About OPKO Health

OPKO Health, Inc. operates as a diversified healthcare company. The company seeks to establish industry-leading positions in large and rapidly growing medical markets. The company’s diagnostics business includes BioReference Health, LLC (BioReference), one of the nation’s largest full service laboratories with a 180-person sales and marketing team to drive growth and leverage new products, and it offers its 4Kscore prostate cancer test through BioReference. The company’s pharmaceutical business features Rayaldee, a U.S. Food and Drug Administration (FDA) approved treatment for secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency, and Somatrogon (hGH-CTP), a once-weekly human growth hormone injection for which the company completed a successful phase 3 study in August 2019 and is partnered with Pfizer Inc. (Pfizer). Regulatory applications for Somatrogon (hGH-CTP) have been submitted to the applicable regulatory bodies for review in several countries around the world. In February 2022, the European Commission granted marketing authorization in the European Union for Somatrogon (hGH-CTP) under the brand name NGENLA to treat children and adolescents from as young as 3 years of age with growth disturbance due to insufficient secretion of growth hormone and has been granted pricing approval in Germany. NGENLA has also been approved in Japan, Canada, and Australia. The company also submitted the initial Biologics License Application (BLA) with the FDA for approval of Somatrogon (hGH-CTP) in the United States and Pfizer received a complete response letter in January 2022. Pfizer and OPKO have evaluated the FDA’s comments and will work with the agency to determine an appropriate path forward for the advancement of Somatrogon (hGH-CTP). In May 2022, the company acquired ModeX Therapeutics, Inc. (ModeX), a biotechnology company focused on developing innovative multi-specific immune therapies for cancer and infectious diseases candidates. ModeX has a robust early-stage pipeline with assets in key areas of immuno-oncology and infectious diseases, and it intends to further expand its pharmaceutical product pipeline through ModeX’s portfolio of development candidates. Through BioReference Health, LLC (BioReference), the company provides 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. The company offers a comprehensive test menu of clinical diagnostics for blood, urine and tissue analysis. This includes hematology, clinical chemistry, immunoassay, infectious disease, serology, hormones, and toxicology assays, as well as Pap smear, anatomic pathology (biopsies) and other types of tissue analysis, as well as testing for COVID-19. The company markets its laboratory testing services directly to physicians, geneticists, hospitals, clinics, correctional and other health facilities. The company operates established pharmaceutical platforms in Spain, Ireland, Chile, and Mexico, which are generating revenue and from which it expects to generate positive cash flow and facilitate future market entry for its products in development. The company has a development and commercial supply pharmaceutical company, as well as a global supply chain operation. The company also owns a specialty active pharmaceutical ingredients (APIs) manufacturer in Israel, which it expects will facilitate the development of its pipeline of molecules and compounds for its proprietary molecular diagnostic and therapeutic products. The company has a highly experienced management team. All product or service marks appearing in type form different from that of the surrounding text are trademarks or service marks owned, licensed to, promoted or distributed by OPKO, its subsidiaries or affiliates, except as noted. All other trademarks or services marks are those of their respective owners. Growth Strategy The company expects to grow by leveraging its commercial infrastructure, proprietary technology and development strengths. The company has under development a broad and diversified portfolio of diagnostic tests, small molecules, and biologics targeting a broad range of unmet medical needs. The company also operates one of the largest full service laboratories in the U.S. The company intends to continue to leverage its proprietary technology and its strengths in all phases of research and development to further develop and commercialize its portfolio of proprietary pharmaceutical and diagnostic products. In support of its strategy, the company plans to continue to enhance its commercialization capability in the U.S. and internationally; obtain requisite regulatory approval and compile clinical data for its most advanced product candidates; expand into other medical markets that provide significant opportunities and that are complementary to and synergistic with its business; continue marketing and commercialization of Rayaldee, and potentially expand the label into additional indications; and continue to support Pfizer’s efforts to secure regulatory approval for Somatrogon (hGH-CTP) in the U.S. and potentially seek approval for additional indications, including adult growth hormone deficiency. Somatrogon under the brand name NGENLA is being sold by Pfizer in 15 countries, including Germany, Japan and the United Kingdom. Pfizer expects to have launched in all priority markets by the end of 2023 and is continuing to work with the FDA to obtain approval in the U.S. Additionally, the company plans to leverage its acquisition of ModeX to further expand its pharmaceutical product line. ModeX is developing next-generation multispecifics biologics antibodies and vaccines for the treatment of cancer and infectious disease. ModeX’s growing portfolio has been developed through its proprietary multispecific antibody technology. As compared to traditional approaches, ModeX’s MSTAR platform unites the power of multiple biologic components in a single molecule to create multispecific antibodies and vaccines with greater versatility and potency to better fight complex disease. Its pipeline includes product candidates intended to treat both solid and liquid tumors, as well as several of the world’s most pressing viral threats. The company also plans to continue to commercialize and increase adoption of its 4K score test for use in men age 45 and older who have not had a prior prostate biopsy or a biopsy negative and have an age specific abnormal total PSA or abnormal digital rectal exam. 4K score is available through BioReference. In addition, the company expects to leverage the BioReference business and infrastructure to drive rapid and widespread uptake of its diagnostic products and additional tests, such as its 4K score test. The company’s strategy with respect to BioReference is comprised two pillars: the core business and strategic ventures. In support of this strategy: The company has made significant investments to rebuild and reconfigure its main laboratory in Elmwood Park, NJ and have also made significant investments in its labs in Melbourne, Florida, Houston, Texas, and California. The company has facilitated increased patient access through preferred relationships with payors. The company is a part of the United Healthcare preferred lab network with access to approximately 45 million patients. The company also has 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. The company intends to continue to expand its offerings among its core laboratory service businesses in clinical, genetics, women’s health, oncology and urology. The company intends to continue to expand and seek new strategic ventures to provide laboratory services for large health care groups and systems. Current Products and Services and Related Markets Diagnostics BioReference Health, LLC Through BioReference, one of the largest full service laboratories in the United States, the company offers 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. The company markets and sells these services to physician offices, clinics, hospitals, employers and governmental units nationally, with the largest concentration of business in the larger metropolitan areas in New York, New Jersey, Florida, Texas, Maryland, California, Pennsylvania, Delaware, Washington DC, Illinois and Massachusetts. BioReference is in network for over 80% of all U.S. insured lives. BioReference has a 180-person sales and marketing team and operates a network of approximately 124 active patient service centers. The company’s BioReference laboratory testing business consists of routine testing and esoteric testing. Routine tests measure various health parameters, such as the functions of the heart, kidney, liver, thyroid and other organs, including such tests as blood cell counts, cholesterol levels, pregnancy, substance abuse and urinalysis. The company typically operates 24 hours per day, 365 days per year and perform and report most routine test results within 24 hours. The esoteric tests the company performs require sophisticated equipment and materials, highly skilled personnel and professional attention. Esoteric tests are ordered less frequently than routine tests and typically are priced higher than routine tests. Esoteric tests include tests related to endocrinology, genetics and genomics, immunology, microbiology, HIV tests, molecular diagnostics, next generation sequencing, oncology, serology, and toxicology. Through BioReference, the company operates in the following highly specialized laboratory divisions: BioReference Health: BioReference constitutes the company’s 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): National oncology presence with expertise in cancer pathology and diagnostics, as well as molecular diagnostics. Core tests include FLOW, IHC, MicroArray, FISH, ISH, Morphology, and full service oncology. GenPath (Women’s Health): Innovative technology platform for sexually transmitted infections has enabled expansion nationally with specimens coming from 41 states, including Image Directed Paps analysis, HPV Plus, and STI Testing. The company has one of the largest marketing staffs of any laboratory in the country with sales and marketing groups dedicated to urology, oncology, women’s health, genetic testing and correctional health, as well as cross-over groups selling to large institutions. Most of the company’s sales personnel operate in a dual capacity, as sales and client support representatives, which provides better customer service and a strong connection with its customers. The company is among the largest providers of large-scale coronavirus (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. The company offers testing across a variety of touch points, including the travel and leisure industry, airlines, cruise industry and education and has developed substantial relationships with local and state governments to provide testing services across all 50 states, with substantial service relationships in New York, New Jersey, and Michigan. The company expects 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. BioReference provides the company with a significant diagnostics commercial infrastructure for marketing and sales that reached approximately 12 million in 2022. In addition, its large team of managed care experts complements the company’s efforts to ensure that payors recognize the value of its diagnostic and laboratory tests for reimbursement purposes. The company continues to leverage the national marketing, sales and distribution resources of BioReference, along with its 180-person sales and marketing team, to enhance sales of and reimbursement for its 4Kscore test, a laboratory developed blood test that provides a personalized risk score for aggressive prostate cancer. The company plans 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. 4Kscore Test The company offers the 4Kscore test through BioReference. The company 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 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. Investigators at the Lund University, Sweden, University of Turku, Finland and Memorial Sloan Kettering Cancer Center, New York, have also demonstrated that the 4Kscore test can risk stratify the 20-year risk for the development of prostate metastases and mortality in men who present at age 50 to 60 years old with an elevated PSA. The 4Kscore test was developed by OPKO and validated in two prospective, blinded studies of 1,012 and 366 men, respectively. The first study was done in collaboration with 26 urology centers across the U.S. and the second study was conducted at eight VA centers in the U.S. with a predominantly African American cohort. African Americans are 1.7 times more likely to be diagnosed with prostate cancer than Caucasian men and 2.2 times more likely to die from the disease. Results showed that the 4Kscore test was highly accurate for predicting the presence of high-grade cancer (Gleason Score 7 or higher) prior to prostate biopsy, regardless of race. The full data from the blinded, prospective U.S. clinical validation studies have been published in peer reviewed medical journals. 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. 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 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 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). A CPT code is used by insurance companies and government payors to describe health care services and procedures. A Category I CPT code is critical to facilitate reimbursement in government programs, such as Medicare and Medicaid, as well as private insurance programs. Effective December 30, 2019, Novitas Solutions (Novitas), the local Medicare Administrative Contractor for the 4Kscore testing laboratory in New Jersey, provided positive coverage through a local coverage determination with defined coverage criteria. Since that date, 4Kscore test orders meeting the coverage criteria have been reimbursed by Novitas and Medicare Advantage Health Plans. Pharmaceutical Business The company has one commercial stage pharmaceutical product and several pharmaceutical compounds and technologies in various stages of research and development for a broad range of indications and conditions, including the following: Renal Products-Rayaldee Rayaldee is a patented extended release product containing 30 mcg of a prohormone, called calcifediol (25-hydroxyvitamin D3), for oral administration. The company launched Rayaldee, its lead renal product, in the U.S. market in November 2016, following receipt in June 2016 of FDA approval for the treatment of SHPT in adults with stage 3 or 4 CKD and vitamin D insufficiency, defined as serum total 25-hydroxyvitamin D levels less than 30 ng/mL. The FDA approval of Rayaldee was supported by successful results from two identical randomized, double-blind, placebo-controlled, multi-site phase 3 studies which established the safety and efficacy of Rayaldee as a new treatment for SHPT in adults with stage 3 or 4 CKD and vitamin D insufficiency. Vitamin D insufficiency can arise in CKD due to the abnormal upregulation of CYP24A1, an enzyme that destroys vitamin D and its metabolites, from obesity and from many other causes as well. Studies in CKD patients have demonstrated that available over-the-counter and prescription vitamin D supplements cannot reliably and sufficiently raise blood vitamin D prohormone levels to effectively treat SHPT, a condition commonly associated with CKD in which the parathyroid glands secrete excessive amounts of parathyroid hormone (PTH). Prolonged elevation of blood PTH causes excessive calcium and phosphorus to be released from bone, leading to elevated serum calcium and phosphorus levels, softening of the bones (osteomalacia) or loss of bone mineral density (osteoporosis), and calcification of vascular and renal tissues. SHPT affects 33% and 54% of patients with stage 3 and 4 CKD respectively, and approximately 95% of patients with stage 5 CKD. The company has a 58-person highly specialized sales, marketing and market access team dedicated to the commercialization of Rayaldee as of December 31, 2022. In the fourth quarter of 2022, total Rayaldee prescriptions decreased approximately 4.9% and 2.0% as compared to the fourth quarter of 2021 and the third quarter of 2022, respectively. Sales of Rayaldee have not increased in accordance with its expected growth trajectory as a result of challenges in onboarding new patients due to several factors, including the COVID-19 pandemic. Efforts are underway to obtain broader commercial and Part D insurance coverage for Rayaldee. The company has already achieved commercial and Medicare Part D formulary coverage for more than 78.8% of U.S. covered lives as of the end of 2022. In May 2016, the company entered into a development and license agreement (as amended, the VFMCRP Agreement) with Vifor Fresenius Medical Care Renal Pharma (VFMCRP, now CLS Vifor) for the development and commercialization of Rayaldee in Europe, Canada, Mexico, Australia, South Korea and certain other international markets for the treatment of SHPT in patients with stage 3, 4 or 5 CKD and vitamin D insufficiency. The VFMCRP Agreement was later amended to exclude South Korea, the Middle East and all of the countries of Africa from the VFMCRP Territory (as defined in the VFMCRP Agreement), and further amended to include Japan as part of the VFMCRP Territory. VFMCRP initiated the commercial launch of Rayaldee in Germany in February 2022 and received marketing authorization from eleven European countries to date and is preparing for product launches in additional territories in 2023. In connection with the VFMCRP Agreement, the parties entered into a letter agreement pursuant to which EirGen granted to VFMCRP an exclusive option (the Option) to acquire an exclusive license under certain EirGen patents and technology to use, import, offer for sale, sell, distribute and commercialize Rayaldee in the U.S. solely for the treatment of SHPT in dialysis patients with CKD and vitamin D insufficiency (the Dialysis Indication). On June 18, 2021, EirGen and NICOYA Macau Limited (Nicoya), a Macau corporation and an affiliate of NICOYA Therapeutics, entered into a Development and License Agreement (as amended, the Nicoya Agreement) granting Nicoya the exclusive rights for the development and commercialization of extended release calcifediol (the Nicoya Product) in Greater China, which includes mainland China, Hong Kong, Macau, and Taiwan (collectively, the Nicoya Territory). The license grant to Nicoya covers the therapeutic and preventative use of the Nicoya Product for SHPT in non-dialysis and hemodialysis chronic kidney disease patients (the Nicoya Field). Nicoya notified EirGen in February 2023 that it had submitted an IND for the Nicoya Product to the Chinese Center of Drug Evaluation (CDE). In October 2020, the company commenced a placebo controlled Phase 2 trial with Rayaldee as a treatment for mild-to-moderate COVID-19. In August 2021, the trial completed enrollment of 171 symptomatic patients from multiple U.S. sites. These patients were randomized in a 1:1 ratio for 4 weeks of treatment with Rayaldee or placebo and a 2-week follow-up. The trial ended in November 2021 and the resulting final data were published in Nutrition in in December 2022. The data indicated that improving vitamin D status with oral Rayaldee resulted in earlier resolution of respiratory symptoms associated with COVID-19. The company has completed a Phase 4 clinical trial comparing Rayaldee with three common treatment regimens for SHPT in adults with stage 3 or stage 4 CKD and vitamin D insufficiency. The company also has completed a retrospective study of medical records for 376 adult patients with stage 3-4 CKD from 15 U.S. nephrology clinics who were treated for SHPT and vitamin D insufficiency with Rayaldee (n=174) or competitive products considered to be standard of care (n=202). The 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 U.S. Renal Data System, CKD afflicts 14% of U.S. adults and its prevalence is highest in non-Hispanic Black individuals (18.9%). ModeX In May 2022, the company acquired ModeX, a biotech company developing multi-specific immune therapies focused on oncology, infectious diseases, vaccines and immunology. ModeX utilizes several platforms in furtherance of its targets: the MSTAR with which can reliably and rapidly generate candidates that target up to six distinct biological pathways in a single molecule; the STEALTH platform which utilizes antibody-masking technology and aims to deliver the power of multispecific immuno-modulation to widely expressed targets by building in a safety net that localizes immune attack specifically to tumors, and the Nanoparticle Vaccine platform, built on naturally occurring and self-assembling ferritin molecules, which ensures the right combination of antigens are presented in the right amount and in the right place to enhance the immune response. ModeX has a tetra-specific antibody developed utilizing the company’s proprietary MSTAR technology platform targeting several types of refractory solid tumors; it is designed to activate and sustain the activation of the T-cells, and simultaneously target two antigens highly expressed on diverse tumors. Dual targeting increases tumor specificity and mitigates escape resistance through loss of a single glycoprotein. Major solid tumor opportunities include lung, triple negative breast cancer, ovarian, prostate, and other solid tumors. The antibody has demonstrated potent in vitro tumor cell killing in multiple cell lines and in vivo tumor regression in mice challenged with cancer cells. This antibody, in preclinical and CMC development stage, is anticipated to enter clinical testing in 2024. ModeX also has a multi-specific antibody developed using the MSTAR technology platform targeting two antigens for hematological tumors, such as several types of lymphomas and leukemias. Dual targeting minimizes chance of resistance due to tumor heterogeneity or downregulation of target levels. The antibody has demonstrated preferential in vitro killing on tumor cells over normal B cells and in vivo anti-tumor efficacy in disseminated mouse tumor model. This project is in preclinical development stage and is anticipated to enter into CMC development in 2023. ModeX’s Epstein Barr Virus (EBV) vaccine is developed using a modular nanoparticle vaccine platform built on naturally occurring and self-assembling ferritin molecules which enables the presentation of a 24-symmetrical array of each antigen that enhances the presentation of key components of the virus and stimulate durable protective immunity. The EBV vaccine presents antigens from four viral proteins involved in viral entry into host cells. These include a recombinant antigen designed from the proteins gH, gL and gp42, as well as an antigen derived from gp350. By using ModeX’s multi-targeted approach, this combination inhibits infection in two cell types, B cells and epithelial cells, which contrasts from efforts that previously focused on gp350 alone. ModeX has a trispecific HIV mAb (SAR441236), licensed from Sanofi, aimed at treatment of HIV infection in combination with other anti-retroviral treatment to achieve viral suppression in adults and pediatric patients with multidrug-resistant HIV that have limited therapeutic options. SAR441236 is being evaluated in a phase I clinical trial sponsored by the National Institute of Allergy and Infectious Diseases. SARM Through the acquisition of Transition Therapeutics, a Toronto-based biotechnology company (Transition), the company acquired OPK88004, an orally administered selective androgen receptor modulator (SARM). The selective and antagonistic properties of OPK88004 on the prostate appear to be well suited to potentially reduce prostate hyperplasia and volume, as well as provide anabolic therapeutic benefits, such as increased lean body mass and physical function, and decreased fat mass in specific patient populations. 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. Oxyntomodulin The company’s internal product development program is also focused on developing a once weekly administered oxyntomodulin for type 2 diabetes and obesity. The company’s most advanced oxyntomodulin product candidate, OPK88003, a once-weekly administered peptide for the treatment of type 2 diabetes and associated obesity, is a dual agonist of the Glucagon-Like Peptide-1 (GLP-1) and glucagon receptors. The receptors play an integral role in regulating appetite, food intake, satiety and energy utilization in the body. Stimulating both of the receptors, OPK88003 has the potential to regulate blood glucose. OPK88003 has been evaluated in a phase 2 study enrolling 420 type 2 diabetes subjects in a 24 week study consisting of a 12-week randomized blinded stage followed by a 12-week open-label stage. The study included four once-weekly dose arms of OPK88003 (10mg, 15mg, 30mg, 50mg), a placebo arm, and an active comparator arm (exenatide extended release – 2mg). The study was completed in February 2016. The company has evaluated OPK88003 in a dose escalation phase 2b trial in 110 type 2 diabetics where patients have been treated with a dose escalation regimen over 3 months intended to optimize dose levels, and increase body weight loss and reduce the adverse event profile, such as nausea and vomiting. The patients were treated for a total of 30 weeks in the study. In March 2019, the company announced positive topline results from that phase 2b trial, which demonstrated that OPK88003 met the primary objective with a statistically significant lowering of hemoglobin A1c (HbA1c) after 30 weeks of treatment versus placebo, as well as an important secondary endpoint, statistically significant weight loss versus placebo. On September 14, 2021, the company and LeaderMed Health Group Limited (LeaderMed), a pharmaceutical development company with operations based in Asia, announced the formation of a joint venture under which it 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. The company retains full rights to oxyntomodulin and Factor VIIa-CTP in all other geographies. Biologics-General The company’s biologics business focuses on developing and commercializing longer-acting proprietary versions of already approved therapeutic proteins. One of the company’s innovative platform technologies uses a short, naturally-occurring amino acid sequence, carboxl terminal peptide (CTP), which has the effect of slowing the removal from the body of the therapeutic protein to which it is attached. This CTP can be readily attached to a wide array of existing therapeutic proteins, stabilizing the therapeutic protein in the bloodstream and extending its life span without additional toxicity or loss of desired biological activity. The company is using the CTP technology to develop new, proprietary versions of certain existing therapeutic proteins that have longer life spans than therapeutic proteins without CTP. Somatrogon (hGH-CTP) The company’s 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, the company 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). Upon the launch of hGH-CTP the company is entitled to either regional, tiered gross profit sharing for both hGH-CTP and Pfizer’s Genotropin once certain necessary pricing approvals are obtained, or tiered royalty payments on sales of Somatrogon (hGH-CTP) with percentage rates ranging from the high teens to mid-twenties until such necessary pricing approval are obtained. The company’s phase 3 trial of hGH-CTP in pediatric patients was initiated in December 2016 and was completed in August 2019. The global study was a 224-patient study in Pediatric GHD patients designed to evaluate weekly treatment with hGH-CTP versus daily injections of Genotropin. hGH-CTP is delivered in a pen device in this multi-regional study in over 21 countries. The GHD subjects were treated weekly for 12 months. On October 21, 2019, the company and Pfizer announced that the global phase 3 trial met its primary endpoint of non-inferiority to daily Genotropin (somatropin) for injection, as measured by annual height velocity (HV) at 12 months. Results from this study demonstrated that treatment with hGH-CTP dosed once-weekly in pre-pubertal children with GHD was non-inferior to Genotropin (somatropin) dosed once-daily with respect to HV at 12 months of treatment (the primary endpoint); the least square mean was higher in the hGH-CTP group (10.12 cm/year) than in the Genotropin (somatropin) group (9.78 cm/year); the treatment difference (hGH-CTP—Genotropin (somatropin)) in HV (cm/year) was 0.33 with a two-sided 95% confidence interval of the difference of (-0.39, 1.05). In addition, change in height standard deviation scores at six and 12 months, key secondary endpoints, were higher in the hGH-CTP dosed once-weekly cohort in comparison to the Genotropin (somatropin) dosed once-daily cohort. hGH-CTP was generally well tolerated in this study and comparable to that of Genotropin (somatropin) dosed once-daily with respect to the types, numbers and severity of the adverse events observed between the treatment arms. In addition to the phase 3 pediatric study, the company has continued without interruption its ongoing phase 2 pediatric open label extension study for hGH-CTP. The company has switched all of the pediatric patients in this study to the disposable pen device. The company submitted the initial Biologics License Application (BLA) with the FDA for approval of Somatrogon (hGH-CTP) in the United States and Pfizer received a Complete Response Letter in January 2022. Pfizer and OPKO have evaluated the FDA’s comments and will work with the agency to determine an appropriate path forward. Regulatory applications for Somatrogon (hGH-CTP) have been submitted to the applicable regulatory bodies for review in several countries around the world. In February 2022, the European Commission granted marketing authorization in the European Union for Somatrogon (hGH-CTP) under the brand name NGENLA to treat children and adolescents from as young as 3 years of age with growth disturbance due to insufficient secretion of growth hormone. In January 2022, the Ministry of Health, Labour and Welfare in Japan approved NGENLA (Somatrogon) for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone. In 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. In December 2016, the company announced preliminary topline data from its phase 3, double blind, placebo controlled study of hGH-CTP in adults with GHD. The multinational, multi-center study, which utilized a 2:1 randomization between hGH-CTP and placebo, enrolled 203 subjects, 198 of whom received at least one dose of study treatment. The company has completed post-hoc sensitivity analyses to evaluate the influence of outliers on the primary endpoint results using multiple statistical approaches. Factor VIIa-CTP In addition to hGH-CTP, the company has a product candidate to extend the duration of the biological activity of Factor VIIa (hemophilia) using its CTP technology. In February 2013, the FDA granted orphan drug designation to the company’s longer-acting version of clotting Factor VIIa, Factor VIIa-CTP, for the treatment of bleeding episodes in patients with hemophilia A or B with inhibitors to Factor VIII or Factor IX. The company has completed a phase 1 single dose subcutaneously administered Factor VIIa-CTP study in healthy volunteers and a phase 2a single dose trial in Hemophilia A patients. Factor VIIa-CTP exhibited a positive safety profile in both hemophiliac patients and healthy subjects following a single IV or subcutaneous injection respectively. Pharmacodynamic assessment of coagulation markers demonstrated pharmacological activity of Factor VIIa-CTP with an extended response. The company also entered into a joint venture with LeaderMed on September 14, 2021, under which it 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 The company engages in research and development efforts to use the CTP technology for the development of a long-acting CTP-IGF-1 for the Treatment of Severe Primary IGF-1 Deficiency. In addition to development efforts using the CTP platform, the company focuses on broadening the approaches used to develop long acting therapies for once weekly therapies in rare diseases. APIs FineTech Pharmaceutical, Ltd. (FineTech), is the company’s Israeli-based subsidiary that develops and produces high value, high potency specialty APIs. FineTech manufactures commercial APIs for sale or license to pharmaceutical companies in Latin America, Canada, Europe and Israel. 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 the company’s pipeline of proprietary molecules and compounds for diagnostic and therapeutic products, while providing revenues and profits from its existing API business. Oligonucleotide Therapeutics OPKO CURNA’s platform technology utilizes a short, single strand oligonucleotide to increase production of endogenous protein through interference with non-coding RNA’s or natural antisense. This strategy contrasts with established approaches which down-regulate protein production. CURNA has designed a novel type of therapeutic modality, termed AntagoNAT, and has initially demonstrated this approach for up-regulation of several therapeutically relevant proteins in in vitro and animal models. The company has filed an investigational new drug application, or IND, for a lead compound to treat Dravet Syndrome. Further preclinical work has been requested by the FDA prior to initiation of a first clinical study. Orphan disease designations have been granted by FDA and EMA. On July 6, 2021, the company entered into an exclusive license agreement (the CAMP4 Agreement) with CAMP4 Therapeutics Corporation (CAMP4), pursuant to which it 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 During 2015, the company acquired EirGen Pharma Limited (EirGen), a specialty pharmaceutical company based in Ireland. EirGen focuses on the development and commercial supply of high potency, high barrier to entry, pharmaceutical products. Through its facility in Waterford, Ireland, EirGen manufactures high potency pharmaceutical products and exports to over 50 countries. As of December 31, 2022, EirGen and its commercial partners had filed several product applications with the FDA in Europe and in Japan. EirGen has a strong research and development portfolio of high barrier to entry drugs and the company expects to expand its drug portfolio. EirGen will play an important role in the development, manufacturing, distribution and approval of a wide variety of drugs in a variety of dosage forms with an emphasis on high potency products. OPKO Health Europe operates primarily in Spain and has more than 20 years of experience in the development, manufacture, marketing and sale of pharmaceutical, nutraceutical and veterinary products in Europe. OPKO Mexico engages in the manufacture, marketing, sale and distribution of ophthalmic and other pharmaceutical products to private and public customers in Mexico. OPKO Mexico is commercializing food supplements and over the counter products, and manufactures and sells products primarily in the generics market in Mexico, although it also has some proprietary products as well. OPKO Chile markets, sells and distributes pharmaceutical products to the private, hospital, pharmacy and public institutional markets in Chile for a wide range of indications, including, cardiovascular products, vaccines, antibiotics, gastro- intestinal products and hormones, among others. ALS Distribuidora Limitada (ALS) is engaged in the business of importation, commercialization and distribution of pharmaceutical products for private markets in Chile. ALS as the exclusive product distributor of Arama Laboratorios y Compañía Limitada (Arama), a company with more than 20 years of experience in the pharmaceutical products market. In connection with the acquisition of ALS, OPKO acquired all of the product registrations and trademarks previously owned by Arama, as well as the Arama name. The company distributes food supplements and over the counter products through Arama. Strategic Investments The company has and may continue to make investments in other early stage companies that it perceives to have valuable proprietary technology and significant potential to create value for OPKO as a shareholder. Research and Development Expenses During the years ended December 31, 2022, the company incurred $73.9 million research and development expenses related to its various product candidates. During the year ended December 31, 2022, the company’s research and development expenses primarily consisted of hGH-CTP and Rayaldee development programs. Intellectual Property The company has adopted a comprehensive intellectual property strategy which blends the efforts to innovate in a focused manner with the efforts of its business development activities to strategically in-license intellectual property rights. The company develops, protects, and defends its own intellectual property rights as dictated by the developing competitive environment. The company values its intellectual property assets and it has benefited from early and insightful efforts at understanding diagnostics, as well as the disease and the molecular basis of potential pharmaceutical intervention. The company actively seeks, when appropriate and available, protection for its products and proprietary information by means of the U.S. and foreign patents, trademarks, trade secrets, copyrights, and contractual arrangements. The company owns or license-ins thousands of the U.S. and foreign patents and applications for its products, product candidates and its outlicensed product candidates. These patents cover pharmaceuticals, diagnostics and other products and their uses, pharmaceutical and diagnostic compositions and formulations and product manufacturing processes. The company’s patents are filed in various locations worldwide as is appropriate to the particular patent and its use. Rayaldee The company has multiple U.S. patent families relating to Rayaldee. These patents are also filed in multiple countries worldwide. One patent family claims a sustained release oral dosage formulation and a method of treating 25-hydroxyvitamin Dinsufficiency or deficiency and will not expire until at least February 2027. A second patent family claims a method of administering 25-hydroxyvitamin D3 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. The company also has 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. 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 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). The company intends to seek patent term extensions in those countries for which such protection is potentially available. The company also continues to file and seek patent protection on various uses of extended release dosage forms of 25-hydroxyvitamin D3 and new formulations of this drug. EirGen’s patent publication US2021/0308151 disclosing and claiming the use of 25-hydroxyvitamin D3 and controlled release formulations thereof to treat SARS-CoV-2 infection was published on October 7, 2021. Somatrogon (hGH-CTP) 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 (hGH-CTP) in adult and pediatric patient populations, and methods of making Somatrogon (hGH-CTP). 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). Additional U.S. patent applications are pending which cover Somatrogon (hGH-CTP) 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; 8,426,166; 8,999,670; and 9,896,494, and no Patent Term Adjustment was issued). Multiple other U.S. patents cover Somatrogon (hGH-CTP) and its uses or methods of making, including U.S. Pat. Nos. 7,553,941; 8,450,269; 8,946,155; 10,351,615; and 11,197,915, where no Patent Term Adjustment was awarded by the USPTO. The equivalent foreign patents and applications are granted or pending in several major market countries and regions. In addition to the CTP patents and applications licensed to Pfizer, OPKO has multiple patent families covering similar biologicals with patents and applications pending in the U.S. and internationally. Patent term extensions will be sought in those countries where Somatrogon (hGH-CTP) is approved. OPK88003 and OPK88004 In 2016, the company acquired Transition, which is developing multiple drug candidates that include OPK88003 (a long acting oxyntomodulin) and OPK88004 (SARM), each of which are licensed from Eli Lilly and have granted patents worldwide covering the compounds and their use in their respective indications. U.S. Pat. No. 8367607 covers OPK88003 and expires in December 2030, without extension. OPKO has also filed a formulation patent on a long acting oxyntomodulin formulation. U.S. Pat. No. 7968587 covers OPK88004 (SARM) and expires, without extension, in November 2027. In addition to the molecule patent covering the selective androgen receptor modulator, Transition Therapeutics (Transition) exclusively licensed a method of use patent family covering its use in treating androgen deprivation therapy associated symptoms. These patents expire in 2035. OPKO has also filed additional patent applications on expanded uses of OPK88004. In addition, Transition and its affiliates have patented compounds (scyllo-inositol) for the treatment of Alzheimer’s disease. The patents are pending or granted in many countries of the world. OPKO and/or its affiliates or licensees will seek all available patent term extensions for its product candidates and products. Licenses and Collaborative Relationships The company’s strategy is to develop a portfolio of product candidates through a combination of internal development, acquisition, and external partnerships. Collaborations are key to the company’s strategy and it continues to build relationships and forge partnerships in various areas where unmet medical need and commercial opportunities exist. In October 2017, the company entered into a license and development agreement with JT for the development and commercialization of Rayaldee in Japan for the treatment of SHPT in non-dialysis and dialysis patients with CKD. Immediately following JT’s termination of this Agreement in May 2021, VFMCRP entered into an agreement with OPKO pursuant to which VFMCRP assumed JT’s rights in Rayaldee in Japan. Under the VFMCRP Agreement, as amended from time to time, the company has 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, the company entered into a license agreement with Nicoya to distribute and sell Rayaldee in China and certain other countries. In July 2021, the company licensed out its AntagoNAT portfolio owned by CURNA, INC. to CAMP4. In September 2021, the company 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, the company entered into the Pfizer Transaction for the development and commercialization of its 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. Competition The company’s major competitors in the New York metropolitan area are two of the largest national laboratories, Quest Diagnostics and Laboratory Corporation of America. Government Regulation Certain of the company’s diagnostic products in development are subject to regulation by the FDA and similar international health authorities. For these products, the company has an obligation to adhere to the FDA’s current good manufacturing practices regulations. Additionally, it is subject to periodic FDA inspections, quality control procedures, and other detailed validation procedures. As a provider of clinical laboratory services and as the company launches commercial diagnostic tests, it must continue to implement policies and procedures related to compliance with the Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (the HITECH Act, and collectively, HIPAA) privacy and security regulations, as required by law. The privacy and security regulations provide for significant fines and other penalties for wrongful use or disclosure of PHI, including potential civil and criminal fines and penalties. The company is also subject to the physician self-referral laws, commonly referred to as the Stark law. With the launch of Rayaldee, part of the company’s business is 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 company is also subject to the U.S. Foreign Corrupt Practices Act. With the launch of Rayaldee, part of the company’s business is 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. History OPKO Health, Inc. was incorporated in Delaware in 1991.