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Item 1. Business

2025-03-03 compared with 2024-03-01 · 139 added, 142 removed, 551 unchanged (34% 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 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 have partnered with Pfizer Inc.

(“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.

Our pharmaceutical business features Somatrogon (hGH-CTP), a once-weekly human growth hormone injection.

We have partnered with Pfizer Inc.

(“Pfizer”) for further development and commercialization of Somatrogon (hGH-CTP).

Regulatory approvals 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 secured in more than 50 markets worldwide, including in the United States, European Union Member States, Japan, Canada, and Australia under the brand name NGENLA ® .

Also, through our pharmaceutical division, we manufacture and sell 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.

Our subsidiary, ModeX Therapeutics, Inc.

(“ModeX”), which we acquired in May 2022, is 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.

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.

This includes hematology, clinical chemistry, immunoassay, infectious disease, serology, hormones, and toxicology assays, as well as Pap smear, anatomic pathology (biopsies) and other types of tissue analysis, as well as testing for COVID-19.

Our diagnostics business, BioReference Health, LLC (“BioReference”), is a highly specialized laboratory in the United States, with a sales and marketing team focused on growth and new product integration, including the 4Kscore ® prostate cancer test.

BioReference® offers a broad spectrum of diagnostic testing services for oncology, urology ( 4Kscore ), and corrections nationwide, setting new standards with our industry-leading turnaround times.

BioReference also provides comprehensive clinical and women’s health testing in New York and New Jersey.

Our test offerings are backed by a team of board-certified medical professionals and driven by the latest healthcare guidelines and standards-marketed directly to physicians, geneticists, hospitals, clinics, correctional facilities, and other healthcare providers.

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

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.

On September 16, 2024 we consummated the sale of certain assets of BioReference to Laboratory Corporation of America Holdings (“Labcorp”), as described below.

We operate established, revenue-generating pharmaceutical platforms in Spain, Ireland, Chile, and Mexico, our most such significant platforms, which contribute to positive cash flow and facilitate future market entry for our products currently in development.

In addition to these platforms, we have a development and commercial supply pharmaceutical company, as well as a global supply chain operation.

We also manufacture specialty active pharmaceutical ingredients (“APIs”) in Israel through our subsidiary, FineTech.

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.

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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 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;

continue to support Pfizer’s efforts to seek approval for additional indications for Somatrogon (hGH-CTP).

Somatrogon under the brand name NGENLA® is currently sold by Pfizer in over 50 markets, including in 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.

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

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

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We were originally incorporated in Delaware in October 1991 under the name Cytoclonal Pharmaceutics, Inc., which was later changed to eXegenics, Inc.

On March 27, 2007, we were part of a three-way merger with Froptix Corporation and Acuity Pharmaceuticals, Inc., both research and development companies.

On March 27, 2007, we were part of a merger with Froptix Corporation and Acuity Pharmaceuticals, Inc., both research and development companies.

On June 8, 2007, we changed our name to OPKO Health, Inc.

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We evaluate the performance of each segment based on operating profit or loss.

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

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

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.

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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.

BioReference is in network for over 80% of all U.S.

insured lives.

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

Laboratory testing and diagnostic excellence remain the cornerstones 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 at the same time focusing on expanding our reach to match the dynamic needs of an ever-changing healthcare system.

At BioReference, we offer comprehensive laboratory testing services utilized by healthcare providers in the detection, diagnosis, evaluation, monitoring, and treatment of diseases, including, but not limited to, the following:

esoteric testing, molecular diagnostics, anatomical pathology, genetics, women’s health and correctional healthcare.

BioReference markets and sell these services to physician offices, clinics, hospitals, employers and governmental units.

Our clinical and women’s health testing services are concentrated in New York and New Jersey.

For oncology, urology and corrections health services, we offer a full service menu with a national scope.

BioReference’s laboratory testing business consists of routine 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.

BioReference is in-network with the largest health plans in the United States and many regional plans throughout the country.

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

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

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.

Additionally, BioReference operates the following highly specialized laboratory departments:

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.

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

As a follow-up blood test after an abnormal PSA or DRE, the 4Kscore Test helps assess the probability of finding aggressive prostate cancer on biopsy.

GenPath (Oncology).

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.

A national leading provider of cutting-edge diagnostics with industry-leading turnaround times, GenPath offers a comprehensive test portfolio to provide a single-source solution to support the continuum of care of cancer patients.

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

Core testing includes (but not limited to):

FLOW, HIC, MicroArray, FISH , ISH, Morphology, and full-service oncology genomics menu.

GenPath (Women ’ s Health).

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.

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 in New York and New Jersey, GenPath Women’s Health offers testing for cervical and vaginal health, reproductive health, and hereditary cancer screening.

BioReference has a sales and marketing team and operates a network of approximately 76 active patient service centers.

Our sales and marketing groups are 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 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.

BioReference provides us with a significant diagnostics commercial infrastructure for marketing and sales that reached approximately 6.5 million patients in 2024.

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

Disposition of Assets to Labcorp

On September 16, 2024, the Company and BioReference consummated the sale of select assets of BioReference to Labcorp (the “BioReference Transaction”).

At closing, Labcorp paid us aggregate consideration of $237.5 million in cash, subject to certain adjustments as set forth in the related purchase agreement.

These assets were part of our diagnostics segment and included BioReference's laboratory testing businesses focused on clinical diagnostics, reproductive health, and women's health across the United States, excluding BioReference’s New York and New Jersey operations.

We offer the 4Kscore test through BioReference.

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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").

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.

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 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:

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

ModeX utilizes several platforms in furtherance of its targets:

the multispecific antibody platform MSTAR, which we believe 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 approaches will enable us to produce therapeutic candidates against complex diseases.

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 minimizes the chance of resistance due to tumor heterogeneity or downregulation of a single antigen .

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.

Phase 1 testing is ongoing.

ModeX also has an MSTAR antibody that targets two antigens for hematological tumors, such as several types of lymphomas and leukemias The antibody has demonstrated in vitro killing of tumor cells and in vivo anti-tumor efficacy in a disseminated mouse tumor model.

This product is in the preclinical and CMC development stage in 2025.

An additional 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, immunology and/or infectious disease indications.

This project is in preclinical and CMC development stage in 2025.

On September 28, 2023, ModeX was awarded a contract (as amended, the “BARDA Contract”) by 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.

This contract aims to advance a platform and product candidates addressing various public health threats, specifically in viral infectious diseases.

The funding enables the research, development, and clinical evaluation of multispecific antibodies based on ModeX's proprietary MSTAR technology.

In September 2024, ModeX entered into two amendments (the “BARDA Amendments”) to modify the scope and funding of the BARDA Contract.

The BARDA Amendments structured the funding thereunder as cost-plus-fixed-fee, which includes a $26.9 million supplement to further advance the development of COVID-19 multispecific antibodies.

This increased funding supports the ongoing development, manufacturing, and execution of a Phase 1 clinical trial for a next-generation MSTAR multispecific antibody with broad neutralizing activity against known SARS-CoV-2 variants.

The BARDA Amendments also provided for BARDA's exercise of the option for the development of a multispecific antibody for prevention of influenza, with $24.1 million allocated to cover the expanded work under this exercised option.

These modifications increased the total value of the BARDA Contract from $59.0 million to $110.0 million, with the potential value if BARDA exercises all options thereunder to expand ModeX's services, increasing from $168.6 million to $205 million.

ModeX’s Epstein Barr Virus (“EBV”) vaccine is developed using a 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.

The EBV vaccine presents antigens from four viral proteins involved in viral entry into host cells.

These include an antigen based on the proteins gH, gL and gp42, as well as an antigen derived from gp350.

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.

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.

In January 2025, ModeX announced that the first participant had been dosed in a Phase 1 study of an EBV vaccine candidate.

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 was evaluated in a phase I clinical trial sponsored by the National Institute of Allergy and Infectious Diseases.

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, 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”).

Final data from these pivotal trials were published in the American Journal of Nephrology in 2016.

Vitamin D insufficiency can arise in CKD from many causes including obesity, proteinuria, and lifestyle changes that reduce exposure to sunlight.

Studies in CKD patients have demonstrated that currently available over-the-counter and prescription vitamin D supplements (i.e., cholecalciferol or ergocalciferol) cannot reliably and sufficiently raise raise serum 25-hydroxyvitamin D concentrations to effectively prevent or treat SHPT, a condition commonly associated with declining kidney function 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 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 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.

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

In the fourth quarter of 2024, total Rayaldee prescriptions increased approximately 3.7% compared to third quarter of 2024.

Sales of Rayaldee increased progressively during 2024 indicating an end to the lingering adverse effects of the COVID-19 pandemic on onboarding new patients, which we believe curtailed the growth of Rayaldee sales.

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

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commercial and Medicare Part D covered lives as of the end of 2024.

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.

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

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.

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, 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.

(“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 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.

solely for the treatment of SHPT in dialysis patients with CKD and vitamin D insufficiency (the “Dialysis Indication”).

solely for the treatment of SHPT in dialysis patients (the “Dialysis Indication”).

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.

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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.

The hard capsule formulation of Rayaldee received marketing approval in Macau in November 2024 and launch is expected by mid-2025.

A phase 3 trial with Rayaldee in mainland China was completed in January 2025, and the analysis of data is ongoing.

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.

The study commenced in the 3rd quarter of 2018 and topline data were presented in an abstract titled “Initial Evaluation of High-Dose Extended-Release Calcifediol (ERC) in Patients with Stage 5 Chronic Kidney Disease on Hemodialysis” at the American Society of Nephrology’s Kidney Week Annual Meeting in November 2021.

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”).

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

nephrology clinics who were treated for SHPT and vitamin D insufficiency with Rayaldee (n=174) or competitive products considered to be standard of care (n=202).

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.

Final data were submitted to a respected nephrology journal in February 2025 and publication is expected by mid-year.

The data showed that Rayaldee safely restored normal vitamin D hormone production in these patients and halted the progression of SHPT.

Further development of Rayaldee for hemodialysis patients is on hold in the U.S.

due to unfavorable reimbursement for new drugs under the current Prospective Payment System established by the Centers for Medicare and Medicaid Services (“CMS”).

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 2024 U.S.

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

Renal Data System Annual Report, CKD afflicts one in seven (14%) of U.S.

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

An estimated 71-97% of CKD patients have vitamin D insufficiency which can lead to SHPT and its debilitating consequences.

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

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 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;

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 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, 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 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.

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.

The EBV vaccine presents antigens from four viral proteins involved in viral entry into host cells.

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 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.

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.

An estimated 71-97% of CKD patients have vitamin D insufficiency which usually leads to SHPT and its debilitating consequences.

Ineffective (or lack of) treatment for SHPT accelerates the onset of dialysis.

Human and healthcare costs related to CKD represent a significant economic burden, which increases with disease severity, highlighting an urgent need to forestall CKD progression.

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

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In addition to diabetes and obesity, we are also considering development of this product candidate for additional indications, including treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatits.

More recently, we announced a research collaboration between OPKO Biologics and Entera Bio ("Entera").

Under the terms of a research collaboration agreement, OPKO supplied its long-acting GLP-2 peptide and oxyntomodulin analogs for the development of oral tablet formulations using Entera's proprietary oral delivery technology.

The program is focused on developing the first oral dual agonist GLP-1/glucagon peptide as a potential once-daily treatment for patients with obesity, metabolic and fibrotic disorders.

In September 2024, the parties announced topline pharmacokinetic/pharmacodynamic results.

The parties completed in vivo proof-of-concept PK/PD studies in rodent and pig models.

The studies' objectives were met, demonstrating that oral oxyntomodulin exhibited significant systemic exposure following a single dose.

A favorable PK profile and bioavailability were also demonstrated with oral OXM.

Biologics-General

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

We have completed the development of CTP- attached human growth hormone, Somatrogon (hGH-CTP), 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.

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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.

These payments are structured to include $175 million for the achievement of milestones in Pediatric GHD and $50 million for milestones in SGA.

To date, the Company has received the full $175 million associated with the Pediatric GHD 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.

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Most of the phase 2 pediatric patients have been treated with hGH-CTP for more than six years, and some patients for more than seven years.

We have switched all of the pediatric patients in this study to the disposable pen device.

We have switched all of the pediatric patients in this study to a disposable pen device.

A 44-patient Phase 3 study in Pediatric GHD patients in Japan was completed in the first quarter of 2020.

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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).

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.

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.

In January 2022, the Ministry of Health, Labour and Welfare in Japan 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 June 2023, the FDA approved NGENLA (Somatrogon) in the United States.

This followed earlier approvals in other major markets.

In January 2022, the Ministry of Health, Labour and Welfare in Japan approved NGENLA® for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.

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

In October 2021, Health Canada approved NGENLA® for the long-term treatment of pediatric patients who have growth hormone deficiency, and in November 2021, Australia’s Therapeutic Goods Administration approved NGENLA® for the long-term treatment of pediatric patients with growth disturbance due to insufficient secretion of growth hormone.

Regulatory approvals for Somatrogon (hGH-CTP) for the treatment of growth hormone deficiency in children and adolescents have now been secured in more than 50 markets, including the United States, European Union (“EU”) Member States, Japan, Canada, and Australia, where it is marketed under the brand name NGENLA®

In December 2016, we announced preliminary topline data from our phase 3, double blind, placebo controlled study of hGH-CTP in adults with GHD.

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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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Early Stage Biologics Pipeline

In addition to hGH-CTP and Factor VIIa-CTP, we believe that 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.

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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 Mexico is commercializing food supplements and over the counter products and manufactures and sells products primarily in the generics and branded generics market in Mexico.

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.

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INTELLECTUAL PROPERTY

We believe that technology innovation is driving breakthroughs in healthcare.

We believe that technological innovation is driving breakthroughs in healthcare.

We have adopted a comprehensive intellectual property strategy which blends the efforts to innovate in a focused manner with the efforts of our business development activities to strategically in-license intellectual property rights.

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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.

Our affiliate, ModeX Therapeutics has multiple patents and/or patent applications either owned or co-owned by ModeX or licensed-in from a third party such as Sanofi, 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 has and will continue to file patent applications covering compositions and indications within their development program.

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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.

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.

There are two other pharmaceutical and biopharmaceutical companies that we are aware of that have successfully developed and commenced commercialization 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.

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

We are commercializing our 4Kscore product in the U.S.

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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If that were to occur we would be required to undertake the more complex and costly PMA process.

However, for either the 510(k) or the PMA process, the FDA could require us to run clinical trials, which would pose all of the same risks and uncertainties associated with the clinical trials of drugs, described above.

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

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.

Even when a clinical study has been approved by the FDA or deemed approved, the study is subject to factors beyond a manufacturer’s control, including, but not limited to the fact that the institutional review board at a given clinical site might not approve the study, might decline to renew approval which is required annually, or might suspend or terminate the study before the study has been completed.

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A large number of laboratory testing in the United States consists of LDTs.

However, the FDA has consistently asserted that it has the regulatory authority to regulate LDTs despite historically exercising enforcement discretion.

On April 29, 2024, the FDA announced a final rule on LDTs.

Under this final rule, FDA clarified that LDTs are regulated devices, subject to the FDA's oversight and regulation under the Federal Food, Drug, and Cosmetic Act.

The FDA adopted a four-year phasing out of its blanket enforcement discretion policy for LDTs.

At each phase out stage, FDA expects LDTs will become subject to specific regulatory requirements.

We are evaluating whether this final rule is applicable to our operations and if so, the best ways to comply.

Previously, the FDA has consistently asserted that it has the regulatory authority to regulate LDTs despite historically exercising enforcement discretion.

In furtherance of that position, the FDA issued two draft guidance documents in October 2014:

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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.

We discourage these practices from our employees and agents.

However, our existing safeguards and any future improvements may prove to be less than effective, and our employees, consultants, sales agents or distributors may engage in conduct for which we might be held responsible.

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SALES & MARKETING

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 sales and marketing team in the United States dedicated to the launch and commercialization of Rayaldee.

Our diagnostics business includes BioReference’s United States based sales and marketing team to drive growth and leverage new products.

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

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

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health benefits package is above the competitive range for similar companies in our comparative industries and is one of the key tools we use for recruitment.

Inclusion and Diversity

We recognize the importance of and value diversity and inclusion in our workplace.

As such, we have celebrated our diversity through employee and social media announcements in conjunction with company newsletters and employee events.

We welcome discussions about our differences, embracing them and learning from them to move forward as a stronger, more productive organization.

These differences are not limited to ethnicity or religion, but also in the way we process information and communicate with our colleagues.

We are in a unique position where our workforce is already quite diverse and according to feedback from employee surveys, there is great pride and respect shared among our teams.

In addition, one of our strategic business goals is to recognize and serve diverse communities.

Through BioReference, we work closely with clients in these communities by offering excellent customer service and patient care.

Talent Development

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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, 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