What changed in this filing

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Item 1A. Risk Factors

2024-03-01 compared with 2023-02-27 · 60 added, 107 removed, 733 unchanged (19% of the section changed)

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BioReference’s COVID-19 testing volume positively impacted our profitability during 2020-2021.

Prior to 2020, we had incurred losses since our inception, and after achieving profitability for the years ended December 31, 2020 and 2021, we incurrent a net loss for the year ended December 31, 2022.

We may not continue to generate substantial revenue from COVID-19 testing as vaccine use is adopted and infection rates decline, unless such decline is offset by significant revenue generation from our other income streams.

We have historically generated only limited revenue from operations and we may not generate substantial revenue from the sale of proprietary pharmaceutical products or certain of our diagnostic products for some time, if at all.

Other than NGENLA (Somatrogon), which has been approved in the EU, Japan, Canada and Australia, Rayaldee is our only pharmaceutical product that has been approved for marketing in the U.S.

Prior to 2020, we had incurred losses since our inception, and after achieving profitability for the years ended December 31, 2020 and 2021, we incurred a net loss for the years ended December 31, 2022 and 2023.

In response to the global COVID-19 pandemic, BioReference conducted a substantial amount of COVID-19 testing that positively impacted our revenues 2020-2021.

Simultaneously, however, the volume of its core testing business decreased as a result of COVID-10.

During 2022-2023, testing needs for COVID-19 decleined as a result of declining infection rates and the normalization of living with COVID-10 following the increase in accessibility to COVID-19 vaccines and antiviral treatments.

As COVID-19 testing volumes decreased, we experienced a return to our core business testing, but growth in BioReference's core business, however, has been gradual and has not offset the substantial decline in revenue from COVID-19 testing.

Our pharmaceutical business has historically generated only limited revenue from operations and we may not generate substantial revenue from the sale of proprietary pharmaceutical products or certain of our diagnostic products for some time, if at all.

Other than NGENLA (Somatrogon), which has been approved in many territories including the U.S., EU, Japan, Canada and Australia, Rayaldee is our only other proprietary pharmaceutical product that has been approved for marketing in the U.S.

or elsewhere.

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We may continue to incur losses from our operations in the future and these losses could increase as we continue our research activities and conduct development of, and seek regulatory approvals and clearances for, our product candidates, particularly if we are unable to generate or sustain profits and cash flow from sales of Rayaldee, NGENLA, or our operations at BioReference.

If we are unable to generate or sustain profits and cash flow from our operations, our product candidates fail in clinical trials or do not gain regulatory approval or clearance, or if our approved

products and product candidates do not achieve market acceptance, we may not achieve profitability.

If we are unable to generate or sustain profits and cash flow from our operations, our product candidates fail in clinical trials or do not gain regulatory approval or clearance, or if our approved products and product candidates do not achieve market acceptance, we may not achieve profitability.

In particular, if we are unable to successfully commercialize Rayaldee or NGENLA, we may never generate substantial revenues from Rayaldee or NGENLA.

If we are unable to obtain FDA approval for Somatrogon (hGH-CTP) in the U.S., we will not be able to commercialize Somatrogon (hGH-CTP) in the U.S.

and will therefore not generate revenues from NGENLA in the U.S.

In addition, if we are required by the FDA to perform studies in addition to those we currently anticipate, our expenses will increase beyond current expectations and the timing of any potential product approval may be delayed.

We may require additional funding, which may not be available to us on acceptable terms, or at all.

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Prior to 2020, we had not generated sustained positive cash flows sufficient to offset our operating and research and development expenses and our primary sources of cash has been from the public and private placement of stock, the issuance of convertible notes and credit facilities available to us.

While we have generated significant cash from operations as a result of testing related to the COVID-19 pandemic, demand for our COVID-19 related testing has waned, and we are unable to predict whether pricing and reimbursement policies for testing will sustain, or whether restrictions will be placed on elective procedures or if stay at home orders will be reinstated and accordingly, the sustainability of the cash flow is uncertain.

While we have generated significant cash from operations as a result of testing related to the COVID-19 pandemic, demand for our COVID-19 related testing waned during 2022 and 2023, and revenues from other sources have not offset the substantial decline in revenue from COVID-19 testing.

If we are unable to generate a sufficient amount of product and service revenue to finance our cash requirements for research, development and operations, we will need to finance future cash needs primarily through public or private equity offerings, debt financings, or strategic collaborations.

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To the extent that we raise additional funds through collaboration and licensing arrangements, it may be necessary to relinquish some rights to our technologies or our products and product candidates or grant licenses on terms that may not be favorable to us.

Our business has been, and may continue to be, affected by the coronavirus disease 2019 (COVID-19) outbreak.

The outbreak of the coronavirus disease 2019 (COVID-19) evolved into a global pandemic, significantly affecting the U.S.

and most countries around the world.

In 2022, testing needs for COVID-19 declined as a result of declining infection rates and the normalization of living with COVID-19 following the increase in accessibility to COVID-19 vaccines and antiviral treatments.

The extent to which this coronavirus continues to impact our business and operating results will depend on future developments that are highly uncertain and cannot be accurately predicted, including new information that may emerge concerning the virus, including variants of the virus, and the actions to contain the spread of or to detect, prevent, or treat COVID-19, among others.

As a result of the demand for COVID-19 testing, the Company’s overall testing volume increased significantly in 2020 and 2021, which positively impacted its operations in such years.

Simultaneously, however, demand for tests that comprise the Company’s core testing business has declined.

As the demand for COVID-19 PCR testing declined in 2022, we have seen a gradual increase in the demand for services of our core testing business.

The demand and duration of the need for COVID-19 testing are uncertain, however, and the Company could experience significant volatility in its results of operations if the demand for testing increases again and the demand for the services provided by the Company’s core testing business decreases.

We may also experience supply chain disruptions, including shortages, delays and price increases in testing equipment and supplies as a result of global disruptions in healthcare markets, which could materially adversely impact our business.

It is also possible that the Company will experience an adverse impact on cash collections as a result of the COVID-19 pandemic.

COVID-19 could also disrupt our operations due to absenteeism by infected or ill members of management or other employees, or absenteeism by members of management and other employees who elect not to come to work due to the illness affecting others in our office or laboratory facilities, or due to quarantines.

The regulatory framework governing laboratories, diagnostic and pharmaceutical companies may be affected as governmental authorities divert resources to respond to the COVID-19 outbreak, which may have an unanticipated and unforeseen impact on our operations.

It is possible that the timing of regulatory submissions and approvals for our productswill be adversely impacted or delayed.

With respect to our ongoing and planned clinical trials, restrictions and efforts to avoid further spread of COVID-19 may present challenges to the conduct of these trials consistent with normally applicable approaches and good clinical practice standards, and although regulators including the FDA have offered guidance applicable during the COVID-19 pandemic allowing for flexibility of standards in certain areas and alternate methods of meeting trial oversight obligations (for example, via remote monitoring), the potential impact of these challenges cannot be fully predicted at this time.

Our research and development activities may not result in commercially viable products.

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regulatory authorities.

We rely on licensing agreements with Vifor, Nicoya, and international partners for the international development and marketing of Rayaldee.

We rely on licensing agreements with VFMCRP, Nicoya, and international partners for the international development and marketing of Rayaldee.

Failure to maintain these license agreements could prevent us from successfully developing and commercializing Rayaldee worldwide.

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Effective May 5, 2020, we entered into the VFMCRP Amendment, pursuant to which the parties agreed to exclude Mexico, South Korea, the Middle East and all of the countries of Africa from the VFMCRP Territory.

In May 2021, we further amended the VFMCRP Agreement for VFMCRP to assume all the rights to Rayaldee in Japan that had been previously granted to JT.

In May 2021, we further amended the VFMCRP Agreement for VFMCRP to assume all the rights to Rayaldee in Japan that had been previously granted to Japan Tobacco.

In addition, the parties agreed to certain amendments to the milestone structure and to reduce minimum royalties payable.

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In the event that VFMCRP, for any reason, including but not limited to early termination of the agreement, fails to devote sufficient resources to successfully develop and market Rayaldee internationally, our ability to earn milestone payments or receive royalty payments would be adversely affected, which would have a material adverse effect on our financial condition and prospects.

In October 2017, we entered into a Development and License Agreement (the “JT Agreement”) with JT under which JT was granted the exclusive rights for the development and commercialization of Rayaldee in Japan.

The JT Agreement was terminated in May 2021.

On June 18, 2021, EirGen and Nicoya entered into the Nicoya Agreement granting Nicoya the exclusive rights for the development and commercialization of the Nicoya Product in the Nicoya Territory.

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However, the parties amended the Nicoya Agreement to provide that Nicoya pay $2.5 million plus accrued interest by October 31, 2022 in partial satisfaction of the First Milestone, and $2.5 million upon the earlier of (i) submission of the investigational new drug application by Nicoya or its affiliated party, and (ii) February 15, 2023.

EirGen received the additional $2.5 million upon Nicoya's submission of an investigation new drug (IND) application to the center for drug evaluation of China in March 2023.

EirGen is also eligible to receive up to an additional aggregate amount of $115 million upon the achievement of certain development, regulatory and sales-based milestones by Nicoya for the Nicoya Product in the Nicoya Territory.

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In December 2014, we entered into a development and commercialization agreement with Pfizer relating to our long-acting hGH-CTP for the treatment of GHD in adults and children (the “Original Pfizer Agreement”).

Under the Pfizer Agreement, we are eligible to receive up to $275 million upon the achievement of certain regulatory milestones.

Under the Restated Pfizer Agreement, we are eligible to receive up to $275 million upon the achievement of certain regulatory milestones.

Upon the launch of Somatrogon (hGH-CTP) for pediatric GHD, we are eligible to receive a regional, tiered gross profit share based upon sales of both Somatrogon (hGH-CTP) and Pfizer’s Genotropin® (somatropin).

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The Restated Pfizer Agreement did not change the milestone payments, royalties and profit share provisions under the Original Pfizer Agreement.

While hGH-CTP has been approved in the EU, Japan, Canada and Australia under the name NGENLA, Pfizer received a Complete Response Letter from the FDA in January 2022 in response to the BLA we and Pfizer submitted in 2020.

We and Pfizer have evaluated the FDA’s comments and will work with the agency to determine an appropriate path forward.

In the event that the parties are able to obtain regulatory approvals to market a product covered by the Restated Pfizer Agreement, we will be substantially dependent on Pfizer for the successful commercialization of such product.

hGH-CTP has been approved in the U.S., EU, Japan, Canada and Australia under the name NGENLA.

We are substantially dependent on Pfizer for the successful commercialization of such product.

The success of the collaboration arrangement with Pfizer is dependent in part on, among other things, the skills, experience and efforts of Pfizer’s employees responsible for the project and Pfizer’s commitment to the arrangement.

The Restated Pfizer Agreement is terminable for any reason by Pfizer upon ninety days written notice to OPKO.

In the event that Pfizer terminates the Agreement or fails to devote sufficient resources to continue to successfully develop and commercialize any product resulting from the collaboration arrangement, our ability to earn milestone payments or receive royalty or profit sharing payments would be adversely affected, which would have a material adverse effect on our financial condition and prospects and the trading prices of our securities.

In the event that Pfizer terminates the Restated Pfizer Agreement or fails to devote sufficient resources to continue to successfully develop and commercialize any product resulting from the collaboration arrangement, our ability to earn milestone payments or receive royalty or profit sharing payments would be adversely affected, which would have a material adverse effect on our financial condition and prospects and the trading prices of our securities.

Our business is substantially dependent on our ability to achieve regulatory approval for the marketing of Somatrogon (hGH-CTP) in pediatric and adult patients and the commercial success of this product.

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There can be no assurance that the FDA or regulatory agencies in other countries will consider the sensitivity analysis or consider the product for approval for adults with GHD.

In January 2021, we and Pfizer announced that the FDA had accepted for filing the BLA submission for the pediatric indication which was submitted in October 2020.

In January 2022, Pfizer received a Complete Response Letter with respect to the pediatric indication.

Pfizer and the Company have evaluated the best path forward for hGH-CTP in the U.S.

but there can be no assurances that we will receive an approval for hGH-CTP for the treatment of pediatric GHD by the FDA.

There can be no assurance that we will obtain marketing approval for either the pediatric or adult indication.

Before they can be marketed, our products in development must be approved by the FDA or similar foreign governmental agencies.

In June 2023, the FDA approved NGENLA (Somatrogon (hGH-CTP)) for the treatment of pediatric GHD in the United States.

However, there can be no assurance that NGENLA (Somatrogon (hGH-CTP)) for the treatment of pediatric GHD will be commercially successful in the United States or that we will obtain marketing approval for the adult indication.

Before it can be marketed, Somatrogon (hGH-CTP) for the adult indication must be approved by the FDA or similar foreign governmental agencies.

The process for obtaining FDA marketing approval is both time-consuming and costly, with no certainty of a successful outcome.

If we are unable to achieve regulatory approval for hGH-CTP to treat pediatric patients or adults with GHD, our business will be significantly adversely impacted, which could have a materially adverse effect on our business, financial condition and results of operations.

Japan’s Ministry of Health, Labour and Welfare approved NGENLA (Somatrogon) for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.

In October 2021, Health Canada approved NGENLA for the long-term treatment of pediatric patients who have GHD, and Australia’s Therapeutic Goods Administration (TGA) approved NGENLA for the long-term treatment of pediatric patients with growth disturbance.

NGENLA may fail to be successfully commercialized in these territories which would adversely impact our anticipated milestone payments under the Restated Pfizer Agreement and negatively affect our business, financial condition and results of operations.

Protein therapeutics have the potential to cause an immune or antibody response in patients.

Antibodies may be transient or persistent and can have no effect or can neutralize the therapeutic effect of the protein.

Antibodies that neutralize the activity of a therapeutic protein are known as neutralizing antibodies.

As previously reported, low titers of anti-hGH-CTP non-neutralizing antibodies were noted over a four year period in 17 subjects, or approximately 35% of the subjects, in our phase 2 open label extension study in children with GHD.

The low titer non-neutralizing antibodies did not affect growth parameters or IGF-1 levels in the patients.

Immunogenicity testing and analysis for our phase 3 study is ongoing, and we expect that the full results of the study will be submitted for presentation at a future scientific meeting.

The FDA reviews information on immune responses observed during clinical studies and the implications on safety and efficacy and could request additional studies or analyses of hGH-CTP or could decline to approve hGH-CTP for the indications we seek.

Any of these occurrences could have a material adverse impact on our business, results of operation and financial condition.

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with NGENLA may develop antibodies to Somatrogon (hGH-CTP).

Antibodies may be transient or persistant and can have no effect or can neutralize the therapeutic effect of the protein.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies to Somatrogon (hGH-CTP) in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

If we are unable to successfully commercialize NGENLA (Somatrogon (hGH-CTP)) to treat pediatric GHD and/or receive regulatory approval for hGH-CTP to treat adults with GHD, our business could be significantly adversely impacted.

NGENLA has been approved in over 50 territories for the long-term treatment of pediatric patients with growth disturbance.

NGENLA may nevertheless fail to be successfully commercialized in these territories which would adversely impact our anticipated milestone payments under the Restated Pfizer Agreement and negatively affect our business, financial condition and results of operations.

Our business is dependent on our ability to develop, launch and generate revenue from our diagnostic products.

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To offset efforts by payors to reduce the cost and utilization of clinical laboratory services, we will need to obtain and retain new clients and business partners and grow the laboratory operations.

In response to the global pandemic, BioReference conducted a substantial amount of COVID-19 testing that positively impacted our revenues in previous years.

In response to the global COVID-19 pandemic, BioReference conducted a substantial amount of COVID-19 testing that positively impacted our revenues in previous years.

Simultaneously, however, the volume of its core testing business decreased as a result of COVID-19.

As COVID-19 testing volumes decrease, we have seen a return to our core business testing.

Growth in our core business, however, has been gradual.

If we are unable to return to and surpass adequate

growth in our core business testing or client base, it could have a material adverse impact on our ability to generate profits and cash flow from the laboratory operations in the future.

During 2022-2023, testing needs for COVID-19 declined as a result of declining infection rates and the normalization of living with COVID-19 following the increase in accessibility to COVID-19 vaccines and antiviral treatments.

As COVID-19 testing volumes decreased, we experienced a return to our core business testing but growth in BioReference's core business, however, has been gradual and has not offset the subtantial decline in revenue from COVID-19 testing.

We have engaged in significant cost reduction efforts, including reducing our workforce, in an effort to make the diagnostic business profitable and align our core business testing needs with the size of our operations.

If we are unable to return to and surpass adequate growth in our core business testing or client base, it could have a material adverse impact on our ability to generate profits and cash flow from the laboratory operations in the future.

Discontinuation or recalls of existing testing products, failure to develop, or acquire, licenses for new or improved testing technologies or our clients using new technologies to perform their own tests could adversely affect our business.

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We manufacture pharmaceutical products in Ireland, Mexico, Spain, and Israel.

We also prepare necessary test reagents and assemble and package the cassettes for our point-of-care diagnostic system at our facility in Woburn, Massachusetts.

Any quality control issues at our facilities may weaken our competitive position and have a material adverse effect on our business results of operations and financial condition.

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Moreover, seeking acquisition and divestiture opportunities and evaluating and completing them require significant investment of time and resources, may disrupt the Company’s business and distract management’s attention from day-to-day business operations.

We may fail to realize the anticipated benefits of the sale of GeneDx.

We may fail to realize the anticipated benefits of the sale to GeneDx.

Pursuant to the GeneDx Merger Agreement, on April 29, 2022, GeneDx Holdings Corp.

(formerly, Sema4), acquired GeneDx from us for an upfront payment of $150 million in cash, together with 80.0 million Closing Shares, subject to a

customary purchase price adjustment mechanism.

Additionally, subject to GeneDx achieving certain revenue targets for the fiscal years ending December 31, 2022 and 2023, we are eligible to receive an earnout payment in cash or stock, at GeneDx Holdings’ discretion, (the “Milestone Consideration”) equal to a maximum of 30.9 million shares of GeneDx Holdings’ Class A common stock if paid in stock.

Based on the closing price of GeneDx Holdings Common Stock on the closing date, the total upfront consideration was approximately $322 million, and the total aggregate consideration, including the potential Milestone Consideration, was approximately $447 million.

If GeneDx does not successfully achieve its growth objectives for 2023, some of the anticipated benefits of the sale may not be realized fully, as we may then not be entitled to receive the full Milestone Consideration.

(formerly, Sema4), acquired GeneDx from us for an upfront payment of $150 million in cash, together with 80.0 million shares of GeneDx Holdings Common Stock, subject to a customary purchase price adjustment mechanism.

Subject to GeneDx achieving certain revenue targets for the fiscal years ending December 31, 2022 and 2023, we are eligible to receive an earnout payment in cash or stock (at GeneDx Holdings' discretion) equal to a maximum of 30.9 million shares of GeneDx Holdings Common Stock if paid in stock.

Based on the closing price of GeneDx Holdings Common Stock on April 29, 2022, the total upfront consideration was approximately $322 million, and the total aggregate consideration, including the potential GeneDx Milestone Consideration, was approximately $447 million.

We received 23.1 million shares of Class A Common Stock as a result of GeneDx satisfactorily achieving revenue targets as of December 31, 2022.

As of the date of this Annual Report on Form 10-K however, we do not anticipate that GeneDx will satisfy the revenue targets as of December 31, 2023 to achieve the remaining GeneDx Milestone Consideration, so we may not receive some of the anticipated benefit of the disposition of GeneDx.

In addition, as of December 31, 2023, the aggregate value of our investments in GeneDx Holdings based on the quoted market price of their respective shares of common stock and the number of shares held by us was $9.8 million, which is significantly below the value of our investment in GeneDx Holdings as of the closing date of the GeneDx Transaction.

There can be no guarantee that the price of GeneDx Holdings Common Stock will return to its value as of the closing date of the GeneDx Transaction.

Fluctuations in the price of GeneDx Holdings Common Stock are subject to market fluctuations and other factors outside our control, which are not directly linked to the financial and operational performance of the Company, but the fluctuations in the value of this investment may adversely impact the Company's financial condition and results of operations.

If the FDA or other applicable regulatory authorities approve generic products that compete with any of our products or product candidates, the sale of our products or product candidates may be adversely affected.

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Further, the FDA requires that we comply with standards, commonly referred to as good clinical practice, for conducting, recording and reporting clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.

independent clinical investigators and contract research organizations fail to comply with good clinical practice, the results of our clinical trials could be called into question and the clinical development of our product candidates could be delayed.

If our independent clinical investigators and contract research organizations fail to comply with good clinical practice, the results of our clinical trials could be called into question and the clinical development of our product candidates could be delayed.

Failure of clinical investigators or contract research organizations to meet their obligations to us or comply with federal regulations and good clinical practice procedures could adversely affect the clinical development of our product candidates and harm our business, results of operations, and financial condition.

If the validity of an informed consent from a subject was to be challenged, it may negatively impact our product development efforts.

We take steps to ensure that all clinical data and genetic and other biological samples are collected from subjects who provide informed consent for the data and samples as required by applicable laws and we work to ensure that the subjects from whom our data and samples are collected do not retain any proprietary or commercial rights to the data or samples or any discoveries derived from them.

However, because we may collect data and samples from countries that are governed by a number of different regulatory regimes, there are many complex legal questions relating to the adequacy of informed consent that we must continually address.

The adequacy of any given subject’s informed consent may be challenged in the future, and any given informed consent may prove unlawful or otherwise inadequate for our purposes.

Any findings against us, or our clinical collaborators, could obligate us to stop using some of our clinical samples, which in turn may hinder our product development efforts.

Such a result would also likely involve legal challenges that may consume our management and financial resources.

Failure to timely or accurately bill and collect for our services could have a material adverse effect on our revenues and our business.

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If such attacks are successful, they could disrupt our operations and result in unauthorized persons gaining access to confidential or proprietary information.

A breach or security

incident affecting these third parties could harm our business, results of operations and reputation, and subject us to liability, governmental investigation, significant damage to our reputation or otherwise adversely affect our business.

A breach or security incident affecting these third parties could harm our business, results of operations and reputation, and subject us to liability, governmental investigation, significant damage to our reputation or otherwise adversely affect our business.

Although the Company has security measures implemented, cyber-attacks and threats against us and our third-party providers continue to evolve and are often not recognized until such attacks are launched against a potential target.

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Any patents we have obtained, or obtain in the future, may be challenged, invalidated, unenforceable, or circumvented.

In addition, court decisions may introduce uncertainty

in the enforceability or scope of patents owned by biotechnology, pharmaceutical, and medical device companies.

In addition, court decisions may introduce uncertainty in the enforceability or scope of patents owned by biotechnology, pharmaceutical, and medical device companies.

Any challenge to, finding of unenforceability or invalidation or circumvention of, our patents or patent applications would be costly, would require significant time and attention of our management, and could have a material adverse effect on our business, results of operations and financial condition.

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Intellectual property litigation, regardless of outcome, is expensive and time-consuming, could divert management’s attention from our business and have a material negative effect on our business, operating results or financial condition.

If there is a successful claim of infringement against us, we may be required to pay substantial damages (including treble damages if we were to be found to have willfully infringed a third party’s patent) to the party claiming infringement, develop non-infringing technology, stop selling our tests or using technology that contains the allegedly infringing intellectual property or enter into royalty or license agreements that may not be available on

acceptable or commercially practical terms, if at all.

Our failure to develop non-infringing technologies or license the proprietary rights on a timely basis could harm our business.

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(vii) establish a disclosure program for whistleblowers;

and (viii) report or disclose certain events

and physician payments.

and (viii) report or disclose certain events and physician payments.

The Company’s or BioReference’s failure to comply with its obligations under the CIA could result in monetary penalties and the exclusion from Medicare, Medicaid, and TRICARE.

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Further, the legal actions and government investigations could damage our reputation with investors and adversely affect the trading prices of our securities.

The ongoing Russia-Ukraine conflict and the recent escalation of the Israel-Hamas conflict may adversely impact our business operations and financial performance.

United States and global markets are experiencing volatility and disruption following the geopolitical instability resulting from the ongoing Russia-Ukraine conflict and the recent escalation of the Israel-Hamas conflict.

In response to the ongoing Russia-Ukraine conflict, the North Atlantic Treaty Organization (“NATO”) deployed additional military forces to eastern Europe, and the United States, the United Kingdom, the European Union and other countries have announced various sanctions and restrictive actions against Russia, Belarus and related individuals and entities, including the removal of certain financial institutions from the Society for Worldwide Interbank Financial Telecommunication (SWIFT) payment system.

Certain countries, including the United States, have also provided and may continue to provide military aid or other assistance to Ukraine and to Israel, increasing geopolitical tensions among a number of nations.

The invasion of Ukraine by Russia and the escalation of the Israel-Hamas conflict and the resulting measures that have been taken, and could be taken in the future, by NATO, the United States, the United Kingdom, the European Union, Israel and its neighboring states and other countries have created global security concerns that could have a lasting impact on regional and global economies.

Although the length and impact of the ongoing conflicts are highly unpredictable, they could lead to market disruptions, including significant volatility in commodity prices, credit and capital markets, as well as supply chain interruptions and increased cyber attacks against U.S.

Additionally, any resulting sanctions could adversely affect the global economy and financial markets and lead to instability and lack of liquidity in capital markets.

These ongoing conflicts and the resulting geopolitical instability can adversely impact our business operations and financial performance.

RISKS RELATED TO REGULATORY COMPLIANCE

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To date, we have only submitted one NDA which was approved in June 2016, and one BLA which was approved for filing in January 2021.

We have received FDA approval for our 4Kscore test for use in men age 45 and older who have not had a prior prostate biopsy or are biopsy negative and have an age-specific abnormal total PSA and/or abnormal digital rectal exam, but we have not received marketing approval or clearance for any of our other diagnostic product candidates that we currently plan to market.

In response to the BLA we submitted for Somatrogon (hGH-CTP) Pfizer received a Complete Response Letter, to which we and Pfizer are responding.

We have received FDA approval for our 4Kscore test for use in men age 45 and older who have not had a prior prostate biopsy or are biopsy negative and have an age-specific abnormal total PSA and/or abnormal digital rectal exam, but we have not received marketing approval or clearance from FDA for any of our other diagnostic product candidates that we currently plan to market.

Obtaining approval of a NDA or PMA can be a lengthy, expensive, and uncertain process.

With respect to medical devices, while the FDA reviews and clears a premarket notification in as little as three months, there is no guarantee that our products will qualify for this more expeditious regulatory process, which is reserved for Class I and II devices, nor is there any assurance that even if a device is reviewed under the 510(k) process that the FDA will review it expeditiously or determine that the device is substantially equivalent to a

lawfully marketed non-PMA device.

If the FDA fails to make this finding, then we cannot market the device.

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civil and criminal penalties;

▪ injunctions;

suspension or withdrawal of regulatory approvals or clearances;

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We train our marketing and sales force against promoting our products for uses outside of the cleared or approved indications for use, known as “off-label uses.” If the FDA determines that our promotional materials or training constitute promotion of unsupported claims or an off-label use, it could request that we modify our training or promotional materials or subject us to regulatory or enforcement actions, including the issuance of an untitled letter, a warning letter, injunction, seizure, civil fine or criminal penalties.

It is also possible that other federal, state or foreign enforcement authorities might take action if they

consider our business activities to constitute promotion of an off-label use, which could result in significant penalties, including, but not limited to, criminal, civil and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government healthcare programs, and the curtailment of our operations.

It is also possible that other federal, state or foreign enforcement authorities might take action if they consider our business activities to constitute promotion of an off-label use, which could result in significant penalties, including, but not limited to, criminal, civil and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government healthcare programs, and the curtailment of our operations.

We and the manufacturers of our products are also required to comply with current Good Manufacturing Practices (“cGMP”) regulations or the FDA’s QSR regulations, which include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and documentation.

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Under the False Claims Act (“FCA”), whistleblower or qui tam provisions allow a private individual to bring actions on behalf of the federal government alleging that the defendant has submitted a false claim to the federal government, and to share in any monetary recovery.

In recent years, the number of suits brought by private individuals has increased

dramatically and we may be subject to such suits.

In recent years, the number of suits brought by private individuals has increased dramatically and we may be subject to such suits.

Violations of the FCA could result in enormous economic liability and could have a material impact on us.

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Congress has considered, at least yearly in conjunction with budgetary legislation, changes to one or both of the Medicare fee schedules under which we receive reimbursement, which include the physician fee schedule for anatomical pathology services, and the clinical laboratory fee schedule for our clinical laboratory services.

For example, currently there is no copayment or coinsurance required for clinical laboratory services, although there is for our services that are paid under the

physician fee schedule.

For example, currently there is no copayment or coinsurance required for clinical laboratory services, although there is for our services that are paid under the physician fee schedule.

However, Congress has periodically considered imposing a 20 percent coinsurance on laboratory services.

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While we have employed economic cash flow and fair value hedges to minimize the risks associated with these exchange rate fluctuations, the hedging activities may be ineffective or may not offset more than a portion of the adverse financial impact resulting from currency variations.

Accordingly, we cannot assure you that

fluctuations in the values of the currencies of countries in which we operate will not materially adversely affect our future results of operations.

Accordingly, we cannot assure you that fluctuations in the values of the currencies of countries in which we operate will not materially adversely affect our future results of operations.

We may be exposed to liabilities under the Foreign Corrupt Practices Act, and any determination that we violated the Foreign Corrupt Practices Act could have a material adverse effect on our business.

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Examples of qualitative factors include our share price, our financial performance compared to budgets, long-term financial plans, macroeconomic, industry and market conditions as well as the substantial excess of fair value over the carrying value of net assets from the annual impairment test previously performed.

Sales of Rayaldee and our operations at EirGen, are currently underperforming expectations and if we do not achieve our planned operating results, we may be required to incur a non-cash impairment charge.

Based on the current financial performance of our diagnostics segment and our Ireland reporting unit, which includes Eirgen and Rayaldee , if future results are not consistent with our estimates and assumptions, then we may be exposed to impairment charges, which could be material.

At December 31, 2023 , the combined goodwill of our diagnotics segment and our Ireland reporting unit was $367.3 million.

There can be no assurance that future reviews of our goodwill and other intangible assets will not result in impairment charges.

1 unchanged sentence

A significant write down of goodwill and/or other intangible assets would have a material adverse effect on our reported results of operations and net worth and the trading price of our securities.

We submitted the initial BLA with the FDA for approval of Somatrogon (hGH-CTP) in the U.S.

and Pfizer received a Complete Response Letter in January 2022.

Pfizer and OPKO have evaluated the FDA’s comments and will work with the agency to determine the best path forward for Somatrogon (hGH-CTP) in the United States.

If we are unable to successfully commercialize Somatrogon (hGH-CTP) in the U.S., or changes in projections and assumptions negatively impact our forecast of net cash flows, we may be exposed to a material impairment charge related to the IPR&D for Somatrogon.

RISKS RELATED TO OWNERSHIP OF OUR COMMON STOCK

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Directors, executive officers, principal stockholders and affiliated entities own a substantial amount of our capital stock, and they may make decisions that you do not consider to be in the best interests of our stockholders.

As of February 15, 2023, our directors, executive officers, principal stockholders and affiliated entities beneficially owned, in the aggregate, approximately 47.4% of our outstanding voting securities.

Phillip Frost, M.D., our Chairman and CEO, is deemed to beneficially own, in the aggregate, approximately 31.6% of our Common Stock as of February 15, 2023.

a result, Dr.

As of January 31, 2024, our directors, executive officers, principal stockholders and affiliated entities beneficially owned, in the aggregate, approximately 52.4% of our outstanding voting securities.

Phillip Frost, M.D., our Chairman and CEO, is deemed to beneficially own, in the aggregate, approximately 34.6% of our Common Stock as of January 31, 2024.

As a result, Dr.

Frost, acting with other members of management, would have the ability to significantly impact the election of our Board of Directors, the adoption or amendment of provisions in our Certificate of Incorporation, the approval of mergers and other significant corporate transactions and the outcome of issues requiring approval by our stockholders.

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If our efforts to comply with new or changed laws, regulations, and standards differ from the activities intended by regulatory or governing bodies, we could be subject to liability under applicable laws or our reputation may be harmed, which could materially adversely affect our business, results of operations and financial condition.

UNRESOLVED STAFF COMMENTS.

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

What changed 10-K

Item 1A. Risk Factors