What changed in this filing

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Item 1. Business

2021-02-18 compared with 2020-03-02 · 135 added, 88 removed, 599 unchanged (27% of the section changed)

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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, a selective androgen receptor modulator which we are exploring for various potential indications, and a once weekly oxyntomodulin for type 2 diabetes and obesity which is a clinically advanced drug candidate among the new class of GLP-1 glucagon receptor dual agonists (phase 2b).

Our pharmaceutical business also features hGH-CTP, a once-weekly human growth hormone injection which completed a successful phase 3 study in August 2019 and is partnered with Pfizer, Inc.

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.

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.

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

We have a development and commercial supply pharmaceutical company as well as a global supply chain operation and holding company in Ireland, which we expect will play an important role in the development, manufacturing, distribution and approval of a wide variety of drugs with an emphasis on high potency products.

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

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

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GROWTH STRATEGY

We expect our future growth to come from leveraging our commercial infrastructure, proprietary technology and development strengths, and by opportunistically pursuing complementary and strategic acquisitions and investments.

We expect our future growth to come from leveraging our commercial infrastructure, proprietary technology and development strengths.

We launched our first pharmaceutical product, Rayaldee, in the U.S.

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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.

We also intend to leverage the genetic and genomic data generated and accumulated through BioReference’s genetic sequencing laboratory to enhance drug discovery and clinical trial programs.

We have been, and may continue to be, opportunistic and pursue complementary and strategic acquisitions, licenses and investments.

Our management team has significant experience in identifying, executing and integrating these transactions.

have and may continue to use well-timed, carefully selected acquisitions, licenses and investments to drive our growth, including:

Products and technologies.

We may continue to pursue product and technology acquisitions and licenses that will complement our existing businesses and provide new product and market opportunities, enhance our profitability, leverage our existing assets, and contribute to our own organic growth.

Commercial businesses.

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

Early stage investments.

We have made and may continue to make investments in early stage companies that we perceive to have valuable proprietary technology and significant potential to create value for OPKO as a shareholder.

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.

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 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 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.

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

• We intend to initiate digital health advances that aim to increase flexibility and convenience for patients.

We recently introduced an important initiative in digital health through the launch of Scarlet™ Health, a fully-integrated digital platform providing mobile phlebotomy and laboratory services to patient’s homes, offices and other preferred locations.

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

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 across New York, New Jersey, Florida, Texas, Maryland, California, Pennsylvania, Delaware, Washington DC, Illinois and Massachusetts.

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.

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

We 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.

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

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

We offer testing across a variety of touch points, including the travel and leisure industry, airlines, cruise industry and education.

We have substantial relationships with local and state governments to provide testing services across all 50 states, with substantial service relationships in New York, New Jersey, and Michigan.

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.

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

personalized medicine.

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

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

These biomarkers are then combined with a patient’s age, 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 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.

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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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.

We have and intend to continue to commit substantial efforts to obtaining broad reimbursement coverage for the 4Kscore test.

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

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A Category I CPT code is critical to facilitate reimbursement in government programs such as Medicare and Medicaid, as well as private insurance programs.

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

In January 2019, Novitas Solutions (“Novitas”), the local Medicare Administrative Contractor (“MAC”) for our laboratory in New Jersey, issued a notice of a future non-coverage determination for the 4KScore test to be effective March 20, 2019.

Subsequently, we announced that Novitas issued a new proposed local coverage determination (an “LCD”) for the 4Kscore test with defined coverage criteria.

Under the proposed LCD, which became effective on December 30, 2019, Medicare would reimburse the test for patients who meet the defined criteria.

Effective December 30, 2019, Novitas Solutions (“Novitas”), the local Medicare Administrative Contractor (“MAC”) for the 4Kscore testing laboratory in New Jersey, provided positive coverage through a local coverage determination (an “LCD”) with defined coverage criteria.

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.

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 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 arises in CKD due to the abnormal upregulation of CYP24A1, an enzyme that destroys vitamin D and its metabolites, 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 raise blood vitamin D prohormone levels and 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.

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

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.

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.

In the fourth quarter of 2019, total Rayaldee prescriptions increased approximately 141% and 17% as compared to the fourth quarter of 2018 and the third quarter of 2019, respectively.

In the fourth quarter of 2020, total Rayaldee prescriptions decreased approximately 15.9% and 10.2% as compared to the fourth quarter of 2019 and the third quarter of 2020, respectively.

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

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

We have already achieved commercial and Medicare Part D formulary coverage for more than eight-three percent (83%) of U.S.

We have already achieved commercial and Medicare Part D formulary coverage for more than 82.3% of U.S.

covered lives as of the end of 2020.

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

In addition, VFMCRP will pay OPKO tiered, double digit royalties on sales of the product at percentage rates that range from the mid-teens to the mid-twenties or a minimum royalty, whichever is greater, upon commencement of sales of the product.

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

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 double digit royalties.

VFMCRP filed Marketing Authorization Application with a number of European countries, and VFMCRP expects to receive approvals in several European countries to market Rayaldee for the treatment of SHPT in adult non-dialysis patients with CKD during 2020.

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.

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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.

We are also developing Rayaldee for other indications, including for SHPT in patients with vitamin D insufficiency and stage 5 CKD requiring regular hemodialysis.

A phase 2 study of a higher dose product commenced in the stage 5 CKD patient population during the third quarter of 2018.

We expect to receive initial data from the study in the first quarter of 2020.

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.

We intend to commence a phase 2 study in this population in late 2020.

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.

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

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.

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;

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

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

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

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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.

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

Our lead product candidate utilizing CTP, 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.

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.

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”).

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

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

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

The GHD subjects were treated weekly for 12 months.

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

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

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

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

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

Immunogenicity testing and analysis of additional data are ongoing, and full results of this study will be submitted for presentation at future scientific meetings.

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.

We currently anticipate that Pfizer will submit a Biologics License Application (“BLA”) for hGH-CTP dosed once-weekly in pre-pubertal children with GHD in the second half of 2020.

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.

The phase 2 pediatric patients have been treated with hGH-CTP for over four years, and some patients for over five years.

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 also initiated a 44-patient study in Pediatric GHD patients in Japan which is expected to be completed in the first quarter of 2020.

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

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

The Japan Phase 3 clinical trial met its primary and secondary objectives, and demonstrated that the efficacy and safety of hGH-CTP administered weekly was comparable to Genotropin ® as measured by annual height velocity after 12 months of treatment in pre-pubertal children with GHD.

The findings were consistent with the results previously reported in the Phase 3 global study.

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.

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Additional analyses that did not exclude outliers showed mixed results.

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

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

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

We are currently engaged in research and development efforts to use the CTP technology for development of a long-acting CTP-hGH Antagonist for treatment of Acromegaly, as well as a long-acting CTP-IGF-1 for the Treatment of Severe Primary IGF-1 Deficiency.

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.

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

FineTech currently manufactures commercial APIs for sale or license to pharmaceutical companies in the U.S., Canada, Europe and Israel.

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

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

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Orphan disease designations have been granted by FDA and EMA.

We acquired rolapitant and other neurokinin-1 (“NK-1”) assets from Merck & Co.

In December 2010, we exclusively out-licensed the development, manufacture and commercialization of our lead NK-1 candidate, VARUBI™ (rolapitant), to TESARO, Inc.

In November 2015, TESARO commenced the commercial launch of oral VARUBI™ in the U.S.

TESARO’s IV formulation of VARUBI™ was approved by the FDA in October 2017 and commercial sales commenced in November 2017.

In January 2018, the package insert for VARUBI™ was updated to include mention of new adverse effects, including anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions which were reported following its introduction to the market in November 2017.

In late February 2018, TESARO announced it would suspend distribution of VARUBI™ IV, but would continue to support the oral product.

In June 2018, TESARO assigned its rights and obligations under the agreement to TerSera Therapeutics LLC (“TerSera”) pursuant to an asset purchase agreement.

Under the asset purchase agreement, TerSera is responsible for VARUBI in the U.S.and Canada and TESARO was permitted to continue to commercialize VARUBY® in Europe and the rest of the world (“TESARO Territory”) though a sublicense with TerSera.

In September 2019, TESARO informed us and TerSera that it intends to stop selling VARUBY ® in the TESARO Territory and that it intends to withdraw its marketing authorization for VARUBY ® in Europe.

Commercial Operations

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

We also have additional patents and patent applications pending relating to the sustained release formulation and its use which will expire in 2034 and have licensed patents covering the capsule shell.

We also have additional patents and patent applications pending relating to the sustained release formulation and its use which will expire in 2034.

The patents issued in the U.S.

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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).

The rolapitant line of patents, exclusively licensed to TerSera includes multiple patent families that cover anti-nausea treatment for chemotherapy patients.

These patents are maintained in the licensed territory.

One patent family covers the chemical composition of rolapitant and related compounds and expires in December 2023 (with the patent term adjustment).

A patent term extension request was submitted to the U.S.

Patent and Trademark Office (the “USPTO”) in October 2015 to obtain an additional 1,716 days which will, upon approval, extend the rolapitant compound patent expiration date to August 2028.The second patent family covers pharmaceutical formulations, including a capsule formulation with a related method of use and expires in April of 2027.

The third patent family covers particular aspects of the chemical composition of rolapitant as well as certain methods of treating delayed onset nausea and expires in April 2027.

The fourth patent family covers a powdered pharmaceutical composition of a crystalline salt of rolapitant and expires in March 2028.

The current line of rolapitant patents are approved for oral treatment.

Patents and applications directed towards the IV formulation of rolapitant are granted and/or currently pending.

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)

The hGH-CTP line of patents, which is licensed to Pfizer, includes multiple patent families that cover modified human grown hormone (somatrogon), uses of somatrogon in adult and pediatric patient populations, and methods of making somatrogon.

patents have also been filed in multiple countries around the world.

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

patent families that cover modified human grown hormone (somatrogon), uses of somatrogon in adult and pediatric patient populations, and methods of making somatrogon.

Equivalent patents have also been filed in multiple countries around the world.

One patent family covers certain CTP modified hGH polypeptides relating to growth hormones and their method of use and expires in February of 2027 (with the exception of two U.S.

patents, namely US 8304386 and US 8097435, which expire in January 2028 and April 2027, respectively, due to Patent Term Adjustment for each).

A subset of cases in this patent family covers cytokine-based polypeptides relating to human growth hormone treatment and will expire in February 2027 (in the U.S., these cases include registered patents 8,048,849;

Additional U.S.

patent applications are pending which cover somatrogon formulations, methods of manufacture and pediatric dosing regimens and, if granted, would expire in 2033.

Equivalent patents are granted in Europe and Japan and which expire in 2032 and 2034.

A subset of cases in the patent estate covers cytokine-based polypeptides relating to human growth hormone treatment and will expire in February 2027 (in the U.S., these cases include registered patents 8,048,849;

and 9,896,494, and no Patent Term Adjustment was issued).

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and internationally.

Patent term extensions will be sought in those countries where somatrogon is approved.

OPK88003 and OPK88004

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

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

may prevent the sale of our products or require licensing and the payment of significant fees or royalties.

Furthermore, to the extent that any of our future products or methods are not patentable, that such products or methods infringe upon the patents of third parties, or that our patents or future patents fail to give us an exclusive position in the subject matter claimed by those patents, we will be adversely affected.

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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.

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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hospital laboratories, physician-office laboratories and other independent clinical laboratories.

competitors in the New York metropolitan area are two of the largest national laboratories, Quest Diagnostics and Laboratory Corporation of America.

Our major competitors in the New York metropolitan area are two of the largest national laboratories, Quest Diagnostics and Laboratory Corporation of America.

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.

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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 Biologics License Application (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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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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Second, the FDA must review the company’s PMA application, which contains, among other things, clinical information acquired under the IDE.

The FDA will approve the PMA application if it finds there is reasonable assurance that the device is safe and effective for its

intended use.

The FDA will approve the PMA application if it finds there is reasonable assurance that the device is safe and effective for its intended use.

The PMA process takes substantially longer than the 510(k) process and it is conceivable that the FDA would not agree with our assessment that a device that we propose to distribute should be a Class I or Class II device.

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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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In addition, in the U.S.

and elsewhere, sales of therapeutic and other pharmaceutical products are dependent in part on the availability and adequacy of reimbursement from third party payors, such as the government or private

insurance plans.

Third party payors are increasingly challenging established prices, and new products that are more expensive than existing treatments may have difficulty finding ready acceptance unless there is a clear therapeutic benefit.

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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.

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.

However, conduct and business arrangements that do not fully satisfy each applicable safe harbor may result in increased scrutiny by government enforcement authorities, such as the OIG.

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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.

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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Open Payments Program

With the launch of Rayaldee , part of our business is now subject to the federal Physician Payments Sunshine Act under the Affordable Care Act, and its implementing regulations, which is implemented though the physicians Open Payments

Program (the “Open Payments Program”).

The Open Payments Program requires manufacturers of drugs, devices, biological and medical supplies covered by Medicare, Medicaid or the Children’s Health Insurance Program, to report information related to certain payments or other transfers of value made or distributed to physicians and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, the physicians and teaching hospitals.

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

HUMAN CAPITAL RESOURCES

Employees and Labor Relations

As of December 31, 2020, we had 5,269 full-time employees worldwide.

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

Overall, we consider our employee relations to be good.

Health and Safety

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.

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.

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

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

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

Competitive Pay and Benefits

We are committed to fair pay and we offer competitive medical benefits to all of our employees.

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

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.

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.

Code of Ethics

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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