What changed in this filing

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Item 1. Business

2022-03-01 compared with 2021-02-18 · 126 added, 149 removed, 585 unchanged (32% of the section changed)

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Our diagnostics business includes BioReference Laboratories, Inc.

(“BioReference”), one of the nation’s largest full service laboratories with a core genetic testing business and an almost 300-person sales and marketing team to drive growth and leverage new products, including the 4Kscore test.

(“BioReference”), one of the nation’s largest full service laboratories with an almost 250-person sales and marketing team to drive growth and leverage new products.

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 a pipeline of products in various stages of development.

Our leading product in development is hGH-CTP (Somatrogon), a once-weekly human growth hormone injection which completed a successful phase 3 study in August 2019 and is partnered with Pfizer, Inc.

We have submitted the initial Biologics License Application (“BLA”) with the FDA for approval of Somatrogon in the United States as well as a New Drug Application (an “NDA”) with the Ministry of Health, Labour and Welfare in Japan.

Our leading product in development is 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 have been submitted to several countries around the world for review.

In February 2022, the European Commission granted marketing authorization in the European Union for Somatrogon 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 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.

We also submitted the initial Biologics License Application (“BLA”) with the FDA for approval of Somatrogon in the United States and Pfizer received a complete response letter in January 2022.

Pfizer and OPKO are evaluating the FDA’s comments and will work with the agency to determine an appropriate path forward for the advancement of hGH (Somatrogon).

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.

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.

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

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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.

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.

In support of our strategy, we intend to:

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• expand into other medical markets that provide significant opportunities and that we believe are complementary to and synergistic with our business.

In addition, we expect to leverage the BioReference business and infrastructure to drive rapid and widespread uptake of our diagnostic products, including the 4Kscore test.

In addition, we expect to leverage the BioReference business and infrastructure to drive rapid and widespread uptake of our diagnostic products.

Our strategy with respect to BioReference Laboratories is comprised of three pillars:

the core business, digital health and strategic ventures.

Because of the COVID-19 outbreak, we have added a fourth pillar as the COVID-19 impacted all parts of our organization.

Because of the COVID-19 outbreak, we have added a fourth pillar as the COVID-19 pandemic impacted all parts of our organization.

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, California and the GeneDx laboratory in Maryland.

• Increased patient access through preferred relationships with payers.

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

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

• 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 large-scale COVID-19 screening programs nationwide.

We offer customized solutions to a different types of environments and to different types of clients.

We offer customized solutions to different types of environments and to different types of clients.

We are one of the largest providers of these programs, which include both PCR COVID-19 testing and point of care testing, across a variety of touch points, including the travel and leisure industry, airlines, cruise industry and education.

BioReference Laboratories has been selected to support the NFL, NBA, NHL, US National Soccer Teams, Winter X Games and the US Golf Association, among other organizations.

BioReference has provided COVID-19 testing to the NFL, NBA, NHL, US National Soccer Teams, Winter X Games and the US Golf Association, among other organizations.

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

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

• We intend to continue to innovate and expand our offerings at GeneDx.

GeneDx is a global leader in genomics, providing testing to patients and their families from more than 55 countries, with an expertise in rare and ultra-rare genetic disorders.

In 2020, we launched a new joint venture, called Detect Genomics, in partnership with Pediatrics Medical Group, a leading provider of maternal-fetal and pediatric physician services, to offer rapid exome and genome testing in neonatal intensive care units.

CORPORATE INFORMATION

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(“eXegenics”).

On March 27, 2007, we were part of a three-way merger with Froptix Corporation (“Froptix”) and Acuity Pharmaceuticals, Inc.

(“Acuity”), both research and development companies.

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

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insured lives.

BioReference has an almost 300-person sales and marketing team and operates a network of approximately 200 patient service centers.

BioReference has an almost 250-person sales and marketing team and operates a network of 128 active patient service centers.

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

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• BioReference Laboratories.

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

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 (Oncology).

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

We recently 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 has agreed to acquire our wholly-owned subsidiary, GeneDx, Inc.

(“GeneDx”), subject to the satisfaction of customary closing conditions.

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.

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Through our relationships with CVS and RiteAid, we provide access to testing services for the general public and currently provide testing at more than 700 CVS and RiteAid storefronts.

BioReference has also been selected to provide COVID-19 testing for the NFL, NBA, NHL, U.S.

BioReference has provided COVID-19 testing for the NFL, NBA, NHL, U.S.

National Soccer Teams, Winter X Games and the US Golf Association, among other organizations.

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 almost 19 million patients in 2020.

BioReference provides us with a significant diagnostics commercial infrastructure for marketing and sales that reached approximately 21 million and 19 million patients, respectively, in 2021 and 2020.

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

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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.

We offer the 4Kscore test through our BioReference laboratory located in Elmwood Park, New Jersey.

We offer the 4Kscore test through BioReference.

We began selling the 4Kscore test in the U.S.

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

Total PSA, Free PSA, Intact PSA and Human Kallikrein-2 (“hK2”).

These biomarkers are then combined with a patient’s age, optional Digital Rectal Exam (“DRE”) status (nodule / no nodule), and prior negative biopsy status (yes, prior negative biopsy / no prior biopsy) using a proprietary algorithm to calculate the risk (probability) of finding a Gleason Score 7 or higher prostate cancer.

These biomarkers are then combined with a patient’s age, optional DRE status (nodule / no nodule), and prior negative biopsy status (yes, prior negative biopsy / no prior biopsy) using a proprietary algorithm to calculate the risk (probability) of finding a Gleason Score 7 or higher prostate cancer.

The four kallikrein panel of biomarkers utilized in the 4Kscore test is based on decades of research conducted by scientists at Memorial Sloan-Kettering Cancer Center and leading European institutions.

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The clinical data from both studies demonstrated the ability of the 4Kscore test to discriminate between men with high-grade, aggressive prostate cancer and those men who had no findings of cancer or had low-grade or indolent form of the disease.

The discrimination, measured by Area Under the Curve (“AUC”) analysis, was greater than 0.80 and is significantly higher than previously developed tests.

Furthermore, the 4Kscore test demonstrated excellent risk calibration, indicating the accuracy of the result for an individual patient, both Caucasian and African American.

The high value of the AUC and the excellent risk calibration make the 4Kscore test result valuable information for the shared decision-making between the urologist and patient on whether or not to perform a prostate biopsy.

A separate clinical utility study indicated that the 4Kscore test led to 64.6% fewer biopsies.

The study, “The 4Kscore ® Test Reduces Prostate Biopsy Rates in Community and Academic Urology Practices”, was published in a peer reviewed medical journal.

The study, which included 611 patients seen by 35 academic and community urologists across the U.S., evaluated the influence of the 4Kscore test on urologist- patient decisions about whether to perform a biopsy in men who had an abnormal PSA and or DRE result.

Test results for patients were stratified into low risk (< 7.5%), intermediate risk (7.5%-19.9%) and high risk (≥20%) for developing aggressive prostate cancer.

Nearly half (49.3%) of the men were categorized as low risk;

25.7% and 25.0% fell into the intermediate-risk and high-risk categories, respectively.

Notably, the 4Kscore test results influenced biopsy decisions in 88.7% of the men.

In the three risk groups, a biopsy was avoided in 94.0%, 52.9% and 19.0% of men in the low, intermediate and high-risk categories, respectively.

In separate clinical studies, use of the 4Kscore test led to 64.6% fewer biopsies and was able to discriminate between men with high-grade aggressive prostate cancer and those with no findings of cancer.

The National Comprehensive Cancer Network (“NCCN”) has included the 4Kscore test as a recommended test in its Guidelines for Prostate Cancer Early Detection since 2015.

The panel making this recommendation concluded that the 4Kscore test is indicated for use prior to a first prostate biopsy, or after a negative biopsy, to assist patients and physicians in further defining the probability of high-grade cancer.

In addition, the European Association of Urology (“EAU”) Prostate Cancer Guidelines Panel included the 4Kscore test in the 2018 and 2019 EAU Guidelines for Prostate Cancer, concluding that the 4Kscore , as a blood test with greater specificity over the PSA test, is indicated for use prior to a first prostate biopsy or after a negative biopsy to assist patients and physicians in further defining the probability of high-grade cancer.

In addition, the European Association of Urology (“EAU”) Prostate Cancer Guidelines Panel included the 4Kscore test in their Guidelines for Prostate Cancer since 2018, concluding that the 4Kscore , as a blood test with greater specificity over the PSA test, is indicated for use prior to a first prostate biopsy or after a negative biopsy to assist patients and physicians in further defining the probability of high-grade cancer.

The 4Kscore test has been granted a Category I CPT® code by the AMA (CPT Code 81539).

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

We have also successfully been reimbursed for 4Kscore test orders between March and December 2019 through a reconsideration request.

In addition, we have obtained a positive coverage decision from at least one national private payor and pricing agreements from several regional payors.

On June 20, 2019, we announced that we submitted a de novo request to the FDA seeking regulatory clearance for the 4Kscore test.

Based on feedback from the FDA, the Company withdrew its de novo request and requested a meeting with the FDA to discuss a premarket approval (“PMA”) submission for the test.

A PMA submission by the Company for the 4Kscore test was accepted for review by the FDA in January 2020 and is under review.

Point-of-Care Diagnostics

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The credit card-sized test cassette works with a sophisticated desktop analyzer to provide high performance quantitative blood test results within 10-15 minutes and permits the transition of immunoassays from the centralized reference laboratory to the physician’s office, hospital nurses station, or other decentralized location.

We completed multiple in vitro analytical validation and field use tests for the PSA test in mid-2017 and filed the PMA for the Claros Analyzer and Sangia Total PSA Test with the FDA in November 2017.

We completed multiple in vitro analytical validation and field use tests for the PSA test in mid-2017 and filed the premarket approval application (“PMA”) for the Claros Analyzer and Sangia Total PSA Test with the FDA in November 2017.

The FDA approved the PMA for the Sangia Total PSA Test using the Claros Analyzer in January 2019.

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The FDA has categorized Sangia total PSA test as a moderately complex device under Clinical Laboratory Improvement Amendments of 1988 (“CLIA”).

The Company is taking steps to obtain a CLIA waiver for the Sangia Total PSA test and the Claros system, which should permit the test to be performed by most medical office personnel with minimal additional training.

We encountered significant technical challenges for a testosterone test using the platform technology and have currently suspended further development of the testosterone test.

We are currently evaluating commercialization strategies for the Claros system, as well as potential development of other tests for this platform technology, including markers with high volume assays in therapeutic areas such as nephrology, neurology, cardiology, infection and veterinary markets.

We are currently evaluating commercialization strategies for the Claros system, and have several tests in development on the Claros system biomarkers.

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

Renal Products-Rayaldee

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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 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) and calcification of

vascular and renal tissues.

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 an approximately 75-person highly specialized sales, marketing and market access team dedicated to the commercialization of Rayaldee as of December 31, 2020.

We have a 57-person highly specialized sales, marketing and market access team dedicated to the commercialization of Rayaldee as of December 31, 2021.

In the fourth quarter of 2021, total Rayaldee prescriptions decreased approximately 28.8% and 1.4% as compared to the fourth quarter of 2020 and the third quarter of 2021, respectively.

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covered lives as of the end of 2021.

In May 2016, we entered into a collaboration 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.

Under the terms of the agreement, OPKO received an upfront payment of $50 million.

We also received a $2 million payment triggered by the marketing approval of Rayaldee in Canada.

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

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

As revised, the Company has received a $3 million payment triggered by the first marketing approval of Rayaldee in Europe and is eligible to receive up to an additional $17 million in regulatory milestones and $210 million in milestone payments tied to launch, pricing and sales of Rayaldee , and tiered, double-digit royalties.

OPKO and VFMCRP are also collaborating to develop and commercialize a new higher strength dosage form of Rayaldee for the treatment of SHPT in hemodialysis patients.

A phase 2 study in this population commenced in the third quarter of 2018 and we expect to report topline data in the first half of 2020.

OPKO granted VFMCRP an option to acquire rights to this dosage form for the U.S.

if exercised, OPKO may receive up to $555 million in additional milestones and tiered, double digit royalties.

VFMCRP filed Marketing Authorization Application with a number of European countries, and VFMCRP has received regulatory approvals from eleven European countries to date and is preparing for product launches later in 2021.

On October 12, 2017, we entered into a Development and License Agreement (the “JT Agreement”) with Japan Tobacco Inc.

(“JT”) granting JT the exclusive rights for the development and commercialization of Rayaldee in Japan (the “JT Territory”).

The license grant to JT covers the therapeutic and preventative use of the product for (i) SHPT in non-dialysis and dialysis patients with CKD, (ii) rickets and (iii) osteomalacia, as well as such additional indications as may be added to the scope of the license subject to the terms of the JT Agreement.

Under the terms of the JT Agreement, OPKO received an initial upfront payment of $6 million and received another $6 million milestone payment triggered by the initiation of OPKO’s U.S.

phase 2 study with Rayaldee in dialysis patients.

OPKO is also eligible to receive up to an additional aggregate amount of $31 million upon the achievement of certain regulatory and development milestones by JT for Rayaldee in the JT Territory, and $75 million upon the achievement of certain sales based milestones by JT in the JT Territory.

OPKO will also receive tiered, double digit royalty payments at rates ranging from low double digits to mid-teens on net product sales within the JT Territory.

JT will, at its sole cost and expense, be responsible for performing all development activities necessary to obtain all regulatory approvals for Rayaldee in Japan and for all commercial activities pertaining to Rayaldee in Japan, except for certain preclinical expenses which OPKO has agreed to reimburse JT up to a capped amount.

In May 2016, we entered into a development and license agreement (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, 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 has received marketing authorization from eleven European countries to date and is preparing for product launches in additional territories in 2022.

The launch in Germany triggered a $3 million payment to EirGen Pharma Ltd.

(“EirGen”), our wholly owned subsidiary.

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 the Product in the U.S.

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

Upon exercise of the Option, VFMCRP will reimburse EirGen for all of the development costs incurred by EirGen with respect to the Product 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 the Product in the U.S.

for the Dialysis Indication.

To date, VFMCRP has not exercised its option.

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 (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”).

Extended release calcifediol is marketed in the U.S.

by OPKO under the tradename Rayaldee .

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”).

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.

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

The trial is expected to enroll approximately 160 subjects, some of whom may have stage 3 or 4 CKD which may put them at higher risk for developing more severe illness due to the COVID-19 infection.

We filed an IND for Rayaldee in January 2019 for the treatment of SHPT arising from vitamin D insufficiency in patients who have undergone bariatric surgery.

Plans to commence a phase 2 study in this population have been postponed from late 2020 to redirect internal resources to the ongoing conduct of the phase 2 trial in patients with COVID-19.

In August 2014, we also announced the submission of an Investigational New Drug Application (“IND”) to the FDA to evaluate Rayaldee as an adjunctive therapy for the prevention of skeletal-related events in patients with bone metastases undergoing anti-resorptive therapy.

We commenced a phase 1 dose escalation study in the fourth quarter of 2014 in breast and prostate cancer patients with bone metastases who were receiving anti-resorptive therapy.

The study, which has been completed, was designed to evaluate safety, markers of vitamin D and mineral metabolism and tumor progression.

We are currently collecting the final data and will subsequently complete a final analysis of the study.

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

sites and 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 topline data were reported in December 2021 which indicated that improving vitamin D status with oral Rayaldee results in earlier resolution of respiratory symptoms associated with COVID-19.

Data from the trial and potential next steps in the development program for this indication will be reviewed with the FDA later this year.

We have also 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.

Preliminary results indicate that a daily dose of 60 micrograms of Rayaldee is the only treatment that reliably and sufficiently raises serum total 25-hydroxyvitamin D to effectively suppress elevated plasma parathyroid hormone levels in CKD patients.

Preliminary results indicate that a daily dose of 60 micrograms of Rayaldee is the only one of four treatment regimens that reliably raises serum total 25-hydroxyvitamin D to the range of 50-100 mg/ml level required to effectively suppress elevated plasma parathyroid hormone 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.

We anticipate presenting the final data at an upcoming scientific meeting.

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

therefore this patient population represents a significant global market opportunity.

According to the National Kidney Foundation, CKD afflicts over 40 million people in the U.S., including more than 21 million patients with stage 3 or 4 CKD.

According to the U.S.

Renal Data System, CKD afflicts over 37 million people in the U.S., including more than 18 million patients with stage 3 or 4 CKD.

In stage 5 CKD, kidney function is minimal to absent and most patients require regular dialysis or a kidney transplant for survival.

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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 and/or hyperphosphatemia.

Renal Products-Other

Another renal product in our development pipeline, Alpharen (Fermagate Tablets), is a new and potent non-absorbed phosphate binder to treat hyperphosphatemia in stage 5 CKD patients requiring regular hemodialysis.

Alpharen (Fermagate Tablets) has been shown to be safe and effective in treating hyperphosphatemia in phase 2 and 3 trials in stage 5 CKD patients undergoing chronic hemodialysis.

Hyperphosphatemia, or elevated serum phosphorus, contributes to soft tissue mineralization, affects approximately 90% of dialysis patients and is tightly linked to the progression of SHPT and vascular calcification, both of which drive morbidity and mortality.

An additional phase 3 clinical trial is required to support marketing approvals for Alpharen in North America and in Europe, and the Company is seeking potential partners to participate in this trial.

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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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.

A phase 2 study of 350 male subjects for another indication showed significantly increased lean body mass and muscle strength and significant fat mass reduction with no change or lowering of PSA levels.

OPK88004 is currently being studied in a phase 2 study in prostate cancer patients who have undergone radical prostatectomy.

The main objective of the study is to examine the effect of OPK88004 on sexual function and quality of life issues associated with this patient population.

An additional phase 2b study to determine the optimal dose to treat patients with Benign Prostatic Hypertrophy (“BPH”) commenced in November 2017 and we completed enrollment and randomized 114 patients in the U.S.

in December 2018.

The main focus of the study was to determine the optimal dose of OPK88004 that will reduce prostate volume and PSA levels, and increase anabolic effects such as lean body and decreased fat mass in BPH patients.

As previously reported, blinded data from the phase 2b study have shown significant variability in the measurement of prostate volume, rendering the assessment of prostate volume from treatment impractical.

Additionally, a small number of subjects have shown increased liver enzymes.

We suspended the trial but continue to analyze data relating to the study’s other primary endpoint, the effect of OPK88004 on serum PSA levels, and the secondary endpoints, changes in lean body mass and fat mass.

Additional indications including treatment of symptoms associated with androgen deprivation therapy in prostate cancer patients and low testosterone levels, muscle weakness and general frailty in kidney dialysis patients are being evaluated.

Oxyntomodulin

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The safety profile was similar to that expected for the incretin class of drugs, with GI side effects such as nausea, vomiting and diarrhea mostly mild and occurring during the dose-escalation phase.

On September 14, 2021, we and LeaderMed Health Group Limited (“LeaderMed”), a pharmaceutical development company with operations based in Asia, announced the formation of a joint venture under which we granted the joint venture exclusive rights to develop, manufacture and commercialize (a) OPK88003, an oxyntomodulin analog being developed for the treatment of obesity and diabetes, and (b) Factor VIIa-CTP, a novel long-acting coagulation factor being developed to treat hemophilia, in exchange for a 47% ownership interest in the joint venture.

In addition, we have received an upfront payment of $1 million and will be reimbursed for clinical trial material and technical support it provides the joint venture.

LeaderMed will be responsible for funding the joint venture’s operations, development and commercialization efforts and will, with its syndicate partners, initially invest $11 million in exchange for a 53% ownership interest in the joint venture.

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 II patients, representing significant market opportunities.

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

hGH-CTP (Somatrogon)

Our lead product candidate utilizing CTP, hGH-CTP (Somatrogon), 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.

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.

In addition, we are eligible to receive initial tiered royalty payments associated with the commercialization of hGH-CTP for Adult GHD with percentage rates ranging from the high teens to mid-twenties.

Upon the launch of hGH-CTP for Pediatric GHD in certain major markets, the royalties will transition to regional, tiered gross profit sharing for both hGH-CTP and Pfizer’s Genotropin®.

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 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 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.

Pfizer submitted a Biologics License Application (“BLA”) for hGH-CTP dosed once-weekly in pre-pubertal children with GHD in October 2020.

The FDA accepted the BLA for review and the target Prescription Drug User Fee Act (PDUFA) action date for a decision by the FDA is in October 2021.

In addition to the phase 3 pediatric study, we have continued without interruption our ongoing phase 2 pediatric open label extension study for hGH-CTP.

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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).

Pfizer submitted a New Drug Application to the Ministry of Health, Labour and Welfare in Japan for Somatrogon in January 2021.

The submission to EMA is expected to occur in the first half of 2021.

Somatrogon (hGH-CTP) has orphan drug designation in the U.S.

and Europe for both adults and children with GHD.

We submitted the initial Biologics License Application (“BLA”) with the FDA for approval of Somatrogon in the United States and Pfizer recently received a Complete Response Letter.

Pfizer and OPKO are evaluating the FDA’s comments and will work with the agency to determine an appropriate path forward.

Regulatory applications for Somatrogon have been submitted to several countries around the world for review.

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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We will need to conduct additional toxicity studies before we are in a position to present a clinical study plan.

We also entered into a joint venture with LeaderMed on September 14, 2021, under which we granted the joint venture exclusive rights to develop, manufacture and commercialize (a) OPK88003, an oxyntomodulin analog being developed for the treatment of obesity and diabetes, and (b) Factor VIIa-CTP, a novel long-acting coagulation factor being developed to treat hemophilia.

Early Stage Biologics Pipeline

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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.

Apart from development efforts using the CTP platform, we are also focused on development of a once weekly GLP-2 agonist for treatment of Small Bowel Syndrome and other potential indications.

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.

FineTech Pharmaceutical, Ltd.

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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.

Commercial Operations

We may continue to leverage our global commercialization expertise to pursue acquisitions of commercial businesses that will both drive our growth and provide geographically diverse sales and distribution opportunities.

During 2015, we acquired EirGen Pharma Ltd.

(“EirGen”), a specialty pharmaceutical company based in Ireland.

During 2015, we acquired EirGen, a specialty pharmaceutical company based in Ireland.

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

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covering Rayaldee are listed in the Approved Drug Products with Therapeutic Equivalence Evaluations, or the Orange Book.

OPKO and/or its affiliates have entered into two exclusive license agreements with respect to Rayaldee patents in certain territories outside of North America with VFMCRP (Europe and many other countries throughout the rest of the world) and JT (Japan).

OPKO and/or its affiliates have entered into exclusive license agreements with respect to Rayaldee patents in certain territories outside of North America with VFMCRP (Europe and many other countries throughout the rest of the world), and Nicoya Macau Limited (China).

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.

hGH-CTP (somatrogon)

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)

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

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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.

In May 2016, we entered into a license and collaboration with 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 CKD and vitamin D insufficiency, which was amended in May 2020 to exclude Mexico, South Korea, the Middle East and all of the countries of Africa from the VFMCRP Territory.

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

In July 2021, we licensed out our AntagoNAT portfolio owned by CURNA, INC.

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.

to distribute Rayaldee in Israel.

In December 2014, we entered into the Pfizer Transaction for the development and commercialization of our long-acting hGH-CTP for the treatment of GHD in adults and children, as well as for the treatment of growth failure in children born small for gestational age.

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This enables them, among other things, to make greater research and development investments and efficiently utilize their research and development costs, as well as their marketing and promotion costs, over a broader revenue base.

This also provides our competitors with a competitive advantage in connection with the highly competitive product acquisition and product in-licensing process, which may include auctions in which the highest bidder wins.

This also provides our competitors with a competitive advantage in connection with the highly competitive product acquisition and product in-licensing process, which may include auctions in

which the highest bidder wins.

Our competitors may also have more experience and expertise in obtaining marketing approvals from the FDA and other regulatory authorities.

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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 growth hormone deficiency (GHD), and a number of companies currently market generic daily human growth hormone products for GHD.

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.

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

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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 expect to leverage BioReference’s national marketing, sales and distribution resources, along with its almost 300-person sales and marketing team to support commercialization of the 4Kscore and other diagnostic products.

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

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(ii) the Centers for Medicare & Medicaid Services (“CMS”), which administers the Medicare and Medicaid programs;

(iii) the Office of Inspector General (“OIG”), which enforces various laws aimed at curtailing fraudulent or abusive practices, including by way of example, the Anti-Kickback Statute, the Physician Self-Referral Law, commonly referred to as the Stark law, the Civil Monetary Penalty Law (including the beneficiary inducement prohibition) (“CMP”), and the laws that authorize the OIG to exclude healthcare providers and others from participating in federal healthcare programs;

(iii) the Office of

Inspector General (“OIG”), which enforces various laws aimed at curtailing fraudulent or abusive practices, including by way of example, the Anti-Kickback Statute, the Physician Self-Referral Law, commonly referred to as the Stark law, the Civil Monetary Penalty Law (including the beneficiary inducement prohibition) (“CMP”), and the laws that authorize the OIG to exclude healthcare providers and others from participating in federal healthcare programs;

and (iv) the Office of Civil Rights, which administers the privacy aspects of the Health Insurance Portability and Accountability Act of 1996.

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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 Federal Clinical Laboratory Improvement Amendments (“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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phase 1 consists of testing the drug product in a small number of humans, normally healthy volunteers, to determine preliminary safety and tolerable dose range.

Phase 2 usually involves studies in a limited patient population to evaluate the effectiveness of the drug product in humans having the disease or medical condition for which the product is indicated, determine dosage tolerance and optimal dosage, and identify possible common adverse effects and safety risks.

Phase 2 usually involves studies in a limited patient population to evaluate the

effectiveness of the drug product in humans having the disease or medical condition for which the product is indicated, determine dosage tolerance and optimal dosage, and identify possible common adverse effects and safety risks.

Phase 3 consists of additional controlled testing at multiple clinical sites to establish clinical safety and effectiveness in an expanded patient population of geographically dispersed test sites to evaluate the overall benefit-risk relationship for administering the product and to provide an adequate basis for product labeling.

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After completion of clinical trials of a new drug product, FDA and foreign regulatory authority marketing approval must be obtained.

Assuming that the clinical data support the product’s safety and effectiveness for its intended use, a Biologics License Application (BLA) or an NDA is submitted to the FDA for its review.

Assuming that the clinical data support the product’s safety and effectiveness for its intended use, a BLA or an NDA is submitted to the FDA for its review.

Since the early 1990s, the FDA has managed a user fee program whereby sponsors of drug applications pay a fee to the agency and the agency commits to meeting a series of performance goals designed to reduce drug review times.

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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 Rayaldee , none of our pharmaceutical products under development have been approved for marketing in the U.S.

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.

or elsewhere.

We may not be able to obtain regulatory approval for any such products under development in a timely manner, if at all.

We may not be able to obtain regulatory approval for any of our other products under development in a timely manner, if at all.

Failure to obtain requisite governmental approvals or failure to obtain approvals of the scope requested will delay or preclude us, or our licensees or marketing partners, from marketing our products, or limit the commercial use of our products, and thereby would have a material adverse effect on our business, financial condition, and results of operations.

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The FDA classifies medical devices into one of three classes based upon their risk profile (both to the patient and provider):

Class I devices are relatively

simple “low risk” technologies, and can be manufactured and distributed with general controls without a premarket clearance or approval from the FDA;

Class I devices are relatively simple “low risk” technologies, and can be manufactured and distributed with general controls without a premarket clearance or approval from the FDA;

Class II devices are somewhat more complex “moderate risk” devices, and require greater scrutiny from the agency, requiring a premarket clearance from the FDA before market entry;

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The FDA review process for premarket notifications submitted pursuant to section 510(k) takes, on average, about 90 days, but it can take substantially longer if the FDA has concerns, and there is no guarantee that the FDA will “clear” the device for marketing, in which case the device cannot be distributed in the U.S.

There is also no guarantee that the FDA will deem the applicable device subject to the 510(k) process, as opposed to the more time-consuming, resource-intensive and problematic, PMA process described below.

There is also no

guarantee that the FDA will deem the applicable device subject to the 510(k) process, as opposed to the more time-consuming, resource-intensive and problematic, PMA process described below.

The second, more comprehensive, PMA process, which can take a year or longer, applies to a new device that is not substantially equivalent to a pre-1976 product or that is to be used in supporting or sustaining life or preventing impairment.

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To the extent the FDA finalizes and implements these documents, the average 510(k) and PMA submission requirements and review times may change and devices that might previously have been cleared under the 510(k) process may require approval under the PMA process (and vice-versa).

Additionally, since 2012, the FDA has collected user

fees for the review of certain premarket submissions received on or after October 1, 2012, including 510(k) and PMA applications.

Additionally, since 2012, the FDA has collected user fees for the review of certain premarket submissions received on or after October 1, 2012, including 510(k) and PMA applications.

These fees are intended to improve the device review process, but it is still too early to assess the actual impact on the industry.

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Additionally, we are subject to periodic FDA inspections, quality control procedures, and other detailed validation procedures.

If the FDA finds deficiencies in the validation of our manufacturing and quality control practices, it may impose restrictions on marketing specific products until corrected.

If the FDA finds deficiencies in the validation of our manufacturing and quality control practices, it may impose restrictions on marketing these specific products until corrected.

Regulation by governmental authorities in the U.S.

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Diagnostic tests like ours may not fall squarely within the regulatory approval process for pharmaceutical or device products as described above, and the regulatory pathway is not as clear.

Although the FDA regulates in vitro diagnostic devices, some companies have successfully commercialized diagnostic tests for various conditions and disease states without seeking clearance or approval for such tests through a 510(k) or PMA approval process.

These tests are known as laboratory developed tests (“LDTs”) and are designed, manufactured, and used within a single laboratory that is certified under the Clinical Laboratory Improvement Amendments of 1988 (“CLIA”).

Although the FDA regulates in vitro diagnostic devices, some laboratory companies have successfully commercialized diagnostic tests for various conditions and disease states without seeking clearance or approval for such tests through a 510(k) or PMA approval process.

These tests are known as laboratory developed tests (“LDTs”) and are designed, manufactured, and used within a single laboratory that is certified under the CLIA.

CLIA is a federal law that regulates clinical laboratories that perform testing on specimens derived from humans for the purpose of providing information for diagnostic, preventative or treatment purpose.

Such LDT testing is currently under the purview of CMS and state agencies that provide oversight of the safe and effective use of LDTs.

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.

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(1) Framework for Regulatory Oversight of Laboratory Developed Tests (the “Framework Guidance”);

and (2) FDA Notification and Medical Device Reporting for Laboratory Developed Tests (the “Notification Guidance”).

The Framework Guidance outlines the FDA’s plan to adopt over time a risk-based approach to regulating LDTs whereby different classifications of LDTs would be subject to different levels of FDA oversight and enforcement, including, for example, prohibitions on adulteration and misbranding, establishment registration and device listing, premarket notification, banned devices, records and reports, good manufacturing practices, adverse event reporting, premarket review of safety, effectiveness, and clinical validity, and quality system requirements.

The Notification Guidance is intended to explain how clinical laboratories should notify the FDA of the LDTs they develop and how to satisfy Medical Device Reporting requirements.

However, the FDA indicated in November 2016 that it would delay implementation of the Framework Guidance and the Notification Guidance, and seek additional input from industry.

In addition, on January 13, 2017, the FDA published a synthesis of feedback on the Framework Guidance and Notification Guidance titled, Discussion Paper on Laboratory Developed Tests (the “Discussion Paper”).

The Discussion Paper provided notice that the FDA would not issue a final guidance on the oversight of LDTs to allow for further public discussion on appropriate oversight approach, and to give congressional authorizing committees the opportunity to develop a legislative solution.

If finalized in the October 2014 format, the Framework Guidance and the Notification Guidance may have a materially adverse effect on the time, cost, and risk associated with the Company’s development and commercialization of LDTs for the U.S.

and (2) FDA Notification and Medical Device Reporting for Laboratory Developed Tests (the “Notification Guidance”), but has taken no action on the draft guidance.

Rather, Congress is considering various legislation that, if enacted, could formalize an FDA oversight role for LDTs, including both the Verifying Accurate Leading-edge IVCT Development (VALID) Act, and the Verified Innovative Testing in American Laboratories (VITAL) Act.

The FDA has informally indicated that it is giving Congress the opportunity to develop a legislative solution.

If enacted, legislation such as the VALID Act or the VITAL Act may have a materially adverse effect on the time, cost, and risk associated with the Company’s development and commercialization of LDTs for the U.S.

market, and there can be no assurance that clearances or approvals sought by the Company will be granted and maintained.

However, the FDA’s authority to regulate LDTs continues to be challenged and the regulatory situation remains fluid.

The FDA has indicated that it will continue dialogue with the industry, and the timeline and process for finalizing the draft guidance documents is unknown.

To date, the FDA has not issued any further guidance to the laboratory community at large (although it does from time to time issue warning letters to individual laboratories), nor has Congress enacted any specific legislative solution.

However, the FDA’s authority to regulate LDTs continues to be challenged, the proposed VALID Act and VITAL Act have faced opposition, and the regulatory situation remains fluid.

The FDA has indicated that it will continue dialogue with the industry, and the timeline and process for action by Congress or the FDA is unknown.

We will continue to monitor changes to all domestic and international LDT regulatory policy so as to ensure compliance with the current regulatory scheme.

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For example, in certain foreign markets, pricing or profitability of therapeutic and other pharmaceutical products is subject to governmental control.

In the U.S., there have been, and we expect that there will continue to be, a number of federal and state proposals to implement similar governmental control.

In the U.S., there have been, and we expect that there will continue to be, a number of federal and state proposals to implement

similar governmental control.

In addition, in the U.S.

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Recognizing that the Anti-Kickback Statute is broad and may technically prohibit many innocuous or beneficial arrangements, Congress authorized the U.S.

Department of Health and Human Services Office of Inspector General, or OIG, to issue a series of regulations, known as “safe harbors.” These safe harbors set forth requirements that, if met in their entirety, will assure health care providers and other parties that they will not be prosecuted under the Anti-Kickback Statute.

Department of Health and Human Services Office of Inspector General, or OIG, to issue a series of regulations, known as “safe harbors.” These safe harbors set forth requirements that, if met

in their entirety, will assure health care providers and other parties that they will not be prosecuted under the Anti-Kickback Statute.

The failure of a transaction or arrangement to fit precisely within one or more safe harbors does not necessarily mean that it is illegal, or that prosecution will be pursued.

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Another development affecting the health care industry is the increased use of the federal civil False Claims Act and, in particular, actions brought pursuant to the False Claims Act’s “whistleblower” or “qui tam” provisions.

The False Claims Act, as amended by the Fraud Enforcement and Recovery Act of 2009 and the Patient Protection and Affordable Care Act of 2010 (“Affordable Care Act”), imposes liability on any person or entity who, among other things, knowingly presents, or causes to be

presented, a false or fraudulent claim for payment by a federal health care program.

We submit claims for services performed at our laboratories.

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In addition to such facilities, we have entered into agreements with various third parties for the formulation and manufacture of our pharmaceutical clinical supplies.

These suppliers and their manufacturing facilities must comply with FDA regulations, current good laboratory practices (“cGLPs”) and current good manufacturing practices (“cGMPs”).

These suppliers and their manufacturing facilities must comply with FDA regulations, current good laboratory practices and current good manufacturing practices (“cGMPs”).

We plan to continue to outsource the manufacturing and formulation of our clinical supplies.

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Our diagnostics business includes BioReference’s almost 250-person sales and marketing team in the U.S.

to drive growth and leverage new products, including the 4Kscore prostate cancer test.

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.

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As a company in the healthcare industry, employee safety is a key focus of our leadership, communications, and training.

We are required to comply with the College of American Pathologists and Clinical Laboratory Improvemen t Amendments laboratory safety requirements in addition to OSHA regulations.

We are required to comply with the College of American Pathologists and CLIA laboratory safety requirements in addition to OSHA regulations.

With a clear leader in our EHS Manager, direction, standards of practice, training and auditing are consolidated and then disseminated to our managers, supervisors and all employees.

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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.

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.

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We recognize it is important that our employees are able to develop and grow their careers.

We recently hired a Head of Learning and Training to enhance employee training and development as well as to ensure compliance while working in a collaborative environment.

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.

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We are required to file annual, quarterly and current reports, proxy statements and other information with the SEC.

Information that we file with the SEC is available at the SEC’s web-site at www.sec.gov.

Information that we file with the Securities and Exchange Commission is available at the SEC’s web-site at www.sec.gov.

We also make available free of charge on or through our web site, at www.opko.com, our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and all amendments to those reports as soon as reasonably practicable after such material is electronically filed with the SEC.

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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