe to test the device in humans and that the testing protocol is scientifically sound.

The IDE must be approved in advance by the FDA for a specific number of patients at specified study sites.

During the study, the sponsor must comply with the FDA’s IDE requirements for investigator selection, study monitoring, reporting and recordkeeping.

The investigators must obtain patient informed consent, rigorously follow the investigational plan and study protocol, control the disposition of investigational devices and comply with all reporting and recordkeeping requirements.

Clinical studies for significant risk devices may not begin until the IDE application is approved by the FDA and the appropriate IRBs at the clinical study sites.

An IRB is an appropriately constituted group that has been formally designated to review and monitor medical research involving subjects and which has the authority to approve, require modifications in, or disapprove research to protect the rights, safety, and welfare of human research subjects.

A nonsignificant risk device does not require FDA approval of an IDE;

however, the clinical study must still be conducted in compliance with various requirements of FDA’s IDE regulations and be approved by an IRB at the clinical study sites.

The FDA or the IRB at each site at which a clinical study is being performed may withdraw approval of a clinical study at any time for various reasons, including a belief that the risks to study subjects outweigh the benefits or a failure to comply with FDA or IRB requirements.

Even if a study is completed, the results of clinical testing may not demonstrate the safety and effectiveness of the device, may be equivocal or may otherwise not be sufficient to obtain approval or clearance of the product.

Sponsors of clinical studies of devices are required to register with clinicaltrials.gov, a public database of clinical study information.

Information related to the device, patient population, phase of investigation, study sites and investigators and other aspects of the clinical study is made public as part of the registration.

Marketing approval —

Assuming successful completion of the required clinical testing, the results of the preclinical and clinical studies, together with detailed information relating to the product’s pharmacology chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA or BLA requesting approval to market the product for one or more indications.

FDA approval of the NDA or BLA is required before marketing of the product may begin in the United States.

Under federal law, the submission of most NDAs and BLAs is subject to a substantial application user fee, and the sponsor of an approved NDA or BLA is also subject to annual product or program fees.

Marketing approval

Assuming successful completion of the required clinical testing, the results of the preclinical and clinical studies, together with detailed information relating to the product’s pharmacology chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.

FDA approval of the NDA is required before marketing of the product may begin in the United States.

Under federal law, the submission of most NDAs is subject to a substantial application user fee, and the sponsor of an approved NDA is also subject to annual product or program fees.

These fees may be increased or decreased annually.

The FDA conducts a preliminary review of all NDAs and BLAs within the first 60 days after receipt before accepting them for filing based on the agency’s threshold determination that they are sufficiently complete to permit substantive review.

The FDA may request additional information rather than accept an NDA or BLA for filing.

The FDA conducts a preliminary review of all NDAs within the first 60 days after receipt before accepting them for filing based on the agency’s threshold determination that they are sufficiently complete to permit substantive review.

The FDA may request additional information rather than accept an NDA for filing.

In this event, the application must be resubmitted with the additional information, which would also be subject to review before the FDA accepts it for filing.

Once the submission is accepted for filing, the FDA begins an in-depth substantive review.

The FDA has agreed to specified performance goals in the review of NDAs and BLAs.

The FDA has agreed to specified performance goals in the review of NDAs.

Most such applications for non-priority products are reviewed within ten to twelve months after filing, and most applications for priority review products, that is, drugs and biologics that the FDA determines represent a significant improvement over existing therapy, are reviewed in six to eight months after filing.

The review process may be extended by the FDA for three additional months to consider certain late-submitted information or clarification regarding information already provided in the submission.

and other experts, for review, evaluation and a recommendation as to whether the application should be approved.

The FDA may also refer applications for novel drugs or biological products or products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA or BLA, the FDA typically will inspect the facility or facilities where the product is manufactured.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

In addition, before approving an NDA or BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP and integrity of the clinical data submitted.

In addition, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP and integrity of the clinical data submitted.

The testing and approval process requires substantial time, effort and financial resources, and each may take many years to complete.

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We may encounter difficulties or unanticipated costs in our efforts to develop our product candidates and secure necessary governmental approvals, which could delay or preclude us from marketing our products.

After the FDA’s evaluation of the NDA or BLA and inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter.

After the FDA’s evaluation of the NDA and inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter.

An approval letter authorizes commercial marketing of the drug or biological product with specific prescribing information for specific indications.

A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application.

If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter.

The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.

Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

Even if the FDA approves a product, the agency may limit the approved indications for use for the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions through a Risk Evaluation and Mitigation Strategy or other risk management mechanisms, which can materially affect the potential market and profitability of the product.

The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs.

After approval, some types of changes to the approved product, such as changes in indications, manufacturing changes and labeling, are subject to further testing requirements and FDA review and approval.

FDA’s Pre-market Clearance and Approval Requirements —

In vitro diagnostic tests such as our REVDx-501 diagnostic program is regulated as medical devices.

Each medical device we seek to commercially distribute in the United States will require either a prior 510(k) clearance, de novo classification or PMA, unless it is exempt, or a pre-market approval from the FDA.

In the United States, the FD&C Act, and its implementing regulations, and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance.

Unless an exemption or FDA exercise of enforcement discretion applies, diagnostic tests generally require marketing clearance or approval from the FDA prior to commercialization.

The primary types of FDA marketing authorization applicable to a medical device are clearance of a premarket notification, 510(k), or de novo classification, and approval of a PMA.

To obtain 510(k) clearance for a medical device, or for certain modifications to devices that have received 510(k) clearance, a manufacturer must submit a premarket notification demonstrating that the proposed device is substantially equivalent to a previously cleared 510(k) device or to a pre-amendment device that was in commercial distribution before May 28, 1976, or a predicate device, for which the FDA has not yet called for the submission of a PMA.

In making a determination that the device is substantially equivalent to a predicate device, the FDA compares the proposed device to the predicate device and assesses whether the subject device is comparable to the predicate device with respect to intended use, technology, design and other features which could affect safety and effectiveness.

If the FDA determines that the subject device is substantially equivalent to the predicate device, the subject device

may be cleared for marketing.

The 510(k) premarket notification pathway generally takes from three to twelve months from the date the application is completed, but can take significantly longer.

The de novo classification process, provides a pathway to classify novel medical devices for which general controls alone, or general and special controls, provide reasonable assurance of safety and effectiveness for the intended use, but for which there is no legally marketed predicate device.

A de novo classification is a risk-based classification process through which devices are classified into class I or class II.

Devices classified in response to a de novo classification request may be marketed and used as predicates for future premarket notification 510(k) submissions.

A PMA must be supported by valid scientific evidence, which typically requires extensive data, including technical, preclinical, clinical and manufacturing data, to demonstrate to the FDA’s satisfaction the safety and effectiveness of the device.

For diagnostic tests, a PMA typically includes data regarding analytical and clinical validation studies.

As part of its review of the PMA, the FDA will conduct a pre-approval inspection of the manufacturing facility or facilities to ensure compliance with the quality system regulation, or QSR, which requires manufacturers to follow design, testing, control, documentation and other quality assurance procedures.

The FDA’s review of an initial PMA is required by statute to take between six to ten months, although the process typically takes longer, and may require several years to complete.

If the FDA evaluations of both the PMA and the manufacturing facilities are favorable, the FDA will either issue an approval letter or an approvable letter, which usually contains a number of conditions that must be met in order to secure the final approval of the PMA.

If the FDA’s evaluation of the PMA or manufacturing facilities is not favorable, the FDA will deny the approval of the PMA or issue a not approvable letter.

A not approvable letter will outline the deficiencies in the application and, where practical, will identify what is necessary to make the PMA approvable.

Once granted, PMA approval may be withdrawn by the FDA if compliance with post-approval requirements, conditions of approval or other regulatory standards is not maintained or problems are identified following initial marketing.

We expect that REVDx-501 will be subject to review as a de novo clearance.

A de novo clearance pathway may be a lengthier and a more rigorous process than the 510(k) clearance pathway, which may delay or terminate this program down the road, which could adversely affect our ability to grow our business.

Ongoing Regulation by the FDA —

Even after a device receives clearance or approval and is placed on the market, numerous regulatory requirements apply.

These include:

establishment registration and device listing;

the QSR, which requires manufacturers, including third-party manufacturers, to follow stringent design, testing, control, documentation and other quality assurance procedures during all aspects of the manufacturing process;

labeling regulations and the FDA prohibitions against the promotion of products for uncleared, unapproved or “off-label”

uses, and other requirements related to promotional activities;

medical device reporting regulations, which require that manufactures report to the FDA if their device may have caused or contributed to a death or serious injury, or if their device malfunctioned and the device or a similar device marketed by the manufacturer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur;

corrections and removal reporting regulations, which require that manufactures report to the FDA field corrections or removals if undertaken to reduce a risk to health posed by a device or to remedy a violation of the FD&C Act that may present a risk to health;

post market surveillance regulations, which apply to certain Class II or III devices when necessary to protect the public health or to provide additional safety and effectiveness data for the device.

After a device receives 510(k) clearance or de novo classification, any modification that could significantly affect its safety or effectiveness, or that would constitute a major change in its intended use, will require a new clearance or possibly a pre-market approval.

The FDA requires each manufacturer to make this determination initially, but the FDA can review any such decision and can disagree with a manufacturer’s determination.

If the FDA disagrees with our determination not to seek a new 510(k) clearance, the FDA may retroactively require us to seek 510(k) clearance or possibly a pre-market approval.

The FDA could also require us to cease marketing and distribution and/or recall the modified device until 510(k) clearance or pre-market approval is obtained.

Also, in these circumstances, we may be subject to significant regulatory fines and penalties.

Some changes to an approved PMA device, including changes in indications, labeling or manufacturing processes or facilities, require submission and FDA approval of a new PMA or PMA supplement, as appropriate, before the change can be implemented.

Supplements to a PMA often require the submission of the same type of information required for an original PMA, except that the supplement is generally limited to that information needed to support the proposed change from the device covered by the original PMA.

The FDA uses the same procedures and actions in reviewing PMA supplements as it does in reviewing original PMAs.

FDA regulations require us to register as a medical device manufacturer with the FDA.

Additionally, the CDHS, requires us to register as a medical device manufacturer within the state.

Because of this, the FDA and the CDHS inspect us on a routine basis for compliance with the QSR.

These regulations require that we manufacture our products and maintain related documentation in a prescribed manner with respect to manufacturing, testing and control activities.

We have undergone and expect to continue to undergo regular QSR inspections in connection with the manufacture of our products at our facilities.

Further, the FDA requires us to comply with various FDA regulations regarding labeling.

Failure by us or by our suppliers to comply with applicable regulatory requirements can result in enforcement action by the FDA or state authorities, which may include any of the following sanctions:

warning or untitled letters, fines, injunctions, consent decrees and civil penalties;

customer notifications, voluntary or mandatory recall or seizure of our products;

operating restrictions, partial suspension or total shutdown of production;

delay in processing submissions or applications for new products or modifications to existing products

withdrawing approvals that have already been granted;

criminal prosecution.

The Medical Device Reporting laws and regulations require us to provide information to the FDA when we receive or otherwise become aware of information that reasonably suggests our device may have caused or contributed to a death or serious injury as well as a device malfunction that likely would cause or contribute to death or serious injury if the malfunction were to recur.

In addition, the FDA prohibits an approved device from being marketed for off-label use.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including substantial monetary penalties and criminal prosecution.

Newly discovered or developed safety or effectiveness data may require changes to a product’s labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures.

Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory clearance or approval of our products under development.

We are also subject to other federal, state and local laws and regulations relating to safe working conditions, laboratory and manufacturing practices.

European Union

We anticipate that our products will be regulated in the European Union as medical devices per the European Union Directive (93/42/EEC), also known as the Medical Device Directive.

An authorized third party, Notified Body, must approve products for CE marking.

The CE Mark is contingent upon continued compliance to the applicable regulations and the quality system requirements of the ISO 13485 standard.

Other Regions

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or knowingly making a false statement to improperly avoid, decrease or conceal an obligation to pay money to the federal government.

A claim includes “any request or demand”

for money or property presented to the U.S.

Although we would not submit claims directly to payors, manufacturers can be held liable under these laws if they are deemed to “cause”

the submission of false or fraudulent claims by, for example, providing inaccurate billing or coding information to customers or promoting a product off-label.

In addition, our future activities relating to the reporting of wholesaler or estimated retail prices for our products, the reporting of

prices used to calculate Medicaid rebate information and other information affecting federal, state, and third-party reimbursement for our products, and the sale and marketing of our products, are subject to scrutiny under this law.

A claim includes “any request or demand” for money or property presented to the U.S.

Although we would not submit claims directly to payors, manufacturers can be held liable under these laws if they are deemed to “cause” the submission of false or fraudulent claims by, for example, providing inaccurate billing or coding information to customers or promoting a product off-label.

In addition, our future activities relating to the reporting of wholesaler or estimated retail prices for our products, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state, and third-party reimbursement for our products, and the sale and marketing of our products, are subject to scrutiny under this law.

For example, pharmaceutical companies have been prosecuted under the FCA in connection with their alleged off-label promotion of drugs, purportedly concealing price concessions in the pricing information submitted to the government for government price reporting purposes, and allegedly providing free product to customers with the expectation that the customers would bill federal health care programs for the product.

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HIPAA requires covered entities to limit the use and disclosure of protected health information to specifically authorized situations and requires covered entities to implement security measures to protect health information that they maintain in electronic form.

The federal government may impose civil, criminal, and administrative fines and penalties and/or additional reporting or oversight obligations for a violation of HIPAA’s requirements.

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to business associates that receive or obtain protected health information in connection with providing a service on behalf of a covered entity.

HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorneys’

fees and costs associated with pursuing federal civil actions.

The federal government may impose civil, criminal, and administrative fines and penalties and/or additional reporting or oversight obligations for a violation of HIPAA’s requirements.

In addition to HIPAA and HITECH, many state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways, are often not pre-empted by federal law, and may have a more prohibitive effect than federal law, thus complicating compliance efforts.

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law, certain products not usually self-administered (including injectable drugs) may be eligible for coverage under Medicare through Medicare Part B.

Medicare Part B is the part of Medicare that covers outpatient services and supplies, including certain pharmaceutical products, that are medically necessary to treat a beneficiary’s health condition.

As a condition of receiving Medicare Part B reimbursement for a manufacturer’s eligible drugs, the manufacturer is required to participate in other government healthcare programs, including the Medicaid Drug Rebate Program and the 340B Drug Pricing Program.

The Medicaid Drug Rebate Program requires pharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the Secretary of HHS as a condition for states to receive federal matching funds for the manufacturer’s outpatient drugs furnished to Medicaid patients.

Under the 340B Drug Pricing Program, the manufacturer must extend discounts to entities that participate in the program.

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Penalties may apply in some cases when such metrics are not submitted accurately and timely.

Additionally, the Sunshine Act within the Affordable Care Act, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) report annually to CMS information related to certain payments or other transfers of value made or distributed to physicians and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, the physicians and teaching hospitals and to report annually certain ownership and investment interests held by physicians and their immediate family members.

This information is made publicly available on a CMS website, and failure to report accurately could result in penalties.

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Ensuring business arrangements with third parties comply with applicable healthcare laws and regulations is a costly endeavor.

actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

If our operations are found to be in violation of any of the federal and state healthcare laws described above or any other current or future governmental regulations that apply to us, we may be subject to significant penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, imprisonment, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

Coverage, Pricing and Reimbursement

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Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which therapeutics they will pay for and establish reimbursement levels.

Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a therapeutic is:

• a covered benefit under its health plan;

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Obtaining coverage and reimbursement approval of a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide to each payor supporting scientific, clinical and cost-effectiveness data for the use of our product on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained.

A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.

Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage for the product.

A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.

Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage for the product.

Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.

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Healthcare Reform

approval of product candidates, restrict or regulate post-approval activities, and affect the ability to profitably sell product candidates for which marketing approval is obtained.

In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities, and affect the ability to profitably sell product candidates for which marketing approval is obtained.

Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access.

In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives.

For example, the Affordable Care Act has substantially changed healthcare financing and delivery by both governmental and private insurers.

The Affordable Care Act and its implementing regulations, among other things, revised the methodology for calculating rebates for covered outpatient drugs and certain biologics owed by manufacturers to the state and federal government under the Medicaid Drug Rebate Program, increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program, extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations, subjected manufacturers to new annual fees and taxes for certain branded prescription drugs, and expanded programs designed to test innovative payment models, service delivery models, or value-based arrangements, and fund comparative effectiveness research.

Some of the provisions of the Affordable Care Act have yet to be implemented, and there have been legal and political challenges to certain aspects of the Affordable Care Act.

We anticipate that the Affordable Care Act, if substantially maintained in its current form, will continue to result in additional downward pressure on coverage and the price that we receive for any approved product, and could seriously harm our business.

For example, Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the ACA, has substantially changed healthcare financing and delivery by both governmental and private insurers.

Among the ACA provisions of importance to the pharmaceutical and biotechnology industries, in addition to those otherwise described above, are the following:

• an annual, nondeductible fee on any entity that manufactures or imports certain specified branded prescription drugs and biologic agents apportioned among these entities according to their market share in some government healthcare programs that began in 2011;

• an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program, retroactive to January 1, 2010, to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively, and capped the total rebate amount for innovator drugs at 100% of the Average Manufacturer Price, or AMP;

• a Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts, which through subsequent legislative amendments, will be increased to 70%, starting in 2019, off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

• extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

• expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals beginning in 2014 and by adding new mandatory eligibility categories for individuals with income at or below 133% of the federal poverty level, thereby potentially increasing manufacturers’ Medicaid rebate liability;

• expansion of the entities eligible for discounts under the 340B Drug Discount Program;

• a Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;

• expansion of healthcare fraud and abuse laws, including the FCA and the Anti-Kickback Statute, new government investigative powers, and enhanced penalties for noncompliance;

• a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted, or injected;

• a requirement to annually report certain information regarding drug samples that manufacturers and distributors provide to physicians;

• establishment of a Center for Medicare and Medicaid Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending that began on January 1, 2011;

• a licensure framework for follow on biologic products.

Since its enactment, there have been executive, legal and Congressional challenges to certain aspects of the ACA.

On June 17, 2021 the U.S.

Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.

Further, prior to the U.S.

Supreme Court ruling, President Biden issued an executive order that initiated a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental authorities to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

On August 16, 2022, President Biden signed the Inflation Reduction Act of 2022, or IRA, into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and through a newly established manufacturer discount program.

It is unclear how other healthcare reform measures, if any, will impact our business.

Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payors.

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Such reforms could have an adverse effect on anticipated revenue from product candidates that we may successfully develop and for which we may obtain regulatory approval and may affect our overall financial condition and ability to develop product candidates.

In addition, further legislation or regulation could be passed that could harm our business, financial condition and results of operations.

Other legislative changes have been proposed and adopted since the Affordable Care Act was enacted.

For example, in August 2011, President Obama signed into law the Budget Control Act of 2011, which, among other things, created the Joint Select Committee on Deficit Reduction to recommend to Congress proposals in spending reductions.

The Joint Select Committee on Deficit Reduction did not achieve a targeted deficit reduction of at least $1.2 trillion for fiscal years 2012 through 2021, triggering the legislation’s automatic reduction to several government programs.

This includes aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect beginning on April 1, 2013 and will stay in effect through 2027 unless additional Congressional action is taken.

In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Additionally, there has been increasing legislative and enforcement interest in the United States with respect to specialty drug pricing practices.

Specifically, there have been several recent U.S.

Congressional inquiries and proposed federal legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

For example, after some pharmacy benefit managers and insurers adopted policies stating that the amount of a copay coupon would not be applied to the enrollee’s deductible or out-of-pocket maximum (referred to as “accumulator adjustment programs”), some states passed legislation banning these policies.

Based on a rule that will take effect in the 2020 plan year, CMS will allow accumulator adjustment programs only when used for a branded drug that has a generic equivalent.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our product candidates, if approved.

Future legislation or regulation

Other legislative changes have been adopted since the Affordable Care Act was enacted.

The Coronavirus Aid, Relief and Economic Security Act, or CARES Act, which was signed into law in March 2020 and was designed to provide financial support and resources to individuals and businesses affected by the COVID-19 pandemic, suspended the 2% reductions from May 1, 2020 through December 31, 2020, and extended the sequester by one year, through 2030.

Further legislation or regulation could be passed that could harm our business, results of operations and financial condition.

Other legislative changes have been proposed and adopted since the ACA was enacted.

For example, in August 2011, the Budget Control Act of 2011 was signed into law, which, among other things, included aggregate reductions to Medicare payments to providers, which went into effect beginning on April 1, 2013 and, due to subsequent legislative amendments, will stay in effect through 2032.

More recently, on May 30, 2018, the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017, or the Right to Try Act, was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase I clinical trial and that are undergoing investigation for FDA approval.

Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

There is no obligation for a pharmaceutical manufacturer to make its product candidates available to eligible patients as a result of the Right to Try Act.

Additionally, there has been increasing legislative and enforcement interest in the United States with respect to specialty drug pricing practices.

Specifically, there have been several recent U.S.

Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

For example, the IRA, among other things, (1) directs HHS to negotiate the price of certain single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions took effect progressively in fiscal year 2023, although they may be subject to legal challenges.

The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

HHS has and will continue to issue and update guidance as these programs are implemented.

It is currently unclear how the IRA will be implemented but it is likely to have a significant effect on the pharmaceutical industry.

Further, in response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Based on a rule that will take effect in the 2020 plan year, CMS will allow accumulator adjustment programs only when used for a branded drug that has a generic equivalent.

We expect additional state, federal and foreign healthcare reform measures to be adopted in the future, any of which could limit the amounts that federal, state and foreign governments will pay for health products, which could result in reduced demand for our products, if approved or additional pricing pressure.

For instance, in December 2021, the EU Regulation No 2021/2282 on Health Technology Assessment, or HTA, amending Directive 2011/24/EU, was adopted.

While the Regulation entered into force in January 2022, it will only begin to apply from January 2025 onwards, with preparatory and implementation-related steps to take place in the interim.

Once the Regulation becomes applicable, it will have a phased implementation depending on the concerned products.

This regulation is intended to boost cooperation among EU member states in assessing health technologies, including new medicinal products, as well as certain high-risk medical devices, and providing the basis for cooperation at the EU level for joint clinical assessments in these areas.

The regulation will permit EU member states to use common HTA tools, methodologies, and procedures across the EU, working together in four main areas, including joint clinical assessment of the innovative health technologies with the most potential impact for patients, joint scientific consultations whereby developers can seek advice from HTA authorities, identification of emerging health technologies to identify promising technologies early, and continuing voluntary cooperation in other areas.

Individual EU member states will continue to be responsible for assessing non-clinical (e.g., economic, social, ethical) aspects of health technologies, and making decisions on pricing and reimbursement.

Additional Regulation

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Government Regulation and Product Approval

post-approval monitoring and reporting, import and export of pharmaceutical products, biological products and medical devices, such as those we are developing.

Government authorities in the United States, at the federal, state and local level, and in other countries extensively regulate, among other things, the research, development, testing, manufacture, including any manufacturing changes, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, import and export of pharmaceutical products, biological products and medical devices, such as those we are developing.

Disclosure of clinical study information

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These programs include Fast Track designation, Breakthrough Therapy designation, Priority Review and Accelerated Approval.

These programs can significantly reduce the time it takes for the FDA to review a BLA or NDA, but they do not guarantee that a product will receive FDA approval.

These programs can significantly reduce the time it takes for the FDA to review a NDA, but they do not guarantee that a product will receive FDA approval.

Even if a product qualifies initially, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review will not be shortened.

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Products are eligible for accelerated approval if they can be shown to have an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or an effect on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality which is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatment.

Accelerated approval is usually contingent on a sponsor’s agreement to conduct additional post-approval studies to verify and describe the product’s clinical benefit.

In addition, unless otherwise informed by the FDA, the FDA currently requires, as a condition for accelerated approval, that all advertising and promotional materials that are intended for dissemination or publication be submitted to FDA for review before the initial dissemination or publication.

Under the Orphan Drug Act, the FDA may grant orphan drug designation to drugs or biologics intended to treat a rare disease or condition, which is generally defined as a disease or condition that affects fewer than 200,000 individuals in the United States.

Orphan drug designation must be requested before submitting an NDA or BLA.

Orphan drug designation must be requested before submitting an NDA.

After the FDA grants orphan drug designation, the generic identity of the drug or biologic and its potential orphan use are disclosed publicly by the FDA.

Orphan drug designation is taken into consideration but generally does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The first NDA or BLA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing period in the United States for that product, for that indication.

The first NDA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing period in the United States for that product, for that indication.

During the seven-year exclusivity period, the FDA may not approve any other applications to market the same drug or biologic for the same orphan indication, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity in that it is shown to be safer, more effective or makes a major contribution to patient care.

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Orphan drug exclusivity does not prevent the FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition.

Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the NDA or BLA application user fee.

Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the NDA application user fee.

Pediatric information and exclusivity

Under the Pediatric Research Equity Act of 2003, an NDA, BLA or supplement to an NDA or BLA must contain data from pediatric studies that are adequate to assess the safety and effectiveness of the drug or biological product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

Under the Pediatric Research Equity Act of 2003, an NDA or supplement to an NDA must contain data from pediatric studies that are adequate to assess the safety and effectiveness of the drug or biological product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

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The data do not need to show the product to be effective in the pediatric population studied;

rather, if the clinical study is deemed to fairly respond to the FDA’s request, the additional protection is granted.

The Hatch-Waxman Act

Abbreviated new drug applications

In seeking approval for a drug through an NDA, applicants are required to list with the FDA each patent that claims to cover the applicant’s product.

Upon approval of a drug, each of the patents listed in the application for the drug is then published in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book.

In seeking approval for a drug through an NDA, applicants are required to list with the FDA each patent that claims to cover the applicant’s product.

Drugs listed in the Orange Book can, in turn, be cited by potential competitors in support of approval of an ANDA.

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Other than the requirement for bioequivalence testing, ANDA applicants are not required to conduct or submit results of preclinical or clinical tests to prove the safety or effectiveness of their drug product.

Drugs approved in this way are commonly referred to as “generic equivalents”

to the listed drug and can often be substituted by pharmacists under prescriptions written for the original listed drug.

The ANDA applicant is required to certify to the FDA concerning any patents listed for the approved product in the FDA’s Orange Book.

Drugs approved in this way are commonly referred to as “generic equivalents” to the listed drug and can often be substituted by pharmacists under prescriptions written for the original listed drug.

The ANDA applicant is required to certify to the FDA concerning any patents listed for the approved product in the FDA’s Orange Book.

Specifically, the applicant must certify that:

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• the listed patent is invalid or will not be infringed by the new product.

A certification that the new product will not infringe the already approved product’s listed patents or that such patents are invalid is called a Paragraph IV certification.

If the ANDA applicant does not challenge the listed patents, the ANDA will not be approved until all the listed patents claiming the referenced product have expired.

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Federal law provides for a period of three years of exclusivity following approval of a listed drug that contains previously approved active ingredients but is approved in a new dosage form, route of administration or combination, or for a new use, the approval of which was required to be supported by new clinical studies conducted by or for the sponsor, during which the FDA cannot grant effective approval of an ANDA based on that listed drug.

The FDA must establish a priority review track for certain generic drugs, requiring the FDA to review a drug application within eight months for a drug that has three or fewer approved drugs listed in the Orange Book and is no longer protected by any patent or regulatory exclusivities, or is on the FDA’s drug shortage list.

The FDA must also expedite review of “competitor generic therapies”

or drugs with inadequate generic competition, including holding meetings with or providing advice to the drug sponsor prior to submission of the application.

The FDA must also expedite review of “competitor generic therapies” or drugs with inadequate generic competition, including holding meetings with or providing advice to the drug sponsor prior to submission of the application.

Patent term extension

After NDA approval, owners of relevant drug patents may apply for up to a five year patent term extension.

The allowable patent term extension is calculated as half of the drug’s testing phase, based on the time between IND application and submission of the NDA, and all of the review phase, based on the time between the NDA submission and approval up to a maximum of five years.

The time can be shortened if the FDA determines that the applicant did not pursue approval with due diligence.

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Most drug products obtain FDA marketing approval pursuant to an NDA or an ANDA.

A third alternative is a special type of NDA, commonly referred to as a Section 505(b)(2) NDA, which enables the applicant to rely, in part, on the FDA’s previous approval of a similar product, or published literature, in support of its application.

Section 505(b)(2) NDAs often provide an alternate path to FDA approval for new or improved formulations or new uses of previously approved products.

Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.

If the Section 505(b)(2) applicant can establish that reliance on the FDA’s previous approval is scientifically appropriate, it may eliminate the need to conduct certain preclinical or clinical studies of the new product.

The FDA may also require companies to perform additional studies or measurements to support the change from the approved product.

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After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.

There also are continuing user fee requirements, under which FDA assesses an annual program fee for each product identified in an approved BLA or NDA.

There also are continuing user fee requirements, under which FDA assesses an annual program fee for each product identified in an approved NDA.

Biologic manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.

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Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties.

Physicians may prescribe legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA.

Such off-label uses are common across medical specialties.

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The FDA does not regulate the behavior of physicians in their choice of treatments.

The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

Biosimilars and Reference Product Exclusivity

The Patient Protection and Affordable Care Act, as amended by the Affordable Care Act, signed into law in 2010, includes a subtitle called the BPCIA, which created an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-approved reference biological product.

To date, a number of biosimilars have been licensed under the BPCIA, and numerous biosimilars have been approved in Europe.

The FDA has issued several guidance documents outlining an approach to review and approval of biosimilars.

Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical study or studies.

Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

Complexities associated with the larger, and often more complex, structures of biological products, as well as the processes by which such products are manufactured, pose significant hurdles to implementation of the abbreviated approval pathway that are still being worked out by the FDA.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA.

In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed.

During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well-controlled clinical studies to demonstrate the safety, purity and potency of its product.

The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products.

At this juncture, it is unclear whether products deemed “interchangeable”

by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.

The BPCIA is complex and continues to be interpreted and implemented by the FDA.

In addition, recent government proposals have sought to reduce the 12-year reference product exclusivity period.

Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation.

As a result, the ultimate impact, implementation, and impact of the BPCIA is subject to significant uncertainty.

The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

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

What changed 10-K

Item 1. Business