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Item 1. Business

2024-03-01 compared with 2023-02-27 · 154 added, 190 removed, 539 unchanged (39% of the section changed)

We are a diversified healthcare company that seeks to establish industry-leading positions in large and rapidly growing medical markets.

Our diagnostics business includes BioReference Health, LLC (“BioReference”), one of the nation’s largest full service laboratories with a 180-person sales and marketing team to drive growth and leverage new products, and we offer our 4Kscore prostate cancer test through BioReference.

Our pharmaceutical business features Rayaldee , a U.S.

Food and Drug Administration (“FDA”) approved treatment for secondary hyperparathyroidism (“SHPT”) in adults with stage 3 or 4 chronic kidney disease (“CKD”) and vitamin D insufficiency, and Somatrogon (hGH-CTP), a once-weekly human growth hormone injection for which we completed a successful phase 3 study in August 2019 and is partnered with Pfizer Inc.

Regulatory applications for Somatrogon (hGH-CTP) have been submitted to the applicable regulatory bodies for review in several countries around the world.

In February 2022, the European Commission granted marketing authorization in the European Union for Somatrogon (hGH-CTP) under the brand name NGENLA® to treat children and adolescents from as young as 3 years of age with growth disturbance due to insufficient secretion of growth hormone and has been granted pricing approval in Germany.

NGENLA® has also been approved in Japan, Canada, and Australia.

We also submitted the initial Biologics License Application (“BLA”) with the FDA for approval of Somatrogon (hGH-CTP) in the United States 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 an appropriate path forward for the advancement of Somatrogon (hGH-CTP).

In May 2022, we acquired ModeX Therapeutics, Inc.

(“ModeX”), a biotechnology company focused on developing innovative multi-specific immune therapies for cancer and infectious diseases candidates.

(“Pfizer”) with respect to Somatrogon (hGH-CTP)’s further development and commercialization.

Regulatory applications for Somatrogon (hGH-CTP) for the treatment of children and adolescents as young as three years of age with growth disturbance due to insufficient secretion of growth hormone, have been approved in more than 50 markets worldwide, including the United States, European Union Member States, Japan, Canada, and Australia under the brand name NGENLA ® .

Additionally, in May 2022, we acquired ModeX Therapeutics, Inc.

(“ModeX”), a biotechnology company focused on developing innovative multi-specific immune therapies for cancer and infectious disease candidates.

ModeX has a robust early-stage pipeline with assets in key areas of immuno-oncology and infectious diseases, and we intend to further expand our pharmaceutical product pipeline through ModeX’s portfolio of development candidates.

Through BioReference, we provide laboratory testing services, primarily to customers in the larger metropolitan areas in New York, New Jersey, Florida, Texas, Maryland, California, Pennsylvania, Delaware, Washington, DC, Illinois and Massachusetts, as well as to customers in a number of other states.

Our diagnostics business includes BioReference Health, LLC (“BioReference”), one of the nation’s largest full service laboratories with a significant sales and marketing team designed to drive growth and leverage new products.

Through BioReference, we offer our 4Kscore prostate cancer test.

Through BioReference, we provide laboratory testing services, primarily to customers in the larger metropolitan areas in New York, New Jersey, Florida, Texas, Maryland, Indiana, Virginia, California, Pennsylvania, Delaware, Washington, DC, Illinois and Massachusetts, as well as to customers in a number of other states.

We offer a comprehensive test menu of clinical diagnostics for blood, urine and tissue analysis.

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We market our laboratory testing services directly to physicians, geneticists, hospitals, clinics, correctional and other health facilities.

We operate established pharmaceutical platforms in Spain, Ireland, Chile, and Mexico, which are generating revenue and from which we expect to generate positive cash flow and facilitate future market entry for our products currently in development.

We operate established, revenue-generating pharmaceutical platforms in Spain, Ireland, Chile, and Mexico, from which we expect to generate positive cash flow and facilitate future market entry for our products currently in development.

We have a development and commercial supply pharmaceutical company as well as a global supply chain operation.

We also own a specialty active pharmaceutical ingredients (“APIs”) manufacturer in Israel, which we expect will facilitate the development of our pipeline of molecules and compounds for our proprietary molecular diagnostic and therapeutic products.

We have a highly experienced management team.

Based on the members’ respective experience in the industry, we believe that our management team has extensive development, regulatory and commercialization expertise and relationships that provide access to commercial opportunities.

We also own a specialty active pharmaceutical ingredients (“APIs”) manufacturer in Israel.

We have a highly experienced management team, composed of individuals with solid industry experience and extensive development, regulatory and commercialization expertise and relationships that provide access to commercial opportunities.

All product or service marks appearing in type form different from that of the surrounding text are trademarks or service marks owned, licensed to, promoted or distributed by OPKO, its subsidiaries or affiliates, except as noted.

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GROWTH STRATEGY

We expect to grow by leveraging our commercial infrastructure, proprietary technology and development strengths.

We expect to build a leading portfolio of next-generation therapies leveraging our proprietary technology and development strengths.

We have under development a broad and diversified portfolio of diagnostic tests, small molecules, and biologics targeting a broad range of unmet medical needs.

We also operate one of the largest full service laboratories in the U.S.

We intend to continue to leverage our proprietary technology and our strengths in all phases of research and development to further develop and commercialize our portfolio of proprietary pharmaceutical and diagnostic products.

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continue marketing and commercialization of Rayaldee , and potentially expand the label into additional indications;

• Continue to support Pfizer’s efforts to secure regulatory approval for Somatrogon (hGH-CTP) in the U.S.

and potentially seek approval for additional indications, including adult growth hormone deficiency.

Somatrogon under the brand name NGENLA® is being sold by Pfizer in 15 countries, including Germany, Japan and the United Kingdom.

Pfizer expects to have launched in all priority markets by the end of 2023 and is continuing to work with the FDA to obtain approval in the U.S.

continue to support Pfizer’s efforts to seek approval for additional indications for Somatrogon (hGH-CTP), including adult growth hormone deficiency.

Somatrogon under the brand name NGENLA® is currently sold by Pfizer in over 50 markets, including the United States, European Union Member States, Japan, Canada, and Australia;

enter into collaborations and strategic partnerships designed to help advance and develop our product candidates.

Additionally, we plan to leverage our acquisition of ModeX to further expand our pharmaceutical product line.

ModeX is developing next-generation multispecifics biologics antibodies and vaccines for the treatment of cancer and infectious disease.

ModeX is developing next-generation multispecific antibodies and vaccines for the treatment of cancer and infectious disease.

ModeX’s growing portfolio has been developed through its proprietary multispecific antibody technology.

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Its pipeline includes product candidates intended to treat both solid and liquid tumors, as well as several of the world’s most pressing viral threats.

We also plan to continue to commercialize and increase adoption of our 4K score test for use in men age 45 and older who have not had a prior prostate biopsy or a biopsy negative and have an age specific abnormal total PSA or abnormal digital rectal exam.

We also plan to continue to commercialize and increase adoption of our 4K score test for use in men aged 45 and older who have not had a prior prostate biopsy or a biopsy negative and have an age specific abnormal total PSA or abnormal digital rectal exam.

4K score is available through BioReference.

In addition, we expect to leverage the BioReference business and infrastructure to drive rapid and widespread uptake of our diagnostic products and additional tests such as our 4K score test.

Our strategy with respect to BioReference is comprised two pillars:

the core business and strategic ventures.

In support of this strategy:

• We have made significant investments to rebuild and reconfigure our main laboratory in Elmwood Park, NJ and have also made significant investments in our labs in Melbourne, Florida, Houston, Texas, and California.

• We have facilitated increased patient access through preferred relationships with payors.

We are part of the United Healthcare preferred lab network with access to approximately 45 million patients.

We now also have access to Blue Cross/Blue Shield of Texas with another approximately 5.9 million patients and access to Blue Cross/Blue Shield of Alabama with another approximately 2 million patients.

• We intend to continue to expand our offerings among our core laboratory service businesses in clinical, genetics, women’s health, oncology and urology.

• We intend to continue to expand and seek new strategic ventures to provide laboratory services for large health care groups and systems.

CORPORATE INFORMATION

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The pharmaceutical segment consists of the pharmaceutical operations we operate in Chile, Mexico, Ireland, Israel, Spain, Ecuador, France, the United States, and our global pharmaceutical research and development operations.

The diagnostics segment primarily consists of the clinical laboratory operations of BioReference, as well as our point-of-care operations.

The diagnostics segment primarily consists of the clinical laboratory operations of BioReference.

There are no significant inter-segment sales.

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There is no inter-segment allocation of interest expense and income taxes.

Refer to Note 18 of our audited consolidated financial statements contained in this Annual Report on Form 10-K for financial information about our segments and geographic areas.

Refer to Note 18 of our audited consolidated financial statements contained in this Annual Report on Form 10-K (the "Consolidated Financial Statements") for financial information about our segments and geographic areas.

CURRENT PRODUCTS AND SERVICES AND RELATED MARKETS

BioReference Health, LLC

Through BioReference, one of the largest full service laboratories in the United States, we offer comprehensive laboratory testing services utilized by healthcare providers in the detection, diagnosis, evaluation, monitoring, and treatment of diseases, including esoteric testing, molecular diagnostics, anatomical pathology, genetics, women’s health and correctional healthcare.

BioReference has a legacy of scientific excellence, innovation, and world-class service in laboratory testing solutions.

Healthcare has changed in recent years, and BioReference has evolved by adapting our services and solutions aimed at addressing the needs of today’s customers.

Laboratory testing remains the cornerstone of the services we provide.

As we challenge the limits of specialty diagnostics, we are making strategic efforts to continue to drive innovation and cultivate a unique customer experience, as we focus on expanding our reach to match the dynamic needs of an ever-changing healthcare system.

BioReference is one of the largest full service laboratories in the United States, we offer comprehensive laboratory testing services utilized by healthcare providers in the detection, diagnosis, evaluation, monitoring, and treatment of diseases, including esoteric testing, molecular diagnostics, anatomical pathology, genetics, women’s health and correctional healthcare.

We market and sell these services to physician offices, clinics, hospitals, employers and governmental units nationally, with the largest concentration of business in the larger metropolitan areas in New York, New Jersey, Florida, Texas, Maryland, California, Pennsylvania, Delaware, Washington DC, Illinois and Massachusetts.

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insured lives.

BioReference has a 180-person sales and marketing team and operates a network of approximately 124 active patient service centers.

Our BioReference laboratory testing business consists of routine testing and esoteric testing.

Routine tests measure various health parameters, such as the functions of the heart, kidney, liver, thyroid and other organs, including such tests as blood cell counts, cholesterol levels, pregnancy, substance abuse and urinalysis.

BioReference operates 9 laboratory facilities around the country, is in-network with the largest health plans in the United States.

We typically operate 24 hours per day, 365 days per year and perform and report most routine test results within 24 hours.

The esoteric tests we perform require sophisticated equipment and materials, highly skilled personnel and professional attention.

Esoteric tests are ordered less frequently than routine tests and typically are priced higher than routine tests.

Esoteric tests include tests related to endocrinology, genetics and genomics, immunology, microbiology, HIV tests, molecular diagnostics, next generation sequencing, oncology, serology, and toxicology.

Through BioReference, we operate in the following highly specialized laboratory divisions:

• BioReference Health.

BioReference constitutes our core clinical testing laboratory offering automated, high volume routine testing services, COVID-19 testing, STAT testing, informatics, HIV, Hep C and other molecular tests.

GenPath (Urology).

Provides cutting-edge Uropatholgy, including the proprietary prostate cancer biomarker test, The 4Kscore Test®.

As a follow-up to a suspicious PSA test or DRE, The 4Kscore Test helps clarify the biopsy decision-making process by determining a patient-specific probability of finding aggressive prostate cancer on biopsy.

GenPath (Oncology).

National oncology presence with expertise in cancer pathology and diagnostics, as well as molecular diagnostics.

National oncology presence offers a comprehensive portfolio to support the continuum care of cancer patients – from risk assessment to treatment planning.

Backed by a team of specialized pathologists, GenPath Oncology delivers cutting-edge solutions that meet the unique needs of oncologists and pathologists, ranging from routine clinical and special coagulation to complex genomic testing for tumor sequencing and hereditary cancer syndromes.

Core tests include FLOW, IHC, MicroArray, FISH, ISH, Morphology, and full service oncology.

GenPath (Women ’ s Health).

Innovative technology platform for sexually transmitted infections has enabled expansion nationally with specimens coming from 41 states, including Image Directed Paps analysis, HPV Plus, and STI Testing.

We have one of the largest marketing staffs of any laboratory in the country with sales and marketing groups dedicated to urology, oncology, women’s health, genetic testing and correctional health, as well as cross-over groups selling to large institutions.

Most of our sales personnel operate in a dual capacity, as sales and client support representatives, which we believe provides better customer service and a strong connection with our customers.

We are among the largest providers of large-scale COVID-19 screening programs across the country, with the capacity to run approximately 100,000 PCR tests a day.

These large-scale screening programs include both PCR COVID-19 testing and point of care testing.

We offer testing across a variety of touch points, including the travel and leisure industry, airlines, cruise industry and education and have developed substantial relationships with local and state governments to provide testing services across all 50 states, with substantial service relationships in New York, New Jersey, and Michigan.

Innovative technology platform which provides end-to-end laboratory solutions for all women at every stage in their lives.

With an evidence-based portfolio designed for OBGYNs, MFMs, and women’s healthcare providers, GenPath Women’s Health offers testing for cervical and vaginal health, reproductive health, and hereditary cancer screening.

In addition, esoteric tests we perform require sophisticated equipment and materials, highly skilled personnel and professional attention.

Esoteric tests are ordered less frequently than routine tests and typically are priced higher than routine tests.

BioReference has a significant sales and marketing team and operates a network of approximately 104 active patient service centers.

Our marketing staff has sales and marketing groups dedicated to urology, oncology, women’s health, genetic testing, correctional health, and large institutions.

We expect the clinical laboratory testing industry will continue to experience growth in testing volumes due to aging of the population in the U.S., patient awareness of the value of laboratory tests, a decrease in the cost of tests, the development of sophisticated and specialized tests for detection and management of disease, increased recognition of early detection and prevention as a means of reducing healthcare costs, and ongoing research and development in genetics and genomics and personalized medicine.

Our mission is to be recognized by our clients as the premier provider of clinical laboratory testing, information and related services.

BioReference provides us with a significant diagnostics commercial infrastructure for marketing and sales that reached approximately 12 million and 21 million patients, respectively, in 2022 and 2021.

In addition, its large team of managed care experts complements our efforts to ensure that payors recognize the value of our diagnostic and laboratory tests for

reimbursement purposes.

We continue to leverage the national marketing, sales and distribution resources of BioReference, along with its 180-person sales and marketing team, to enhance sales of and reimbursement for our 4Kscore test, a laboratory developed blood test that provides a personalized risk score for aggressive prostate cancer.

We plan to leverage the BioReference commercial infrastructure and capabilities, as well as its extensive relationships with payors, to commercialize OPKO’s other diagnostic products under development.

Disposition of GeneDx

On January 14, 2022, the Company entered into an Agreement and Plan of Merger and Reorganization (the “GeneDx Merger Agreement”) with Sema4 Holdings Corp., a Delaware corporation (“Sema4”), pursuant to which Sema4 acquired the Company’s former subsidiary, GeneDx LLC, (f/k/a GeneDx, Inc.

“GeneDx”), (the “GeneDx Transaction”) in a transaction that closed on April 29, 2022 (the “GeneDx Closing”).

GeneDx is an industry leading national laboratory for testing rare and ultra-rare genetic diseases with international reach, performing testing on specimens from more than 50 countries.

Upon the GeneDx Closing, GeneDx Holdings paid to the Company aggregate consideration of $150 million in cash (before deduction of transaction expenses and other customary purchase price adjustments), together with 80.0 million shares (the “Closing Shares”) of GeneDx Holdings’ Class A common stock, par value $0.0001 per share (“GeneDx Holdings Common Stock”).

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) 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 April 29, 2022, the total upfront consideration was approximately $322 million, and the total aggregate consideration, including the potential Milestone Consideration, was approximately $447 million.

BioReference provides us with a significant diagnostics commercial infrastructure for marketing and sales that reached approximately 9 million, 12 million and 21 million patients, respectively, in 2023, 2022 and 2021.

In addition, its large team of managed care experts complements our efforts to ensure that payors recognize the value of our diagnostic and laboratory tests for reimbursement purposes.

We continue to leverage the national marketing, sales and distribution resources of BioReference to enhance sales of and reimbursement for our 4Kscore test, a laboratory developed blood test that provides a personalized risk score for aggressive prostate cancer.

We offer the 4Kscore test through BioReference.

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in March 2014 and in Europe and Mexico in September 2014 and January 2015, respectively.

The 4Kscore test was approved by the FDA in December 2021 for use in men age 45 and older who have not had a prior prostate biopsy or a biopsy negative and have an age specific abnormal total PSA or abnormal digital rectal exam (“DRE”).

The 4Kscore test was approved by the FDA in December 2021 for use in men aged 45 and older who have not had a prior prostate biopsy or a biopsy negative and have an age specific abnormal total PSA or abnormal digital rectal exam (“DRE”).

The 4Kscore test is a laboratory developed test that measures the blood serum or plasma levels of four different prostate-derived kallikrein proteins:

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Since that date, 4Kscore test orders meeting the coverage criteria have been reimbursed by Novitas and Medicare Advantage Health Plans.

Disposition of GeneDx

On January 14, 2022, we entered into an Agreement and Plan of Merger and Reorganization (the “GeneDx Merger Agreement”) with GeneDx Holdings Corp.

(formerly, Sema4 Holdings Corp., (“GeneDx Holdings”), pursuant to which, on APril 29, 2022, GeneDx Holdings acquired our former subsidiary, GeneDx LLC, (f/k/a GeneDx, Inc.

“GeneDx”, and such transaction, the “GeneDx Transaction”).

GeneDx is an industry leading national laboratory for testing rare and ultra-rare genetic diseases with international reach, performing testing on specimens from more than 50 countries.

Upon closing of the GeneDx Transaction, GeneDx Holdings paid to us aggregate consideration of $150 million in cash (before deduction of transaction expenses and other customary purchase price adjustments), together with 80.0 million shares (the “Closing Shares”) of GeneDx Holdings’ Class A common stock, par value $0.0001 per share (“GeneDx Holdings Common Stock”).

Additionally, subject to GeneDx achieving certain revenue targets for the fiscal years ended December 31, 2022 and 2023, we were 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 (the "GeneDx Milestone Consideration").

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

however, we do not expect to receive any GeneDx Milestone Consideration with respect to the year ended December 31, 2023.

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

Pharmaceutical Business

We currently have one commercial stage pharmaceutical product and several pharmaceutical compounds and technologies in various stages of research and development for a broad range of indications and conditions, including the following:

We currently have two commercial stage pharmaceutical products and several pharmaceutical compounds and technologies in various stages of research and development for a broad range of indications and conditions, including the following:

Renal Products-Rayaldee

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The FDA approval of Rayaldee was supported by successful results from two identical randomized, double-blind, placebo-controlled, multi-site phase 3 studies which established the safety and efficacy of Rayaldee as a new treatment for SHPT in adults with stage 3 or 4 CKD and vitamin D insufficiency.

Vitamin D insufficiency can arise in CKD due to the abnormal upregulation of CYP24A1, an enzyme that destroys vitamin D and its metabolites, from obesity and from many other causes as well.

Vitamin D insufficiency can arise in CKD due to the abnormal upregulation of CYP24A1, an enzyme that destroys vitamin D and its metabolites, from obesity, from common but ineffective treatment with unapproved dietary vitamin D supplements, and from many other causes as well.

Studies in CKD patients have demonstrated that currently available over-the-counter and prescription vitamin D supplements cannot reliably and sufficiently raise blood vitamin D prohormone levels to effectively treat SHPT, a condition commonly associated with CKD in which the parathyroid glands secrete excessive amounts of parathyroid hormone (“PTH”).

Prolonged elevation of blood PTH causes excessive calcium and phosphorus to be released from bone, leading to elevated serum calcium and phosphorus levels, softening of the bones (osteomalacia) or loss of bone mineral density (osteoporosis), and calcification of vascular and renal tissues.

Prolonged elevation of blood PTH causes excessive calcium and phosphorus to be released from bone, leading to elevated serum calcium and phosphorus levels, softening of the bones (osteomalacia) or resulting in a loss of bone mineral density (osteoporosis), calcification of vascular and renal tissues, and acceleration of dialysis onset.

SHPT affects 33% and 54% of patients with stage 3 and 4 CKD respectively, and approximately 95% of patients with stage 5 CKD.

We have a 58-person highly specialized sales, marketing and market access team dedicated to the commercialization of Rayaldee as of December 31, 2022.

In the fourth quarter of 2022, total Rayaldee prescriptions decreased approximately 4.9% and 2.0% as compared to the fourth quarter of 2021 and the third quarter of 2022, respectively.

Sales of Rayaldee have not increased in accordance with its expected growth trajectory as a result of challenges in onboarding new patients due to several factors, including the COVID-19 pandemic.

We have a highly specialized sales, marketing and market access team dedicated to the commercialization of Rayaldee as of December 31, 2023.

In the fourth quarter of 2023, total Rayaldee prescriptions increased approximately 13.6% and 3.8% as compared to the fourth quarter of 2022 and the third quarter of 2023, respectively.

Sales of Rayaldee increased progressively during 2023 indicating an end to the lingering adverse effects of the COVID-19 pandemic on onboarding new patients, which we believe encumbered the growth of Rayaldee sales below their expected growth trajectory.

Efforts are underway to obtain broader commercial and Part D insurance coverage for Rayaldee .

We have already achieved commercial and Medicare Part D formulary coverage for more than 78.8% of U.S.

covered lives as of the end of 2022.

In May 2016, we entered into a development and license agreement (as amended, the “VFMCRP Agreement”) with Vifor Fresenius Medical Care Renal Pharma (“VFMCRP”, now CLS Vifor) for the development and commercialization of Rayaldee in Europe, Canada, Mexico, Australia, South Korea and certain other international markets for the treatment of SHPT in patients with stage 3, 4 or 5 CKD and vitamin D insufficiency.

The VFMCRP Agreement was later amended to exclude South Korea, the Middle East and all of the countries of Africa from the VFMCRP Territory (as defined in the VFMCRP Agreement), and further amended to include Japan as part of the VFMCRP Territory.

VFMCRP initiated the commercial launch of Rayaldee in Germany in February 2022 and received marketing authorization from eleven European countries to date and is preparing for product launches in additional territories in 2023.

We have negotiated payer contracts that afford unrestricted access for 63% and 71% of U.S.

commercial and Medicare Part D covered lives as of the end of 2023.

In May 2016, we entered into a development and license agreement (as amended, the “VFMCRP Agreement”) with Vifor Fresenius Medical Care Renal Pharma (“VFMCRP”) for the development and commercialization of Rayaldee in Europe, Canada, Mexico, Australia, South Korea and certain other international markets for the treatment of SHPT in patients with stage 3, 4 or 5 CKD and vitamin D insufficiency.

The VFMCRP Agreement was later amended to exclude South Korea, Mexico, the Middle East and all of the countries of Africa from the VFMCRP Territory (as defined in the VFMCRP Agreement), and further amended to include Japan as part of the VFMCRP Territory.

VFMCRP initiated the commercial launch of Rayaldee in Germany and Switzerland in February and March 2022, respectively, and received marketing authorization from eleven European countries to date and is preparing for product launches in additional territories in 2024.

The launch in Germany triggered a $3 million payment to our wholly-owned subsidiary, EirGen Pharma Ltd.

(“EirGen”), and another $7 million payment to EirGen in February 2023 tied to achievement of an acceptable final price in Germany as of the 1 year anniversary of launch.

(“EirGen”), and another $7 million payment to EirGen in February 2023 tied to achievement of an acceptable final price in Germany as of the 1 year anniversary of launch, and is eligible to receive up to an additional $15 million in regulatory milestones and $200 million in milestone payment tied to launch, pricing and sales of Rayaldee , and tiered, double-digit royalties.

In connection with the VFMCRP Agreement, the parties entered into a letter agreement pursuant to which EirGen granted to VFMCRP an exclusive option (the “Option”) to acquire an exclusive license under certain EirGen patents and technology to use, import, offer for sale, sell, distribute and commercialize Rayaldee in the U.S.

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Upon exercise of the Option, VFMCRP has agreed to reimburse EirGen for all of the development costs incurred by EirGen with respect to Rayaldee for the Dialysis Indication in the U.S.

VFMCRP would also pay EirGen up to an additional aggregate amount of $555 million of sales-based milestones upon the achievement of certain milestones and would be obligated to pay royalties at percentage rates that range from the mid-

teens to the mid-twenties on sales of Rayaldee in the U.S.

for the Dialysis Indication.

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On June 18, 2021, EirGen and NICOYA Macau Limited (“Nicoya”), a Macau corporation and an affiliate of NICOYA Therapeutics, entered into a Development and License Agreement (as amended, the “Nicoya Agreement”) granting Nicoya the exclusive rights for the development and commercialization of extended release calcifediol (the “Nicoya Product”) in Greater China, which includes mainland China, Hong Kong, Macau, and Taiwan (collectively, the “Nicoya Territory”).

The license grant to Nicoya covers the therapeutic and preventative use of the Nicoya Product for SHPT in non-dialysis and hemodialysis chronic kidney disease patients (the “Nicoya Field”).

Nicoya notified EirGen in February 2023 that it had submitted an IND for the Nicoya Product to the Chinese Center of Drug Evaluation (“CDE”) which triggered a $2.5M milestone payment to EirGen.

The license grant to Nicoya covers the therapeutic and preventative use of the Nicoya Product for SHPT in non-dialysis and hemodialysis CKD patients (the “Nicoya Field”).

Nicoya notified EirGen in February 2023 that it had submitted an IND for the Nicoya Product to the Chinese Center of Drug Evaluation (“CDE”) which triggered a $2.5 million milestone payment to EirGen.

OPKO and VFMCRP collaborated to complete a phase 2 study evaluating a higher strength dosage form of Rayaldee for the treatment of SHPT in hemodialysis patients.

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Further development of Rayaldee for hemodialysis patients is on hold due to unfavorable reimbursement for new drugs for the care of these patients under the current Prospective Payment System established by the Centers for Medicare and Medicaid Services (“CMS”).

In October 2020, we commenced a placebo controlled Phase 2 trial with Rayaldee as a treatment for mild-to-moderate COVID-19.

In August 2021, the trial completed enrollment of 171 symptomatic patients from multiple U.S.

These patients were randomized in a 1:1 ratio for 4 weeks of treatment with Rayaldee or placebo and a 2-week follow-up.

The trial ended in November 2021 and the resulting final data were published in Nutrition in in December 2022.

The data indicated that improving vitamin D status with oral Rayaldee resulted in earlier resolution of respiratory symptoms associated with COVID-19.

We have completed a Phase 4 clinical trial comparing Rayaldee with three common treatment regimens for SHPT in adults with stage 3 or stage 4 CKD and vitamin D insufficiency.

We have completed a Phase 4 clinical trial comparing Rayaldee with three common treatment regimens for SHPT in adults with stage 3 or stage 4 CKD and vitamin D insufficiency, the results of which were published in February 2023 in Kidney Diseases .

Final data show that a daily dose of 60 micrograms of Rayaldee is the only one of four competitive treatment regimens that reliably raises serum total 25-hydroxyvitamin D to the range of 50-100 mg/mL, a level required to effectively suppress elevated plasma PTH levels in CKD patients.

We presented interim results in an abstract titled “Comparison of Extended-Release Calcifediol (ERC), Immediate-Release Calcifediol, Cholecalciferol, and Paricalcitol for Treating Secondary Hyperparathyroidism (SHPT) in CKD” at the American Society of Nephrology’s Kidney Week Annual Meeting in October 2020.

Final results of the study are scheduled for publication in March 2023 in Kidney Diseases.

We also have completed a retrospective study of medical records for 376 adult patients with stage 3-4 CKD from 15 U.S.

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The data, published in part in the American Journal of Nephrology in October 2021 and in full in BMC Nephrology in November 2022, confirmed the efficacy and safety of Rayaldee in real world clinical practice and demonstrated its superiority versus dietary vitamin D supplements and vitamin D hormones for reducing elevated PTH levels and correcting vitamin D insufficiency.

In November 2023, we presented late-breaking clinical data on Rayaldee at the American Society of Nephrology Kidney Week which indicate that early, sustained and effective treatment of SHPT with Rayaldee is associated with significantly slower progression of CKD in pre-dialysis patients.

We believe the CKD patient population is large and growing as a result of obesity, hypertension and diabetes;

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According to the 2023 U.S.

Renal Data System, CKD afflicts 14% of U.S.

Renal Data System Annual Report, CKD afflicts 14% of U.S.

adults and its prevalence is highest in non-Hispanic Black individuals (18.8%).

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CKD continues to be associated with poor outcomes, reflecting the inadequacies of the current standard of care.

We intend to develop and commercialize Rayaldee to constitute part of the foundation for a new and markedly improved standard of care for CKD patients having SHPT.

In May 2022, we acquired ModeX, a biotech company developing multi-specific immune therapies focused on oncology, infectious diseases, vaccines and immunology.

ModeX utilizes several platforms in furtherance of its targets:

the MSTAR with which we believe we can reliably and rapidly generate candidates that target up to six distinct biological pathways in a single molecule;

the STEALTH platform which utilizes antibody-masking technology and aims to deliver the power of multispecific immuno-modulation to widely expressed targets by building in a safety net that localizes immune attack specifically to tumors, and the Nanoparticle Vaccine platform, built on naturally occurring and self-assembling ferritin molecules, which ensures the right combination of antigens are presented in the right amount and in the right place to enhance the immune response.

the multispecific antibody MSTAR, which we believe we can reliably and rapidly generate candidates that target up to six distinct biological pathways in a single molecule;

and the Nanoparticle Vaccine platform, built on naturally occurring and self-assembling ferritin molecules, which ensures the right combination of antigens are presented in the right amount and in the right place to enhance the immune response.

We believe the versatility and potency of our approach will enable us to tackle many major infectious diseases that have eluded effective vaccination due to their continual evolution and immune evasion.

ModeX currently has a tetra-specific antibody developed utilizing our proprietary MSTAR technology platform targeting several types of refractory solid tumors;

it is designed to activate and sustain the activation of the T-cells, and simultaneously target two antigens highly expressed on diverse tumors.

ModeX currently has a tetra-specific antibody developed utilizing its proprietary MSTAR technology targeting several types of refractory solid tumors;

it is designed to activate and sustain the function of the T-cells, and simultaneously target two antigens highly expressed on diverse tumors.

Dual targeting increases tumor specificity and mitigates escape resistance through loss of a single glycoprotein.

Major solid tumor opportunities include lung, triple negative breast cancer, ovarian, prostate, and other solid tumors.

Major solid tumor opportunities include lung, ovarian, prostate, and other solid tumors.

The antibody has demonstrated potent in vitro tumor cell killing in multiple cell lines and in vivo tumor regression in mice challenged with cancer cells.

This antibody, currently in preclinical and CMC development stage, is anticipated to enter clinical testing in 2024.

ModeX also has a multi-specific antibody developed using the MSTAR technology platform targeting two antigens for hematological tumors, such as several types of lymphomas and leukemias.

ModeX also has multi-specific antibodies developed using the MSTAR technology platform.

One antibody targets two antigens for hematological tumors, such as several types of lymphomas and leukemias.

Dual targeting minimizes chance of resistance due to tumor heterogeneity or downregulation of target levels.

The antibody has demonstrated preferential in vitro killing on tumor cells over normal B cells and in vivo anti-tumor efficacy in disseminated mouse tumor model.

This project is in preclinical development stage and is anticipated to enter into CMC development in 2023.

The other antibody stimulates T cells and enhances their survival and proliferation, specifically activating antigen-specific memory T cells;

and it could be used alone or in combination for immune-oncology and/or infectious disease indications.

This project is anticipated to enter into preclinical and CMC development stage in 2024.

In September 2023, ModeX was awarded a contract (the "BARDA Contract") from the Biomedical Advanced Research and Development Authority ("BARDA"), part of the Administration for Strategic Preparedness and Response at the U.S.

Department of Health and Human Services, to advance a platform and specific candidates designed to address a range of public health threats in viral infectious diseases.

The awarded funding will enable research, development and clinical evaluation of potent multispecific antibodies, based on ModeX proprietary MSTAR technology.

ModeX’s Epstein Barr Virus (“EBV”) vaccine is developed using a modular nanoparticle vaccine platform built on naturally occurring and self-assembling ferritin molecules which enables the presentation of a 24-symmetrical array of each antigen that enhances the presentation of key components of the virus and stimulate durable protective immunity.

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These include a recombinant antigen designed from the proteins gH, gL and gp42, as well as an antigen derived from gp350.

By using ModeX’s multi-targeted approach, this combination inhibits infection in two cell types, B cells and epithelial cells, which contrasts from efforts that previously focused on gp350 alone.

ModeX has a trispecific HIV mAb (SAR441236), licensed from Sanofi, aimed at treatment of HIV infection in combination with other anti-retroviral treatment to achieve viral suppression in adults and pediatric patients with multidrug-resistant HIV that have limited therapeutic options.

By using ModeX’s multi-targeted approach, this combination is designed to elicit antibodies that inhibit infection in two cell types, B cells and epithelial cells, which contrasts from efforts that previously focused on gp350 alone.

In March 2023, ModeX, OPKO, and Merck Sharp & Dohme LLC (“Merck”) entered into a License and Research Collaboration Agreement (the “Merck Agreement”), pursuant to which ModeX granted to Merck an exclusive, sublicensable, royalty-bearing license to certain patent rights and know-how in connection with the development of ModeX’s preclinical nanoparticle vaccine candidate targeting the Epstein-Barr Virus.

Certain of the rights subject to such license were obtained by ModeX from Sanofi pursuant to the Sanofi In-License Agreement, and a portion of the upfront payment, milestones and royalties received by ModeX under the Merck Agreement may be payable to Sanofi under the terms of the Sanofi In-License Agreement.

ModeX has a trispecific HIV mAb (SAR441236), licensed from Sanofi ("Sanofi"), pursuant to that certain License Agreement entered into as of July 1, 2019 ("Sanofi In-License Agreement") between ModeX and Sanofi, aimed at treatment of HIV infection.

SAR441236 is currently being evaluated in a phase I clinical trial sponsored by the National Institute of Allergy and Infectious Diseases.

Through the acquisition of Transition Therapeutics, a Toronto-based biotechnology company (“Transition”), we acquired OPK88004, an orally administered selective androgen receptor modulator (“SARM”).

The selective and antagonistic properties of OPK88004 on the prostate appear to be well suited to potentially reduce prostate hyperplasia and volume, as well as provide anabolic therapeutic benefits such as increased lean body mass and physical function, and decreased fat mass in specific patient populations.

We believe that SARMs hold considerable promise as a new class of anabolic therapies for a variety of clinical indications, such as frailty and functional limitations associated with aging and chronic illnesses, cancer and osteoporosis.

The selective and potent effects of OPK88004 on the anabolic androgen receptors appear to be well suited to potentially increase lean body mass, physical function, and decrease fat mass, whereas the antagonistic effect on the prostate reduces the risk of prostate hyperplasia and volume in specific patient populations.

In view of these properties, we believe that SARMs hold considerable promise as a new class of anabolic therapies for a variety of clinical indications resulting in the loss of muscle and physical function, such as frailty and functional limitations associated with aging and chronic illnesses, cancer and osteoporosis.

Oxyntomodulin

Our internal product development program is also currently focused on developing a once weekly administered oxyntomodulin for type 2 diabetes and obesity.

Our most advanced oxyntomodulin product candidate, OPK88003, a once-weekly administered peptide for the treatment of type 2 diabetes and associated obesity, is a dual agonist of the Glucagon-Like Peptide-1 (GLP-1) and glucagon receptors.

Our most advanced oxyntomodulin analog product, OPK88003, a once-weekly administered peptide is a dual agonist of the Glucagon-Like Peptide-1 (GLP-1) and glucagon receptors.

The receptors play an integral role in regulating appetite, food intake, satiety and energy utilization in the body.

Stimulating both of the receptors, OPK88003 has the potential to regulate blood glucose.

Stimulating both receptors, OPK88003 has demonstrated the potential to regulate blood glucose and reduce body weight.

OPK88003 has been evaluated in a phase 2 study enrolling 420 type 2 diabetes subjects in a 24 week study consisting of a 12-week randomized blinded stage followed by a 12-week open-label stage.

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OPK88003 also provided a reduction in HbA1c, a marker of sugar metabolism, similar to exenatide at weeks 12 and 24.

We have evaluated OPK88003 in a dose escalation phase 2b trial in 110 type 2 diabetics where patients have been treated with a dose escalation regimen over 3 months intended to optimize dose levels, and increase body weight loss and reduce the adverse event profile, such as nausea and vomiting.

We have evaluated OPK88003 in a dose escalation phase 2b trial in 110 type 2 diabetics with dose titration over 3 months for the purpose of dose optimization for adequate body weight reduction and minimize the adverse nausea and vomiting events.

The patients were treated for a total of 30 weeks in the study.

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We retain full rights to oxyntomodulin and Factor VIIa-CTP in all other geographies.

We believe oxyntomodulin has potential to be a safe, long term therapy for obesity and diabetes type 2 patients, representing significant market opportunities.

We believe oxyntomodulin analog has potential to be a safe, long term therapy for obesity and diabetes type 2 patients, representing significant market opportunities.

More than 380 million are living with diabetes worldwide, of which approximately 90% have type 2 diabetes.

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Biologics-General

Our biologics business focuses on developing and commercializing longer-acting proprietary versions of already approved therapeutic proteins.

One of our innovative platform technologies uses a short, naturally-occurring amino acid sequence, carboxl terminal peptide (“CTP”) which has the effect of slowing the removal from the body of the therapeutic protein to which it is attached.

This CTP can be readily attached to a wide array of existing therapeutic proteins, stabilizing the therapeutic protein in the bloodstream and extending its life span without additional toxicity or loss of desired biological activity.

Our biologics business focuses on developing long-acting proprietary versions of approved therapeutic proteins or peptides.

One of our innovative platform technologies uses a small peptide, carboxyl terminal peptide (“CTP”) which is part of endogenous human chorionic gonadotropin hormone produced by the placenta during pregnancy.

The effect of the additional CTP to is to increase the circulating half-life of luteinizing hormone.

We are using the CTP technology to develop new, proprietary versions of certain existing therapeutic proteins that have longer life spans than therapeutic proteins without CTP.

We believe that our products will have greatly improved therapeutic profiles and distinct market advantages.

Somatrogon (hGH-CTP)

We have completed the development of CTP- attached human growth hormone, Somatrogon (hGH-CTP) (see below), which is approved in over 40 countries.

In addition to hGH-CTP and Factor VIIa-CTP, we believe that the CTP technology may also be broadly applicable to other therapeutic proteins in the market and provide a reduction in the number of injections required for treatment.

We are currently engaged in research and development efforts to use the CTP technology for development of a long-acting CTP-IGF-1 for the Treatment of Severe Primary IGF-1 Deficiency.

We are also developing long-acting therapies biologics molecule for once weekly therapies in rare diseases by different technologies to extend the circulating half-life of known therapeutic targets.

NGENLA ® Somatrogon (hGH-CTP)

Our lead product candidate utilizing CTP, Somatrogon (hGH-CTP), is a recombinant human growth hormone product under development for the treatment of growth hormone deficiency (“GHD”), which is a pituitary disorder resulting in short stature in children and other physical ailments in both children and adults.

In December 2014, we entered into an exclusive worldwide agreement with Pfizer (the “Pfizer Transaction”) for the development and commercialization of hGH-CTP for the treatment of GHD in adults (“Adult GHD”) and in children (“Pediatric GHD”), as well as for the treatment of growth failure in children born small for gestational age (“SGA”).

In connection with the Pfizer Transaction, we granted Pfizer an exclusive license to commercialize hGH-CTP worldwide, and we received non-refundable and non-creditable upfront payments aggregating $295 million and are eligible to receive up to an additional $275 million upon the achievement of certain regulatory milestones.

Upon the launch of hGH-CTP we are entitled to either regional, tiered gross profit sharing for both hGH-CTP and Pfizer’s Genotropin® once certain necessary pricing approvals are obtained, or tiered royalty payments on sales of Somatrogon (hGH-CTP) with percentage rates ranging from the high teens to mid-twenties until such necessary pricing approval are obtained.

GHD occurs when the production of growth hormone, secreted by the pituitary gland, is disrupted.

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We believe a significant market opportunity exists for a longer-lasting version of hGH that would require fewer injections.

Our phase 3 trial of hGH-CTP in pediatric patients was initiated in December 2016 and was completed in August 2019.

The global study was a 224-patient study in Pediatric GHD patients designed to evaluate weekly treatment with hGH-CTP versus daily injections of Genotropin.

hGH-CTP is delivered in a pen device in this multi-regional study in over 21 countries.

The GHD subjects were treated weekly for 12 months.

On October 21, 2019, we and Pfizer announced that the global phase 3 trial met its primary endpoint of non-inferiority to daily Genotropin® (somatropin) for injection, as measured by annual height velocity (“HV”) at 12 months.

Results from this study demonstrated that treatment with hGH-CTP dosed once-weekly in pre-pubertal children with GHD was non-inferior to Genotropin® (somatropin) dosed once-daily with respect to HV at 12 months of treatment (the primary endpoint);

the least square mean was higher in the hGH-CTP group (10.12 cm/year) than in the Genotropin® (somatropin) group (9.78 cm/year);

the treatment difference (hGH-CTP—Genotropin® (somatropin)) in HV (cm/

year) was 0.33 with a two-sided 95% confidence interval of the difference of (-0.39, 1.05).

In addition, change in height standard deviation scores at six and 12 months, key secondary endpoints, were higher in the hGH-CTP dosed once-weekly cohort in comparison to the Genotropin® (somatropin) dosed once-daily cohort.

hGH-CTP was generally well tolerated in this study and comparable to that of Genotropin® (somatropin) dosed once-daily with respect to the types, numbers and severity of the adverse events observed between the treatment arms.

We believe hGH-CTP represents a significant advancement in the treatment of children with GHD compared to the current standard of one injection per day that could enhance a patient’s adherence to treatment and quality of life.

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The least squared means for the annual height velocity was higher in the Somatrogon group (9.65 cm/year) than in the Genotropin group (7.87 cm/year).

We submitted the initial Biologics License Application (“BLA”) with the FDA for approval of Somatrogon (hGH-CTP) in the United States 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 an appropriate path forward.

Regulatory applications for Somatrogon (hGH-CTP) have been submitted to the applicable regulatory bodies for review in several countries around the world.

In June 2023, the FDA approved NGENLA (Somatrogon).

Regulatory applications for Somatrogon (hGH-CTP) were also submitted to the applicable regulatory bodies for review in several countries around the world.

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Additional analyses that did not exclude outliers showed mixed results.

Further, significant changes were observed with hGH-CTP treatment in secondary endpoints such as lean body mass and compared to placebo.

We believe there is a path for submission of a BLA with respect to hGH-CTP for adults with GHD on the basis that the FDA may assess the totality of the data, including all relevant efficacy and safety data in adult and pediatric patients.

We plan to continue to assess with Pfizer the regulatory strategy for the adult indication going forward, including the timing of a possible submission.

Further, significant changes were observed with hGH-CTP treatment in secondary endpoints such as % fat mass, lean body mass and normalization of IGF-1 levels compared to placebo.

These data demonstrated that Somatrogon treatment improved key body composition parameters, meeting criteria recommended by the Endocrinology Association.

We are continuing to assess with Pfizer the regulatory strategy for the adult indication going forward, including the timing of possible submissions.

Factor VIIa-CTP

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In addition to development efforts using the CTP platform, we are also focused on broadening the approaches used to develop long acting therapies for once weekly therapies in rare diseases.

Active Pharmaceutical Ingredients (APIs)

FineTech Pharmaceutical, Ltd.

(“FineTech”), is our Israeli-based subsidiary that develops and produces high value, high potency specialty APIs.

FineTech currently manufactures commercial APIs for sale or license to pharmaceutical companies in Latin America, Canada, Europe and Israel.

We believe that FineTech’s significant know-how and experience with analytical chemistry and organic syntheses, together with its production capabilities, may play a valuable role in the development of our pipeline of proprietary molecules and compounds for diagnostic and therapeutic products, while providing revenues and profits from its existing API business.

Oligonucleotide Therapeutics

OPKO CURNA’s platform technology utilizes a short, single strand oligonucleotide to increase production of endogenous protein through interference with non-coding RNA’s or natural antisense.

This strategy contrasts with established approaches which down-regulate protein production.

CURNA has designed a novel type of therapeutic modality, termed AntagoNAT, and has initially demonstrated this approach for up-regulation of several therapeutically relevant proteins in in vitro and animal models.

We have filed an investigational new drug application, or IND, for a lead compound to treat Dravet Syndrome.

Further preclinical work has been requested by the FDA prior to initiation of a first clinical study.

Orphan disease designations have been granted by FDA and EMA.

On July 6, 2021, we entered into an exclusive license agreement (the “CAMP4 Agreement”) with CAMP4 Therapeutics Corporation (“CAMP4”), pursuant to which we granted to CAMP4 an exclusive license to develop, manufacture, commercialize or improve therapeutics utilizing the AntagoNAT technology, which includes the molecule for the treatment of Dravet syndrome, together with any derivative or modification thereof (the “CAMP4 Licensed Compound”) and any pharmaceutical product that comprises or contains the CAMP4 Licensed Compound, alone or in combination with one or more other active ingredients (“CAMP4 Licensed Product”), worldwide.

The CAMP4 Agreement grant covers human pharmaceutical, prophylactic, and therapeutic and certain diagnostic uses.

(“FineTech”), is our Israeli-based subsidiary that develops and manufactures high value, high potency specialty APIs.

FineTech currently manufactures GMP grade APIs for sale or license to pharmaceutical companies in the United States, Latin America, Canada, Europe and Israel.

Commercial Operations

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EirGen is focused on the development and commercial supply of high potency, high barrier to entry, pharmaceutical products.

Through its facility in Waterford, Ireland, EirGen currently

manufactures high potency pharmaceutical products and exports to over 50 countries.

Through its facility in Waterford, Ireland, EirGen currently manufactures high potency pharmaceutical products and exports to over 50 countries.

High potency drugs such as those used for cancer chemotherapy are typically unsuitable for manufacture in normal multi-product facilities due to cross contamination risks.

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We believe EirGen will play an important role in the development, manufacturing, distribution and approval of a wide variety of drugs in a variety of dosage forms with an emphasis on high potency products.

OPKO Health Europe (previously Farmadiet Group Holding, S.L.) operates primarily in Spain and has more than 20 years of experience in the development, manufacture, marketing and sale of pharmaceutical, nutraceutical and veterinary products in Europe.

OPKO Mexico (previously Pharmacos Exakta S.A.

de C.V.), is engaged in the manufacture, marketing, sale and distribution of ophthalmic and other pharmaceutical products to private and public customers in Mexico.

OPKO Mexico is commercializing food supplements and over the counter products, and manufactures and sells products primarily in the generics market in Mexico, although it also has some proprietary products as well.

OPKO Chile (previously Pharma Genexx, S.A.) markets, sells and distributes pharmaceutical products to the private, hospital, pharmacy and public institutional markets in Chile for a wide range of indications, including, cardiovascular products, vaccines, antibiotics, gastro- intestinal products and hormones, among others.

ALS Distribuidora Limitada (“ALS”) is engaged in the business of importation, commercialization and distribution of pharmaceutical products for private markets in Chile.

ALS started operations in 2009 as the exclusive product distributor of Arama Laboratorios y Compañía Limitada (“Arama”), a company with more than 20 years of experience in the pharmaceutical products market.

In connection with the acquisition of ALS, OPKO acquired all of the product registrations and trademarks previously owned by Arama, as well as the Arama name.

We distribute food supplements and over the counter products through Arama.

OPKO Health Europe operates primarily in Spain and has more than 22 years of experience in the development, manufacture, marketing and sale of pharmaceutical, nutraceutical and veterinary products in Europe and Latin America.

OPKO Mexico is engaged in the manufacture, marketing, sale and distribution of ophthalmic and other pharmaceutical products to private and public customers in Mexico and Chile.

OPKO Mexico is commercializing food supplements and over the counter products and manufactures and sells products primarily in the generics market in Mexico, although it also has some branded generic products as well.

OPKO Chile markets, sells and distributes pharmaceutical products to the private, hospital, pharmacy and public institutional markets in Chile for a wide range of indications, including, cardiovascular products, vaccines, antibiotics, gastro- intestinal products and hormones, among others.

ARAMA Natural Products Distribuidora Limitada (“ARAMA”) is engaged in the business of importation, commercialization and distribution of pharmaceutical and OTC products for private and public markets in Chile.

ARAMA (previously ALS Distribuidora Limitada) is a company with more than 30 years of experience in the pharmaceutical and OTC products market.

Strategic Investments

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During the years ended December 31, 2023, 2022, and 2021, we incurred $89.6 million, $73.9 million, and $76.9 million, respectively, of research and development expenses related to our various product candidates.

During the years ended December 31, 2022, 2021, and 2020, our research and development expenses primarily consisted of hGH-CTP and Rayaldee development programs.

During the years ended December 31, 2023, 2022, and 2021, our research and development expenses primarily consisted of a pipeline of immuno-oncology and infectious disease programs, hGH-CTP, and Rayaldee development programs.

INTELLECTUAL PROPERTY

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These patents are also filed in multiple countries worldwide.

One patent family claims a sustained release oral dosage formulation and a method of treating 25-hydroxyvitamin D

insufficiency or deficiency and will not expire until at least February 2027.

One patent family claims a sustained release oral dosage formulation and a method of treating 25-hydroxyvitamin D insufficiency or deficiency and will not expire until at least February 2027.

A second patent family claims a method of administering 25-hydroxyvitamin D 3 by controlled release, a formulation for controlled release of a vitamin D compound, a controlled release oral dosage formulation of a vitamin D compound and a method of treatment, and will not expire until at least April 2028.

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We intend to seek patent term extensions in those countries for which such protection is potentially available.

We also continue to file and seek patent protection on various uses of extended release dosage forms of 25-hydroxyvitamin D3 and new formulations of this drug.

EirGen’s patent publication US2021/0308151 disclosing and claiming the use of 25-hydroxyvitamin D3 and controlled release formulations thereof to treat SARS-CoV-2 infection was published on October 7, 2021.

Somatrogon ( hGH-CTP)

We also continue to file and seek patent protection on various uses of extended release dosage forms of 25-hydroxyvitamin D 3 and new formulations or presentations of this drug.

NGENLA ® -- Somatrogon ( hGH-CTP)

The hGH-CTP line of patents, which is exclusively licensed to Pfizer, includes multiple U.S.

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and internationally.

Patent term extensions will be sought in those countries where Somatrogon (hGH-CTP) is approved.

Patent term extensions and/or similar extensions such as supplementary protection certificates (SPCs) have been filed in the United States Patent and Trademark Office (USPTO) and in multiple foreign jurisdictions where NGENLA (Somatrogon) has been approved and have been granted and/or are pending.

OPK88003 and OPK88004

In 2016, we acquired Transition which is developing multiple drug candidates that include OPK88003 (a long acting oxyntomodulin) and OPK88004 (SARM), each of which are licensed from Eli Lilly and have granted patents worldwide covering the compounds and their use in their respective indications.

In 2016, we acquired Transition Therapeutics, which was developing multiple drug candidates that included OPK88003 (a long acting oxyntomodulin) and OPK88004 (SARM), each of which is licensed from Eli Lilly and has patents granted worldwide covering the compounds and their use in their respective indications.

8367607 covers OPK88003 and expires in December 2030, without extension.

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OPKO has also filed additional patent applications on expanded uses of OPK88004.

In addition, Transition and its affiliates have patented compounds (scyllo-inositol) for the treatment of Alzheimer’s disease.

In addition, Transition Therapeutics and its affiliates have patented compounds (scyllo-inositol) for the treatment of Alzheimer’s disease.

The patents are pending or granted in many countries of the world.

OPKO and/or its affiliates or licensees will seek all available patent term extensions for our product candidates and products.

New patents and applications continue to be filed covering new compositions of matter and/or new uses of the above compounds or variants thereof.

Multispecific Antibodies and Vaccines

Our affiliate, ModeX Therapeutics, Inc.

(“ModeX”) has multiple patents and/or patent applications either licensed-in from a third party such as Sanofi or owned or co-owned by ModeX, and which cover vaccine candidates such as a bivalent Epstein-Barr virus vaccine and its use in multiple indications (out-licensed to Merck & Co) or covers therapeutic multispecific antibodies for the treatment of various diseases or conditions such as infectious disease or cancer.

ModeX also has pending patent applications which are co-owned by ModeX and the federal government and which were filed pursuant to a Cooperative Research and Development Agreement (“CRADA”) with the Viral Research Center (“VRC”) and the National Institute of Allergy and Infectious Disease (“NIAID) and which cover therapeutic multispecific antibodies to treat COVID-19 infections and/or associated long-COVID.

ModeX has and will continue to file patent applications covering compositions and indications within their development program.

Because the patent positions of pharmaceutical, biotechnology, and diagnostics companies are highly uncertain and involve complex legal and factual questions, the patents owned and licensed by us, or any future patents, may not prevent other companies from developing similar or therapeutically equivalent products or ensure that others will not be issued patents that may prevent the sale of our products or require licensing and the payment of significant fees or royalties.

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Collaborations are key to our strategy and we continue to build relationships and forge partnerships in various areas where unmet medical need and commercial opportunities exist.

In October 2017, we entered into a license and development agreement with JT for the development and commercialization of Rayaldee in Japan for the treatment of SHPT in non-dialysis and dialysis patients with CKD.

Immediately following JT’s termination of this Agreement in May 2021, VFMCRP entered into an agreement with OPKO pursuant to which VFMCRP assumed JT’s rights in Rayaldee in Japan.

Under the VFMCRP Agreement, as amended from time to time, we have a license and collaboration agreement for the development and commercialization of Rayaldee in Europe, Canada, Australia, and certain other international markets for the treatment of SHPT in patients with CKD and vitamin D insufficiency.

In May 2021, VFMCRP entered into an agreement with us, pursuant to which it assumed our prior strategic partner's rights to develop and commercialize Rayaldee for the treatment of SHPT in non-dialysis and dialysis patients with CKD in Japan.

Under the VFMCRP Agreement, as amended from time to time, we have a license and collaboration agreement for the development and commercialization of Rayaldee in Europe, Australia, and certain other international markets for the treatment of SHPT in patients with CKD and vitamin D insufficiency.

In June 2021, we entered into a license agreement with Nicoya to distribute and sell Rayaldee in China and certain other countries.

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In September 2021, we also entered into specific arrangements with LeaderMed in certain countries in Asia with respect to OPK-88003 and Factor VIIa.

In November 2021, EirGen licensed out Rayaldee patent estate to Progenetics Ltd.

In November 2021, EirGen licensed out the Rayaldee patent estate to Progenetics Ltd.

to distribute Rayaldee in Israel.

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Previously, we (or entities we have acquired) have completed strategic licensing transactions with the President and Fellows of Harvard College, Academia Sinica, The Scripps Research Institute, TESARO, INEOS Healthcare, and Arctic Partners, among others.

ModeX and Sanofi, a French corporation are parties to a license agreement dated July 1, 2021, as amended, pursuant to which ModeX licenses certain intellectual property underlying its EBV technology.

ModeX and Sanofi are parties to the Sanofi In-License Agreement pursuant to which ModeX licenses certain intellectual property underlying its Epstein-Barr Virus technology.

ModeX and Merck are parties to the Merck Agreement, pursuant to which ModeX granted to Merck a license in connection with the development of ModeX's preclinical nanopartcile vaccine candidate targeting the Epstein-Barr Virus.

The pharmaceutical and diagnostic testing industries are highly competitive and require an ongoing, extensive search for technological innovation.

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Although we believe that Rayaldee offers substantial benefits over these products, Rayaldee may be competing with these and other lower priced products and products which are marketed by larger pharmaceutical companies with substantially greater resources.

We are aware of a number of pharmaceutical and biopharmaceutical companies that have commenced clinical studies of products or have successfully commercialized products addressing areas that we are targeting with our long acting hGH-CTP.

For example, several companies are developing sustained release or long-acting products for the treatment of GHD, and a number of companies currently market generic daily human growth hormone products for GHD.

There are two other pharmaceutical and biopharmaceutical companies that we are aware of that have successfully developed and commenced commercilization of products addressing areas that we are targeting with our long acting hGH-CTP.

Additionally, a number of companies currently market generic daily human growth hormone products for GHD.

In our clinical laboratory operations, we compete with three types of providers in a highly fragmented and competitive industry:

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Although we are much smaller than these national laboratories, we believe that we compete successfully with them in our region due to our innovative testing services and our level of service.

We believe our responses to medical consultation are faster and more personalized than those of the national laboratories.

Our client service staff deals only with basic technical questions and those that have medical or scientific significance are referred directly to our senior scientists and medical staff.

We are commercializing our 4Kscore product in the U.S., Europe and Mexico in a laboratory setting and seek to capitalize on commercialization opportunities for our proprietary diagnostic point-of-care system by transitioning laboratory-based tests, including PSA and other tests to our point-of-care system.

We are commercializing our 4Kscore product in the U.S., Europe and Mexico in a laboratory setting.

Competitors to our diagnostics business are many and include major diagnostic companies, molecular diagnostic firms, universities, and research institutions.

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our ability to develop a commercial scale infrastructure either on our own or with a collaborator, which would include expansion of existing facilities, including our manufacturing facilities, development of a sales and distribution network, and other operational and financial systems necessary to support our increased scale;

• our ability to maintain a proprietary position in our technologies;

ability to maintain a proprietary position in our technologies;

our ability to rapidly expand the existing information technology infrastructure and configure existing operational, manufacturing, and financial systems (on our own or with third party collaborators) necessary to support our increased scale, which would include existing or additional facilities and or partners.

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Our clinical laboratory operations are subject to regulations, which are designed to ensure the quality and reliability of clinical laboratories by mandating specific standards in the areas of personnel qualifications, administration and participation in proficiency testing, patient test management, quality control, quality assurance and inspections.

Laboratories must undergo on-

site surveys at least every two years, which may be conducted by CMS under the CLIA program or by a private CMS approved accrediting agency.

Laboratories must undergo on-site surveys at least every two years, which may be conducted by CMS under the CLIA program or by a private CMS approved accrediting agency.

The sanction for failure to comply with CLIA requirements may be suspension, revocation or limitation of a laboratory’s CLIA certificate, which is necessary to conduct business, as well as significant fines and/or criminal penalties.

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Even if regulatory approvals are obtained, a marketed product is subject to continual review, and later discovery of previously unknown problems or failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market as well as possible civil or criminal sanctions.

For marketing outside the U.S., we also will be subject to foreign regulatory requirements governing human clinical trials and marketing approval for

pharmaceutical products.

For marketing outside the U.S., we also will be subject to foreign regulatory requirements governing human clinical trials and marketing approval for pharmaceutical products.

The requirements governing the conduct of clinical trials, product licensing, pricing, and reimbursement vary widely from country to country.

In addition to clinical trial rules, FDA imposes other requirements on applicants including obligations related to Good Manufacturing Practices (GMPs), proper labeling, and other issues related to manufacturing and marketing a drug.

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

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

or elsewhere.

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In December of 2016, Congress enacted the 21st Century Cures Act (P.L.

approved or cleared treatment exists or that offer significant advantages over existing approved or cleared alternatives.

114-255) which contained provisions establishing a new Breakthrough Device pathway to allow faster patient access to devices and breakthrough technologies that provide for more effective treatment or diagnosis for life-threatening or irreversibly debilitating diseases, for which no approved or cleared treatment exists or that offer significant advantages over existing approved or cleared alternatives.

It is not clear if any of our products would be eligible.

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We are also subject to the physician self-referral laws, commonly referred to as the Stark law, which is a strict liability statute that generally prohibits physicians from referring Medicare patients to providers of “designated health services,” including clinical laboratories, with whom the physician or the physician’s immediate family member has an ownership interest or compensation arrangement, unless an applicable exception applies.

Moreover, many states have adopted or are considering adopting similar laws, some of which extend beyond the scope of the Stark law to prohibit the payment or receipt of

remuneration for the prohibited referral of patients for designated healthcare services and physician self-referrals, regardless of the source of the payment for the patient’s care.

Moreover, many states have adopted or are considering adopting similar laws, some of which extend beyond the scope of the Stark law to prohibit the payment or receipt of remuneration for the prohibited referral of patients for designated healthcare services and physician self-referrals, regardless of the source of the payment for the patient’s care.

If it is determined that certain of our practices or operations violate the Stark law or similar statutes, we could become subject to civil and criminal penalties, including exclusion from the Medicare programs and loss of government reimbursement.

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The FCPA also requires public companies to make and keep books and records that accurately and fairly reflect their transactions and to devise and maintain an adequate system of internal accounting controls.

international activities create the risk of unauthorized payments or offers of payments by our employees, consultants, sales agents or distributors, even though they may not always be subject to our control.

Our international activities create the risk of unauthorized payments or offers of payments by our employees, consultants, sales agents or distributors, even though they may not always be subject to our control.

We discourage these practices by our employees and agents.

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They may also impose restrictions on distribution of specific products until the violations are corrected.

Our point-of-care diagnostic system consists of a disposable test cassette and an analyzer.

We prepare all necessary test reagents and assemble and package the disposable cassettes at our facility in Woburn, Massachusetts.

We rely on third parties for the manufacture of the analyzer.

We are committed to providing high quality products to our customers, and we plan to meet this commitment by working diligently to continue implementing updated and improved quality systems and concepts throughout our organization.

SALES & MARKETING

Our diagnostics business includes BioReference’s 180-person sales and marketing team in the U.S.

Our diagnostics business includes BioReference’s significant sales and marketing team in the U.S.

to drive growth and leverage new products.

We have a highly specialized, field based 57-person sales and marketing team in the United States dedicated to the launch and commercialization of Rayaldee.

We have a highly specialized, field based sales and marketing team in the United States dedicated to the launch and commercialization of Rayaldee.

We also have limited sales and marketing personnel in Ireland, Chile, Spain, Mexico and Israel.

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As of December 31, 2023, we had 3,930 full-time employees worldwide.

With the exception of the employees of one of our subsidiaries, OPKO Spain, based in one of our factories in Spain, none of our employees are represented by a collective bargaining agreement.

With the exception of an immaterial number of employees of OPKO Spain, none of our employees are represented by a collective bargaining agreement.

Overall, we consider our employee relations to be good.

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We continually align our health and safety goals with those prescribed by applicable regulatory agencies and balance these goals with the needs of our employees.

During the COVID-19 pandemic, we transitioned non-essential workers from the office to working from home, and we optimized our essential worker stations in our laboratories and other key process areas to provide for appropriate sanitation, social distancing and other appropriate measures to address the risks of the pandemic.

Using guidance provided by the CDC and OSHA among other agencies, we worked to ensure proper personal protective equipment, spacing, workstation design and information support were available to our essential employees who continued working in our offices and facilities during the pandemic.

For example, during the COVID-19 pandemic, we transitioned non-essential workers from the office to working from home, worked to ensure proper personal protective equipment using guidance provided by the CDC and OSHA where applicable, and we optimized our essential worker stations in our laboratories and other key process areas to provide for appropriate sanitation, social distancing and other appropriate measures to address the risks of the pandemic.

Competitive Pay and Benefits

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We have a Head of Learning and Training whose responsibility is to enhance employee training and development as well as to ensure compliance while working in a collaborative environment.

Our talent acquisition team is undergoing a transformation that is changing recruitment strategies to source from more diverse channels, which we anticipate will lead to more candidate hiring options, enhance our recruitment platform and eventually strengthen employee retention.

In addition, we have changed recruitment strategies to source from more diverse channels, which we anticipate will lead to more candidate hiring options, enhance our recruitment platform and eventually strengthen employee retention.

Code of Ethics

We have adopted a Code of Business Conduct and Ethics.

We require all employees, including our principal executive officer and principal accounting officer and other senior officers and our employee directors, to read and to adhere to the Code of Business Conduct and Ethics in discharging their work-related responsibilities.

We require all employees, including our principal executive officer, principal financial officer, principal accounting officer and other senior officers and our employee directors, to read and to adhere to the Code of Business Conduct and Ethics in discharging their work-related responsibilities.

Employees are required to report any conduct that they believe in good faith to be an actual or apparent violation of the Code of Business Conduct and Ethics.

The Code of Business Conduct and Ethics is available on our website at http://www.OPKO.com.

Any amendment to, or waivers of, the Code of Business Conduct and Ethics will be disclosed on our website promptly following the date of such amendment or waiver.

Available Information

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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-K

Item 1. Business