What changed in this filing

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Item 1. Legal Proceedings

2022-05-04 compared with 2021-11-03 · 340 added, 307 removed, 1229 unchanged (34% of the section changed)

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Legal Proceedings”

of our Annual Report on Form 10-K for the fiscal year ended December 31, 2020 includes a discussion of our current legal proceedings.

of our Annual Report includes a discussion of our current legal proceedings.

Refer to Note 5 –

Commitments and Contingencies in the accompanying Notes to the Condensed Consolidated Financial Statements in this Form 10-Q for further details on our legal proceedings during the nine months ended September 30, 2021.

Commitments and Contingencies to our unaudited condensed consolidated financial statements included elsewhere in this Quarterly Report for further details on our legal proceedings during the three months ended March 31, 2022.

Ri sk Factors

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Because our actual results may differ materially from any forward-looking statements that we make or that are made on our behalf, this section includes a discussion of important factors that could affect our actual future results, including, but not limited to, our ability to successfully commercialize VASCEPA and VAZKEPA, collectively referred to as VASCEPA, our capital resources, the progress and timing of our clinical programs, the safety and efficacy of our product candidates, risks associated with regulatory filings, the potential clinical benefits and market potential of our product candidates, commercial market estimates, future development efforts, patent protection, effects of healthcare reform, reliance on third parties effects of tax reform, and other risks set forth below.

Except those denoted below with a “*”, these risk factors have not been materially updated from our Annual Report on 10-K for the year ended December 31, 2020 filed with the SEC on February 25, 2021, or our Annual Report.

These risk factors have not been materially updated from our Annual Report on 10-K for the year ended December 31, 2021 filed with the SEC on March 1, 2022, or our Annual Report.

Summary Risk Factors

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In the United States, VASCEPA is facing increasing competition from generic versions of the drug.

In Europe, VAZKEPA was recently granted approval from the central regulatory authority and we are in the process of obtaining relevant pricing approvals in various countries;

In Europe, VAZKEPA launched in Germany following approval from the central regulatory authority and we are in the process of obtaining relevant pricing approvals in various countries;

however, we may not be successful in obtaining such approvals in a timely manner, or at all and, even if successfully obtained, we may not be successful in commercializing VAZKEPA in Europe or elsewhere.

In the United States, we face increasing competition from generic drug companies in the near term and our revenues and results of operations could be materially and adversely affected.

Factors outside of our control make it more difficult for VASCEPA to achieve a level of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary to meet expectations for commercial success.

The continued scale, scope and duration of business interruptions caused by the COVID-19 pandemic and related recovery efforts are uncertain as the impact of the pandemic continues to cause negative effects on our business.

Our current and planned commercialization efforts, including our recently announced Go-to-Market strategy, may not be successful in increasing sales of VASCEPA in the United States and developing sales internationally.

Factors outside of our control may make it more difficult for VASCEPA to achieve a level of market acceptance by physicians, patients, healthcare payors and others in the medical community at levels sufficient to meet our expectations for commercial success.

The continued scale, scope and duration of business interruptions caused by the ongoing COVID-19 pandemic and related recovery efforts are uncertain as the impact of the pandemic continues to cause negative effects on our business.

Our current and planned commercialization efforts, including our implemented Go-to-Market strategy, may not be successful in increasing sales of VASCEPA in the United States and developing sales internationally.

Our promotion and supply of VASCEPA is subject to regulatory scrutiny and associated risk.

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As a result, VASCEPA is subject to non-prescription competition and consumer substitution.

The commercial value to us of sales of VASCEPA outside the United States may be smaller than we anticipate, including adequacy of product reimbursement which can vary from country to country resulting in potential patient access restrictions.

The commercial value of VASCEPA outside the United States may be smaller than we anticipate, including adequacy of product reimbursement which can vary from country to country.

If we are unable to realize product reimbursement rates at reasonable levels, or at all, patient access to VASCEPA may be limited.

Our supply of product for the commercial market and clinical trials is dependent upon relationships with third-party manufacturers and suppliers.

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Our commercialization of VASCEPA outside the United States is substantially dependent on third parties and other circumstances outside our control.

We are dependent on patents, proprietary rights and confidentiality to protect the commercial potential of VASCEPA.

Our issued patents may not prevent competitors from competing with VASCEPA, even if we are successful in our current efforts to enforce our patent rights.

We are dependent on patents, proprietary rights and confidentiality to protect the commercial value and potential of VASCEPA.

Our issued patents may not prevent competitors from competing with VASCEPA, even if we are successful in enforcing our patent rights.

There can be no assurance that any of our pending patent applications relating to VASCEPA or its use will issue as patents.

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Risks Related to the Commercialization and Development of VASCEPA

* We are substantially dependent upon VASCEPA (icosapent ethyl), its commercialization in the United States and its development and commercialization in Europe and other major markets.

We are substantially dependent upon VASCEPA (icosapent ethyl), its commercialization in the United States and its development, launch and commercialization in Europe and other major markets.

In the United States, VASCEPA is facing increasing competition from generic versions of the drug.

In Europe, VAZKEPA was recently granted approval from the central regulatory authority and we are in the process of obtaining relevant pricing approvals in various countries;

In Europe, VAZKEPA launched in Germany following approval from the central regulatory authority and we are in the process of obtaining relevant pricing approvals in various countries;

however, we may not be successful in obtaining such approvals in a timely manner or at all and even if successfully obtained, we may not be successful in commercializing VAZKEPA in Europe or elsewhere.

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In recent years and currently, much of our financial results and revenue has been dependent on our ability to execute our development and commercial strategy for VASCEPA in the United States.

One generic version of VASCEPA launched in the United States in November 2020 and another launched in June 2021.

Generic version of VASCEPA launched in the United States in November 2020, June 2021 and January 2022.

We expect that VASCEPA could face more competition from generic companies in the United States in the near term in light of the patent litigation rulings against us, applicable only in this territory.

Increasing sales of generic versions of VASCEPA could continue to have a material and adverse impact on our revenues and results of operations in the United States.

We are implementing a new Go-to-Market strategy in an effort to accelerate growth of VASCEPA in the United States by shifting reliance on sales force interactions with healthcare professionals to providing managed care and prescription access through an omnichannel platform, and, in connection with this initiative, we reduced our U.S.

We implemented a Go-to-Market strategy in an effort to optimize provider engagement and drive demand of VASCEPA in the United States by shifting reliance on sales force interactions with healthcare professionals to providing managed care and prescription access through an omnichannel platform, and, in connection with this initiative, we reduced our U.S.

field force to approximately 300 sales representatives.

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In March 2021 we announced that the European Commission, or the EC, approved the marketing authorization application for icosapent ethyl, under the brand name VAZKEPA, hereafter along with VASCEPA, collectively referred to as VASCEPA, to reduce the risk of cardiovascular events in high-risk, statin-treated adult patients who have elevated triglycerides (≥150 mg/dL) and either established cardiovascular disease or diabetes and at least one additional cardiovascular risk factor.

In September 2021, we launched VAZKEPA in Germany, representing our first European launch of VAZKEPA, and are in the process of obtaining pricing and reimbursement approvals for VAZKEPA in relevant jurisdictions in Europe.

In September 2021, we launched VAZKEPA in Germany, representing our first European launch, In March 2022, we received national reimbursement for VAZKEPA in Sweden, representing our first national reimbursement in a European country.

We are in the process of obtaining further pricing and reimbursement approvals for VAZKEPA in relevant jurisdictions in Europe.

This process is conducted on a country-by-country basis and is time-consuming and complex.

And we may not be successful in obtaining such approvals in a timely manner with acceptable terms, or at all.

On March 25, 2022, Amarin received its first national reimbursement in a European country with official confirmation that the Swedish Dental and Pharmaceutical Benefits Agency (TLV) approved VAZKEPA for national reimbursement in Sweden.

W e may not be successful in obtaining such approvals in a timely manner with acceptable terms, or in additional countries.

Our expansion and development of VASCEPA outside the United States is generally not subject to the adverse patent ruling in the United States.

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That second indication, which we believe has significantly more value potential, is for use of the drug in the reduction of cardiovascular risk in select high-risk patients.

We have been developing VASCEPA on our own in Europe for the approved cardiovascular risk reduction indication and are exploring possible strategic collaborations in smaller markets within Europe and in other major markets.

We currently have multiple partners for the development and commercialization of VASCEPA in select geographies and intend to consider both self-launch and potential additional partners to commercialize VASCEPA in other parts of the world.

We have been developing VAZKEPA on our own in Europe for the approved cardiovascular risk reduction indication and are exploring possible strategic collaborations in smaller markets within Europe and in other major markets.

We currently have multiple partners for the development and commercialization of VASCEPA in select geographies and intend to assess potential partners to

commercialize VASCEPA in other parts of the world.

For example, we have strategic collaborations for the development and commercialization of VASCEPA in Canada, the Middle East and Greater China.

However, we cannot make any guarantees as to the success of these efforts or that our beliefs about the value potential are accurate, and if commercialization

plans for VASCEPA do not meet expectations in major markets such as the United States and Europe, our business and prospects could be materially and adversely affected.

However, we cannot make any guarantees as to the success of these efforts or that our beliefs about the value potential are accurate, and if commercialization plans for VASCEPA do not meet expectations in major markets such as the United States and Europe, our business and prospects could be materially and adversely affected.

The development and commercial time cycle for VASCEPA or other products that we may develop from our research and development efforts could result in delays in our ability to achieve commercial success.

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Reddy’s Laboratories, Inc., or Dr.

Reddy’s, and Hikma Pharmaceuticals USA Inc., or Hikma, (formerly known as West-Ward), and certain of their affiliates, or, collectively, the Defendants, that declared as invalid several patents of ours protecting the first FDA-approved use of our drug, for use to reduce severely high triglyceride levels, which is known as the MARINE indication.

Reddy’s, and Hikma Pharmaceuticals USA Inc., or Hikma, and certain of their affiliates, or, collectively, the Defendants, that declared as invalid several patents of ours protecting the first U.S.

FDA-approved use of our drug, for use to reduce severely high triglyceride levels, which is known as the MARINE indication.

We sought appeals of the Nevada Court judgment up to the United States Supreme Court, but, we were unsuccessful.

In November 2020, Hikma launched its generic version of VASCEPA on a limited scale and with a label that reflects the first VASCEPA FDA-approved indication, for the MARINE indication, and revised labeling based on the results of the REDUCE-IT trial.

On November 30, 2020, we filed a patent infringement lawsuit against Hikma affiliate for making, selling, offering to sell and importing generic icosapent ethyl capsules in and into the United States in a manner that we allege has induced the infringement of patents covering the use of VASCEPA to reduce specified cardiovascular risk.

In November 2020, Hikma launched its generic version of VASCEPA on a limited scale and with a label that reflects the MARINE indication, and revised labeling based on the results of the REDUCE-IT trial.

On November 30, 2020, we filed a patent infringement lawsuit against a Hikma affiliate for making, selling, offering to sell and importing generic icosapent ethyl capsules in and into the United States in a manner that we allege has induced the infringement of patents covering the use of VASCEPA to reduce specified cardiovascular risk.

On January 25, 2021 we expanded the scope of this patent infringement lawsuit to include a health care insurance provider, Health Net, LLC.

This litigation is ongoing.

We intend to vigorously pursue this ongoing litigation matter, but cannot predict the outcome or the impact on our business.

On January 4, 2022, the district court hearing the case granted Hikma's motion to dismiss.

We intend to appeal the decision of the district court when permitted and also intend to continue to vigorously pursue our ongoing litigation with Health Net, LLC, but cannot predict the outcome or the impact on our business.

In June 2021, Dr.

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On June 30, 2021, Apotex Inc.'s, or Apotex's, ANDA was approved by the U.S.

The rulings of the Nevada Court and related appeal loses detailed above could permit each of Teva and Apotex to launch a generic version of VASCEPA under certain circumstances pursuant to their respective settlement agreement with us.

In January 2022, Apotex launched its generic version of VASCEPA with labeling that is substantially consistent with the labeling of the Hikma and Dr.

Reddy's generic product, not the cardiovascular risk reduction indication.

The rulings of the Nevada Court and related appeal losses detailed above could permit each of Teva and Apotex to launch a generic version of VASCEPA under certain circumstances pursuant to their respective settlement agreement with us.

For example, Teva and Apotex settlement agreements permit such companies to launch their generic version of VASCEPA under royalty-free licenses from us given that our petition for en banc Federal Circuit review was not granted, after issuance of the Federal Circuit mandate on November 12, 2020.

Each generic launch is subject to procurement of adequate product supply.

Once a generic version of a drug is available in the market, the generic version is typically used in many U.S.

Generally, once a generic version of a drug is available in the market, the generic version is typically used in many U.S.

states to fill a prescription for any use of the drug, subject, to state reimbursement laws.

Although, in our case, use of generic versions of VASCEPA, whether with primarily a MARINE indication label or REDUCE-IT indication label, could be further subject to the potential for patent infringement under certain case law and subject to certain Teva and Apotex settlement agreement terms, we currently face generic competition from Hikma's and Dr.

Reddy’s generic versions of VASCEPA in the United States, and could face increased competition from additional generic entrants in the near term, which could have a material and adverse impact on our revenues and our results of operations.

Reddy’s generic versions of VASCEPA in the United States, and could face increased competition from these or additional generic entrants in the near term, which could have a material and adverse impact on our revenues and our results of operations.

There can be no assurance that we will be successful in preventing use of generic versions of VASCEPA in indications for which they have not been approved by U.S.

FDA, even if such use is determined to infringe certain of our patent claims.

We believe that VASCEPA is difficult to manufacture and that building capacity to manufacture VASCEPA is time-consuming and expensive.

These factors may limit the amount of VASCEPA supply available to generic companies, as we believe to be experienced by Hikma and Dr.

We do not have direct visibility into the supply levels of any of the generic companies and we rely on our own experience together with information from third parties, which information may not be reliable.

The generic companies could potentially find or develop sources of qualified VASCEPA supply that are not known to us and that are more efficient or less expensive than our sources.

Although we continue to believe that VASCEPA is difficult to manufacture and that building capacity to manufacture VASCEPA would be time-consuming and expensive for generic companies, such as Hikma, Dr.

Reddy and Apotex, we do not have direct visibility into the supply levels of any of the generic companies and we rely on our own experience together with information from third parties, which information may not be reliable.

As such, generic companies could potentially find or develop sources of qualified

VASCEPA supply that are not known to us and that are more efficient or less expensive than our sources.

Furthermore, generic companies could potentially convince our suppliers to prioritize supply to the generic companies ahead of any applicable contractual commitments to supply us.

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In addition, we may need to litigate with such suppliers to protect our rights, which can be costly and distracting to management.

Such circumstances

could have a material and adverse impact on our revenues and results of operations directly in the United States and potentially outside of the United States as well if supply costs and availability are affected or promotion and education programs reduced.

Such circumstances could have a material and adverse impact on our revenues and results of operations directly in the United States and potentially outside of the United States as well if supply costs and availability are affected or promotion and education programs reduced.

We have limited experience as a company in commercializing VASCEPA outside of the United States and may be unsuccessful in developing sales internationally.

While we have been working internally and with partners to support efforts toward approvals and commercialization outside the United States in light of the REDUCE-IT results and the recent EC approval of VAZKEPA, we may be unsuccessful in expanding our global footprint.

For example, we plan to launch VAZKEPA on our own in the most commercially significant markets in Europe and recently launched VAZKEPA in Germany, representing our first European launch of VAZKEPA.

For example, we plan to launch VAZKEPA on our own in the most commercially significant markets in Europe and launched VAZKEPA in Germany, representing our first European launch.

The commercial launch of a new pharmaceutical product is a complex and resource heavy undertaking for a company to manage, and we have no prior experience as a company operating a commercial-stage pharmaceutical business in Europe.

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Factors that could inhibit our efforts to successfully commercialize VASCEPA include:

the impact the expiration of regulatory exclusivities and entry into the market of additional generic versions of VASCEPA;

our inability to attract and retain adequate numbers of effective sales and marketing personnel, particularly in light of our recently announced reduction in force;

our inability to adequately train our sales and marketing personnel and our inability to adequately monitor compliance with these requirements;

the impact of the expiration of regulatory exclusivities and entry into the market of additional generic versions of VASCEPA;

our inability to attract and retain adequate numbers of effective sales and marketing personnel, particularly in light of our recent reduction in force;

our inability to adequately train our sales and marketing personnel and our inability to adequately monitor compliance with applicable regulatory and other legal requirements;

the inability of our new sales personnel, to obtain access to or persuade adequate numbers of physicians to prescribe VASCEPA;

if our new Go-to-Market strategy and omnichannel approach does not provide improved managed care and prescription access, or if healthcare providers are reluctant or delayed in shifting to the omnichannel platform;

if our Go-to-Market strategy and omnichannel approach does not provide improved managed care and prescription access, or if healthcare providers are reluctant or delayed in shifting to the omnichannel platform;

regulators may impose restrictions on VASCEPA’s conditions for use, distribution or marketing, and may impose ongoing requirements for post-market surveillance, post-approval studies or clinical trials, which may be costly or result in label or other use restrictions;

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Our ability to generate meaningful revenues outside of the United States may be limited, including due to the strict price controls and reimbursement limitations imposed by payors outside of the United States.

Our ability to generate meaningful revenues of VASCEPA outside of the United States is dependent on the availability and extent of coverage and reimbursement from third-party payers.

In many markets around the world, these payers, including government health systems, private health insurers and other organizations, remain focused on reducing the cost of healthcare, and their efforts have intensified as a result of rising healthcare costs and economic challenges.

Our ability to generate meaningful revenues of VASCEPA outside of the United States is dependent on the availability and extent of coverage and reimbursement from third-party payors.

In many markets around the world, these payors, including government health systems, private health insurers and other organizations, remain focused on reducing the cost of healthcare, and their efforts have intensified as a result of rising healthcare costs and economic challenges.

Drugs remain heavily scrutinized for cost containment.

As a result, payers are becoming more restrictive regarding the use of biopharmaceutical products and scrutinizing the prices of these products while requiring a higher level of clinical evidence to support the benefits such products bring to patients and the broader healthcare system.

As a result, payors are becoming more restrictive regarding the use of biopharmaceutical products and scrutinizing the prices of these products while requiring a higher level of clinical evidence to support the benefits such products bring to patients and the broader healthcare system.

These pressures are intensified where our products are subject to competition, including from biosimilars.

In many countries outside the United States, government-sponsored healthcare systems are the primary payers for drugs.

With increasing budgetary constraints and differing views on or challenges in valuing medicines, governments and payers in many countries are applying a variety of measures to exert downward price pressure.

In many countries outside the United States, government-sponsored healthcare systems are the primary payors for drugs.

With increasing budgetary constraints and differing views on or challenges in valuing medicines, governments and payors in many countries are applying a variety of measures to exert downward price pressure.

These measures can include mandatory price controls, price referencing, therapeutic-reference pricing, increases in mandates, incentives for generic substitution and biosimilar usage and government-mandated price cuts.

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The dynamics and developments discussed above serve to create pressure on the pricing and potential usage of our products and the industry.

Given the diverse interests in play among payers, biopharmaceutical manufacturers, policy makers, healthcare providers and independent organizations, if and whether the parties involved can achieve alignment on the matters discussed above remains unclear and the outcome of any such alignment is difficult to predict.

Given the diverse interests in play among payors, biopharmaceutical manufacturers, policy makers, healthcare providers and independent organizations, if and whether the parties involved can achieve alignment on the matters discussed above remains unclear and the outcome of any such alignment is difficult to predict.

We are committed to working with the entire healthcare community to ensure continued innovation and to facilitate patient access to needed medicines;

however, if reimbursement of VASCEPA is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our ability to successfully commercialize VASCEPA outside of the United States may be harmed, which could have a material and negative impact on our overall business.

* Government and commercial payer actions outside the United States have affected and will continue to affect access to and sales of our products

Government and commercial payor actions outside the United States have affected and will continue to affect access to and sales of our products

Outside the United States, we expect countries will continue to take actions to reduce their drug expenditures.

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Some countries decide on reimbursement between potentially competing products through national or regional tenders that often result in one product receiving most or all of the sales in that country or region.

Thus, there can be no certainty that we will negotiate satisfactory reimbursement or pricing rates in markets outside the United States in a timely manner, or at all, or even if we are successful in obtaining satisfactory coverage and reimbursement, we may be unsuccessful in sustaining such coverage and reimbursement, or could face challenges as to the timeliness or certainty of payment by payers to physicians and other providers, which would have a material and adverse impact on our commercialization efforts outside of the United States.

Furthermore, despite having skilled and experienced individuals deployed in such efforts, we as an organization have limited experience in navigating the pricing and reimbursement regimes, which are varied and complex, outside of the United States, which might hinder our effectiveness in establishing satisfactory pricing, coverage and reimbursement levels in a timely manner or at all.

* Factors outside of our control make it more difficult for VASCEPA to achieve a level of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary to meet expectations for commercial success.

Thus, there can be no certainty that we will negotiate satisfactory reimbursement or pricing rates in markets outside the United States in a timely manner, or at all, or even if we are successful in obtaining satisfactory coverage and reimbursement, we may be unsuccessful in sustaining such coverage and reimbursement, or could face challenges as to the timeliness or certainty of payment by payors to physicians and other providers, which would have a material and adverse impact on our commercialization efforts outside of the United States.

Furthermore, despite having skilled and experienced individuals deployed in such efforts, we as an organization have limited experience in navigating the pricing and reimbursement regimes, outside of the United States, which foreign regimes are varied and complex, which might hinder our effectiveness in establishing satisfactory pricing, coverage and reimbursement levels in a timely manner or at all.

Factors outside of our control may make it more difficult for VASCEPA to achieve market acceptance by physicians, patients, healthcare payors and others in the medical community at levels sufficient to meet our expectations for commercial success.

In January 2013, we launched VASCEPA based on the U.S.

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75 mg/dL) and other CV risk factors, including persistent elevated TG 150-499 mg/dL (median baseline TG:

REDUCE-IT topline results showed the trial met its primary endpoint demonstrating an approximately 25% relative risk reduction, to a high degree of statistical significance (p<0.001), in MACE in the intent-to-treat patient population with use of VASCEPA 4 grams/day as compared to placebo.

MACE events were defined as a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

This result was supported by robust

demonstrations of efficacy across multiple secondary endpoints.

This result was supported by robust demonstrations of efficacy across multiple secondary endpoints.

VASCEPA was well tolerated in REDUCE-IT with a safety profile generally consistent with clinical experience associated with omega-3 fatty acids and current U.S.

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In December 2019, the U.S.

FDA approved a new indication and label expansion for VASCEPA as an adjunct to statin therapy to reduce the risk of MACE events in adult patients with elevated TG levels (≥150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease.

FDA approval for this new indication and expanded label for VASCEPA, we may not meet expectations for market acceptance by physicians, patients, healthcare payors and others in the medical community for this approved use, especially in light of our unsuccessful appeals efforts.

FDA approved another indication and label expansion for VASCEPA as an adjunct to statin therapy to reduce the risk of MACE events in adult patients with elevated TG levels (≥150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease.

FDA approval for this indication and expanded label for VASCEPA, we may not meet expectations for market acceptance by physicians, patients, healthcare payors and others in the medical community for this approved use, especially in light of our unsuccessful appeals efforts.

If VASCEPA does not achieve an adequate level of acceptance, we may not generate product revenues sufficient to become profitable on an ongoing basis.

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sufficient third-party coverage or reimbursement for VASCEPA and its prescribed uses, on-label and off-label;

natural disasters, including pandemics such as COVID-19 and political unrest that could inhibit our ability to promote VASCEPA regionally and can negatively affect product demand by creating obstacles for patients to seek treatment and fill prescriptions;

natural disasters, including pandemics such as COVID-19 and political unrest that could inhibit our ability to promote VASCEPA regionally and that could negatively affect product demand by creating obstacles for patients to seek treatment and fill prescriptions;

new policies or laws affecting VASCEPA sales, such as state and federal efforts to affect drug pricing and provide or remove healthcare coverage that includes reimbursement for prescription drugs;

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FDA labeling, U.S.

FDA-approved labeling that is more closely tied to the patient population studied in a clinical trial could limit use generally and by making reimbursement more difficult.

* The continued scale, scope and duration of business interruptions caused by the COVID-19, pandemic are uncertain as the impact of the pandemic continues to cause negative effects on our business.

FDA-approved labeling that is more closely tied to the patient population studied in a clinical trial could limit use generally and could make reimbursement more difficult.

The continued scale, scope and duration of business interruptions caused by the ongoing COVID-19 pandemic are uncertain as the impact of the pandemic continues to cause negative effects on our business.

The global spread of COVID-19, has created significant volatility, uncertainty and disruption in healthcare, social, supply and economic infrastructures.

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ability to access supplies of VASCEPA and the willingness of patients to visit doctors for non-urgent medical examination or to visit labs for blood tests to assess biomarkers such as lipid levels;

our ability to commercialize VASCEPA, including as a result of travel restrictions, social distancing and other containment measures;

our ability to commercialize VASCEPA, including as a result of ongoing travel restrictions, social distancing and other containment measures or the restoration of such measures;

the enrolment or monitoring of patients in clinical trials, particularly at clinical trial sites located in highly impacted jurisdictions and jurisdictions where vaccination rates are low;

the ability to access, secure and otherwise obtain and deliver sufficient and timely commercial or clinical supplies of VASCEPA to meet demand if the production capabilities of suppliers is disrupted;

the ability to access, secure and otherwise obtain and deliver sufficient and timely commercial or clinical supplies of VASCEPA at reasonable prices and sufficient to meet demand if the production capabilities of suppliers is disrupted;

disruptions in regulatory oversight and actions if regulators and industry professionals continue to expend significant and unexpected resources addressing COVID-19;

the availability of coverage and reimbursement from government and health administration authorities, private health insurers and other third-party payors if the system becomes overly strained;

the availability of coverage and reimbursement from government and health administration authorities, private health insurers and other third-party payors if the system continues to be overly strained;

the ability of regulators to complete inspections and reviews of operations and applications, respectively, in a timely manner;

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To comply with travel restrictions, social distancing, quarantines and other containment measures implemented in various geographies, in March 2020, we suspended field based face-to-face interactions.

We resumed on a limited basis field-based, face-to-face interactions with healthcare providers beginning in June 2020.

During the late part of the summer of 2020, substantially all of our field force personnel had the ability to resume face-to-face customer interactions, in a manner consistent with state and local guidance.

In the fourth quarter of 2020 and in early 2021, the impact of COVID-19 worsened in some parts of the United States, with some healthcare professionals again limiting access to face-to-face interactions.

Additionally although we have started to see signs of recovery in light of the availability of vaccines during the second and third quarters, the number of patient visits to doctors’

Although by the end of summer of 2020, substantially all of our field force personnel had the ability to resume face-to-face customer interactions, in a manner consistent with state and local guidance, limitations on such interactions have been imposed.

As variants emerge and as vaccine protocols develop, face-to-face interactions are challenging for us to predict and the number of patient visits to doctors’

offices and patients undergoing blood testing remains down considerably from pre-COVID-19 levels.

These circumstances vary geographically and vary over time, with continued risk of resurgences in COVID-19 cases, and reinstitution of protocols, in various geographies and as the efficacy of the vaccine on various strains remains uncertain.

We hope to be able to maintain our substantial resumption of our business efforts, however, given the dynamics related to COVID-19, there can be no assurance that this will be the case.

While we have supplemented these face-to-face interactions with virtual outreach and our omnichannel platform, these efforts

may not be as impactful as traditional, in-person interactions.

In September 2021, to optimize provider engagement and drive demand for VASCEPA in the United States and to counteract the changing engagement dynamics, including those introduced as a result of COVID-19, we announced our Go-to-Market strategy which incorporates omnichannel communications with healthcare providers.

The circumstances surrounding COVID-19 vary geographically and vary over time, with continued risk of resurgences in COVID-19 cases, and reinstitution of protocols, in various geographies and as the efficacy of the vaccine on various strains remains uncertain.

While we have supplemented our face-to-face interactions with virtual outreach and our omnichannel platform, these efforts may not

be as impactful as traditional, in-person interactions.

Specifically, access to healthcare professionals through the internet or other channels, may not be as productive as in-person interactions.

Although we have a geographically diversified supply chain for VASCEPA and believe we have sufficient inventory on hand at pharmacies throughout the United States and other markets where it is approved for sale, and at various stages of manufacturing with our suppliers, the global spread of the outbreak and containment measures has been unprecedented and could have a negative impact on the availability of VASCEPA at various points in our supply chain, including limiting the ability of new suppliers to be inspected, which would have a material and adverse effect on our business.

Although we have a geographically diversified supply chain for VASCEPA and believe we have sufficient inventory on hand at pharmacies throughout the United States and other markets where it is approved for sale, and at various stages of manufacturing with our suppliers, the global spread of the pandemic and containment measures has been unprecedented and could have a negative impact on the availability of VASCEPA at various points in our supply chain, including limiting the ability of new suppliers to be inspected, which would have a material and adverse effect on our business.

Since the beginning of the COVID-19 pandemic, three vaccines for COVID-19 have received Emergency Use Authorization by the U.S.

FDA and two of those later received marketing approval.

Additional vaccines may be authorized or approved in the future.

The ongoing demand for vaccines, including boosters, and potential for manufacturing facilities and materials to be commandeered under the Defense Production Act of 1950, or equivalent foreign legislation, may make it more difficult to obtain materials or manufacturing slots for the products needed for our commercial product, which could lead to issues with our commercial supply.

The disruptions associated with the coronavirus pandemic could also delay the timing of a determination on our ability to seek legal remedies as travel, operational resources and personnel are disrupted or slow to resume pre-pandemic levels, with respect to our efforts and capabilities, as well as those of our advisors and the courts.

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In December 2019, the U.S.

Even though U.S.

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When new data are assessed and released or presented it could exceed, match or may not meet investor expectations.

In addition, the same set of data can sometimes be interpreted to reach different conclusions.

This was the case when Health Canada approved an indication based on REDUCE-IT data that was different in certain respects than that approved by U.S.

In addition, the same set of data can sometimes be interpreted to reach different conclusions, as when Health Canada approved an indication based on REDUCE-IT data that was different in certain respects than that approved by U.S.

FDA and by the EC in Europe.

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UMIN Clinical Trials Registry number, UMIN000012069) is a study examining Japanese patients with chronic coronary artery disease receiving LDL-C lowering treatment by statin therapy.

Patients will be randomized to either a control group (standard treatment) or EPA group (standard treatment plus 1.8 grams/day of eicosapentaenoic acid), to examine the effects of a different formulation of icosapent ethyl than VASCEPA on the incidence of cardiovascular events.

Patients will be randomized to either a control group (standard treatment) or EPA group (standard treatment plus 1.8 grams per day of eicosapentaenoic acid), to examine the effects of a different formulation of icosapent ethyl than VASCEPA on the incidence of cardiovascular events.

The relationship between the ratio of EPA to arachidonic acid and incidence of events will also be examined.

Results from this study are expected in the second half of 2021, though results could be delayed as a result of COVID-19 impacts.

Results from this study are expected in the second half of 2022, though the study and results are not under the Company's control and may be delayed as a result of COVID-19 impacts.

In November 2020, we announced statistically significant topline results from a Phase 3 clinical trial of VASCEPA, conducted by our partner in China, Eddingpharm (Asia) Macao Commercial Offshore Limited, or Edding, which investigated VASCEPA as a treatment for patients with very high triglycerides (≥500 mg/dL).

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On December 12, 2020, we announced at the National Lipid Association Scientific Sessions 2020 positive clinical results from the CardioLink-9 Trial, the first results of a study of VASCEPA in COVID-19 infected outpatients.

Results from the investigator initiated study in Argentina called PREPARE-IT-1 were presented by the lead trial investigator at the European Society of Cardiology on August 29, 2021 and the results did not meet the primary and/or other endpoints studied.

Results from the other investigational studies are expected over the next year.

Results from the investigator sponsored study in Argentina called PREPARE-IT-1 were presented by the lead trial investigator at the European Society of Cardiology on August 29, 2021 and the results did not meet the primary and/or other endpoints studied.

Results from the investigator sponsored study in Argentina called PREPARE-IT-2 were presented by the lead trial investigator at the American Heart Association Scientific Sessions in November 2021 and the results did not meet the primary and/or other endpoints studied.

Results from the other investigational study, called MITIGATE, is expected during 2022.

If the outcomes of one or more of these studies do not meet expectations, the perception of existing clinical results of VASCEPA, such as MARINE or REDUCE-IT, or the perceived clinical profile and commercial value of VASCEPA and its regulatory status may suffer.

If this occurs our revenue and business could suffer and our stock price could significantly decline.

* Our current and planned commercialization efforts may not be successful in increasing sales of VASCEPA in the United States.

It is estimated that over 25 million adults in the United States have elevated triglyceride levels ≥200 mg/dL and that more than 50 million adults in the United States have elevated triglyceride levels ≥150 mg/dL.

Approximately two to three million adults in the United States have very high (≥500mg/dL) triglyceride levels, the MARINE patient population.

There are approximately five to 15 million people in the United States who meet the specific REDUCE-IT inclusion criteria.

Since 1976, mean triglyceride levels have increased in concert with the growing epidemic of obesity, insulin resistance, and type 2 diabetes mellitus.

In contrast, mean LDL-C levels have decreased.

As a result of the COVID-19 pandemic and the related social distancing, in March 2020, we suspended face-to-face interactions between our sales representatives and healthcare professionals.

We resumed on a limited basis field-based, face-to-face interactions with healthcare providers beginning in June 2020.

During the late part of the summer of 2020, substantially all of our field force personnel were able to resume face-to-face customer interactions in a manner consistent with guidelines from local, state and government health officials in the United States.

In the fourth quarter of 2020 and early 2021, the impact of COVID-19 worsened in much of the United States, with some physicians again limiting access to face-to-face interactions with our field force personnel.

Thus, despite the size of our sales team, it is not large enough to call upon all physicians and we may not have sufficient sales personnel and resources to maximize the sales potential of VASCEPA.

If we are not successful in maintaining a sales force that is rightsized for our efforts to market and sell VASCEPA in the United States, including in light of our new Go-to-Market strategy, including our omnichannel approach and reduced sales force, our anticipated revenues or our expenses could be materially and negatively affected, and we may not obtain profitability, may need to cut back on research and development activities or implement other cost-containment measures, or we may need to raise additional funding that could result in substantial dilution or impose considerable restrictions on our business.

Although substantially all of our sales force personnel have the ability to resume face-to-face customer interactions in a manner consistent with state and local guidance, given the dynamics related to COVID-19, there can be no assurance that/as to when we will be able to substantially resume and sustain our business efforts.

While we have supplemented these face-to-face interactions with virtual outreach, including our omnichannel platform, these efforts may not be as successful as traditional, in-person interactions.

Specifically, access to healthcare professionals through digital or other channels, may not be as productive as in-person interactions.

In the United States, in July 2020 we launched our first ever direct-to-consumer promotional campaign regarding VASCEPA demonstrating results in lowering cardiovascular risk in patients with persistent cardiovascular risk in high risk patients.

In September 2020, we launched a new, nationwide television advertisement campaign in connection with our expanded promotional campaign which was further complemented by additional digital, point-of-care and other forms of healthcare professional and patient

educational outreach.

As the impact of COVID-19 on much of the United States worsened in the fourth quarter of 2020, we suspended television-based promotion of VASCEPA as we determined that the cost was not sufficiently justified in light of the COVID-19 pandemic on patient visits to doctors.

We resumed a limited direct-to-consumer campaign in January 2021, including television-based promotion, digital and social media promotion to continue to grow consumer awareness of VASCEPA.

In June 2021, we launched an educational campaign, It's Clear to Me Now , to help physicians and patients learn more about the differentiation between VASCEPA and fenofibrates for CV risk reduction.

There can be no assurance that the efforts described above will have the intended positive increase in patients asking their healthcare providers regarding VASCEPA or that prescription rates for VASCEPA will increase in the near future or at all from such efforts.

Data on increased product usage from similar promotion of other products suggests that the impact of television-based promotion can be positive and sustained but is rarely immediate in its effect.

After assessing the scope, timing and pricing of generic competition, we may also decide to contract our VASCEPA promotional efforts.

If we are not successful in maintaining a sales force that is rightsized for our efforts to market and sell VASCEPA in the United States, including in light of our Go-to-Market strategy, including our omnichannel approach and reduced sales force, our anticipated revenues or our expenses could be materially and negatively affected, and we may not obtain profitability, may need to cut back on research and development activities or implement other cost-containment measures, or we may need to raise additional funding that could result in substantial dilution or impose considerable restrictions on our business.

Given the dynamics related to COVID-19, we cannot predict when we will be able to substantially resume and sustain our business efforts, or how those efforts will be impacted in the long term.

While we have supplemented traditional face-to-face interactions with virtual outreach, including our omnichannel platform, these efforts may not be as successful as in-person interactions.

Specifically, access to healthcare professionals through digital or other channels, may not be as productive as in-person interactions in promoting use of VASCEPA.

We continued to adjust our promotional initiatives, including pursuing increased face-to-face interactions with health care professionals and expanding various forms of direct-to-patient promotion based on COVID-19 protocols that are in place.

Such efforts are costly and there can be no assurance that they will result in an increase in VASCEPA prescriptions and sales in the near future, or at all.

Our promotion and supply of VASCEPA is subject to regulatory scrutiny and associated risk.

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FDA, the U.S.

government, our competitors and other interested parties may not agree on the truthfulness and non-misleading

nature of our promotional materials.

government, our competitors and other interested parties may not agree on the truthfulness and non-misleading nature of our promotional materials.

Federal and state governments or agencies may also seek to find other means to prevent our promotion of unapproved truthful and non-misleading information about VASCEPA.

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We cannot predict when these investigations will be resolved, the outcome of the investigations or their potential impact on our business.

Such investigations can be lengthy, costly and could materially affect and disrupt our business.

Such investigations can be

lengthy, costly and could materially affect and disrupt our business.

If the government determines that we have violated the U.S.

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pharmaceutical products.

Further, results of trials for similar or competing products could have a negative impact on the perceived safety and efficacy of VASCEPA, which could have a materially adverse impact on sales of VASCEPA.

The biotechnology and pharmaceutical industries are highly competitive.

There are many pharmaceutical companies, biotechnology companies, public and private universities and research organizations actively engaged in the research and development of products that may be similar to our product.

It is probable that the number of companies seeking to develop products and therapies similar to our product will increase.

It is probable that the number of companies seeking to develop products and therapies similar to VASCEPA will increase.

Many of these and other existing or potential competitors may have substantially greater financial, technical and human resources than we do and may be better equipped to develop, manufacture and market products.

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In addition, other technologies or products may be developed that have an entirely different approach or means of accomplishing the intended purposes of our products, which might render our technology and products noncompetitive or obsolete.

Our competitors both in the United States and abroad include large, well-established pharmaceutical and generic companies, specialty and generic pharmaceutical sales and marketing companies, and specialized cardiovascular treatment companies.

With a generic version of VASCEPA launched by Hikma in November 2020 and by Dr.

Reddy's in June 2021 and with further generic competition anticipated, it may not be viable for us to invest in market education to grow the United States market and our ability to maintain current promotional efforts and attract favorable commercial terms in several aspects of our business will likely be adversely affected as we face increased generic competition, or if we launch our own generic version of VASCEPA.

Woodward Pharma Services LLC currently sells Lovaza ® , which it acquired from GlaxoSmithKline plc in Q3 2021.

Lovaza ® a prescription-only omega-3 fatty acid indicated for patients with severe hypertriglyceridemia, was approved by U.S.

Our competitors include large, well-established pharmaceutical and generic companies, specialty and generic pharmaceutical sales and marketing companies, and specialized cardiovascular treatment companies.

With generic versions of VASCEPA launched in the U.S.

by Hikma in November 2020, Dr.

Reddy's in June 2021 and Apotex in January 2022, and with the potential for further generic versions being launched, it may not be viable for us to continue to invest in market education to grow the market and our ability to maintain current promotional efforts and attract favorable commercial terms in several aspects of our business will likely be adversely affected as we face increased generic competition, or if we launch our own generic version of VASCEPA.

Woodward Pharma Services LLC currently sells Lovaza ® , which it acquired from GlaxoSmithKline plc in the third quarter of 2021.

Lovaza ® a prescription-only omega-3 fatty acid indicated for patients with severe hypertriglyceridemia, was approved by the U.S.

FDA in 2004 and has been on the market in the United States since 2005.

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FDA approval to reduce CV risk on top of statin therapy.

In addition, in May 2014, Epanova ® (omega-3-carboxylic acids) capsules, a free fatty acid form of omega-3 (comprised of 55% EPA and 20% DHA), was approved by the U.S.

FDA for patients with severe hypertriglyceridemia and is currently commercialized by AstraZeneca Pharmaceuticals LP, or AstraZeneca.

Also, in April 2014, Omtryg, another omega-3-acid fatty acid composition developed by Trygg Pharma AS, received U.S.

In addition, in April 2014, Omtryg (omega-3-acid ethyl esters A) capsules, a free fatty acid form of omega-3 (comprised of 50% EPA and 40% DHA), developed by Trygg Pharma AS, received U.S.

FDA approval for severe hypertriglyceridemia.

Neither Epanova nor Omtryg have been commercially launched, but could launch at any time.

AstraZeneca has greater resources than we do, including financial, product development, marketing, personnel and other resources.

AstraZeneca conducted a long-term outcomes study to assess Statin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs With Hypertriglyceridemia (STRENGTH).

Omtryg has not been commercially launched, but could launch at any time.

AstraZeneca conducted a long-term outcomes study to assess Statin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs With Hypertriglyceridemia, or STRENGTH.

The study was a randomized, double-blind, placebo-controlled (corn oil), parallel group design that is believed to have enrolled approximately 13,000 patients with hypertriglyceridemia and low HDL and high risk for cardiovascular disease randomized 1:1 to either corn oil plus statin or Epanova plus statin, once daily.

On January 13, 2020 following the recommendation of an independent Data Monitoring Committee, AstraZeneca decided to close the STRENGTH trial due to its low likelihood of demonstrating benefit to patients with mixed dyslipidemia who are at increased risk of

cardiovascular disease.

Full data from the STRENGTH trial was presented at the American Heart Association’s, or the AHA's, Scientific Sessions in November 2020, confirming that Epanova failed to meet the primary endpoint of CV risk reduction.

Full data from the STRENGTH trial was presented at the AHA's Scientific Sessions in November 2020, confirming that Epanova failed to meet the primary endpoint of CV risk reduction, and published in Journal of the American Medical Association (JAMA) in December 2020.

In addition, in March 2017, Kowa Research Institute (a subsidiary of the Japanese company Kowa Co., Ltd) initiated a Phase 3 cardiovascular outcomes trial titled PROMINENT examining the effect of pemafibrate (experimental name K-877) in reducing cardiovascular events in Type II diabetic patients with hypertriglyceridemia.

Kowa Research Institute has publicly estimated study completion in May 2022, and if successful, U.S.

regulatory approval is estimated in mid-2023.

During 2018, two outcomes studies, the VITamin D and OmegA-3 TriaL (VITAL) and A Study of Cardiovascular Events iN Diabetes (ASCEND) trial were completed of omega-3 mixtures which both failed to achieve their primary endpoints of cardiovascular risk reduction and two meta-analyses were published showing that omega-3 mixtures of both EPA and DHA are not effective in lowering cardiovascular risk.

Results of these failed outcomes studies and analysis, while not done with VASCEPA, may negatively affect sales of VASCEPA.

For example, VITAL was an NIH funded randomized double-blind, placebo-controlled, 2x2 factorial trial of 2000 IU per day of vitamin D3 and 1 gram per day of omega-3 fatty acid mixture supplementation (Lovaza) for the primary prevention of cancer and cardiovascular disease in a nationwide USA cohort of 25,874 adults not selected for elevated cardiovascular or cancer risk and its results were announced immediately before the presentation of REDUCE-IT results at the 2018 Scientific Sessions of the AHA on November 10, 2018, which may have caused concerns about the effectiveness of omega-3 mixtures generally, including VASCEPA.

Likewise, in 2018, results from the ASCEND trial were released and showed negligible results for omega-3 fatty acid mixtures 1 gram daily.

ASCEND was a British Heart Foundation funded 2x2 factorial design, randomized study to assess whether aspirin 100 mg daily versus placebo and separately, omega-3 fatty acid mixtures 1 gram daily versus placebo, reduce the risk of cardiovascular events in a nationwide UK cohort of over 15,000 individuals with diabetes who do not have atherosclerotic cardiovascular disease.

More recently, in 2020, an additional Nordic trial known as OMEMI failed to demonstrate a reduction in cardiovascular events with an omega-3 fatty acid mixture.

OMEMI, an investigator-initiated, multi-center, randomized clinical trial, was designed to evaluate the effects of daily treatment with omega-3 fatty acids compared with placebo among elderly patients (ages 70-82) with recent myocardial infarction.

Patients received 1.8 g omega-3 fatty acids (930 mg EPA and 660 mg DHA) or placebo (corn oil) daily added to standard of care.

Results presented in November 2020 at the American Heart Association’s Scientific Sessions showed no significant differences in cardiovascular events between the treatment groups for the composite primary endpoint (non-fatal MI, unscheduled revascularization, stroke, hospitalization for heart failure or all-cause mortality), nor for the individual components of this endpoint after two years.

In April 2022, Kowa Research Institute announced the decision to not continue the PROMINENT study as the primary endpoint was unlikely to be met.

During 2018, two outcomes studies were completed of omega-3 mixtures which both failed to achieve their primary endpoints of cardiovascular risk reduction and two meta-analyses were published showing that omega-3 mixtures of are not effective in lowering cardiovascular risk.

Results of these failed outcomes studies, as described below and analysis, while not done with VASCEPA, may negatively affect sales of VASCEPA if omega-3 mixtures are broadly viewed as ineffective.

For example, results of one of these two studies, the VITamin D and OmegA-3 TriaL, or VITAL, as announced immediately before the presentation of REDUCE-IT results at the 2018 Scientific Sessions of the AHA on November 10, 2018, failed to achieve its

primary endpoint of lowering cardiovascular events.

VITAL was an NIH funded randomized double-blind, placebo-controlled, 2x2 factorial trial of 2000 IU per day of vitamin D3 and 1 gram per day of omega-3 fatty acid mixture supplementation (Lovaza) for the primary prevention of cancer and cardiovascular disease in a nationwide USA cohort of 25,874 adults not selected for elevated cardiovascular or cancer risk.

Likewise, in 2018, results from the other outcome study, A Study of Cardiovascular Events iN Diabetes (ASCEND) trial were released and showed negligible results for omega-3 fatty acid mixtures 1 gram daily.

ASCEND was a British Heart Foundation funded 2x2 factorial design, randomized study to assess whether aspirin 100 mg daily versus placebo and separately, omega-3 fatty acid mixtures 1 gram daily versus placebo, reduce the risk of cardiovascular events in a nationwide United Kingdom, or UK, cohort of over 15,000 individuals with diabetes who do not have ASCVD.

In a meta-analysis, presented in 2018 by the Cochrane Foundation and separately as published in JAMA, additional omega-3 studies were evaluated.

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The negative results from such omega-3 mixture studies could create misleading impressions about the use of omega-3s generally, including VASCEPA, despite REDUCE-IT positive results and the highly-pure and stable EPA active ingredient in VASCEPA and its higher dose regimen.

We believe Micelle BioPharma Inc., or Micelle, is also developing potential treatments for hypertriglyceridemia based on omega-3 fatty acids.

To our knowledge, Micelle, after acquiring SC401 from Sancilio & Company, or Sancilio, is pursuing a regulatory pathway under section 505(b)(2) of the FDCA for its product and submitted an Investigational New Drug Application, or IND, in July 2015.

Micelle (Sancilio) completed two pharmacokinetic studies and Phase 2 bioavailability studies (FASTR I&II), with one comparing SC401 to Lovaza.

We expect the company or a potential partner to initiate a pivotal clinical Phase 3 study as the next step in development.

Matinas BioPharma, Inc., or Matinas, is developing an omega-3-based therapeutic, MAT9001, for the treatment of severe hypertriglyceridemia and mixed dyslipidemia.

More recently, in 2020, an additional Nordic trial known as OMEMI failed to demonstrate a reduction in cardiovascular events with an omega-3 fatty acid mixture.

Patients received 1.8 g omega-3 fatty acids (930 mg EPA and 660 mg DH) or placebo (corn oil) daily added to standard of care.

Results presented in November 2020 at the AHA’s Scientific Sessions showed no significant differences in cardiovascular events between the treatment groups for the composite primary endpoint (non-fatal MI, unscheduled revascularization, stroke, hospitalization for heart failure or all-cause mortality), nor for the individual component of this endpoint after 2 years.

Matinas BioPharma, Inc., or Matinas, is developing an omega-3-based therapeutic (MAT9001 also known as LYPDISO) for the treatment of severe hypertriglyceridemia and mixed dyslipidemia.

In the fourth quarter of 2014 Matinas filed an IND with the U.S.

FDA to conduct a human study in the treatment of severe hypertriglyceridemia and, in June 2015, the company announced topline results for its head-to-head comparative short duration pharmacokinetic and pharmacodynamic study of MAT9001 versus VASCEPA in patients under conditions inconsistent with the U.S.

FDA to conduct a human study in the treatment of severe hypertriglyceridemia and, in June 2015, the company announced topline results for its head-to-head comparative short duration pharmacokinetic and pharmacodynamic study of LYPDISO versus VASCEPA in patients under conditions inconsistent with the U.S.

FDA-approved label for VASCEPA and presented results based on biomarker modification without outcomes data.

In September 2017, Matinas announced that it will be seeking a partner company to develop and commercialize MAT9001.

In March 2019, Matinas announced that net proceeds from a public offering of common stock would be used for development activities for MAT9001.

In March 2020, Matinas announced that it completed the clinical dosing for a comparative clinical bridging bioavailability study and the in-life portion of a 90-day comparative toxicology study.

In September 2017, Matinas announced that it will be seeking a partner company to develop and commercialize LYPDISO In March 2019, Matinas announced that net proceeds from a public offering of common stock would be used for development activities for LYPDISO In March 2020, Matinas announced that it completed the clinical dosing for a comparative clinical bridging bioavailability study and the in-life portion of a 90-day comparative toxicology study in the first quarter of 2020.

Both studies were conducted to support a planned 505(b)(2) registration pathway.

In March, Matinas also initiated an additional Phase 2 head-to-head pharmacokinetic and pharmacodynamic study, ENHANCE-IT, against VASCEPA in patients with elevated triglycerides (150-499 mg/dL), while the study was paused in the first quarter of 2020 due to the COVID-19 pandemic, enrollment resumed in June and was completed in August 2020.

In the first quarter of 2021, Matinas announced topline results from the ENHANCE-IT study, stating that LYPDISO, or MAT9001, did not meet statistical significance over VASCEPA on the primary endpoint of percent change from baseline to end of treatment in triglycerides in the pharmacodynamic, or PD, population.

A key secondary endpoint in ENHANCE-IT

was the measurement of eicosapentaenoic acid levels in the blood, which is regarded as a key surrogate marker in determining cardiovascular risk reduction.

In ENHANCE-IT, plasma EPA concentrations were significantly higher with LYPDISO vs.

VASCEPA (46% relative percent increase in the change from baseline EPA level vs VASCEPA).

Matinas stated that the results from ENHANCE-IT suggest potential for LYPDISO as a drug for cardiovascular risk reduction and announced that it is pursuing external partnerships to further develop LYPDISO for cardiovascular outcomes indication.

As a result, Matinas no longer plans to pursue an indication for the treatment of severe hypertriglyceridemia, instead focusing on the broader cardiovascular risk reduction indication.

A key secondary endpoint in ENHANCE-IT was the measurement of eicosapentaenoic acid levels in the blood, which is regarded as a key surrogate marker in determining cardiovascular risk reduction.

In ENHANCE-IT, plasma EPA concentrations were significantly higher with LYPDISO versus VASCEPA, with a 46% relative percentage increase in the change from baseline EPA level versus VASCEPA.

Matinas has announced that the results from ENHANCE-IT suggest potential for LYPDISO as a drug for cardiovascular risk reduction and announced that it is pursuing external partnerships to further develop LYPDISO for cardiovascular outcomes indication.

As a result, Matinas no longer plans to pursue an indication for the treatment of severe HTG, instead focusing on the broader cardiovascular risk reduction indication.

In June 2018, NeuroBo Pharmaceuticals, Inc.

(then-named Gemphire Therapeutics) announced positive topline results from a Phase 2b trial (INDIGO-1) of its drug candidate, gemcabene, in patients with severe hypertriglyceridemia.

(previously named Gemphire Therapeutics) announced positive topline results from a Phase 2b trial, or INDIGO-1, of its drug candidate, Gemcabene, in patients with severe hypertriglyceridemia.

Gemcabene is an oral, once-daily pill for a number of hypercholesterolemic populations and severe hypertriglyceridemia.

In August 2018, the U.S.

FDA requested that Gemphire conduct an additional long-term toxicity study before commencing any further clinical testing, thereby effectively placing gemcabene on a partial clinical hold.

FDA requested that Gemphire conduct an additional long-term toxicity study before commencing any further clinical testing, thereby effectively placing Gemcabene on clinical hold.

In March 2020 NeuroBo announced the completion of the requested studies, and in May 2020 the company announced that it received written communication from the U.S.

FDA that the clinical development program for Gemcabene remains on partial clinical hold.

FDA that the clinical development program for Gemcabene remains on partial clinical hold for severe HTG.

In June 2019, Gemphire announced top-line clinical results from a Phase 2 trial in Familial Partial Lipodystrophy (FPL)/NASH in which Gemcabene safely met the primary endpoint in a sub-set of patients.

Phase 3 studies for homozygous familial hypercholesterol emia (HoFH), heterozygous familial hypercholesterolemia (HeFH) and non-familial hypercholesterolemia in ASCVD patients are planned.

Phase 3 studies for homozygous familial (hypercholesterolemia, or HoFH), heterozygous familial hypercholesterolemia, or HeFH, and non-familial hypercholesterolemia in ASCVD patients are planned.

NeuroBO is currently assessing Gemcabene as an acute treatment for COVID-19.

Afimmune Ltd.

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announced positive results from an exploratory Phase 2 study of epeleuton in patients with NAFLD in which the molecule decreased triglycerides, improved glycemic control, and decreased markers of inflammation.

In August 2020, Afimmune reported Phase 2a study results of epeleuton in patients with NAFLD.

In August 2020, Afimmune reported Ph2a study results of epeleuton in patients with NAFLD.

Although epeleuton failed to meet the primary endpoint to demonstrate effects on liver enzyme elevation, it demonstrated significant reduction of triglycerides, HbA1c and potential for CV risk reduction.

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FDA, including communications in connection with its review of the ANCHOR indication for VASCEPA, it is our understanding that the U.S.

FDA is not prepared to approve any therapy for treatment of cardiovascular risk based on biomarker modification without cardiovascular outcomes study data, with the exception of therapies which lower LDL-cholesterol, depending on the circumstances.

FDA is not prepared to approve any therapy for treatment of cardiovascular risk based on biomarker modification without cardiovascular outcomes study data, with the potential exception of therapies which lower LDL-cholesterol, depending on the circumstances.

In particular, it is our understanding that the U.S.

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In our view, this position from the U.S.

FDA would likely not change based on the REDUCE-IT study particularly in light of significant independence of the positive benefit demonstrated in the REDUCE-IT study from triglyceride levels and benefit from the REDUCE-IT study supporting that the positive effects of VASCEPA are unique to VASCEPA extending beyond triglyceride reduction.

FDA were to take a different position, it could potentially have a negative impact on Amarin by making it easier for other products to achieve a cardiovascular risk reduction indication without the need in advance to conduct a long and expensive cardiovascular outcomes study.

FDA did not change based on the REDUCE-IT study particularly in light of significant independence of the positive benefit demonstrated in the REDUCE-IT study from triglyceride levels and benefit from the REDUCE-IT study supporting that the positive effects of VASCEPA are unique to VASCEPA and extend beyond triglyceride reduction.

FDA were to change this position, it could potentially have a negative impact on us by making it easier for other products to achieve a cardiovascular risk reduction indication without the need in advance to conduct a long and expensive cardiovascular outcomes study.

VASCEPA also faces competition from dietary supplement manufacturers marketing omega-3 products as nutritional supplements.

Such products are classified as food, not as prescription drugs or as over-the-counter drugs, by the U.S.

Such products are classified as food, not as prescription drugs or over-the-counter drugs, by the U.S.

FDA in the United States.

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Some of the promoters of such products have greater resources than us and are not restricted to the same standards as are prescription drugs with respect to promotional claims or manufacturing quality, consistency and subsequent product stability.

We have taken successful legal action against supplement manufacturers attempting to use the REDUCE-IT results to promote their products in the United States.

Still, we cannot be sure physicians and pharmacists will view the U.S.

Although we have taken successful legal action against supplement manufacturers attempting to use the REDUCE-IT results to promote their products, we cannot be sure physicians and pharmacists will view the U.S.

FDA-approved, prescription-only status, and EPA-only purity and stability of VASCEPA or U.S.

FDA’s stringent regulatory oversight, as significant advantages versus omega-3 dietary supplements regardless of clinical study results and other scientific data.

A similar competitive dynamic for VASCEPA exists in the jurisdictions outside the United States, including Europe, Canada and the greater China region.

In March 2021, we announced that the EC has approved the marketing authorization application for VAZKEPA to reduce the risk of cardiovascular events in certain high-risk, statin treated adult patients.

With the approval by the EC of VAZKEPA, there is currently no other drug that is approved for cardiovascular risk reduction in Europe in the at-risk patient population studied in REDUCE-IT.

In addition, there is currently no other direct competition for Canada and the Middle East.

However, consistent with the U.S., our competitors include large, well-established and experienced pharmaceutical companies, specialty and generic pharmaceutical companies, marketing companies, and specialized cardiovascular treatment companies and we have no experience as a company self-commercializing a product outside of the United States.

Although VASCEPA is currently the only drug that is approved for cardiovascular risk reduction in Europe in the at-risk patient population studied in REDUCE-IT, and there is currently no other direct competition for Canada and the Middle East, consistent with the U.S., our competitors include large, well-established and experienced pharmaceutical companies, specialty and generic pharmaceutical companies, marketing companies, and specialized cardiovascular treatment companies and we have no experience as a company self-commercializing a product outside of the United States.

Recent CV outcomes trials and meta-analyses with low and high dose omega-3 fatty acid mixtures containing DHA have not shown substantial benefit in patients receiving contemporary medical therapy, including statins.

Due to failed low dose omega-3 CV

outcomes trials, the European regulatory authorities have concluded that omega-3 fatty acid medicines (specifically Lovaza ® /Omacor ® ) at a dose of 1-gram per day are not effective in preventing further events for patients who have had a heart attack.

Due to failed low dose omega-3 CV outcomes trials, the European regulatory authorities have concluded that omega-3 fatty acid medicines (specifically Lovaza ® /Omacor ® ) at a dose of 1-gram per day are not effective in preventing further events for patients who have had a heart attack.

The STRENGTH trial of an omega-3 mixture studied at 4-grams per day also failed to demonstrate cardiovascular benefit.

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FDA approval based on preclinical or clinical studies conducted by others.

In addition to relying on U.S.

In addition to

relying on U.S.

FDA prior findings of safety and effectiveness for a referenced drug product, the U.S.

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Specifically, the applicant must certify in the application that:

(I) there is no patent information listed for the reference drug;

(II) the listed patent has expired for the reference drug;

(III) the listed patent for the reference drug has not expired, but will expire on a particular date and approval is sought after patent expiration;

(IV) the listed patent for the reference drug is invalid, unenforceable, or will not be infringed by the manufacture, use or sale of the product for which the ANDA or 505(b)(2) NDA is submitted.

there is no patent information listed for the reference drug;

the listed patent has expired for the reference drug;

the listed patent for the reference drug has not expired, but will expire on a particular date and approval is sought after patent expiration;

the listed patent for the reference drug is invalid, unenforceable, or will not be infringed by the manufacture, use or sale of the product for which the ANDA or 505(b)(2) NDA is submitted.

The Hatch-Waxman Amendments require an applicant for a drug product that relies, in whole or in part, on the U.S.

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We may also face challenges to the validity of our patents through a procedure known as inter partes review.

Inter partes review is a trial proceeding conducted through the Patent Trial and Appeal Board, of the U.S.

Patent and Trademark Office.

Inter partes review is a trial proceeding conducted through the Patent Trial and Appeal Board, of the USPTO.

Such a proceeding could be introduced against us within the statutory one-year window triggered by service of a complaint for infringement related to an ANDA filing or at any time by an entity not served with a complaint.

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Generic versions of VASCEPA made available in the market, even if based on a MARINE indication, only are often used to fill a prescription for any intended use of the drug.

If any approved ANDA filers are able to supply the product in significant commercial quantities, generic companies could introduce generic versions of VASCEPA in the market, as Hikma and Dr.

Reddy's did in November 2020 and June 2021, respectively, although each on a limited scale.

If any approved ANDA filers are able to supply the product in significant commercial quantities, generic companies could introduce generic versions of VASCEPA in the market, as did Hikma in November 2020, Dr.

Reddy's in June 2021 and Apotex in January 2022, although each on a limited scale to date.

Although any such introduction of a generic version of VASCEPA would also be subject to any litigation settlement terms and patent infringement claims (including any new claims and those that may then be subject to an appeal), pursuing such litigation may be prohibitively costly or could put a substantial constraint on our resources.

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sales, which would have a significant adverse impact on our business and results of operations.

In addition, even if a competitor’s effort to introduce a generic product is ultimately unsuccessful, the perception that such development is in progress and/or news related to such progress could materially affect the reputation of VASCEPA or the perceived value of our company and our stock price.

In addition, even if a competitor’s effort to introduce a generic product is ultimately unsuccessful, the perception that such development is in progress and/or news related to such progress or news related to litigation outcomes could materially affect the reputation of VASCEPA or the perceived value of our company and our stock price.

In addition, generic market entry, whether limited to its approved indication or not, can create market disruption which leads to an overall slowing of market growth regardless of whether the net price of the generic entry is higher or lower than the net price of the branded drug.

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While some companies with generic competition elect to launch an authorized generic form of the drug to counter the perception, real or imagined, that generics are less expensive, if launched, an authorized generic is typically aligned with reduction or elimination of promotion of the associated branded drug, thus limiting the extent of market growth and potentially contracting the overall size of the realized market penetration.

While an authorized generic could be profitable the market opportunity for growth from an authorized generic is likely less than from promotion of a branded drug, and as such we have not launched an authorized generic version of VASCEPA.

The active pharmaceutical ingredient in VASCEPA is difficult and time consuming to manufacture, often requires considerable advanced planning and long-term financial commitments to ensure sufficient capacity is available when needed and, perhaps not surprisingly, is reportedly in limited supply to our generic competitors, one of which has filed a lawsuit against us claiming we have engaged in anticompetitive practices related to our building of adequate supply for our needs and, in activities we believe were prompted by the generic competitor, government agencies are investigating our business as it relates to the supply of the active pharmaceutical ingredient in VASCEPA.

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We have invested over a decade to develop with individual members of our third-party, active pharmaceutical ingredient supply chain the technical knowhow, manufacturing processes and related regulatory approvals that have helped enable our suppliers to supply our clinical and commercial needs globally.

We have invested over a decade of resources and expenses to develop with our third-party, active pharmaceutical ingredient supply chain the technical knowhow, manufacturing processes and related regulatory approvals that have helped enable our suppliers to supply our clinical and commercial needs globally.

Based on statements made by Hikma and Dr.

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We believe such contact from the governments may have been prompted by a generic competitor.

We are cooperating with the agencies.

The government inquiries require us to produce documents and answer related questions relevant to specified time periods.

We are cooperating with the agencies.

Such investigations can be lengthy, costly and could materially affect and disrupt our business.

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Omega-3 fatty acids are marketed by others in a number of chemical forms as non-prescription dietary supplements.

We cannot be sure physicians and other providers will view the pharmaceutical grade purity and proven efficacy and safety of VASCEPA as having a superior therapeutic profile to unproven and loosely regulated omega-3 fatty acid dietary supplements.

We cannot be sure physicians and other providers will view the U.S.

FDA approval, pharmaceutical grade purity and proven efficacy and safety of VASCEPA as having a superior therapeutic profile to unproven and loosely regulated omega-3 fatty acid dietary supplements.

In addition, the U.S.

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Under the settlements, Coromega and Omax agreed to publicly correct their prior statements that wrongly suggested the REDUCE-IT cardiovascular outcomes trial supports the safety and efficacy of omega-3 dietary supplements.

dietary supplement company also acknowledged that as a general matter under federal law dietary supplements may be lawfully marketed to supplement the diet, but they cannot be lawfully marketed to treat, mitigate, or prevent disease, such as cardiovascular disease.

Each dietary supplement company also acknowledged that as a general matter under federal law dietary supplements may be lawfully marketed to supplement the diet, but they cannot be lawfully marketed to treat, mitigate, or prevent disease, such as cardiovascular disease.

Similarly, on August 30, 2017, we filed a lawsuit with the United States International Trade Commission, or the ITC, against manufacturers, importers, and distributors of products containing synthetically produced omega-3 products in ethyl ester or re-esterified triglyceride form that contain more EPA than DHA or any other single component for use in or as dietary supplements.

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FDA on the topic of synthetically produced omega-3 products through the citizen’s petition process and otherwise.

In addition, to the extent the net price of VASCEPA after insurance and offered discounts is significantly higher than the prices of commercially available omega-3 fatty acids marketed by other companies as dietary supplements (through that lack of coverage by insurers or otherwise), physicians and pharmacists may recommend these retail alternatives instead of writing or filling prescriptions for VASCEPA or patients may elect on their own to take commercially available omega-3 fatty acids.

In addition, to the extent the net price of VASCEPA after insurance and offered discounts is significantly higher than the prices of commercially available omega-3 fatty acids marketed by other companies as dietary supplements (through the lack of coverage by insurers or otherwise), physicians and pharmacists may recommend these retail alternatives instead of writing or filling prescriptions for VASCEPA or patients may elect on their own to take commercially available omega-3 fatty acids.

Also, insurance plans may increasingly impose policies that directly or indirectly favor supplement use over VASCEPA.

While VASCEPA is priced comparatively with, or in some cases lower than, many competing treatments, particularly when taking into account insurance coverage, such pricing might not be sufficient for healthcare providers or patients to elect VASCEPA over alternative treatments that may be perceived as less expense or more convenient to access.

If healthcare providers or patients favor dietary supplements over prescribing VASCEPA, we may be constrained in how we price our product of VASCEPA’s market acceptance may be less than expected, which would have a negative impact on our revenues and results of operations.

If healthcare providers or patients favor dietary supplements over prescribing VASCEPA, we may be constrained in how we price our product or VASCEPA’s market acceptance may be less than expected, which would have a negative impact on our revenues and results of operations.

The commercial value to us of sales of VASCEPA outside the United States may be smaller than we anticipate, including adequacy of product reimbursement such as in Europe, which can vary from country to country resulting in potential patient access restrictions.

There can be no assurance as to the adequacy for commercial success of VASCEPA outside the United States.

For example, despite having received EC approval to commercialize VAZKEPA in Europe and as we expect to obtain, through our partner Edding, marketing approval for VASCEPA in Mainland China, Hong Kong, Macau and Taiwan, or the China Territory, applicable regulatory agencies may impose restrictions on the product’s conditions for use, distribution or marketing and in some cases may impose ongoing requirements for post-market surveillance, post-approval studies or clinical trials.

There can be no assurance as to the market for VASCEPA outside the United States.

For example, despite having received EC approval to commercialize VAZKEPA in Europe and as we expect to obtain further, through our partner Edding, marketing approval for VASCEPA in Mainland China, Hong Kong, Macau and Taiwan, or the China Territory, applicable regulatory agencies may impose restrictions on the product’s conditions for use, distribution or marketing and in some cases may impose ongoing requirements for post-market surveillance, post-approval studies or clinical trials.

Further, securing adequate reimbursement is critical for commercial success of any therapeutic and pricing and reimbursement levels of medications in markets outside the United States can be unpredictable and vary considerably on a country-by-country basis.

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FDA approval for product and manufacturing changes, depending on the nature of the change.

We also are subject to the federal transparency requirements under the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively the ACA, enacted in March 2010, which require manufacturers of certain drugs, devices, biologics, and medical supplies to report to the Centers for Medicare & Medicaid Services, or CMS, information related to payments and other transfers of value to physicians and teaching hospitals and physician ownership and investment interests.

We may also be subject, directly or indirectly through our customers and partners, to various fraud and abuse laws, including, without limitation, the U.S.

Anti-Kickback Statute, U.S.

FCA, and similar state laws, which impact, among other things, our proposed sales, marketing, and scientific/educational grant programs.

In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are subject to periodic unannounced inspections by the U.S.

FDA and state agencies for compliance with cGMP requirements.

We participate in the U.S.

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As discussed above, in June 2020, we received a CID from the DOJ informing us that the DOJ is investigating whether aspects of our promotional speaker programs and copayment waiver programs during the period from January 1, 2015 to the present violated the U.S.

Anti-Kickback Statute and the U.S.

Anti-Kickback

Statute and the U.S.

FCA in relation to the sale and marketing of VASCEPA by us and our previous co-marketing partner, Kowa America.

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The continuing efforts of the U.S.

and foreign governments, insurance

companies, managed care organizations and other payors of healthcare services to contain or reduce healthcare costs may adversely affect our ability to set prices for our products which we believe are fair, and our ability to generate revenues and achieve and maintain profitability.

and foreign governments, insurance companies, managed care organizations and other payors of healthcare services to contain or reduce healthcare costs may adversely affect our ability to set prices for our products which we believe are fair, and our ability to generate revenues and achieve and maintain profitability.

Specifically, in both the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes to the healthcare system in ways that could affect our ability to sell our products profitably.

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The Joint Select Committee did not achieve a targeted deficit reduction, which triggered the legislation’s automatic reductions.

In concert with subsequent legislation, this has resulted in aggregate reductions to Medicare payments to providers of, on average, 2% per fiscal year through 2030 unless Congress takes additional action.

In concert with subsequent legislation, this has resulted in aggregate reductions to Medicare payments to providers of, on average, 2% per fiscal year through 2030 with the exception of a temporary suspension from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic.

Following the suspension, a 1% payment reduction took place beginning April 1, 2022 and will continue through June 30, 2022, and the 2% payment reduction will resume on July 1, 2022.

These cuts reduce reimbursement payments related to our products, which could potentially negatively impact our revenue.

However, these Medicare sequester reductions have been suspended through December 31, 2021 due to the COVID-19 pandemic.

Also for example, the ACA has substantially changed the way healthcare is financed by both governmental and private insurers and has significantly impacted the U.S.

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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 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.

On July 24, 2020 and September 13, 2020, President Trump announced several executive orders related to prescription drug pricing that sought to implement several of the administration’s proposals.

In response, the U.S.

FDA released a final rule on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020 CMS issued an Interim Final Rule implementing the Most Favored Nation Model, or the MFN Model, under which Medicare Part B reimbursement rates will be calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita.

The MFN Model regulations mandate participation by identified Part B providers and would have applied to all U.S.

states and territories for a seven-year period beginning January 1, 2021 and ending December 31, 2027.

However, on August 6, 2021, CMS announced a proposed rule to rescind the MFN Model.

Further, authorities in Canada have passed rules designed to safeguard the Canadian drug supply from shortages.

If implemented, importation of drugs from Canada and regulations similar to the MFN Model, or if the MFN Model is reinstated, may materially and adversely affect the price we receive for any of our products and product candidates.

On November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

Specifically, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several 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, and review the relationship between pricing and manufacturer patient programs.

At a federal level, President Biden signed an Executive Order on July 9, 2021 affirming the administration's policy to (i) support legislative reforms that would lower the prices of prescription drug and biologics, including by allowing Medicare to negotiate drug prices, by imposing inflation caps, and, by supporting the development and market entry of lower-cost generic drugs and biosimliars;

and (ii) support the enactment of a public health insurance option.

Among other things, the Executive Order also directs HHS to provide a report on actions to combat excessive pricing of prescription drugs, enhance the domestic drug supply chain, reduce the price that the federal government pays for drugs,

and address price gouging in the industry;

and directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA's implementing regulations.

FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

On September 25, 2020, CMS stated drugs imported by states under this rule will not be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers would not report these drugs for "best price" or Average Manufacturer Price purposes.

Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average Drug Acquisition Cost for these drugs.

If implemented, importation of drugs from Canada may materially and adversely affect the price we receive for any of our product candidates.

Further, on November 20, 2020 CMS issued an Interim Final Rule implementing the Most Favored Nation, or MFN, Model under which Medicare Part B reimbursement rates would have been calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita.

However, on December 29, 2021 CMS rescinded the Most Favored Nations rule.

Additionally, on November 30, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Pursuant to an order entered by the U.S.

District Court for the District of Columbia, the portion of the rule eliminating safe harbor protection for certain rebates related to the sale or purchase of a pharmaceutical product from a manufacturer to a plan sponsor under Medicare Part D has been delayed to January 1, 2023.

Further, implementation of this change and new safe harbors for point-of-sale reductions in price for prescription pharmaceutical products and pharmacy benefit manager service fees are currently under review by the Biden administration and may be amended or repealed.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, Congress has indicated that it will continue to seek new legislative measures to control drug costs.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological 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, the State of California enacted legislation that requires notice for exceeding specified limits on annual drug price increases and other legislation that seeks to limit the use of co-pay cards in certain situations.

Pursuant to court order, the removal and addition of the aforementioned safe harbors were delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2026.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

In addition, it is time-consuming and expensive for us to go through the process of seeking coverage and reimbursement from Medicare and private payors.

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For example, proposals are being considered to expand the use of dietary supplements in addition to or in place of drugs in government and private payor plans.

In addition, cost control initiatives

could decrease the price that we or any potential collaborators could receive for any of our future products and could adversely affect our profitability.

In addition, cost control initiatives could decrease the price that we or any potential collaborators could receive for any of our future products and could adversely affect our profitability.

These and similar regulatory dynamics, including the recent entry of generic versions of VASCEPA into the market, and the potential for additional generic versions in the near term, can affect our ability to commercialize VASCEPA on commercially reasonable terms and limit the commercial value of VASCEPA.

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Those rebates are based on pricing data reported by us on a monthly and quarterly basis to CMS, the federal agency that administers the Medicaid Drug Rebate program.

These data include the average manufacturer price and, in the case of innovator products, the best price for each drug which, in general, represents the lowest price available from the manufacturer to any entity in the U.S.

in any pricing structure, calculated to include all sales and associated rebates, discounts and other price concessions.

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These 340B covered entities include a variety of community health clinics and other entities that receive health services grants from the Public Health Service, as well as hospitals that serve a disproportionate share of low-income patients.

The 340B ceiling price is calculated using a statutory formula based on the average manufacturer price and Medicaid rebate amount for the covered outpatient drug as calculated under the Medicaid Drug Rebate program, and in general, products subject to Medicaid price reporting and rebate liability are also subject to the 340B ceiling price calculation and discount requirement.

program, and in general, products subject to Medicaid price reporting and rebate liability are also subject to the 340B ceiling price calculation and discount requirement.

Any additional future changes to the definition of average manufacturer price and the Medicaid rebate amount under the ACA, other legislation, or in regulation could affect our 340B ceiling price calculations and negatively impact our results of operations.

The Health Resources and Services Administration, or HRSA, which administers the 340B program, issued a final regulation regarding the calculation of the 340B ceiling price and the imposition of civil monetary penalties on manufacturers that knowingly and intentionally overcharge covered entities, which became effective on January 1, 2019.

It is currently unclear how HRSA will apply its enforcement authority under the new regulation.

We also are required to report our 340B ceiling prices to HRSA on a quarterly basis.

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In the U.S., Europe and other regions globally, sales of pharmaceutical drugs are dependent, in part, on the availability of reimbursement to the consumer from third-party payors, such as government and private insurance plans.

Third-party payors decide which products and services they will cover and establish reimbursement rates for those products and services.

Third-party payors decide which products and services they will cover and the conditions for such coverage.

Third party payors also establish reimbursement rates for those products and services.

Increasingly, third-party payors are challenging the prices charged for medical products and services.

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We are unable to predict the reimbursement policies employed by third-party healthcare payors.

We expect to experience pricing and reimbursement pressures in connection with the sale of our products due to the trend toward managed healthcare, the increasing influence of health maintenance organizations and additional legislative and executive proposals.

In addition, we may confront limitations in insurance coverage for our products.

proposals, as well as the availability of generic versions of VASCEPA.

In addition, we may confront limitations in, or exclusions from, insurance coverage for our products, particularly as generic competition intensifies.

If we fail to successfully secure and maintain reimbursement coverage for our approved drugs or are significantly delayed in doing so, we may have difficulty achieving market acceptance of our approved drugs and investigational drug candidates for which we obtain approval, and our business may be harmed.

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effective January 1, 2019.

The Bipartisan Budget Act of 2018, or the BBA, among other things, amends the ACA to create a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% (an increase from 50% effective as of January 1, 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturer’s outpatient drugs to be covered under

Medicare Part D.

Under the Trump administration, CMS issued regulations that gave states greater flexibility, starting in 2020, in the identification of the essential health benefits benchmarks for non-grandfathered individual and small group market health insurance coverage, including plans sold through the health insurance exchanges established under the ACA.

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It is unclear how other healthcare reform measures of the Biden administration or other efforts, if any, to challenge, repeal or replace the ACA will impact our business.

The Trump administration’s budget proposal for fiscal year 2021 included a $135.0 billion allowance to support legislative proposals seeking to reduce drug prices, increase competition, lower out-of-pocket drug costs for patients, and increase patient access to lower-cost generic and biosimilar drugs.

On March 10, 2020, the Trump administration sent “principles”

for drug pricing to Congress, calling for legislation that would, among other things, cap Medicare Part D beneficiary out-of-pocket pharmacy expenses, provide an option to cap Medicare Part D beneficiary monthly out-of-pocket expenses, and place limits on pharmaceutical price increases.

Further, the Trump administration also previously released a “Blueprint”

to lower drug prices and reduce out of pocket costs of drugs that contains additional proposals to increase manufacturer competition, increase the negotiating power of certain federal healthcare programs, incentivize manufacturers to lower the list price of their products and reduce the out of pocket costs of drug products paid by consumers.

The HHS has already started the process of soliciting feedback on some of these measures and, at the same time, began implementing others under its existing authority.

For example, in May 2019, CMS issued a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.

However, it is unclear whether the Biden administration will challenge, reverse, revoke or otherwise modify these executive and administrative actions.

In addition, there have been several changes to the 340B drug pricing program, which imposes ceilings on prices that drug manufacturers can charge for medications sold to certain health care facilities.

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which was within the Secretary’s discretion to make but was instead a fundamental change in the reimbursement calculation.

However, most recently, on July 31, 2020, the U.S.

However, on July 31, 2020, the U.S.

Court of Appeals for the District of Columbia Circuit overturned the district court’s decision and found that the changes were within the Secretary’s authority.

On September 14, 2020, the plaintiffs-appellees filed a Petition for Rehearing En Banc (i.e., before the full court), but was denied on October 16, 2020.

On February 10, 2021, plaintiffs-appellees filed a writ of certiorari with the U.S.

Supreme Court.

Supreme Court granted the writ of certiorari on July 2, 2021 and oral arguments were held on November 30, 2021.

The Court's decision should be released in the coming months.

It is unclear how these developments could affect covered hospitals who might purchase our future products and affect the rates we may charge such facilities for our approved products in the future, if any.

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In the United States, numerous federal and state laws and regulations, including federal health information privacy laws, state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws (e.g., Section 5 of the Federal Trade Commission Act), that govern the collection, use, disclosure and protection of health-related and other personal information could apply to our operations or the operations of our collaborators.

In addition, we may obtain health information from third parties (including research institutions from which we obtain

clinical trial data) that are subject to privacy and security requirements under the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA.

In addition, we may obtain health information from third parties (including research institutions from which we obtain clinical trial data) that are subject to privacy and security requirements under the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA.

Although we are not directly subject to HIPAA –

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European data collection is governed by restrictive regulations governing the use, processing and cross-border transfer of personal information.

The REDUCE-IT cardiovascular outcomes trial was conducted in part through clinical sites in the EU.

The REDUCE-IT cardiovascular outcomes trial was conducted in part through clinical sites in the EEA.

As a result, we are subject to additional privacy restrictions.

The collection and use of personal health data in the EU is governed by the provisions of the General Data Protection Regulation, or GDPR.

The collection and use of personal health data in the EU is governed by the provisions of the GDPR.

The GDPR imposes several requirements relating to the legal basis for processing personal data which may include the consent of the individuals to whom the personal data relates, the information provided to the individuals and the security and confidentiality of the personal data.

The GDPR also imposes strict rules on the transfer of personal data out of the EU to the United States.

Failure to comply with the requirements of the GDPR, and the related national data protection laws of the EU Member States may result in restrictions against regulatory approval in the EU or substantial fines for breaches of the data protection rules.

The GDPR also imposes strict rules on the transfer of personal data out of the EEA to the United States.

A decision by the Court of Justice of the European Union, or CJEU, in 2020 invalidated the EU-U.S.

Privacy Shield Framework, which was one of the primary mechanisms used by U.S.

companies to import personal information from Europe in compliance with the GDPR's cross-border data transfer restrictions, and raised questions about whether the EC's Standard Contractual Clauses, or SCCs, one of the primary alternatives to the Privacy Shield, can lawfully be used for personal information transfers from Europe to the United States or most other countries.

Furthermore, on June 4, 2021, the EC issued new forms of standard contractual clauses for data transfers from controllers or processors in the EEA, or otherwise subject to the GDPR, to controllers or processors established outside the EEA, and not subject to the GDPR.

The new forms of standard contractual clauses have replaced the standard contractual clauses that were adopted previously under the Data Protection Directive.

We will be required to transition to the new forms of standard contractual clauses and doing so will require significant effort and cost.

The new standard contractual clauses may also impact our business as companies based in Europe may be reluctant to utilize the new clauses to legitimize transfers of personal information to third countries given the burdensome requirements of transfer impact assessments and the substantial obligations that the new standard contractual clauses impose upon exporters.

Failure to comply with the requirements of the GDPR, and the related national data protection laws of the EEA Member States may result in restrictions against regulatory approval in the EEA or substantial fines for breaches of the data protection rules.

The GDPR may impose additional responsibility and liability in relation to personal data that we process and we may be required to put in place additional mechanisms ensuring compliance with these and/or new data protection rules.

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Even though we received U.S.

FDA marketing approval for VASCEPA for the MARINE indication and for cardiovascular risk reduction based on the REDUCE-IT study, and we believe the First Amendment court ruling and litigation settlement affords us a degree of protection for other promotional efforts, physicians may still prescribe VASCEPA to their patients for use in the treatment of conditions that are not included as part of the indication statement in our U.S.

FDA marketing approval for VASCEPA for the MARINE indication and for cardiovascular risk reduction based on the REDUCE-IT study, and our settlement with the U.S.

FDA affords us a degree of protection for other promotional efforts, physicians may still prescribe VASCEPA to their patients for use in the treatment of conditions that are not included as part of the indication statement in our U.S.

FDA-approved VASCEPA label or our settlement.

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FDA approved VASCEPA for use in the MARINE indication in July 2012, U.S.

FDA did not dispute the veracity of the ANCHOR trial data and, in connection with the March 2016 agreement we reached with the

FDA did not dispute the veracity of the ANCHOR trial data and, in connection with the March 2016 agreement we reached with the U.S.

FDA allowing us to promote the results of the ANCHOR study, the U.S.

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The discovery of previously unknown problems with a clinical trial or product, or in connection with the manufacturer of products, may result in regulatory issues that prevent proposed future approvals of a product and/or restrictions on that product or manufacturer, including withdrawal of an indication or the product from the market, which would have a negative impact on our potential revenue stream.

* As we continue to build our infrastructure for commercializing VASCEPA, we may encounter difficulties in managing our growth and expanding, or streamlining, our operations successfully.

As we continue to build our infrastructure for commercializing VASCEPA, we may encounter difficulties in managing the scale of our operations successfully.

The process of establishing, maintaining, expanding and streamlining a commercial infrastructure is difficult, expensive and time-consuming.

As a result of the COVID-19 pandemic and the related social distancing, in March 2020, we suspended face-to-face interactions between our sales representatives and healthcare professionals.

We resumed on a limited basis field-based, face-to-face interactions with healthcare providers beginning in June 2020.

In the fourth quarter of 2020 and in early 2021, the impact of COVID-19 worsened in some parts of the United States, with some physicians again limiting access to face-to-face interactions with our field force personnel.

Accordingly, we have intentionally slowed the hiring of replacements for our open positions which resulted from ordinary turnover and as announced on September 22, 2021 we have reduced our U.S.

We implemented a Go-to-Market strategy in an effort to optimize provider engagement and drive demand for VASCEPA in the United States by shifting reliance on sales force interactions with healthcare professionals to providing managed care and prescription access through an omnichannel platform.

Accordingly, as announced on September 22, 2021 we reduced our U.S.

field force to approximately 300 sales representatives.

As we observe the results of the new Go-to-Market strategy and witness our sales representatives increasingly able to resume direct interactions with healthcare professionals, we will continue to evaluate our needs and, including the need to fill open positions, or expand or further streamline our sales force, as appropriate to meet our business needs.

As we observe the results of the Go-to-Market strategy and as practices impacted by COVID-19 stabilize, we will continue to evaluate our needs, including the need to fill open positions, or expand or further streamline our sales force, as appropriate to meet our business needs.

Our sales team promotes VASCEPA to a limited group of physicians and other healthcare professionals in select geographies in the United States and is not large enough to call upon all physicians.

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Future growth and streamlining efforts will impose significant added responsibilities on members of management, including the need to identify, recruit, maintain and integrate the right number of employees.

For example, in Europe we commenced 2021 with approximately 50 professionals involved in pre-approval and pre-launch planning and other commercial preparation activities, with plans to continue to expand our European staff as deemed appropriate on a country by country basis.

For example, in Europe we have built out our team subsequent to EC approval of the marketing authorization acceptance in 2021, with plans to continue to expand our European staff as deemed appropriate on a country by country basis.

The time required to secure reimbursement tends to vary from country to country and cannot be reliably predicted at this time.

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We may not be able to accomplish these tasks, and our failure to accomplish any of them could prevent us from successfully growing our company.

Our life-cycle management, in large part, currently depends on our ability to develop, obtain regulatory approval and commercialize a fixed-dose combination of VASCEPA and yet to be disclosed statins.

Specifically, our drug development efforts are subject to the risks and uncertainties inherent in any drug development program.

Due to the risks and uncertainties involved in progressing through development and bioequivalence or even potential additional trials (as may be required by specific regulatory agencies), and the time and cost involved in obtaining regulatory approvals, among other factors, we cannot reasonably estimate the timing, completion dates and costs, or range of costs, of our drug development program, or of the successful development of any particular fixed-dose combination.

The potential success of any fixed-dose combination will depend on a number of factors, including the following:

Our ability to successfully manufacture a combination of VASCEPA and statin;

Our ability to maintain a supply of necessary statin for use in the fixed-dose combination;

Our ability to obtain regulatory approvals for any and all markets in which we intend to commercialize a fixed-dose combination of VASCEPA and a statin;

Our ability to obtain payor acceptance and market access for a fixed-dose combination product of VASCEPA and a statin;

Our ability to achieve market acceptance of a fixed-dose combination of VASCEPA and a statin.

Risks Related to Our Reliance on Third Parties

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We have no in-house manufacturing capacity and rely on contract manufacturers for our clinical and commercial product supply.

We cannot ensure that we will successfully manufacture any product we may develop, either independently or under manufacturing arrangements, if any, with our third-party manufacturers.

We cannot provide assurance that we will successfully manufacture any product we may develop, either independently or under manufacturing arrangements, if any, with our third-party manufacturers.

Moreover, if our manufacturers should cease doing business with us or experience delays, shortages of supply or excessive demands on their capacity, we may not be able to obtain adequate quantities of product in a timely manner, or at all.

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Any unanticipated disruption to future contract manufacture caused by problems at suppliers could delay shipment of products, increase our cost of goods sold and/or result in lost sales.

If our suppliers were unable to supply us with adequate volumes of active pharmaceutical ingredient (drug substance) or encapsulated bulk product (drug product), it would have a material adverse effect on our ability to continue to commercialize VASCEPA.

If our suppliers were unable to supply us with adequate volumes of active pharmaceutical ingredient, API, (drug substance) or encapsulated bulk product (drug product), it would have a material adverse effect on our ability to continue to commercialize VASCEPA.

We have contractual freedom to source the API for VASCEPA and to procure other services supporting our supply chain.

We have entered into supply agreements with multiple suppliers who also rely on other third-party suppliers to manufacture the API and other elements necessary for the sale of VASCEPA.

Our strategy in sourcing API and other components in our supply chain from multiple suppliers has been to expand manufacturing capacity, maintain competitive advantages, and mitigate the risk of reliance on any single supplier.

Our strategy in sourcing API and other components in our supply chain from

multiple suppliers has been to expand manufacturing capacity, maintain competitive advantages, and mitigate the risk of reliance on any single supplier.

Expanding manufacturing capacity and qualifying such capacity is complex and subject to numerous regulations and other operational challenges.

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The resources of our suppliers vary and are limited;

costs associated with projected expansion and qualification can be significant.

And, lead-times for supply purchases and capacity expansion are long requiring certain supply related decisions and commitment to be made in advance, for example, prior to commercial launch in China and in various European countries.

costs associated with projected expansion and qualification can be significant, and lead-times for supply purchases and capacity expansion are long requiring certain supply related decisions and commitment to be made in advance, for example, prior to commercial launch in China and in various European countries.

There can be no assurance that the expansion plans of any of our suppliers will be successful.

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Certain of our agreements also include contractual minimum purchase commitments regardless of the rolling 12-month forecasts.

We may not purchase sufficient quantities of VASCEPA to meet actual demand or our purchase of supply may exceed actual demand.

We may not purchase sufficient quantities of VASCEPA to meet actual demand or we may be required to purchase more supply than needed to meet actual demand.

In either case, such event could have a material adverse effect on our financial results and financial condition.

Our dependence on third parties in the distribution channel from our manufacturers to patients subject us to risks that limit our profitability and could limit our ability to supply VASCEPA to large market segments.

We sell VASCEPA principally to a limited number of major wholesalers, as well as selected regional wholesalers and specialty pharmacy providers, or collectively, our distributors or our customers, that in turn resell VASCEPA to retail pharmacies for subsequent resale to patients and healthcare providers.

We sell VASCEPA principally to a limited number of major wholesalers, as well as selected regional wholesalers and mail order pharmacy providers, or collectively, our distributors or our customers, that in turn resell VASCEPA to retail pharmacies for subsequent resale to patients and healthcare providers.

These parties exercise a substantial amount of bargaining power over us given their control over large segments of the market for VASCEPA.

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FDA and would again require us to demonstrate product comparability to the U.S.

If any third-party manufacturer with whom we contract fails to perform its obligations, we may be forced to manufacture the materials ourselves, for which we may not have the capabilities or resources, or enter into an agreement with a different third-party manufacturer, which we may not be able to do on reasonable terms, if at all.

In either scenario, our clinical trials or commercial distribution could be delayed significantly as we establish alternative supply sources.

In some cases, the technical skills required to manufacture our products or product candidates may be unique or proprietary to the original third-party manufacturer and we may have difficulty, or there may be contractual restrictions prohibiting us from, transferring such skills to a back-up or alternate supplier, or we may be unable to transfer such skills at all.

In addition, if we are required to change third-party manufacturer for any reason, we will be required to verify that the new third-party manufacturer maintains facilities and procedures that comply with quality standards and with all applicable regulations.

We will also need to verify, such as through a manufacturing comparability study, that any new manufacturing process will produce our product according to the specifications previously submitted to or approved by the U.S.

FDA or another regulatory authority.

The delays associated with the verification of a new third-party manufacturer could negatively affect our ability to develop product candidates or commercialize our products in a timely manner or within budget.

Furthermore, a third-party manufacturer may possess technology related to the manufacture of our product candidate that such third-party manufacturer owns independently.

This would increase our reliance on such third-party manufacturer or require us to obtain a license from such third-party manufacturer in order to have another third-party manufacturer manufacture our products or product candidates.

In addition, in the case of the third-party manufacturers that supply our product candidates, changes in manufacturers often involve changes in manufacturing procedures and processes, which could require that we conduct bridging studies between our prior clinical supply used in our clinical trials and that of any new manufacturer.

We may be unsuccessful in demonstrating the comparability of clinical supplies which could require the conduct of additional clinical trials.

There are comparable foreign requirements under ICH guidelines.

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FDA does not consider the result of the process validation or required testing to be satisfactory, the commercial supply of VASCEPA may be delayed, or we may not be able to supply sufficient quantities of VASCEPA to meet anticipated demand.

On March 27, 2020, former President Trump signed into law the CARES Act in response to the COVID-19 pandemic.

Throughout the COVID-19 pandemic, there has been public concern over the availability and accessibility of critical medical products, and the CARES Act enhances U.S.

FDA’s existing authority with respect to drug shortage measures.

Under the CARES Act, we must have in place a risk management plan that identifies and evaluates the risks to the supply of approved drugs for certain serious diseases or conditions for each establishment where the drug or API is manufactured.

The risk management plan will be subject to U.S.

FDA review during an inspection.

If we experience shortages in the supply of our marketed products, our results could be materially impacted.

FDA and similar foreign regulatory bodies may also implement new requirements, or change their interpretation and enforcement of existing requirements, for manufacture, packaging or testing of products at any time.

If we or our approved suppliers are unable to comply, we may be subject to regulatory, civil actions or penalties, or we may be prevented from manufacturing or selling VASCEPA, all of which could significantly and adversely affect our business.

Furthermore, reductions in government operations due to pandemic mitigation efforts, or other factors, may delay timely regulatory review by U.S.

FDA or similar foreign regulatory bodies.

For example, since March 2020 when foreign and domestic inspections of facilities were largely placed on hold, the

FDA has been working to resume routine surveillance, bioresearch monitoring and pre-approval inspections on a prioritized basis.

Since April 2021, the U.S.

FDA has conducted limited inspections and employed remote interactive evaluations, using risk management methods, to meet user fee commitments and goal dates.

Ongoing travel restrictions and other uncertainties continue to impact oversight operations both domestic and abroad and it is unclear when standard operational levels will resume.

FDA is continuing to complete mission-critical work, prioritize other higher-tiered inspectional needs (e.g., for-cause inspections), and carry out surveillance inspections using risk-based approaches for evaluating public health.

Should the U.S.

FDA determine that an inspection is necessary for approval and an inspection cannot be completed during the review cycle due to restrictions on travel, and the U.S.

FDA does not determine a remote interactive evaluation to be adequate, the agency has stated that it generally intends to issue, depending on the circumstances, a complete response letter or defer action on the application until an inspection can be completed.

During the COVID-19 public health emergency, a number of companies announced receipt of complete response letters due to the U.S.

FDA’s inability to complete required inspections for their applications.

Regulatory authorities outside the U.S.

may adopt similar restrictions or other policy measures in response to the ongoing COVID-19 pandemic and may experience delays in their regulatory activities.

Our commercialization of VASCEPA outside the United States is substantially dependent on third parties and other circumstances outside our control.

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Under the DCS Agreement, Edding is responsible for development and commercialization activities in the China Territory and associated expenses.

Additionally, Edding is

required to conduct clinical trials in the China Territory to secure regulatory approval in certain territories.

In December 2017, Edding commenced a pivotal clinical trial aimed to demonstrate that VASCEPA lowers triglyceride levels and otherwise has beneficial effects in Chinese patients with severe hypertriglyceridemia (TG >500 mg/dL), as we previously demonstrated with VASEPA in the more diverse population studied in the MARINE study.

Additionally, Edding is required to conduct clinical trials in the China Territory to secure regulatory approval in certain territories.

In December 2017, Edding commenced a pivotal Phase 3 clinical trial aimed to demonstrate that VASCEPA lowers triglyceride levels and otherwise has beneficial effects in Chinese patients with severe hypertriglyceridemia (TG >500 mg/dL), as we previously demonstrated with VASCEPA in the more diverse population studied in the MARINE study.

In November 2020, we announced statistically significant positive topline results from Edding’s Phase 3 clinical trial of VASCEPA.

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The Chinese National Medical Products Administration, or NMPA, has accepted for review the new drug application for VASCEPA, submitted by Edding, based on the results from the Phase 3 clinical trial and the results from our prior studies of VASCEPA.

We expect to receive a decision from the NMPA in Mainland China near the end of 2021.

The Hong Kong Department of Health is evaluating VASCEPA based on current approvals in the United States and Canada.

The review process in Hong Kong is expected to conclude near the end of 2021.

We expect to receive a decision from the NMPA in Mainland China in the second half of 2022.

On February 23, 2022 the Hong Kong Department of Health completed their evaluation and approved the use of VASCEPA under the REDUCE-IT indication.

Even though such results are similar to the MARINE study, additional clinical development efforts may be necessary in this market to demonstrate the effectiveness of VASCEPA in reducing major adverse cardiovascular events in Chinese patients with persistent cardiovascular risk.

Any development and regulatory efforts in the China Territory may be negatively impacted if the coronavirus pandemic continues or spreads, and if resources by regulators and industry professionals continue to be diverted to address the prolonged coronavirus outbreak.

Any development and regulatory efforts in the China Territory may be negatively impacted by heightened political tension between China and the United States, including in connection with COVID-19 and other issues expressed between the countries regarding trade practices, tariffs and honoring intellectual property rights.

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Under the terms of the distribution agreement, we granted to Biologix a non-exclusive license to use our trademarks in connection with the importation, distribution, promotion, marketing and sale of VASCEPA in the Middle East and North Africa territory.

Biologix obtained approval of VASCEPA in Lebanon in March 2018, in United Arab Emirates in July 2018, in Qatar in January 2020 and Bahrain in December 2020.

Biologix was approved under the MARINE indication in the following countries:

Lebanon in March 2018, United Arab Emirates in July 2018, Qatar in December 2019, Bahrain in April 2021, Kuwait in December 2021 and Saudi Arabia in March 2022.

VASCEPA was approved under the REDUCE-IT indication in the following countries:

Qatar in April 2021, Lebanon in August 2021 and United Arab Emirates in October 2021.

VASCEPA was launched in Lebanon and the United Arab Emirates in June 2018 and February 2019, respectively.

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In January 2020, HLS obtained an extended regulatory exclusivity designation.

In February 2020, HLS launched VASCEPA in Canada, with strong initial uptake before the impact of COVID-19 pandemic.

In February 2020, HLS

launched VASCEPA in Canada, with strong initial uptake before the impact of COVID-19 pandemic.

In July 2020, Patented Medicine Prices Review Board confirmed VASCEPA price is compliant with current guidelines, and CADTH recommended reimbursement for VASCEPA in Canada in secondary prevention population.

However, if HLS is not able to effectively commercialize VASCEPA in Canada through effective pricing (initially and over time), reimbursement or otherwise we may not be able to generate revenue from the sale of VASCEPA in Canada.

Our efforts to launch VAZKEPA on our own in Europe is a complex undertaking for a company that, other than our recent launch of VAZKEPA in Germany in September 2021, has not launched a product in Europe and could be subject to significant risks of execution to our successful development and revenue generation of VAZKEPA in Europe.

Our efforts to launch and support commercialization of VAZKEPA on our own in Europe is a complex undertaking for a company that, other than our recent launch of VAZKEPA in Germany in September 2021, has not launched or otherwise commercialized a product in Europe and could be subject to significant risks of execution to our successful development and revenue generation of VAZKEPA in Europe.

While various of our suppliers have been inspected and we do not anticipate supply availability limiting our launch in Europe, COVID-19 has limited the ability of suppliers to be inspected and not all of our suppliers have completed all of the requirements of the European regulatory authorities.

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Healthcare providers, physicians and third-party payors in the United States and elsewhere play a primary role in the recommendation and prescription of pharmaceutical products.

Arrangements with third-party payors and customers can expose pharmaceutical manufacturers to broadly applicable fraud and abuse and other healthcare laws and regulations, which may constrain

the business or financial arrangements and relationships through which such companies sell, market and distribute pharmaceutical products.

Arrangements with third-party payors and customers can expose pharmaceutical manufacturers to broadly applicable fraud and abuse and other healthcare laws and regulations, which may constrain the business or financial arrangements and relationships through which such companies sell, market and distribute pharmaceutical products.

In particular, the promotion, sales and marketing of healthcare items and services, as well as a wide range of pricing, discounting, marketing and promotion, structuring and commission(s), certain customer incentive programs and other business arrangements, are subject to extensive laws designed to prevent fraud, kickbacks, self-dealing and other abusive practices.

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When an entity is determined to have violated the FCA, the government may impose civil fines and penalties for each false claim, plus treble damages, and exclude the entity from participation in Medicare, Medicaid and other federal healthcare programs.

Pharmaceutical and other healthcare companies also are subject to other federal false claims laws, including, among others, federal criminal healthcare fraud and false statement statutes that extend to non-government health benefit programs;

Pharmaceutical and other healthcare

companies also are subject to other federal false claims laws, including, among others, federal criminal healthcare fraud and false statement statutes that extend to non-government health benefit programs;

HIPAA, which, among other things, imposes criminal and civil liability for knowingly and willfully executing a scheme to defraud any healthcare benefit program, including private third-party payor and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services;

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Such investigations can be lengthy, costly and could materially affect and disrupt our business.

If the government determines that we have violated the U.S Anti-Kickback Statute, the FCA or antitrust regulations, we could be subject to significant civil and criminal fines and penalties.

If the government determines that we have

violated the U.S.

Anti-Kickback Statute, the FCA or antitrust regulations, we could be subject to significant civil and criminal fines and penalties.

The failure to comply with any of these laws or regulatory requirements subjects entities to possible legal or regulatory action.

Depending on the circumstances, failure to meet applicable regulatory requirements can result in significant civil, criminal and administrative penalties, damages, fines, disgorgement, individual imprisonment, exclusion from participation in federal and state funded healthcare programs (such as Medicare and Medicaid), contractual damages and the curtailment or restructuring of our operations, as well as 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.

Any action for violation of these laws, even if successfully

defended, could cause a pharmaceutical manufacturer to incur significant legal expenses and divert management’s attention from the operation of the business.

Any action for violation of these laws, even if successfully defended, could cause a pharmaceutical manufacturer to incur significant legal expenses and divert management’s attention from the operation of the business.

If any of the physicians or other healthcare providers or entities with whom we expect to do business is found not to be in compliance with applicable laws, that person or entity may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

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Although compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent inappropriate conduct may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.

Third party patient assistance programs that receive financial support from companies have become the subject of enhanced government and regulatory scrutiny.

Government enforcement agencies have shown increased interest in pharmaceutical companies' product and patient assistance programs, including reimbursement support services, and a number of investigations into these programs have resulted in significant civil and criminal settlements.

government has established guidelines that suggest that it is lawful for pharmaceutical manufacturers to make donations to charitable organizations who provide co-pay assistance to Medicare patients, provided that such organizations, among other things, are bona fide charities, are entirely independent of and not controlled by the manufacturer, provide aid to applicants on a first-come basis according to consistent financial criteria and do not link aid to use of a donor's product.

However, donations to patient assistance programs have received some negative publicity and have been the subject of multiple government enforcement actions, related to allegations regarding their use to promote branded pharmaceutical products over other less costly alternatives.

Specifically, in recent years there have been multiple settlements resulting out of government claims challenging the legality of their patient assistance programs under a variety of federal and state laws.

It is possible that we may make grants to independent charitable foundations that help financially needy patients with their premium, co-pay, and co-insurance obligations.

If we choose to do so, and if we or our vendors or donation recipients are deemed to fail to comply with relevant laws, regulations or evolving government guidance in the operation of these programs, we could be subject to damages, fines, penalties, or other criminal, civil, or administrative sanctions or enforcement actions.

We cannot ensure that our compliance controls, policies, and procedures will be sufficient to protect against acts of our employees, business partners, or vendors that may violate the laws or regulations of the jurisdictions in which we operate.

Regardless of whether we have complied with the law, a government investigation could impact our business practices, harm our reputation, divert the attention of management, increase our expenses, and reduce the availability of foundation support for our patients who need assistance.

Further, it is possible that changes in insurer policies regarding co-pay coupons and/or the introduction and enactment of new legislation or regulatory measures impacting patients using affected products could have a material adverse effect on our sales, business and financial condition.

For example, on December 31, 2020, CMS published a new rule, effective January 1, 2023, requiring manufacturers to ensure the full value of co-pay assistance is passed on to the patient or these dollars will count toward the Average Manufacturer Price and Best Price calculation of the drug.

On May 21, 2021, PhRMA sued the HHS in the U.S.

District Court for the District of Columbia, to stop the implementation of the rule claiming that the rule contradicts federal law surrounding Medicaid rebates.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the current U.S.

presidential administration may reverse or otherwise change these measures, both the current U.S.

presidential administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

We cannot predict how the implementation of and any further changes to this rule will affect our business.

In addition, with the approval and commercialization of any of our products outside the United States, we will also likely be subject to foreign equivalents of the healthcare laws mentioned above, among other foreign laws.

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Furthermore, patent protection in Europe includes:

One allowed patent related to the use of a pharmaceutical composition comprised of 4g of 96% EPA ethyl ester to treat the REDUCE-IT population expiring 2033.

In addition, pending patent applications in Europe have the potential to extend exclusivity into 2039.

One granted patent related to the use of a pharmaceutical composition comprised of 4g of 96% EPA ethyl ester to treat the REDUCE-IT population expiring 2033.

Pending patent applications in Europe, if granted, may have the potential to extend exclusivity into 2039.

We may be dependent in some cases upon third-party licensors to pursue filing, prosecution and maintenance of patent rights or applications owned or controlled by those parties, including, for example, under our collaboration with Mochida.

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We anticipate that competitors may from time to time oppose our efforts to obtain patent protection for new technologies or to submit patented technologies for regulatory approvals.

opposition in a foreign patent office, even if the opposition or challenge has little or no merit.

Competitors may seek to oppose our patent applications to delay the approval process or to challenge our granted patents, for example, by requesting a reexamination of our patent at the USPTO, or by filing an opposition in a foreign patent office, even if the opposition or challenge has little or no merit.

For example, one of our patents was revoked in an opposition proceeding in Europe due to a determination of improper claim amendments under a provision of law not applicable in the United States.

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On January 25, 2021, we expanded the scope of this patent infringement lawsuit to include a health care insurance provider, Health Net, LLC.

We intend to vigorously pursue these ongoing litigation matters, but cannot predict the outcomes or the impact on our business.

We likewise plan to engage in similar patent litigation should other competitors arise with products that infringe our intellectual property rights.

On January 4, 2022, the district court hearing the case granted Hikma's motion to dismiss.

appeal the decision of the district court when permitted and also intend to continue to vigorously pursue our ongoing litigation with Health Net, LLC, but cannot predict the outcome or the impact on our business.

Patent litigation is a time-consuming and costly process.

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Several of our patent applications contain claims that are based upon what we believe are unexpected and favorable findings from our clinical trials.

If granted, many of the resulting granted patents from REDUCE-IT, for example, would expire in 2039, beyond the 2030 and 2033 expiration dates of currently issued REDUCE-IT patents.

If granted, one or more of the resulting granted patents from REDUCE-IT, for example, would expire in 2039, beyond the 2030 and 2033 expiration dates of currently issued REDUCE-IT patents.

However, no assurance can be given that any of our pending patent applications will be granted or, if they grant, that they will prevent competitors from competing with VASCEPA.

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If the estimates we make, or the assumptions on which we rely, in preparing our projected guidance prove inaccurate, our actual results may vary from those reflected in our projections and accruals.

In January 2021, we issued financial and business guidance, including expectations regarding inventory build, and 2021 operating expenses.

All such guidance and updates are based on estimates, assumptions and the judgment of management.

In January 2022, we disclosed our 2022 financial outlook.

Such outlook is based on estimates, assumptions and the judgment of management.

Because of the inherent nature of estimates, including during the uncertainty of COVID-19’s impact on our business, we have suspended providing net revenue guidance and there could be significant differences between our estimates and the actual amount of product demand.

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The loss of the services of one or more members of senior management could have a material adverse effect on us.

Given our rapidly expanding enterprise coupled with a streamlined management structure and sales force, the departure of any key person could have a significant impact and would be potentially disruptive to our business until such time as a suitable replacement is hired.

In the third quarter of 2021, John Thero and Joseph Kennedy, our President and Chief Executive Officer, and our Executive Vice President and General Counsel, respectively, retired and we welcomed Karim Mikhail, previously our Senior Vice President, Commercial Head Europe and Jason Marks as our new President and Chief Executive Officer and our new Senior Vice President and Chief Legal Officer, respectively.

Although these transitions have been smooth, any such changes to senior management can be disruptive to operations, including by distracting management from our core business and effective employee productivity.

Given our rapidly expanding enterprise coupled with a streamlined management structure and sales force, the departure of any key person could have a significant impact and would be potentially

disruptive to our business until such time as a suitable replacement is hired.

Furthermore, because of the specialized nature of our business, as our business plan progresses, we will be highly dependent upon our ability to attract and retain qualified scientific, technical and key management personnel.

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It is possible that in the future, whether as a result of a change in law or the practice of any relevant tax authority or as a result of any change in the conduct of our affairs, we could become, or be regarded as having become resident in a jurisdiction other than Ireland.

Should we cease to be an Irish tax resident, we may be subject to a charge to Irish capital gains tax on our assets and the basis on which our

income is taxed may also change.

Should we cease to be an Irish tax resident, we may be subject to a charge to Irish capital gains tax on our assets and the basis on which our income is taxed may also change.

Similarly, if the tax residency of our Irish or UK subsidiaries were to change from their current jurisdiction, they may be subject to a charge to local capital gains tax on their assets and the basis on which their income is taxed may also change.

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income tax returns are periodically examined by various tax authorities, including the Internal Revenue Service, or the IRS, and states.

For example, the IRS began an examination of our 2018 US income tax return in the first quarter of 2020.

For example, the IRS began an examination of our 2018 U.S.

income tax return in the first quarter of 2020.

Although the outcome of tax audits is always uncertain and could result in significant cash tax payments, we do not believe the outcome of any ongoing or future audits will have a material adverse effect on our consolidated financial position or results of operations.

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gross product sales.

Customers A, B, and C accounted for 27%, 37%, and 28%, respectively, of gross product sales for the three and nine months ended September 30, 2021 and 2020, and represented 34%, 37%, and 21%, respectively, of the gross accounts receivable balance as of September 30, 2021.

Customers A, B, and C accounted for 25%, 37%, and 30%, respectively, of gross product sales for the nine months ended September 30, 2020, and represented 37%, 32%, and 25%, respectively, of the gross accounts receivable balance as of September 30, 2020.

Customers A, B, and C accounted for 21%, 39%, and 31%, respectively, of gross product sales for the three months ended March 31, 2022, and represented 29%, 37%, and 28%, respectively, of the gross accounts receivable balance as of March 31, 2022.

Customers A, B, and C accounted for 27%, 35%, and 31%, respectively, of gross product sales for the three months ended March 31, 2021, and represented 35%, 36%, and 24%, respectively, of the gross accounts receivable balance as of March 31, 2021.

We expect that we may have customer concentration risk as we enter additional countries.

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We have not yet reached sustained profitability.

For the fiscal years ended December 31, 2020, 2019, and 2018, we reported losses of approximately $18.0 million, $22.6 million, and $116.4 million, and we had an accumulated deficit as of December 31, 2020 of $1.4 billion.

For the three months ended September 30, 2021 and 2020, we reported losses of approximately $13.2 million and $6.8 million, respectively, and we had an accumulated deficit as of September 30, 2021 of $1.4 billion.

For the fiscal years ended December 31, 2021, we reported net income of approximately $7.7 million.

For the fiscal years ended December 31, 2020 and 2019, we reported net losses of approximately $18.0 million and $22.6 million, and we had an accumulated deficit as of December 31, 2021 of $1.4 billion.

For the three months ended March 31, 2022 and 2021, we reported losses of approximately $31.6 million and $1.6 million, respectively, and we had an accumulated deficit as of March 31, 2022 of $1.5 billion.

Substantially all of our operating losses resulted from costs incurred in connection with our research and development programs, from general and administrative costs associated with our operations, and costs related to the commercialization of VASCEPA.

Additionally, as a result of our significant expenses relating to research and development and to commercialization, we expect to continue to incur significant operating losses for an indefinite period.

Because of the numerous risks and uncertainties associated with developing and commercializing pharmaceutical products, we are unable to predict the magnitude of these future losses.

Because of the numerous risks and uncertainties associated with developing and commercializing pharmaceutical products, we are unable to

predict the magnitude of these future losses.

Our historic losses, combined with expected future losses, have had and will continue to have an adverse effect on our cash resources, shareholders’

deficit and working capital.

Although we began generating revenue from VASCEPA in January 2013, we may never be profitable for a full year.

Although we began generating revenue from VASCEPA in January 2013, we may never be consistently profitable for a full year.

Our ability to become profitable on a sustained basis depends upon our ability to generate revenue.

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Even though VASCEPA has been approved by the U.S.

FDA for marketing in the United States for two important indications, recently received marketing authorization in Europe and is approved in smaller jurisdictions, it may not gain enough market acceptance to support profitability.

FDA for marketing in the United States for two important indications, received marketing authorization in Europe and is approved in smaller jurisdictions, it may not gain enough market acceptance to support consistent profitability.

We anticipate continuing to incur significant costs associated with expanding the commercialization of VASCEPA.

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VASCEPA sales are difficult to predict from period to period and as a result, you should not rely on VASCEPA sales results in any period as being indicative of future performance, and sales of VASCEPA may be below the expectation of securities analysts or investors in the future.

We believe that our quarterly and annual results of

operations may be affected by a variety of factors, including those risks and uncertainties described in this Part II, Item 1A and the following:

We believe that our quarterly and annual results of operations may be affected by a variety of factors, including those risks and uncertainties described in this Part II, Item 1A and the following:

the recent and potential launches of additional generic versions of VASCEPA;

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the level of demand for VASCEPA, due to changes in prescriber sentiment, quarterly changes in distributor purchases, and other factors;

the extent to which coverage and reimbursement for VASCEPA is available from government and health administration authorities, private health insurers, managed care programs and other third-party payers and the timing and extent to which such coverage and reimbursement changes;

the timing, cost and level of investment in our sales and marketing efforts to support VASCEPA sales, including our recently announced Go-to-Market strategy, and the resulting effectiveness of those efforts;

the extent to which coverage and reimbursement for VASCEPA is available from government and health administration authorities, private health insurers, managed care programs and other third-party payors and the timing and extent to which such coverage and reimbursement changes;

the timing, cost and level of investment in our sales and marketing efforts to support VASCEPA sales, including our implemented Go-to-Market strategy, and the resulting effectiveness of those efforts;

disruptions or delays in our or our partners’

commercial or development activities, including as a result of political instability, civil unrest, terrorism, pandemics or other natural disasters, such as the coronavirus outbreak;

the timing and ability of efforts outside the United States, to develop, register and commercialize VASCEPA in Europe, China Territory, several Middle Eastern and North African countries, and Canada, for example, including obtaining necessary regulatory approvals, favorable pricing and establishing marketing channels;

commercial or development activities, including as a result of political instability, civil unrest, terrorism, pandemics or other natural disasters, such as the coronavirus pandemic;

the timing and ability of efforts outside the United States, to develop, register and commercialize VASCEPA in Europe, the China Territory, several Middle Eastern and North African countries, and Canada, for example, including obtaining necessary regulatory approvals, favorable pricing and establishing marketing channels;

additional developments regarding our intellectual property portfolio and regulatory exclusivity protections, if any;

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We currently operate with limited resources.

We believe that our cash and cash equivalents balance of $222.9 million and short-term investment balance of $256.3 million as of September 30, 2021 will be sufficient to fund our projected operations for at least 12 months.

We have based this estimate on assumptions that may prove to be wrong, and we could deplete our capital resources sooner than we expect or fail to achieve positive cash flow.

We believe that our cash and cash equivalents balance of $219.2 million and short-term investment balance of $143.4 million as of March 31, 2022 will be sufficient to fund our projected operations for at least 12 months.

We have based this estimate on assumptions that may prove to be wrong, and we could deplete our capital resources sooner

than we expect or fail to achieve positive cash flow.

Depending on the level of cash generated from operations, and depending in part on the rate of prescription growth for VASCEPA, additional capital may be required to support planned VASCEPA promotion and potential VASCEPA promotion beyond which we are currently executing and for commercialization of VAZKEPA in Europe.

If additional capital is required and we are unable to obtain additional capital on satisfactory terms, or at all, we may be forced to delay, limit or eliminate certain promotional activities.

FDA for the new indication and expanded label and the impact from COVID-19 on our operations and those of our customers and any current or potential generic competition.

We anticipate that quarterly net cash outflows in future periods will be variable as a result of the timing of certain items, including our purchases of API, VASCEPA promotional and educational activities, including launch activities in Europe and the impact from COVID-19 on our operations and those of our customers and any current or potential generic competition.

In order to fully realize the market potential of VASCEPA, we may need to enter into a new strategic collaboration or raise additional capital.

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In addition, the market prices of the securities of many pharmaceutical and medical technology companies have been especially volatile in the past, and this trend is expected to continue in the future.

As of October 29, 2021, we had 395,825,887 common shares outstanding including 395,629,060 shares held as ADSs and 196,827 held as ordinary shares (which are not held in the form of ADSs).

As of April 29, 2022, we had 397,008,153 common shares outstanding including 396,811,326 shares held as ADSs and 196,827 held as ordinary shares (which are not held in the form of ADSs).

There is a risk that there may not be sufficient liquidity in the market to accommodate significant increases in selling activity or the sale of a large block of our securities.

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period-to-period variations in our results of operations.

Further, the United Kingdom ceased to be a member of the European Union on January 31, 2020, commonly referred to as Brexit, and the 11-month implementation period ended on December 31, 2020 and a new trade deal between the United Kingdom and the European Union was agreed to on December 24, 2020.

The effects of Brexit are uncertain and may have a negative effect on global economic conditions, financial markets and our business, which could reduce the price of our ADSs and common shares.

Further, the effects of Brexit are uncertain and may have a negative effect on global economic conditions, financial markets and our business, which could reduce the price of our ADSs and common shares.

In particular, Brexit could lead to a period of considerable uncertainty in relation to the UK financial and banking markets, as well as on the regulatory process in Europe, which could cause the broader global financial markets to experience significant volatility.

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Actual or potential sales of our common shares by our employees, including members of our senior management team, pursuant to pre-arranged stock trading plans could cause our stock price to fall or prevent it from increasing for numerous reasons, and actual or potential sales by such persons could be viewed negatively by other investors.

In accordance with the guidelines specified under Rule 10b5-1 of the Securities Exchange Act of 1934 and our policies regarding stock transactions, a number of our directors and employees, including members of our senior management team, have adopted and may continue to adopt pre-arranged stock trading plans to sell a portion of our common stock.

In accordance with the guidelines specified under Rule 10b5-1 under the Exchange Act and our policies regarding stock transactions, a number of our directors and employees, including members of our senior management team, have adopted and may continue to adopt pre-arranged stock trading plans to sell a portion of our common stock.

Generally, sales under such plans by members of our senior management team and directors require public filings.

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corporation will be treated as owning its proportionate share of the assets and earning its proportionate share of the income of any other corporation in which it owns, directly or indirectly, no more than 25% (by value) of the stock.

Based on certain estimates of our gross income and gross assets, the latter determined by reference to the expected value of our ADSs and shares, we believe that we will not be classified as a PFIC for the taxable year ended December 31, 2020 and we do not expect to be treated as a PFIC in any future taxable year for the foreseeable future.

expect to be treated as a PFIC in any future taxable year for the foreseeable future.

However, because PFIC status is based on our income, assets and activities for the entire taxable year, which we expect may vary substantially over time, it is not possible to determine whether we will be characterized as a PFIC for any taxable year until after the close of the taxable year.

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We cannot assure you that research and discoveries by others will not render some or all of our programs or product candidates uncompetitive or obsolete.

Our business strategy is based in part upon new and unproven technologies to the development of therapeutics to improve cardiovascular

Our business strategy is based in part upon new and unproven technologies to the development of therapeutics to improve cardiovascular health.

We cannot assure you that unforeseen problems will not develop with these technologies or applications or that any commercially feasible products will ultimately be developed by us.

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Since the regulatory framework in the UK covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime with respect to the commercialization of our products in the UK.

Any delay in commercializing our products in the UK and/or the EU could restrict our ability to generate revenue and achieve and sustain profitability.

Any delay in commercializing our products in the UK and/or the EU

could restrict our ability to generate revenue and achieve and sustain profitability.

The uncertainty around the UK’s future relationship with the EU continues to cause economic uncertainty which could adversely impact customer confidence resulting in customers reducing their spending budgets on our solutions, which could adversely affect our business, revenue, financial condition, results of operations and could adversely affect the market price of our ADSs.

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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-Q

Item 1. Legal Proceedings