Item 1A. Risk Factors 32

Item 1B. Unresolved Staff Comments 64

Item 2. Property 64

Item 3. Legal Proceedings 64

Item 4. Mine Safety Disclosures 64

PART II

Item 6. [Reserved] 65

Item 7A. Quantitative and Qualitative Disclosure About Market Risk 81

Item 8. Financial Statements and Supplementary Data 81

Item 9A. Controls and Procedures 82

Item 9B. Other Information 82

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 82

PART III

Item 10. Directors, Executive Officers, and Corporate Governance 83

Item 11. Executive Compensation 83

Item 14. Principal Accountant Fees and Services 83

PART IV

Item 15. Exhibits and Financial Statement Schedules 84

FORWARD-LOOKING

STATEMENTS

This

Annual Report on Form 10-K of PAVmed Inc. (“we”, “us”, “our” or “PAVmed” or the “Company”)

contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical

facts, contained in this Annual Report on Form 10-K (this “Form 10-K”), including statements regarding our future results

of operations and financial position, business strategy and plans and objectives of management for future operations, are forward-looking

statements. The words “may,” “will,” “should,” “expects,” “plans,” “anticipates,”

“could,” “intends,” “target,” “projects,” “contemplates,” “believes,”

“estimates,” “predicts,” “potential” or “continue” or the negative of these terms or

other similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these

identifying words. Forward-looking statements are not guarantees of future performance and the Company’s actual results may differ

significantly from the results discussed in the forward-looking statements. Factors that might cause such differences include, but are

not limited to, those discussed in Item 1A of Part I of this Form 10-K under the heading “Risk Factors,” which are incorporated

herein by reference.

Important

factors that may affect our actual results include:

● our limited operating history;

● our financial performance, including our ability to generate revenue;

● our ability of our products to achieve market acceptance;

● our potential ability to obtain additional financing when and if needed;

● our ability to protect our intellectual property;

● our ability to complete strategic acquisitions;

● our ability to manage growth and integrate acquired operations;

● the potential liquidity and trading of our securities;

● regulatory and operational risks;

● cybersecurity risks;

● risks related to SARS-CoV-2 /COVID-19 pandemic;

● the impact of the material weakness identified by our management;

addition, our forward-looking statements do not reflect the potential impact of any future financings, acquisitions, mergers, dispositions,

joint ventures or investments we may make.

may not actually achieve the plans, intentions, and /or expectations disclosed in our forward-looking statements, and you should not

place undue reliance on our forward-looking statements. You should read this Annual Report on Form 10-K and the documents we have filed

as exhibits to this Annual Report on Form 10-K completely and with the understanding our actual future results may be materially different

from what we expect. We do not assume any obligation to update any forward-looking statements, whether as a result of new information,

future events or otherwise, except as required by applicable law.

PART

Item

1. Business

Background

and Overview

PAVmed

is a highly differentiated, multi-product, commercial-stage medical technology company organized to advance a broad pipeline of innovative

medical technologies from concept to commercialization, employing a business model focused on capital efficiency and speed to market.

From inception on June 26, 2014, thru 2020, the Company’s activities were technology-focused on advancing its lead products towards

regulatory approval and pre-commercialization, protecting its intellectual property, and building its corporate infrastructure and management

team. Beginning in 2020 through 2021 our activities and efforts are best described as transition years focused mainly on infrastructure

expansion including personnel, systems, and facilities. Additionally, the focus increasingly involved building out the commercial foundation

including reimbursement with CMS and private payor engagement, sales operations, clinical services and Lucid Test Centers. For the years

2022 and beyond, the central focus will be predominantly on commercial expansion and execution including the acceleration of EsoGuard

commercialization and the transition of NextFlo, EsoCure, Veris, and the next generation of CarpX from pre-commercial activities to commercial

adoption.

The

Company operates in one segment as a medical device company with four operating divisions which include Medical Devices, Diagnostics,

Digital Health, and Emerging Innovations. As resources permit, we will continue to explore internal and external innovations that fulfill

our project selection criteria without limiting ourselves to any target specialty or condition. In addition to activities ongoing at

the parent company level, the Company also has ongoing operations conducted in three majority owned subsidiaries: Lucid Diagnostics,

Inc. (“Lucid Diagnostics” or “LUCID”) incorporated in May 2018, Veris Health, Inc. (“Veris”) founded

in May 2021 with the acquisition of Oncodisc, Inc and its digital health technologies, and Solys Diagnostics, Inc. (“Solys Diagnostics”

or “SOLYS”) incorporated in October 2019.

October 14, 2021, Lucid Diagnostics completed an initial public offering (“IPO”) of its common stock under an effective

registration statement on Form S-1 (SEC File No. 333-259721), wherein a total of 5.0 million IPO shares of common stock of Lucid Diagnostics

Inc. were issued, with such total IPO shares inclusive of 571,428 shares issued to PAVmed Inc., at an IPO offering price of $14.00 per

share, resulting in gross proceeds to Lucid Diagnostics Inc. of $70.0 million, before underwriting fees of $4.9 million,

and approximately $0.7 million of offering costs incurred by Lucid Diagnostics Inc.

PAVmed

Inc. and its subsidiaries have proprietary rights to the trademarks used herein, including, among others, PAVmedTM, Lucid DiagnosticsTM,

LUCIDTM, Veris HealthTM, VERISTM, OncodiscTM, Solys DiagnosticsTM, SOLYSTM, CaldusTM, CarpX®,

DisappEARTM, EsoCheck®, EsoGuard®, EsoCheck Cell Collection Device®, EsoCure Esophageal Ablation DeviceTM, NextCathTM,

NextFloTM, PortIOTM, and “Innovating at the Speed of Life”TM. Solely as a matter of convenience, trademarks

and trade names referred to herein may or may not be accompanied with the requisite marks of “TM” or “®”.

However, the absence of such marks is not intended to indicate, in any way, PAVmed Inc. or its subsidiaries will not assert, to the fullest

extent possible under applicable law, their respective rights to such trademarks and trade names.

Our

multiple products are in various phases of development, regulatory clearances, approvals, and commercialization, including:

discussed herein below, our current lines-of-business are as follows:

Diagnostics

EsoGuard,

EsoCheck, and EsoCure

EsoGuard

and EsoCheck are based on patented technology licensed from Case Western Reserve University (“CWRU”) through our majority-owned

subsidiary, Lucid. EsoGuard and EsoCheck have been developed to provide an accurate, non-invasive, patient-friendly screening test for

the early detection of adenocarcinoma of the esophagus (“EAC”) and Barrett’s Esophagus (“BE”), including

dysplastic BE and related pre-cursors to EAC in patients with chronic gastroesophageal reflux (“GERD”).

EsoGuard

is a bisulfite-converted next-generation sequencing (NGS) DNA assay performed on surface esophageal cells collected with EsoCheck. It

quantifies methylation at 31 sites on two genes, Vimentin (VIM) and Cyclin A1 (CCNA1). The assay was evaluated in a 408-patient multicenter

case-control study published in Science Translational Medicine and showed greater than 90% sensitivity and specificity at detecting esophageal

precancer and all conditions along the BE-EAC spectrum, including on samples collected with EsoCheck (Moinova, et al. Sci Transl Med.

2018 Jan 17;10(424): eaao5848). EsoGuard is commercially available in the U.S. as a Laboratory Developed Test (LDT) performed at our

CLIA-certified laboratory partner, ResearchDx Inc. (“RDx”), which does business as “PacificDx”. Cell samples,

including those collected with EsoCheck, as discussed below, are sent to RDx, for testing and analyses using our proprietary EsoGuard

NGS DNA assay.

EsoCheck

is an FDA 510(k) and CE Mark cleared noninvasive swallowable balloon capsule catheter device capable of sampling surface esophageal cells

in a less than five-minute office. It consists of a vitamin pill-sized rigid plastic capsule tethered to a thin silicone catheter from

which a soft silicone balloon with textured ridges emerges to gently swab surface esophageal cells. When vacuum suction is applied, the

balloon and sampled cells are pulled into the capsule, protecting them from contamination and dilution by cells outside of the targeted

region during device withdrawal. We believe this proprietary Collect+ProtectTM technology makes EsoCheck the only noninvasive esophageal

cell collection device capable of such anatomically targeted and protected sampling.

December 2019, we secured “gapfill” determination for the EsoGuard PLA code 0114U through the United States Department of

Health and Human Services (“HHS”) Centers for Medicare and Medicaid Services (“CMS”) Clinical Laboratory Fee

Schedule (“CLFS”) process, which has allowed us to engage directly with Medicare contractor Palmetto GBA, LLC and its MolDx

Program on CMS payment and coverage. In October 2020, CMS granted EsoGuard final Medicare payment determination of $1,938.01, effective

January 1, 2021. We are still awaiting Medicare local coverage determination from MolDx, which we understand is working to clear a significant

backlog of reviews.

are also aggressively pursuing EsoGuard U.S. private payor payment and coverage. We recently held our initial advisory board meetings

with medical directors of major insurers to obtain feedback and guidance on the type of clinical data that will be helpful in securing

payment and coverage. Although the claim cycle can be prolonged during the early commercialization of a new test, PacificDx is starting

to receive out-of-network private insurance payments on our behalf.

Our

initial EsoGuard commercialization efforts focused on gastroenterology (GI) physicians who have generally embraced our message that EsoGuard

has the potential to expand the funnel of BE-EAC patients who will need long term EGD surveillance and, potentially, treatment with endoscopic

esophageal ablation. We have previously relied upon a hybrid sales model with full-time sales management and approximately fifty independent

sales representatives. We significantly expanded our full-time commercial team in 2021 and are actively recruiting full-time territory

managers and sales representatives nationwide. Our Lucid Vice President of Sales and three Area Sales Directors (“ASD”) oversee

a growing number of Sales Representatives, Market Development Mangers (“MDM”) and Clinical Specialists. EsoGuard testing

has accelerated as pandemic-related healthcare facility limitations have eased.

Our

EsoGuard commercialization efforts span multiple channels including targeting primary care physicians and consumers in addition to GI

physicians. To assure sufficient testing capacity and geographic coverage, as part of this expansion, we are building our own network

of Lucid Test Centers, staffed by Lucid-employed clinical personnel, where patients can undergo the EsoCheck procedure and have the sample

sent for EsoGuard testing, starting with three test centers launched in the Phoenix metropolitan area. We have expanded our test centers

to include Salt Lake City, Utah, Henderson, Nevada, and Denver, Colorado. We are currently expanding into Portland, Oregon, Seattle,

Washington, and Boise, Idaho.

have also established an EsoGuard Telemedicine Program, in partnership with UpScript, LLC, an independent third-party telemedicine provider,

that accommodates EsoGuard self-referrals from direct-to-consumer marketing.

Our

active clinical research and development program seeks to expand the clinical evidence of our products’ efficacy to support our

ongoing regulatory, reimbursement and commercial efforts, including an FDA PMA submission for approval of EsoGuard and EsoCheck as an

in vitro diagnostics (“IVD”) device, as currently, EsoGuard and EsoCheck are permitted to be marketed separately,

but not in combination. We are actively enrolling patients in two international multicenter clinical trials to support FDA PMA approval

of EsoGuard, used with EsoCheck, as an IVD indicated to detect NDBE. ESOGUARD-BE-1 is a screening study which will enroll approximately

500 to 900 male GERD patients over 50 years of age with one other risk factor. ESOGUARD-BE-2 is a case control study which will enroll

approximately 500 male GERD patients with a previous diagnosis of NDBE, LGD, HGD, or EAC, along with normal controls.

February 2020, we received FDA “Breakthrough Device Designation” for EsoGuard as an in-vitro diagnostic medical device (“IVD”).

The FDA Breakthrough Device Program was created to offer patients more timely access to breakthrough technologies which provide for more

effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions by expediting their development,

assessment and review through enhanced communications and more efficient and flexible clinical study design, including more favorable

pre/post market data collection balance. The Centers for Medicare and Medicaid Services and the United States Congress continue to work

to provide an expedited coverage pathway for emerging technologies.

have received ISO 13485:2016 certification for Lucid’s quality management system and received CE Mark certification for EsoCheck

in May 2021 which allows it to be marketed in CE Mark European countries, which include the European Economic Area (the EU, Norway, Iceland,

and Lichtenstein), Switzerland, and, until July 1, 2023, the United Kingdom. In June 2021, we completed the European Directive 98/79/EC

for In-Vitro Diagnostic Medical Devices (“IVDD”) CE Mark certification for EsoGuard after Lucid and its European Union (“EU”)

authorized representative completed the Commission of the European Union (“EC”) declaration of conformity procedure, including

the associated technical documentation, ensuring and declaring EsoGuard meets the essential requirements of the IVDD.

EsoCure

is in development as an Esophageal Ablation Device, with the intent to allow a clinician to treat dysplastic BE before it can progress

to EAC, a highly lethal esophageal cancer, and to do so without the need for complex and expensive capital equipment. We have successfully

completed a pre-clinical feasibility animal study of EsoCure demonstrating excellent, controlled circumferential ablation of the esophageal

mucosal lining. We have also completed an acute and survival animal study of EsoCureTM Esophageal Ablation Device, demonstrating

successful direct thermal balloon catheter ablation of esophageal lining through working channel of standard endoscope. We plan to conduct

additional development work and animal testing of EsoCure to support a future FDA 510(k) submission.

March 2022, both the PAVmed and Lucid board of directors have approved entering into an intercompany license between PAVmed and Lucid

such that Lucid will be granted the rights to commercialize EsoCure for the treating dysplastic Barrett’s Esophagus, including

a royalty arrangement whereby Lucid will pay PAVmed a 5% royalty on all EsoCure sales up to $100 million per calendar year, and 8% above

that threshold. Lucid will obligated to fund ongoing development costs and cumulative patent expenses. EsoCure will become part of an

integrated suite of Lucid products addressing BE-EAC. Furthermore, should PAVmed acquire businesses or commercial products or develop

technologies that may be partially or wholly synergistic with Lucid’s lead products and therefore provide the opportunity to create

value, Lucid may also seek to negotiate an arms-length commercial license from PAVmed to market the relevant commercial products that

may originate from PAVmed’s development or acquisition initiatives. To that end, In March 2022, both the PAVmed and Lucid board

of directors have approved entering into a purchase and sale of the CapNostics, LLC assets from PAVmed to Lucid as well as transferring

the consulting agreement with the previous principal owner of CapNostics, LLC. The transfer price is $2.1 million

for the assets, the same purchase price paid by PAVmed’s subsidiary.

Medical

Devices

CarpX

is a minimally invasive surgical device for use in the treatment of carpal tunnel syndrome which received FDA 510(k) marketing clearance

in April 2020, with the first commercial procedure successfully performed in December 2020. After an initial slowdown in commercialization

related to COVID, more recently we have recruited new sales leadership and have recently trained eight new surgeons to perform the CarpX

procedure with four more scheduled to undergo training in the coming months. Our limited-release commercialization efforts thru 2022

are focused on engaging key opinion hand surgeons designed to solicit input for ergonomic improvements to the device, procedure development

and surgical-time optimization, and ease of use. Concurrently, we are presently working on improvements to the device that will released

in stages over the next several quarters.

believe CarpX is designed to allow the physician to relieve the compression on the median nerve without an open incision or the need

for endoscopic or other imaging equipment. To use CarpX, the operator first advances a guidewire through the carpal tunnel under the

ligament, and then advanced over the wire and positioned in the carpal tunnel under ultrasonic and/or fluoroscopic guidance. When the

CarpX balloon is inflated it creates tension in the ligament positioning the cutting electrodes underneath it and creates space within

the tunnel, providing anatomic separation between the target ligament and critical structures such as the median nerve. Radiofrequency

energy is briefly delivered to the electrodes, rapidly cutting the ligament, and relieving the pressure on the nerve. We believe CarpX

will be significantly less invasive than existing treatments.

presently have a National Sales Director, one Sales Representative, and one Clinical Specialist that are overseeing our CarpX commercial

efforts. As we broaden adoption of the device beyond key opinion leaders. we intend to commercialize CarpX through a network of independent

U.S. sales representatives and/or inventory stocking medical distributors together with our in-house sales management and marketing teams.

Our focus on CarpX, and other high margin products and services, is particularly suitable to this mode of distribution. A high gross

margin allows us to properly incentivize our distributors, which in turn allows us to attract the top distributors with the most robust

networks in our targeted specialties. Independent distributors play an even larger role in many parts of Europe, most of Asia and emerging

markets worldwide.

may also choose to enter into distribution agreements with larger strategic partners whereby we take full responsibility for the manufacturing

of CarpX but outsource some or all of its distribution to a partner, particularly outside the United States, with its own robust distribution

channels.

have received ISO 13485:2016 certification for PAVmed’s quality management system and received CE Mark certification for CarpX

in May 2021 which allows it to be marketed in CE Mark European countries, which include the European Economic Area (the EU, Norway, Iceland,

and Lichtenstein), Switzerland, and, until July 1, 2023, the United Kingdom.

PortIO

is a novel, patented, implantable, intraosseous vascular access device which does not require accessing the central venous system and

does not have an indwelling intravascular component. It is designed to be highly resistant to occlusion and may not require regular flushing.

It features simplified, near-percutaneous insertion and removal, without the need for surgical dissection or radiographic confirmation.

It provides a near limitless number of potential access sites and can be used in patients with chronic total occlusion of their central

veins. The absence of an intravascular component will likely result in a very low infection rate.

Based

on encouraging animal data, we have initiated a long-term (60-day implant duration) first-in-human clinical study in dialysis patients

or those with poor venous access in Colombia, South America and intend to fulfill the likely FDA request for human clinical data with

a clinical safety study in the U.S. following FDA clearance of our Investigational Device Exemption (“IDE”) submission to

begin clinical testing in dialysis patients to support a future de novo regulatory submission. In March of 2022, the First-In-Human implantations

of PortIO devices were successfully performed at the Clinica Porto Azul in Barranquilla, Colombia.

NextFlo

is a patented, disposable, and highly accurate infusion platform technology including intravenous (“IV”) infusion sets and

disposable infusion pumps designed to eliminate the need for complex and expensive electronic infusion pumps for most of the estimated

one million infusions of fluids, medications and other substances delivered each day in hospitals and outpatient settings in the U.S.

NextFlo is designed to deliver highly accurate gravity-driven infusions independent of the height of the IV bag. It maintains constant

flow by incorporating a proprietary, passive, pressure-dependent variable flow-resistor consisting entirely of inexpensive, easy-to-manufacture

disposable mechanical parts. NextFlo testing has demonstrated constant flow rates across a wide range of IV bag heights, with accuracy

rates comparable to electronic infusion pumps.

may seek a long-term strategic partnership or acquiror with respect to NextFlo, as we continue to have periodic discussions continue

with large strategic partners to license the NextFlo technology for disposable infusion pumps. Notwithstanding, we continue to advance

the technology towards self-commercialization. We have initiated design freeze verification testing in preparation for final verification

and validation testing of NextFlo IV Infusion Set, to support FDA 510(k) submission and clearance targeted for the second half of 2022.

recently hired a director of sales who will focus on all aspects of NextFlo’s commercial launch including and not limited to creating

and executing the sales strategy, hiring/mentoring the commercial launch team, and collaborating with internal resources on product development

and marketing. Target customers include Acute Inpatient Care, Outpatient Care, Infusion Centers, Home Infusions, Outpatient Pharmacy,

EMS, and the Department of Defense.

Digital

Health

Veris

May 2021, we formed Veris Health, which is our newest majority majority-owned subsidiary, focused on digital health technology. In connection

with its formation, Veris Health acquired Oncodisc, a digital health company with groundbreaking tools to improve personalized cancer

care through remote patient monitoring.

Oncodisc

was founded by experienced physician entrepreneurs, James Mitchell, M.D., who joins Veris Health as its full-time Chief Medical Officer,

and Andrew Thoreson, M.D., who will serve as a Veris Health consultant. Oncodisc’s core technologies include the first intelligent

implantable vascular access port with biologic sensors and wireless communication, combined with an oncologist-designed remote digital

healthcare platform that provides patients and physicians with new tools to improve outcomes and optimize the delivery of cost-effective

care through remote monitoring and data analytics.

Oncodisc

was founded in 2018 by Mitchell, a radiation oncologist, and Thoreson, an interventional radiologist, who previously co-founded Redsmith,

Inc., an interventional catheter company whose technology was acquired by C.R. Bard Inc., now BD Inc. (NYSE: BDX). Oncodisc received

a National Science Foundation (“NSF”) Small Business Innovation Research (“SBIR”) grant award to support its

early work and completed both the MedTech Innovator Accelerator and UCSF Rosenman Institute Accelerator programs.

Its

groundbreaking vascular access port contains biologic sensors capable of generating continuous data on key physiologic parameters known

to predict adverse outcomes in cancer patients undergoing treatment. Wireless communication to the patient’s smartphone and its

cloud-based digital healthcare platform efficiently and effectively delivers actionable real time data to patients and physicians. The

technologies are the subject of multiple patent applications and one issued patent.

The

planned Veris Health business model seeks to generate 100% recurring revenue through oncology practice and hospital-based subscriptions.

These entities would purchase seats on the platform and pay a monthly remote monitoring charge to drive revenues from remote patient

monitoring and device implantation under existing CPT codes, as well as established CMS Oncology Care Model (OCM) bonuses and CMS Quality

Reporting Program incentives. Veris Health also anticipates strong demand for its intelligent implantable vascular access port and remote

monitoring platform from oncology biotherapeutic companies to support clinical trials of their novel immunotherapy and chemotherapy agents

with continuous physiologic data and transformative analytics.

addition to targeting the oncology market, Veris plan to expand into cardiovascular diseases, end-stage renal disease, and lung disorders

like COPD. We have already initiated R&D efforts around an enhanced implantable cardiac monitor capable of detecting cardiac arrhythmias

and other physiologic parameters critical for high-risk cardiac patients. Future devices will combine novel sensing technology with seamless

communication, engaging user interface design, and data analytics driving actionable clinical insights for patients with congestive heart

failure. These technologies will then be expanded for high-risk kidney disease and pulmonary patients.

Emerging

Medical Devices

Emerging

Innovations include a diversified and expanding portfolio of innovative products designed to address unmet clinical needs across a broad

range of clinical conditions. We are evaluating a number of these product opportunities and intellectual property covering a wide spectrum

of clinical conditions, which have either been developed internally or have been presented to us by clinician innovators and academic

medical institutions for consideration of a partnership to develop and commercialize these products. This collection of products includes:

NextVent (single use ventilators); FlexMO (medical circulatory support cannulas); Veris Cariac monitor; DisappEAR (resorbable

pediatric ear tubes); and Solys (Noninvasive glucose monitoring). In June 2020, we announced the execution of a letter of intent

to consummate a series of agreements to develop and utilize Canon Virginia’s commercial grade and scalable aqueous silk fibroin

molding process to manufacture PAVmed’s DisappEAR molded pediatric ear tubes for commercialization. Furthermore, we are exploring

other opportunities to grow our business and enhance shareholder value through the acquisition of pre-commercial or commercial stage

products and/or companies with potential strategic corporate and commercial synergies.

Diagnostics

Our

majority owned subsidiary, Lucid Diagnostics, Inc. (Nasdaq: LUCD) is a commercial-stage medical diagnostics technology company focused

on the millions of patients with gastroesophageal reflux disease (GERD), also known as chronic heartburn, acid reflux or simply reflux,

who are at risk of developing esophageal precancer and cancer, specifically highly lethal esophageal adenocarcinoma (EAC).

believe that our lead products, the EsoGuard® Esophageal DNA Test performed on samples collected with the EsoCheck®

Esophageal Cell Collection Device, constitute the first and only commercially available diagnostic test capable of serving as a

widespread screening tool to prevent EAC deaths, through early detection of esophageal precancer in at-risk GERD patients. The technologies

were highlighted in the NCI’s Annual Plan and Budget Proposal for FY2020 to Congress as one of the year’s significant advances

in cancer prevention. We believe EsoGuard could have as great an impact in preventing EAC deaths as widespread Pap test screening has

had in preventing cervical cancer deaths.

just over three years since our inception, we have advanced the technologies underlying EsoGuard and EsoCheck from the academic research

laboratory to commercial products within scalable business model. EsoGuard is commercialized in the U.S. as a Laboratory Developed Test

(LDT) and was granted final Medicare payment determination of $1,938.01, effective January 1, 2021. EsoCheck is commercialized in the

U.S. as a 510(k)-cleared esophageal cell collection device. EsoGuard, used with EsoCheck, was granted FDA Breakthrough Device designation

and is the subject of two large, actively enrolling, international multicenter PMA clinical trials.

Gastroesophageal

reflux disease (GERD), a pathologic condition in which stomach fluid, including acid, inappropriately refluxes into the lower esophagus,

is ubiquitous and can lead to highly lethal esophageal adenocarcinoma (EAC). Our opportunity is to prevent EAC deaths through the early

detection of esophageal precancer and cancer in millions of at-risk GERD patients.

2021, approximately 20,000 U.S. GERD patients are projected to be diagnosed with EAC and approximately 16,000 will die from it. Over

80% of EAC patients will die within five years of diagnosis, making it the second most lethal cancer in the U.S. The U.S. incidence of

EAC has increased 500% over the past four decades, while the incidences of other common cancers have declined or remained flat. In nearly

all cases, EAC silently progresses until it manifests itself with new symptoms of advanced disease. EAC is nearly always invasive at

diagnosis, and, unlike other common cancers, mortality rates are high even in its earlier stages.

to 50 million, or one in four, U.S. adults have weekly GERD symptoms. Although symptoms can be ameliorated with medications, including

proton pump inhibitors (PPIs) such as Nexium® and Prilosec®, medications do not prevent progression to esophageal precancer or

cancer.

Barrett’s

Esophagus (BE) is an esophageal precancer and complication of GERD characterized by pathologic transformation of surface esophageal cells.

Dysplastic BE is a late esophageal precancer characterized by further premalignant pathologic transformation called dysplasia. All EAC

is believed to arise from BE as the culmination of pathologic changes along the BE-EAC precancer-cancer spectrum—from nondysplastic

BE (NDBE), to low-grade dysplastic BE (LGD), high-grade dysplastic BE (HGD) and finally EAC. Dysplastic BE can be cured with endoscopic

esophageal ablation which reliably halts progression to EAC.

The

subgroup of long-standing or severe GERD patients at-risk for BE and progression to EAC is

well defined in clinical practice guidelines, including the American College of Gastroenterology

(ACG) BE Guidelines. Risk factors include age over 50 years, male gender, White race, obesity,

smoking history and a family history of BE-EAC. The ACG BE Guidelines recommend screening

for patients with a five-year history of, or severe, GERD and three or more risk factors.

The highest risk symptomatic GERD cohort recommended for screening consists of the estimated

13 million U.S. men over 50 with one additional risk factor. An estimated 60% of at-risk

GERD patients are Medicare beneficiaries.

Unfortunately,

for a variety of reasons, less than 10% of at-risk GERD patients who are recommended for screening undergo traditional invasive upper

gastrointestinal endoscopy (EGD). We believe that the profound tragedy of an EAC diagnosis is that likely death could have been prevented

if the at-risk GERD patient had been screened and then undergone surveillance and curative endoscopic esophageal ablation of dysplastic

BE.

Since

mortality rates are high even in early stage EAC, preventing EAC deaths requires detection and intervention at the precancer stage. Most

of the necessary elements for such an early detection program are already well established—an at-risk population (at-risk GERD

patients), a precancer (BE), and an intervention which can halt progression to EAC (endoscopic esophageal ablation). The only missing

element for such an early detection program is a widespread screening tool that can detect BE prior to EAC.