What changed in this filing

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Item 1. Business

2022-02-24 compared with 2021-02-25 · 429 added, 430 removed, 477 unchanged (64% of the section changed)

We are an established leader and fully integrated provider of innovative imaging diagnostics, targeted therapeutics, and artificial intelligence solutions to Find, Fight and Follow serious medical conditions.

For our imaging diagnostics, we believe that the resulting improved diagnostic information enables healthcare providers to better detect and characterize, or rule out, disease, potentially achieving improved patient outcomes, reducing patient risk and limiting overall costs for payers and the entire healthcare system.

Our commercial products are used by cardiologists, nuclear medicine physicians, radiologists, oncologists, internal medicine physicians, technologists and sonographers working in a variety of clinical settings.

We sell our products to radiopharmacies, PET manufacturing facilities (“PMFs”), integrated delivery networks, hospitals, clinics and group practices.

We sell our products globally and operate our business in two reportable segments, which are further described below:

Segment produces and markets our agents and products throughout the U.S.

In the U.S., we primarily sell to radiopharmacies, PMFs, integrated delivery networks, hospitals, clinics and group practices.

• International Segment operations consist of direct distribution in Canada and Puerto Rico, as well as third-party distribution relationships in Europe, Canada, Australia, Asia-Pacific and Latin America and our EXINI business in Sweden.

We are in the process of evaluating our operating and reporting structure.

We anticipate this evaluation, which we expect to complete during 2021, may result in a change to our existing operating segment reporting structure.

Progenics Acquisition

On June 19, 2020, we completed the Progenics Acquisition.

Progenics is an oncology company focused on developing and commercializing innovative targeted medicines and artificial intelligence to Find, Fight and Follow cancer.

Progenics’ portfolio of products and product candidates includes, among other things, therapeutic agents designed to target cancer (AZEDRA, 1095 and PSMA TTC), diagnostic imaging agents designed to target PSMA for prostate cancer (PyL and 1404), RELISTOR for opioid-induced constipation (“OIC”), artificial intelligence (“AI”) imaging technologies and leronlimab being developed for HIV infection and COVID-19 applications.

Progenics’ current revenue is generated from two principal sources:

first, royalties, development and commercial milestones from strategic partnerships, including royalties from Bausch from sales of RELISTOR;

and second, AZEDRA sales.

Lantheus Holdings issued 26,844,877 shares of Lantheus Holdings common stock and 86,630,633 CVRs to former Progenics stockholders in connection with the Progenics Acquisition.

Lantheus Holdings also assumed 34,000 in-the-money Progenics stock options and 6,507,342 out-of-the-money Progenics stock options, each converted into Replacement Stock Options at an exchange ratio of 0.31.

As a result of the Progenics Acquisition, we added the following products and product candidates to our portfolio:

Product / Product Candidate

Ultra-Orphan Therapeutic

AZEDRA (iobenguane I 131) 555 MBq/mL injection

Unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma

Prostate Cancer Diagnostics and Therapeutics

PyL (18F-DCFPyL)

PSMA-targeted PET/CT imaging agent for prostate cancer

NDA accepted;

PDUFA date of May 28, 2021

Worldwide (ex.

PyL (18F-DCFPyL)

PSMA-targeted PET/CT imaging agent for prostate cancer

Late stage development

1095 (I 131 1095)

PSMA-targeted small molecule therapeutic for metastatic prostate cancer

PSMA TTC (BAY 2315497)

PSMA-targeted antibody conjugate therapeutic for metastatic prostate cancer

Technetium-99m PSMA-targeted SPECT/CT imaging agent for prostate cancer

Discussions with European Medicines Agency (EMA)

Digital Solutions

AI-based imaging analysis technology that assists readers in quantification and standardized reporting of PSMA-targeted PET/CT imaging, providing an objective understanding of disease status Investigational Use Only

Automated Bone Scan Index (aBSI)

Automated reading and quantification of bone scans of prostate cancer patients using AI and deep learning

Approved in the U.S.

(510(k) clearance) and in the E.U.

Automated Bone Scan Index (BONENAVI)

Automated reading and quantification of bone scans of prostate cancer patients using AI and deep learning

Approved in Japan

Other Partnerships

RELISTOR Subcutaneous Injection (methylnaltrexone bromide)

OIC in adults with chronic non-cancer pain or advanced-illness adult patients

RELISTOR Tablets (methylnaltrexone bromide)

OIC in adults with chronic non-cancer pain

leronlimab (PRO 140)

HIV Infection, COVID-19

CytoDyn is working to provide information required by the FDA in order to resubmit a BLA for HIV;

CytoDyn has started recruiting for a Phase 2b/3 trial for COVID-19

See Part I, Item 1A.

“Risk Factors” in this Annual Report on form 10-K for the year ended December 31, 2020, for information regarding certain risks associated with our Progenics Acquisition.

We are an established leader and fully integrated provider committed to innovative imaging diagnostics, targeted therapeutics, and artificial intelligence solutions to Find, Fight and Follow serious medical conditions.

We classify our products in three categories:

precision diagnostics, radiopharmaceutical oncology, and strategic partnerships and other revenue.

Our leading precision diagnostic products assist healthcare professionals (“HCPs”) Find and Follow diseases in non-oncologic conditions.

Our radiopharmaceutical oncology diagnostics and therapeutics help HCPs Find, Fight and Follow cancer.

Our strategic partnerships focus on facilitating precision medicine through the use of biomarkers, digital solutions and radiotherapeutic platforms, and also includes our license of RELISTOR to Bausch Health Companies, Inc.

Our commercial products are used by cardiologists, internal medicine physicians, nuclear medicine physicians, oncologists, radiologists, sonographers, technologists and urologists working in a variety of clinical settings.

We believe that our diagnostic products provide improved diagnostic information that enables HCPs to better detect and characterize, or rule out, disease, with the potential to achieve better patient outcomes, reduce patient risk and limit overall costs for payors and throughout the healthcare system.

We produce and market our products throughout the United States (the “United States” or the “U.S.”), selling primarily to clinics, group practices, hospitals, integrated delivery networks, and radiopharmacies.

We sell our products outside the U.S.

through a combination of direct distribution in Canada and third party distribution relationships in Europe, Canada, Australia, Asia-Pacific, Central America and South America.

Our headquarters are located in North Billerica, MA, with additional offices in Somerset, NJ;

Montreal, Canada and Lund, Sweden.

In the first quarter of 2021, we completed the evaluation of our operating and reporting structure, including the impact on our business of the acquisition of Progenics and the sale of our Puerto Rico subsidiary, which resulted in a change in our operating segments to one reportable business segment.

On May 27, 2021, we announced that the FDA had approved PYLARIFY, an F 18-labeled PET imaging agent targeting prostate-specific membrane antigen (“PSMA”).

PYLARIFY is a product in our radiopharmaceutical oncology product category.

We commercially launched PYLARIFY in the U.S.

in June 2021.

During 2021, we announced that our subsidiary, EXINI, was granted 510(k) clearance by the FDA in the U.S.

and a CE marking in Europe for aPROMISE.

We commercially launched aPROMISE under the name PYLARIFY AI in the U.S.

in November 2021.

Our Portfolio of Commercial Products

Our commercial products now include the following:

• DEFINITY is a microbubble ultrasound enhancing agent used in ultrasound exams of the heart, also known as echocardiography exams.

DEFINITY contains perflutren-containing lipid microspheres and is indicated in the U.S.

Precision Diagnostics

Our commercial products in our precision diagnostics category include the following:

• DEFINITY is an injectable microbubble ultrasound enhancing agent with perflutren-containing lipid microspheres that is used in ultrasound exams of the heart, also known as echocardiography exams.

DEFINITY requires refrigerated storage and is indicated in the U.S.

for use in patients with suboptimal echocardiograms to assist in imaging the left ventricular chamber and left endocardial border of the heart in ultrasound procedures.

In November 2020, the FDA approved our supplemental new drug application (“sNDA”) for DEFINITY RT.

DEFINITY RT is a modified formulation of DEFINITY that allows both storage and shipment at room temperature (DEFINITY’s previously approved formulation requires refrigerated storage).

We believe we are currently the leading provider of ultrasound microbubble enhancing agents in the world.

• TechneLite is a Technetium (“Tc-99m”) generator that provides the essential nuclear material used by radiopharmacies to radiolabel Cardiolite, Neurolite and other Tc-99m-based radiopharmaceuticals used in nuclear medicine procedures.

DEFINITY RT is a modified formulation of DEFINITY that allows both storage and shipment at room temperature and provides clinicians an additional choice for greater utility of this formulation in broader clinical settings.

We believe we are currently the leading worldwide provider of ultrasound microbubble enhancing agents.

• TechneLite is a Technetium (“Tc-99m”) generator that provides the essential nuclear material used by radiopharmacies to radiolabel NEUROLITE, Cardiolite and other Tc-99m-based radiopharmaceuticals used in nuclear medicine procedures.

TechneLite uses Mo-99 as its active ingredient.

• NEUROLITE is an injectable, Tc-99m-labeled imaging agent used with SPECT technology to identify the area within the brain where blood flow has been blocked or reduced due to stroke.

• RELISTOR (methylnaltrexone bromide) is a treatment for OIC that decreases the constipating side effects induced by opioid pain medications such as morphine and codeine without diminishing their ability to relieve pain.

RELISTOR is approved in two forms:

a subcutaneous injection and an oral tablet.

• NEUROLITE is an injectable, Tc-99m-labeled imaging agent used with single-photon emission computed tomography (“SPECT”) technology to identify the area within the brain where blood flow has been blocked or reduced due to stroke.

Although NEUROLITE’s patents and market exclusivity have expired, we are not currently aware of any generic competitors.

• Xenon-133 (“Xenon”) is a radiopharmaceutical gas that is inhaled and used to assess pulmonary function and also to image cerebral blood flow.

Our Xenon is manufactured by a third party as a bi-product of Mo-99 production and is processed and finished by us.

We believe we are currently the leading provider of Xenon in the U.S.

• Cardiolite, also known by its generic name sestamibi, is an injectable, Tc-99m-labeled imaging agent used in myocardial perfusion imaging (“MPI”) procedures to assess blood flow to the muscle of the heart using SPECT.

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We manufacture Thallium using cyclotron technology.

Radiopharmaceutical Oncology

Our commercial products in our radiopharmaceutical oncology category include the following:

• PYLARIFY (also known as piflufolastat F 18, 18F-DCFPyL or PyL) is an F 18-labelled PSMA-targeted PET imaging agent used with PET/computed tomography (“CT”) technology that enables visualization of lymph nodes, bone and soft tissue metastases to determine the presence or absence of recurrent and/or metastatic prostate cancer.

PYLARIFY is indicated in the U.S.

for PET imaging of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy and in men with suspected recurrence based on elevated serum prostate-specific antigen (“PSA”) levels.

• AZEDRA (iobenguane I 131) is a radiotherapeutic, approved for the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.

AZEDRA is the first and only FDA-approved therapy for this indication.

• QUADRAMET is an injectable radiopharmaceutical used to treat severe bone pain associated with osteoblastic metastatic bone lesions.

We serve as the direct manufacturer and supplier of QUADRAMET in the U.S.

Strategic Partnerships and Other Revenue

Our commercial products in our strategic partnerships and other revenue product category include the following:

• RELISTOR (methylnaltrexone bromide) is a treatment for opioid-induced constipation (“OIC”) that decreases the constipating side effects induced by opioid pain medications such as morphine and codeine without diminishing their ability to relieve pain.

RELISTOR is approved in two forms:

a subcutaneous injection and an oral tablet.

We have licensed RELISTOR to Bausch, and we collect quarterly royalties based on RELISTOR sales.

• Automated Bone Scan Index (“aBSI”) calculates the disease burden of prostate cancer by quantifying the hotspots on bone scans and automatically calculating the bone scan index value, representing the disease burden of prostate cancer shown on the bone scan.

This quantifiable and reproducible calculation of the bone scan index value is intended to aid in the diagnosis and treatment of men with prostate cancer and may have utility in monitoring the course of the disease.

The Japanese rights to the stand-alone aBSI have been transferred and sold to FUJIFILM Toyama Chemical Co.

(“FUJIFILM”) under the name BONENAVI ® .

The cloud based aBSI was made available for clinical use in the U.S.

on August 5, 2019.

In February 2020, Progenics received CE marking for the standalone workstation model of aBSI, meeting the quality standards set by the European Economic Area.

In September 2020, the FDA granted 510(k) clearance for the use of aBSI on a GE Healthcare system.

• Cobalt (Co 57) is a non-pharmaceutical radiochemical used in the manufacture of sources for the calibration and maintenance of SPECT imaging cameras.

Sales of our microbubble ultrasound enhancing agent, DEFINITY, are made in the U.S.

and Canada through a DEFINITY direct sales team.

In the U.S., our nuclear imaging products, including TechneLite, Xenon, NEUROLITE and Cardiolite, are primarily distributed through commercial radiopharmacies, the majority of which are controlled by or associated with Cardinal, RLS (previously GE Healthcare), UPPI, Jubilant Radiopharma and PharmaLogic.

A small portion of our nuclear imaging product sales in the U.S.

are made through our direct sales force to hospitals and clinics that maintain their own in-house radiopharmaceutical preparation capabilities.

AZEDRA is also sold in the U.S.

through an AZEDRA direct sales team.

RELISTOR was licensed to Bausch, and we collect quarterly royalties based on those sales.

We also maintain our own direct sales force in Canada for certain of our products.

In Europe, Australia, Asia-Pacific and Latin America, we generally rely on third-party distributors to market, sell and distribute our nuclear imaging and ultrasound enhancing agent products, either on a country-by-country basis or on a multi-country regional basis.

Our headquarters are located in North Billerica, MA with offices in New York, NY;

Somerset, NJ;

Montreal, Canada and Lund, Sweden.

• PYLARIFY AI, which we also refer to as aPROMISE, is an artificial intelligence medical device software designed to allow healthcare professionals and researchers to perform standardized quantitative assessment of PSMA PET/CT images in prostate cancer, including those images obtained by using PYLARIFY.

Additional Information about our Product Categories

Precision Diagnostics

Anticipated Continued Growth of DEFINITY and Expansion of Our Ultrasound Microbubble Franchise

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The term DEFINITY includes its activated and non-activated forms.

DEFINITY is a clear, colorless, sterile liquid, which, upon activation in a VIALMIX apparatus, a medical device specifically designed for DEFINITY, becomes a homogenous, opaque, milky white injectable suspension of perflutren-containing lipid microspheres.

DEFINITY is a clear, colorless, sterile liquid that requires refrigerated storage, and which, upon activation in a VIALMIX apparatus, a medical device specifically designed for DEFINITY, becomes a homogenous, opaque, milky white injectable suspension of perflutren-containing lipid microspheres.

After activation and intravenous injection, DEFINITY opacifies the left ventricular chamber and improves the delineation of the left ventricular endocardial border, or innermost layer of tissue that lines the chamber of the left ventricle.

Better visualization of the left ventricle allows clinicians to make more informed decisions about disease status.

There were approximately 31.5 million echocardiograms performed in the U.S.

in 2020 according to a third party source.

Assuming 20% of echocardiograms produce suboptimal images, as stated in the clinical literature, we estimate that approximately 6.3 million echocardiograms in 2020 produced suboptimal images.

In 2019, a year in which the volume of echocardiograms was not impacted by the COVID-19 pandemic, there were 35.1 million echocardiograms performed in the U.S.

according to a third party source.

Assuming the same 20% of suboptimal images, we estimate that approximately 7.0 million echocardiograms in 2019 produced suboptimal images.

Based on estimates from third party sources, we believe there were approximately 25 to 32 million echocardiograms performed in the U.S.

in 2020 (the latest time period for which full year data is available and which also included the estimated impacts of COVID-19 on procedure volumes).

Assuming that between 20% and 30% of echocardiograms produce suboptimal images, as stated in the clinical literature, we estimate that approximately 5 to 10 million echocardiograms in 2020 produced suboptimal images.

Since its launch in 2001, DEFINITY has been used in imaging procedures in more than 18.0 million studies throughout the world.

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segment for ultrasound enhancing agents in echocardiography procedures as of December 2021.

DEFINITY currently competes with Optison, a GE Healthcare product, Lumason, a Bracco product (known as SonoVue outside the U.S.) as well as echocardiography without ultrasound enhancing agents and non-echocardiography imaging modalities.

DEFINITY currently competes with Optison, a GE Healthcare product, Lumason, a Bracco Diagnostics Inc.

(“Bracco”) product, as well as echocardiography without ultrasound enhancing agents and non-echocardiography imaging modalities.

DEFINITY, Optison and Lumason all carry an FDA-required boxed warning, which has been modified over time, to notify physicians and patients about potentially serious safety concerns or risks posed by the products.

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and internationally.

for DEFINITY we now own a total of four Orange Book-listed method of use patents, one of which expires in 2035 and three of which expire in 2037, as well as additional manufacturing patents that are not Orange Book-listed expiring in 2021, 2023 and 2037.

for DEFINITY RT, we own a total of five Orange Book-listed patents, including a composition of matter patent which expires in 2035.

Outside of the U.S., while our original DEFINITY patent protection and regulatory exclusivity have generally expired, we are currently prosecuting additional DEFINITY and DEFINITY RT patents to obtain similar patent protection as in the U.S.

The Orange Book-listed patents include a patent on the use of VIALMIX RFID which expires in 2037;

additional VIALMIX RFID patent applications have been submitted in major markets throughout the world.

for DEFINITY, we have four Orange Book-listed method of use patents, one of which expires in 2035 and three of which expire in 2037, as well as additional manufacturing patents that are not Orange Book-listed expiring in 2023 and 2037.

for DEFINITY RT, we have five Orange Book-listed patents, including a composition of matter patent which expires in 2035.

Outside of the U.S., we are currently pursuing additional DEFINITY and DEFINITY RT patents to obtain similar patent protection as in the U.S.

The Orange Book-listed patents include a patent on the use of VIALMIX RFID (see below) which expires in 2037;

we have submitted additional VIALMIX RFID patent applications in major markets throughout the world.

• Hatch-Waxman Act - Even though our longest duration Orange Book-listed DEFINITY patent extends until March 2037, because our Orange Book-listed composition of matter patent expired in June 2019, we may face generic DEFINITY challengers in the near to intermediate term.

Under the Hatch-Waxman Act, the FDA can approve Abbreviated New Drug Applications (“ANDAs”) for generic versions of drugs if the ANDA applicant demonstrates, among other things, that (i) its generic candidate is the same as the innovator product by establishing bioequivalence and providing relevant chemistry, manufacturing and product data, and (ii) the marketing of that generic candidate does not infringe an Orange Book-listed patent or that an Orange Book-listed patent is invalid.

With respect to any Orange Book-listed patent covering the innovator product, the ANDA applicant must give a notice to the innovator (a “Notice”) that the ANDA applicant certifies that its generic candidate will not infringe the innovator’s Orange Book-listed patent or that the Orange Book-listed patent is invalid.

The innovator can then challenge the ANDA applicant in court within 45 days of receiving that Notice, and FDA approval to commercialize the generic candidate will be stayed (that is, delayed) for up to 30 months (measured from the date on which a Notice is received) while the patent dispute between the innovator and the ANDA applicant is resolved in court.

Under the Hatch-Waxman Act, the FDA can approve Abbreviated New Drug Applications (“ANDAs”) for generic versions of drugs if the ANDA applicant demonstrates, among other things, that (i) its generic candidate is the same as the innovator product by establishing bioequivalence and providing relevant chemistry, manufacturing and product data, and (ii) either the marketing of that generic candidate does not infringe the Orange Book-listed patent(s) or the Orange Book-listed patent(s) is invalid.

Similarly, the FDA can approve a Section 505(b)(2) NDA from an applicant that relies on some of the information required for marketing approval from studies which the applicant does not own or have a legal right of reference.

With respect to the Orange Book-listed patent(s) covering an innovator product, the ANDA or Section 505(b)(2) applicant (if relying on studies related to the innovator product) (each, the “Applicant”) must give a notice (a “Notice”) to the innovator of its certification that its generic candidate will not infringe the innovator’s Orange Book-listed patent(s) or that the Orange Book-listed patent(s) is invalid.

The innovator can then file suit against the Applicant within 45 days of receiving the Notice, and FDA approval to commercialize the generic candidate will be stayed (that is, delayed) for up to 30 months (measured from the date on which a Notice is received) while the patent dispute between the innovator and the Applicant is resolved in court.

The 30-month stay could potentially expire sooner if the courts determine that no infringement had occurred or that the challenged Orange Book-listed patent is invalid or if the parties otherwise settle their dispute.

As of the date of filing of this Annual Report on Form 10-K, we have not received any Notice from an ANDA applicant.

precluded from commercializing a generic version of DEFINITY prior to the expiration of that 30 month stay period and, potentially, thereafter, depending on how the patent dispute is resolved.

Solely by way of example and not based on any knowledge we currently have, if we received a Notice from an ANDA applicant in March 2021 and the full 30 month stay was obtained, then the ANDA applicant would be precluded from commercialization until at least September 2023.

If we received a Notice some number of months in the future and the full 30 month stay was obtained, the commercialization date would roll forward in the future by the same calculation.

• DEFINITY RT - In November 2020, the FDA approved our sNDA for DEFINITY RT.

DEFINITY RT is a modified formulation of DEFINITY that allows both storage and shipment at room temperature (DEFINITY’s previously approved formulation requires refrigerated storage).

The modified formulation provides clinicians an additional choice and allows for greater utility of this formulation in broader clinical settings.

We believe DEFINITY RT will become commercially available later in 2021, although that timing cannot be assured.

Given its physical characteristics, we believe DEFINITY RT is also well-suited for inclusion in kits requiring microbubbles for other indications and applications (including in kits developed by third parties of the type described in the paragraph entitled New Clinical Applications below).

• VIALMIX RFID – In August 2020, we announced the FDA approved our sNDA for our next-generation activation device designed specifically for both DEFINITY and DEFINITY RT.

The activation rate and time are controlled by VIALMIX RFID through the use of radio-frequency identification technology (“RFID”) to ensure reproducible activation of DEFINITY and DEFINITY RT.

The RFID tag, which is affixed to the vial label, enables the DEFINITY or DEFINITY RT vial to be appropriately activated when utilized with the VIALMIX RFID activation device.

• New Clinical Applications - As we continue to look for other opportunities to expand our microbubble franchise, we are evaluating new indications and clinical applications beyond echocardiography and ultrasound enhancing agent imaging generally.

• In April 2019, we announced a strategic development and commercial collaboration with Cerevast Medical, Inc.

(“Cerevast”) in which our microbubbles will be used in connection with Cerevast’s ocular ultrasound device to improve blood flow in occluded retinal veins in the eye.

Retinal vein occlusion is one of the most common causes of vision loss worldwide.

• In December 2019, we announced a strategic commercial supply agreement with CarThera for the use of our microbubbles in combination with SonoCloud, a proprietary implantable device in development for the treatment of recurrent glioblastoma.

Glioblastoma is a lethal and devastating form of brain cancer with median survival of 15 months after diagnosis.

• In October 2020, we announced a strategic collaboration with Insightec Ltd.

(“Insightec”) which will use our microbubbles in connection with Insightec’s transcranial guided focused ultrasound device for the treatment of glioblastoma as well as other neurodegenerative conditions.

• In-House Manufacturing - We have completed construction of specialized, in-house manufacturing capabilities at our North Billerica, Massachusetts facility for DEFINITY and, potentially, other sterile vial products.

We believe the investment in these efforts will allow us to better control DEFINITY manufacturing and inventory, reduce our costs in a potentially more price competitive environment, and provide us with supply chain redundancy.

We currently expect to make use of this in-house manufacturing capability in late 2021, although that timing cannot be assured.

• DEFINITY in China - In March 2020 in connection with our Chinese development and distribution arrangement with Double-Crane Pharmaceutical Company (“Double-Crane”), we filed an Import Drug License application with the National Medical Products Administration, or the NMPA, for the use of DEFINITY for the echocardiography indication.

We believe this is an important milestone in our efforts to commercialize DEFINITY in China.

Double-Crane is also in the process of analyzing the clinical results relating to the liver and kidney indications and will also work with us to prepare an Import Drug License application for those indications.

As of the date of filing of this Annual Report on Form 10-K, we have not received any Notice from an Applicant.

If we were to (i) receive any such Notice in the future, (ii) bring a patent infringement suit against the Applicant within 45 days of receiving that Notice, and (iii) successfully obtain the full 30-month stay, then the Applicant would be precluded from commercializing a generic version of DEFINITY prior to the expiration of that 30-month stay period and, potentially, thereafter, depending on how the patent dispute is resolved.

Solely by way of example and not based on any knowledge we currently have, if we received a Notice from an Applicant in March 2022 and the full 30-month stay were obtained, then the Applicant would be precluded from commercialization until at least September 2024.

If we received a Notice some number of months in the future and the full 30-month stay were obtained, the commercialization date would roll forward in the future by the same number of months.

In the event a 505(b)(2) applicant does not rely on studies related to the innovator product, the 30-month stay would not apply, but additional clinical studies may be required.

• DEFINITY RT - DEFINITY RT became commercially available in the fourth quarter of 2021.

A modified formulation of DEFINITY that allows both storage and shipment at room temperature, DEFINITY RT provides clinicians an additional choice and allows for greater utility of this formulation in broader clinical settings.

• VIALMIX RFID - VIALMIX RFID, our next-generation activation device designed specifically for both DEFINITY and DEFINITY RT, became commercially available in the fourth quarter of 2021.

The activation rate and time are controlled by VIALMIX RFID through the use of radio-frequency identification technology (“RFID”) to ensure reproducible activation of

DEFINITY and DEFINITY RT.

The RFID tag, which is affixed to the vial label, enables the DEFINITY or DEFINITY RT vial to be appropriately activated with the VIALMIX RFID activation device.

• In-House Manufacturing - We have constructed a specialized in-house manufacturing facility at our North Billerica campus for purposes of producing DEFINITY and, potentially, other sterile vial products.

On February 22, 2022, we received FDA approval of our supplemental new drug application (“sNDA”), authorizing commercial manufacturing of DEFINITY at our new facility.

As of February 23, 2022, DEFINITY manufactured at this facility is commercially available.

We believe this investment will allow us to better manage DEFINITY manufacturing and inventory, reduce our costs in a potentially more price competitive environment, and provide us with supply chain redundancy.

See Part I, Item 1A.

“Risk Factors” for information regarding certain risks associated with DEFINITY and see Part II, Item 7.

“Management’s Discussion and Analysis of Financial Condition and Results of Operations-Comparison of the Periods Ended December 31, 2020 and 2019-Revenues” for further information on total revenue contributed by DEFINITY in each of our last three fiscal years.

TechneLite is a self-contained system or generator of Technetium (“Tc-99m”), a radioactive isotope with a six hour half-life, used by radiopharmacies to prepare various nuclear imaging agents.

“Management’s Discussion and Analysis of Financial Condition and Results of Operations - Comparison of the Periods Ended December 31, 2021 and 2020 and Comparison of the Periods Ended December 31, 2020 and 2019 - Revenues” for further information on total revenue contributed by DEFINITY in each of our last three fiscal years.

TechneLite is a self-contained system or generator of Tc-99m, a radioactive isotope with a six hour half-life, used by radiopharmacies to prepare various nuclear imaging agents.

Tc-99m results from the radioactive decay of Mo-99, itself a radioisotope with a 66-hour half-life produced in nuclear research reactors around the world from enriched uranium.

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Because of the short half-lives of Mo-99 and Tc-99m, radiopharmacies typically purchase TechneLite generators on a weekly basis pursuant to standing orders.

The Tc-99m produced by our TechneLite generator is the medical radioisotope that can be attached to a number of imaging agents, including our own Cardiolite products and NEUROLITE, during the radiolabeling process.

The Tc-99m produced by our TechneLite generator is the medical radioisotope that can be attached to a number of imaging agents, including our own NEUROLITE and Cardiolite products, during the radiolabeling process.

To radiolabel a Tc-99m-based radiopharmaceutical, a vial of sterile saline and a vacuum vial are each affixed to the top of a TechneLite generator.

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See “Raw Materials and Supply Relationships—Molybdenum-99” below.

TechneLite is currently marketed primarily in North America and Latin America, largely to radiopharmacies that prepare unit doses of radiopharmaceutical imaging agents and ship these preparations directly to hospitals for administration to patients.

In the U.S., we have supply contracts with the significant radiopharmacy groups, including Cardinal, RLS, UPPI, Jubilant Radiopharma and PharmaLogic.

TechneLite is currently marketed primarily in North America, Central America and South America, largely to radiopharmacies that prepare unit doses of radiopharmaceutical imaging agents and ship these preparations directly to hospitals for administration to patients.

In the U.S., we have supply contracts with large radiopharmacy groups, including Cardinal Health (“Cardinal”), PharmaLogic Holdings Corp (“PharmaLogic”), RLS (USA) Inc.

(previously GE Healthcare) (“RLS”) and United Pharmacy Partners (“UPPI”).

We also supply generators on a purchase order basis to other customers.

We estimate that TechneLite had approximately one third of the U.S.

generator market as of December 31, 2020, competing primarily with Tc-99m-based generators produced by Curium.

generator market as of December 31, 2021, competing primarily with Tc-99m-based generators produced by Curium and NorthStar Medical Radioisotopes, LLC (“Northstar”).

Outside of the U.S., we sell generators through supply agreements with radiopharmacy chains, through distributors or to separate customers.

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Our LEU TechneLite generator satisfies the reimbursement requirements under the applicable CMS rules.

TechneLite has patent protection in the U.S.

We believe that our substantial capital investments in our highly automated TechneLite production line, which we have made over the years, and our extensive experience in complying with the stringent regulatory requirements for the handling of nuclear materials, create significant and sustainable competitive advantages for us in generator manufacturing and distribution.

Given our significant know-how and trade secrets associated with the methods of manufacturing and assembling the TechneLite generator, we believe we have a substantial amount of valuable and defensible proprietary intellectual property associated with the product.

In addition, TechneLite has patent protection in the U.S.

and various foreign countries on certain component technology currently expiring in 2029, and we are pursuing additional patent protection in the U.S.

and world-wide on other component technology that, if granted, would expire in 2040.

In addition, given the significant know-how and trade secrets associated with the methods of manufacturing and assembling the TechneLite generator, we believe we have a substantial amount of valuable and defensible proprietary intellectual property associated with the product.

We believe that our substantial capital investments in our highly automated TechneLite production line and our extensive experience in complying with the stringent regulatory requirements for the handling of nuclear materials create significant and sustainable competitive advantages for us in generator manufacturing and distribution.

See Part II, Item 7.

Our Portfolio of Clinical Development Candidates

In addition to our commercial products, we now have an extensive portfolio of product candidates in clinical development, including:

• PyL (also known as 18F-DCFPyL) is a fluorine 18-based PSMA-targeted PET imaging agent that enables visualization of primary tumors as well as bone and soft tissue metastases, with potential high clinical utility in the detection of recurrent and/or metastatic prostate cancer.

Progenics has completed a clinical development program that consisted of two pivotal clinical studies, which were designed to provide robust, prospective, well-controlled, and pathology- or composite truth standard-verified data to establish the safety and diagnostic performance of PyL across the disease continuum of prostate cancer.

results from these studies provide data in support of the potential of PyL to reliably detect and localize disease, including in patients with low PSA values, and may help enable appropriate disease management, thus supporting the potential use for detection of recurrent or metastatic prostate cancer.

We filed the PyL NDA with the FDA in September 2020 and received notice of priority review in December 2020 with a PDUFA date of May 28, 2021.

• flurpiridaz F 18 is a fluorine 18-based PET MPI agent designed to assess blood flow to the heart in patients suspected of coronary artery disease (CAD).

In April 2017, we announced entering into a definitive, exclusive Collaboration and License Agreement with GE Healthcare for the agent’s continued Phase 3 development and worldwide commercialization.

The second Phase 3 trial is now underway;

however, because of the COVID-19 pandemic, enrollment in the global clinical development program had been delayed and has now resumed at a slower recruiting pace.

GE Healthcare now expects to complete enrollment in the second half of 2021 and, assuming regulatory approval, begin commercialization in early 2023.

• 1095 (also known as I-131-1095) is a PSMA-targeted iodine-131 labeled small molecule that is designed to deliver a dose of beta radiation directly to prostate cancer cells with minimal impact on the surrounding healthy tissues.

Progenics initiated eleven clinical sites in the U.S.

along with the six active sites in Canada to support enrollment in the Company’s multicenter, randomized, controlled, ARROW Phase 2 study in mCRPC.

Because of the COVID-19 pandemic, Progenics new enrollment in the Phase 2 trial was paused to minimize the risk to subjects and healthcare providers during the pandemic.

Subjects who were active and had been randomized for the study continued to receive treatment doses and were monitored for safety and efficacy in a manner that is permissible by each clinical site.

New enrollment in the ARROW Phase 2 study restarted in October 2020.

• LMI 1195 is a fluorine 18-based PET imaging agent for the norepinephrine pathway.

We have designed but not yet commenced two Phase 3 clinical trials for the use of LMI 1195 for the diagnosis and management of neuroendocrine tumors in pediatric and adult populations, respectively.

The FDA has granted an Orphan Drug designation for the use of LMI 1195 in the management indication.

We have also received notice of eligibility for a rare pediatric disease priority review voucher for a subsequent human drug application so long as LMI 1195 is approved by the FDA for its rare pediatric disease indication.

Pursuant to federal legislation passed and signed into law in late 2020, the expiration date of the rare pediatric disease priority review voucher program was extended from September 30, 2022 to September 30, 2026.

• PSMA TTC is a thorium-227 labeled PSMA-targeted antibody therapeutic.

PSMA TTC is designed to deliver a dose of alpha radiation directly to prostate cancer cells with minimal impact on the surrounding healthy tissues.

Bayer AG (“Bayer”) has exclusive worldwide rights to develop and commercialize products using our PSMA antibody platform in combination with Bayer’s alpha-emitting radionuclides.

Bayer is conducting a Phase 1 trial of PSMA TTC in subjects with metastatic castration-resistant prostate cancer (“mCRPC”).

• 1404 is a Tc-99m labeled small molecule which binds to PSMA and is used as a SPECT/CT imaging agent to diagnose and detect localized prostate cancer as well as soft tissue and bone metastases.

ROTOP has exclusive rights to develop, manufacture and commercialize 1404 in Europe.

• PSMA-AI is an AI-based imaging analysis technology that assists readers in quantification and standardized reporting of PSMA-targeted PET/CT imaging, providing an objective understanding of disease status.

The technology automatically analyzes the CT image to segment anatomical regions – 51 bones and 12 soft tissue organs.

This CT segmentation enables automated localization, detection and quantification of potential PSMA-avid lesions in the PET image, which is incorporated into a standardized report for physicians.

In a recent study, the technology demonstrated better consistency in quantitative assessment across multiple readers and high sensitivity (>90%) in detecting potential lesions in PSMA PET/CT.

The clinical utility of the device is being investigated in multiple outcome-based studies.

• leronlimab (PRO 140) is an investigational humanized monoclonal antibody targeting the CCR5 receptor.

CCR5 appears to act as an HIV entry inhibitor and may play a broader role in tumor metastasis and immune-mediated illnesses.

It is owned by CytoDyn Inc.

(“CytoDyn”) pursuant to our agreement with CytoDyn, as described below.

In May 2020, CytoDyn announced it submitted a Biologics License Application (“BLA”) to the FDA for approval of leronlimab in combination therapy for HIV infection.

On July 13, 2020, CytoDyn announced that it had received a refusal to file letter from the FDA for the BLA.

In August and September 2020, the FDA provided written responses to CytoDyn’s questions and met telephonically with CytoDyn key personnel and its clinical research organization concerning its recent BLA for this HIV combination therapy to expedite the resubmission of its BLA filing for this indication.

CytoDyn is working diligently to resubmit the BLA, which it expects to file in the first half of calendar year 2021.

Leronlimab is also being evaluated by CytoDyn for patients with mild/moderate COVID-19 indications in a Phase 2 randomized clinical trial that was recently completed.

Also, CytoDyn has started recruiting for a Phase 2b/3 trial for 390 severe or critical COVID-19 patients.

For the years ended December 31, 2020, 2019 and 2018, we invested $32.8 million, $20.0 million and $17.1 million in research and development (“R&D”), respectively.

Our R&D team includes our Medical Affairs and Medical Information functions, which educate physicians on the scientific aspects of our commercial products and the approved indications.

Radiopharmaceutical Oncology

PYLARIFY Approval and Commercial Launch

PYLARIFY is a radioactive diagnostic agent indicated for PET imaging of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy and in men with suspected recurrence based on elevated PSA levels.

PYLARIFY works by binding to PSMA, a protein that is overexpressed on the surface of more than 90% of primary and metastatic prostate cancer cells.

PYLARIFY works with PET/CT technology to produce a combined PET/CT scan that enables the reader of the PET/CT scan to detect and locate the disease.

According to the American Cancer Society, prostate cancer is the second most common cancer in American men - one in eight American men will be diagnosed with prostate cancer in their lifetimes and over 3.1 million American men are living with prostate cancer today.

Based on estimates from third party sources regarding the incidence of prostate cancer in men in the U.S., we believe the potential market size for PSMA PET imaging agents could be up to 220,000 annual scans, comprised of 90,000 scans for patients with intermediate, unfavorable or high/very high risk of suspected metastases of prostate cancer and 130,000 scans for patients with suspected recurrence of prostate cancer.

Because we are in the process of launching this imaging agent, we can give no assurance as to how clinical practice may evolve or what our ultimate market penetration may be.

The approval of PYLARIFY was based on data from two Company-sponsored pivotal studies (“OSPREY” and “CONDOR”) designed to establish the safety and diagnostic performance of PYLARIFY across the prostate cancer disease continuum.

Results from OSPREY (Cohort A) demonstrated improvement in specificity and positive predictive value of PYLARIFY PET imaging over conventional imaging in men at risk for metastatic prostate cancer prior to initial definitive therapy.

CONDOR studied men with biochemical recurrent prostate cancer.

In patients with biochemical recurrent prostate cancer and non-informative baseline imaging, PYLARIFY demonstrated high correct localization and detection rates, including in patients with early recurrent disease with low but rising PSA blood levels (median PSA 0.8 ng/mL).

Upon commercial launch in June 2021, PYLARIFY was immediately available in select parts of the U.S.

Over the course of the remainder of 2021, PYLARIFY availability expanded into additional regions and is now broadly available nationwide.

We continue to expand our geographic coverage, customer contracting and market access coverage to serve our customers and the U.S.

prostate cancer community.

The commercial launch of PYLARIFY is complex and expensive.

During 2021, we hired additional employees to assist us with the commercialization of PYLARIFY, including in sales, marketing, reimbursement, quality and medical affairs.

To manufacture PYLARIFY, we assembled and are qualifying a nationwide network of PMFs with radioisotope-producing cyclotrons that make F 18, which has a 110-minute half-life, so PYLARIFY is manufactured and distributed rapidly to end-users.

After being made on a cyclotron at a PMF, the F 18 is then combined with certain chemical ingredients in specially designed chemistry synthesis boxes to manufacture PYLARIFY.

The finished PYLARIFY is then quality control tested and transferred to a radiopharmacist who prepares and dispenses patient-specific doses of the final product.

Because each of the PMFs manufacturing these products is deemed by the FDA to be a separate manufacturing site, each has to be approved by the FDA.

Although PYLARIFY is now broadly available nationwide and we continue to qualify additional PMFs, we can give no assurance that the FDA will continue to approve PMFs in accordance with our planned roll-out schedule.

If FDA approval of manufacturing sites is delayed or withdrawn, our future business, results of operations, financial condition and cash flows could be adversely affected.

In addition to our network of PMFs, we have also been working with academic medical centers in the U.S.

that have radioisotope-producing cyclotrons and which have expressed an interest in manufacturing PYLARIFY.

Under this initiative, we would enter into a fee-for-service arrangement under which the academic medical center’s PMF would manufacture and supply batches of PYLARIFY, and its radiopharmacy would prepare patient-ready unit doses, in each case for and on behalf of us.

We would then sell

those unit doses to the academic medical center’s hospitals and clinics, and in some instances, to additional customers in the academic medical center’s geographic area, in each case, under separate purchase agreements.

The academic medical center’s PMF’s ability to manufacture and supply batches of PYLARIFY will be subject to FDA approval, and we can give no assurance that the FDA will approve such PMFs in accordance with our planned roll-out schedule.

Our commercial launch also required us to obtain adequate coding, coverage and payment for PYLARIFY, including not only coverage from Medicare, Medicaid and other government payors, as well as private payors, but also appropriate payment levels to adequately cover our customers’ costs of using PYLARIFY in PET/CT imaging procedures.

We received notification that our Healthcare Procedure Coding System (“HCPCS”) code, which enables streamlined billing, went into effect as of January 1, 2022.

In addition, effective January 1, 2022, CMS granted Transitional Pass-Through Payment Status in the hospital outpatient setting (“TPT Status”) for PYLARIFY, enabling traditional Medicare to provide an incremental payment to our customers for PET/CT scans performed with PYLARIFY in that setting.

TPT Status for PYLARIFY is expected to expire December 31, 2024.

After TPT Status expires, under current Medicare rules, PYLARIFY, similar to other diagnostic radiopharmaceuticals, would not be separately reimbursed in the hospital outpatient setting but rather would be included as part of the facility fee a hospital otherwise receives for a PET/CT imaging procedure, and the facility fee does not always cover the cost of a drug used in the procedure.

We can give no assurance that any CMS reimbursement in the hospital outpatient setting that follows the expiration of TPT Status will be adequate to cover the cost of PYLARIFY used in a PET/CT imaging procedure.

We actively pursue patents in connection with PYLARIFY, both in the U.S.

and internationally.

for PYLARIFY, we have four Orange Book-listed patents, including composition of matter patents, which expire in 2030 and 2037.

Outside of the U.S., we are currently pursuing additional PYLARIFY patents to obtain similar patent protection as in the U.S.

See Part I, Item 1A.

“Risk Factors” for information regarding certain risks associated with our clinical development programs.

Strategic Partnerships

In connection with our commercial products and product candidates, we now have a number of strategic partnerships, including:

“Risk Factors” for information regarding certain risks associated with PYLARIFY and see Part II, Item 7.

Strategic Partnerships and Other Revenue

We continue to seek ways to further expand our portfolio of products and product candidates and how best to optimize the value of our current assets, evaluating a number of different opportunities to collaborate with others or acquire or in-license additional products, product candidates, businesses and technologies to drive our future growth.

To the extent a strategic partnership relates to an approved product or potential new indication of an approved product, we report our revenue generated by that strategic partnership under the applicable product category.

As we continue to pursue expanding our strategic partnerships, our Pharma Services activities and strategic partnerships in oncology include:

• Prostate Cancer – We collaborate with pharmaceutical companies developing therapies and diagnostics in prostate cancer.

▪ Bayer Agreements – Under Progenics’ April 2016 agreement with a subsidiary of Bayer HealthCare Pharmaceuticals Inc.

(“Bayer”) granting Bayer exclusive worldwide rights to develop and commercialize products using our PSMA antibody platform, in combination with Bayer’s alpha-emitting radionuclides, Progenics received an upfront payment of $4.0 million and milestone payments totaling $5.0 million.

We could receive up to an additional $44.0 million in potential clinical and development milestones under this agreement.

We are also entitled to single-digit royalties on net sales, and potential net sales milestone payments up to an aggregate of $130.0 million.

In addition, in October 2020, we entered into a clinical supply agreement with Bayer to include piflufolastat F 18 in Bayer’s clinical trial for prostate cancer.

Bayer will use piflufolastat F 18 to assess PSMA expression levels at baseline and during treatment.

▪ Curium Agreement – We have licensed exclusive rights to Curium to develop and commercialize piflufolastat F 18 in Europe.

Under the terms of the collaboration, Curium is responsible for the development, regulatory approvals and commercialization of piflufolastat F 18 in Europe, and we are entitled to double-digit royalties on net sales of piflufolastat F 18.

Curium is currently conducting a Phase 3 registration trial in Europe for piflufolastat F 18.

▪ FUJIFILM Agreements – In June 2019, EXINI entered into a transfer agreement with FUJIFILM for the rights to aBSI in Japan for use under the name BONENAVI.

Under the terms of the transfer agreement, FUJIFILM acquired, by a combination of purchase and license, the Japanese software, source code, supporting data and all Japanese patents associated with aBSI from EXINI for use in Japan.

In exchange, EXINI received $4.0 million in an upfront payment and FUJIFILM agreed to pay EXINI support and service fees for aBSI and other AI products over the next three years in Japan.

BONENAVI had been licensed to FUJIFILM for use in Japan since 2011.

In addition, in

February 2021, EXINI entered into a transfer agreement with FUJIFILM for the heart myocardial perfusion analysis software, cREPO, in Japan.

▪ POINT Biopharma Agreement – In December 2020, we entered into a clinical supply agreement with POINT Biopharma US Inc.

(“POINT Biopharma”) under which we will supply piflufolastat F 18 to POINT Biopharma as an imaging agent to evaluate and follow subjects for a Phase 3 clinical study of POINT Biopharma’s PSMA-targeted metastatic castrate-resistant prostate cancer (“mCRPC”) therapeutic candidate.

▪ Prostate Cancer Clinical Trial Consortium Agreement – In January 2022, we announced a collaboration with the Prostate Cancer Clinical Trial Consortium (“PCCTC”), a premier multicenter clinical research organization that specializes in prostate cancer research.

The intent of the strategic collaboration is to integrate our AI platform into PCCTC studies to advance the development and validation of novel AI-enabled biomarkers.

▪ RefleXion Agreement – In September 2021, we entered into a development and commercialization collaboration with RefleXion Medical, Inc.

to evaluate the use of piflufolastat F 18 to enable real-time therapeutic guidance of biology-guided radiotherapy in prostate cancer using the RefleXion X1 TM platform.

Under the terms of the agreement, we will contribute to the cost of RefleXion’s registrational program and will share in any upside created by this collaboration.

▪ Regeneron Agreement – In June 2020, we entered into a clinical supply agreement with Regeneron Pharmaceuticals, Inc.

(“Regeneron”) under which we will supply piflufolastat F 18 to Regeneron as an imaging agent to evaluate and follow subjects for a Phase 1/2 clinical study of Regeneron’s anti-PSMAxCD28-targeted mCRPC therapeutic candidate.

In July 2021, we entered into a second agreement with Regeneron under which we will supply piflufolastat F 18 to Regeneron as an imaging agent to evaluate and follow subjects for a Phase 1/2 clinical study of Regeneron’s anti-PSMAxCD3 Bispecific Antibody in mCRPC patients.

▪ ROTOP Agreement – In May 2019, Progenics entered into an exclusive license agreement with ROTOP Pharmaka GmbH (“ROTOP”), a Germany-based developer of radiopharmaceuticals for nuclear medicine diagnostics, to develop, manufacture and commercialize 1404 in Europe.

Under the terms of the license, ROTOP is responsible for the development, regulatory approvals and commercialization of 1404 in Europe while we are entitled to double-digit, tiered royalties on net sales of 1404 in Europe.

◦ Immuno-Oncology - In May 2019, we commenced an initiative to build out our Pharma Services capabilities, which reside in our strategic partnerships and other revenue product category, by entering into a strategic collaboration and license agreement with NanoMab Technology Limited (“NanoMab”), a privately-held biopharmaceutical company focused on the development of next generation radiopharmaceuticals for cancer precision medicine.

◦ Pan-Oncology - In March 2021, we acquired from Ratio Therapeutics LLC (“Ratio”) (previously Noria Therapeutics, Inc.) exclusive, worldwide rights to NTI-1309, an innovative imaging biomarker that targets fibroblast activation protein, an emerging target with broad potential imaging applicability and use in oncology.

Under the terms of this agreement, Ratio will drive the early clinical development of NTI-1309.

We are integrating NTI-1309 into our portfolio of imaging biomarkers as part of our Pharma Services offering.

Upon further clinical development, we will assess options to bring NTI-1309 to market as a diagnostic or potentially a therapeutic agent.

Microbubble Franchise

In addition, we continue to seek to optimize our microbubble platform through new collaborations.

In April 2021, we announced a strategic collaboration with Allegheny Health Network (“AHN”) which will use our microbubbles in combination with AHN’s ultrasound-assisted non-viral gene transfer technology for the development of a proposed treatment of xerostomia.

Xerostomia is a lack of saliva production leading to dry mouth and has a variety of causes, including radiotherapy and chemotherapy, the chronic use of drugs and rheumatic and dysmetabolic diseases.

Prior to 2021, we entered into microbubble collaborations with the following parties:

(i) Cerevast Medical, Inc.

(“Cerevast”), in which our microbubbles will be used in connection with Cerevast’s ocular ultrasound device to improve blood flow in occluded retinal veins in the eye;

(ii) CarThera SAS (“CarThera”), for the use of our microbubbles in combination with SonoCloud, a proprietary implantable device in development for the treatment of recurrent glioblastoma;

and (iii) Insightec Ltd.

(“Insightec”), which will use our microbubbles in connection with the development of Insightec’s transcranial guided focused ultrasound device for the treatment of glioblastoma as well as other neurodegenerative conditions.

In March 2012, we entered into a development and distribution arrangement with China Resources Double-Crane (“Double-Crane”) for DEFINITY in China, Hong Kong and Macau.

Double-Crane has conducted on our behalf three confirmatory clinical trials in pursuit of cardiac, liver and kidney imaging indications, as well as one small pharmacokinetic study.

In March 2020, we filed an Import Drug License application with the National Medical Products Administration (“NMPA”) for the use of DEFINITY for the echocardiography indication.

Double-Crane is also in the process of analyzing the clinical results relating to liver and kidney indications and will also work with us to prepare an Import Drug License application for those indications, as appropriate.

• Bausch Agreement -- Under its agreement with Salix Pharmaceuticals, Inc., a wholly-owned subsidiary of Bausch, Progenics received a $40.0 million development milestone upon U.S.

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15% on worldwide net sales up to $100.0 million, 17% on the next $400.0 million in worldwide net sales, and 19% on worldwide net sales over $500.0 million each calendar year, and 60% of any upfront, milestone, reimbursement or other revenue (net of costs of goods sold, as defined, and territory-specific research and development expense reimbursement) Bausch receives from sublicensees outside the U.S.

• GE Healthcare Agreement – Under our April 2017 Collaboration and License Agreement, GE Healthcare will complete the worldwide development of flurpiridaz F 18, pursue worldwide regulatory approvals, and, if successful, lead a worldwide launch and commercialization of the agent, with us collaborating on both development and commercialization through a joint steering committee.

We also have the right to co-promote the agent in the U.S.

• aBSI calculates the disease burden of prostate cancer by quantifying the hotspots on bone scans and automatically calculating the bone scan index value, representing the disease burden of prostate cancer shown on the bone scan.

The Japanese rights to the stand-alone aBSI have been transferred and sold to FUJIFILM Toyama Chemical Co.

(“FUJIFILM”) under the name BONENAVI ® .

The cloud based aBSI was made available for clinical use in the U.S.

on August 5, 2019.

In February 2020, Progenics received CE marking for the standalone workstation model of aBSI, meeting the quality standards set by the European Economic Area.

In September 2020, the FDA granted 510(k) clearance for the use of aBSI as software-as-a-medical device on a GE Healthcare imaging system.

PYLARIFY AI has demonstrated improved consistency, accuracy and efficiency in quantitative assessment of PSMA PET/CT.

The technology automatically analyzes the PET/CT image to segment anatomical regions – 51 bones and 12 soft tissue organs.

This image segmentation enables automated localization, detection and quantification of potential PSMA-avid lesions in the PET/CT image, which is incorporated into a standardized report for physicians.

PYLARIFY AI can be deployed either as a secure web cloud application or within the secure firewall of the institution on a local server.

Once deployed, the adaptive application can be integrated into an institution’s existing clinical workflow, delivering a unique combination of clinical utility and technical flexibility.

We believe that PYLARIFY AI when used with PYLARIFY will provide us an important competitive advantage in what we expect will be a highly competitive PET PSMA diagnostic imaging agent market, although we can give no assurances to that effect.

Our subsidiary, EXINI, was granted 510(k) clearance by the FDA in the U.S.

and received a CE marking in Europe for aPROMISE.

We commercially launched aPROMISE under the name PYLARIFY AI in the U.S.

in November 2021.

FLURPIRIDAZ F 18

• GE Healthcare Agreement – In April 2017, we announced entering into a definitive, exclusive Collaboration and License Agreement with GE Healthcare for the continued Phase 3 development and worldwide commercialization of flurpiridaz F 18, a fluorine 18-based PET MPI agent designed to assess blood flow to the heart in patients suspected of coronary artery disease.

Under our agreement, GE Healthcare will complete the development of flurpiridaz F 18, pursue worldwide regulatory approvals, and, if successful, lead a worldwide launch and commercialization of the agent, with us collaborating on both development and commercialization through a joint steering committee.

We also have the right to co-promote the

agent in the U.S.

GE Healthcare’s development plan initially focuses on obtaining regulatory approval in the U.S., Japan, Europe and Canada.

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sales, and mid-single digit royalties on sales outside of the U.S.

• Curium Agreement – Curium has licensed exclusive rights to develop and commercialize PyL in Europe.

Under the terms of the collaboration, Curium is responsible for the development, regulatory approvals and commercialization of PyL in Europe, and we are entitled to double-digit royalties on net sales of PyL.

Curium is currently in late-stage development in Europe.

• Bayer Agreements – Under Progenics’ April 2016 agreement with a subsidiary of Bayer granting Bayer exclusive worldwide rights to develop and commercialize products using our PSMA antibody platform, in combination with Bayer’s alpha-emitting radionuclides, Progenics received an upfront payment of $4.0 million and milestone payments totaling $5.0 million.

We could receive up to an additional $44.0 million in potential clinical and development milestones.

We are also entitled to single-digit royalties on net sales, and potential net sales milestone payments up to an aggregate of $130.0 million.

In addition, in October 2020, we entered into a PyL Clinical Supply Agreement with Bayer to include PyL in their clinical trial for prostate cancer.

PyL will be used by Bayer to assess PSMA expression levels at baseline and during treatment.

• CytoDyn Agreement -- Progenics sold leronlimab to CytoDyn in 2012, which sale included milestone and royalty payment obligations to Progenics.

GE Healthcare is conducting a second Phase 3 trial and expects to complete enrollment in 2022 and, assuming completion of the Phase 3 trial and regulatory approval, begin commercialization in 2024, although completion, approval and that timing cannot be assured.

• CytoDyn Agreement – Progenics entered into an agreement with CytoDyn Inc.

(“CytoDyn”) in 2012 to sell Progenics’ rights in leronlimab (PRO 140), an investigational humanized monoclonal antibody targeting the CCR5 receptor.

CCR5 appears to act as a human immunodeficiency virus (“HIV”) entry inhibitor and may play a broader role in tumor metastasis and immune-mediated illnesses.

The sale included milestone and royalty payment obligations to Progenics.

Under the agreement, CytoDyn is responsible for all development, manufacturing and commercialization efforts.

Pursuant to such agreement, Progenics received $5.0 million in upfront and milestone payments, and we have the right to receive an additional $5.0 million upon the first U.S.

Pursuant to such agreement, Progenics received $5.0 million in upfront and milestone payments, and has the right to receive an additional $5.0 million upon the first U.S.

approval for the sale of the drug, and a 5% royalty on the net sales of approved products.

• ROTOP Agreement -- In May 2019, Progenics entered into an exclusive license agreement with ROTOP, a Germany-based developer of radiopharmaceuticals for nuclear medicine diagnostics, to develop, manufacture and commercialize 1404 in Europe.

Under the terms of the collaboration, ROTOP is responsible for the development, regulatory approvals and

commercialization of 1404 in Europe while we are entitled to double-digit, tiered royalties on net sales of 1404 in Europe.

ROTOP is in discussions with EMA regarding the development path in Europe.

• FUJIFILM Agreement -- In June 2019, EXINI entered into a transfer agreement with FUJIFILM for the rights to the bone scan index product in Japan for use under the name BONENAVI.

In exchange, EXINI received $4.0 million in an upfront payment and FUJIFILM agreed to pay EXINI support and service fees for bone scan index and other AI products over the next three years in Japan.

BONENAVI has been licensed to FUJIFILM for use in Japan since 2011.

In February 2021, EXINI entered into a new agreement with FUJIFILM for the heart myocardial perfusion analysis software, cREPO, in Japan.

• Regeneron Agreement – In June 2020, we entered into a PyL Clinical Supply Agreement with Regeneron Pharmaceuticals, Inc.

(“Regeneron”) under which we will supply PyL to Regeneron as an imaging agent to evaluate and follow subjects for a Phase 1/2 clinical study of Regeneron’s PSMA-targeted mCRPC therapeutic candidate.

• POINT Biopharma – In December 2020, we entered into a PyL Clinical Supply Agreement with POINT Biopharma US Inc.

(“POINT Biopharma”) under which we will supply PyL to POINT Biopharma as an imaging agent to evaluate and follow subjects for a Phase 3 clinical study of POINT Biopharma’s PSMA-targeted mCRPC therapeutic candidate.

See Part I, Item 1A.

“Risk Factors” for information regarding certain risks associated with our strategic activities.

Our Clinical Development Candidates

In addition to our commercial products and strategic partnerships with third parties, we also have ongoing clinical development programs that we are currently funding and managing ourselves:

Progenics initiated eleven clinical sites in the U.S.

along with the six active sites in Canada to support enrollment in our multicenter, randomized, controlled, ARROW Phase 2 study in mCRPC.

During 2020, the study was paused to minimize risk to subjects and healthcare providers during the COVID-19 pandemic, and new enrollment in that study restarted in October 2020.

In the fourth quarter of 2021, we completed an interim analysis of the ARROW Phase 2 study.

The Independent Data Monitoring Committee recommended the study continue without modifications.

We currently expect to complete enrollment in the ARROW Phase 2 study later in 2022.

• LMI 1195 is a fluorine 18-based PET imaging agent for the norepinephrine pathway.

We have commenced a Phase 3 clinical trial for the use of LMI 1195 for the diagnosis and management of neuroblastoma tumors in pediatric and adult populations.

We expect to initiate approximately 20 clinical sites in the U.S.

to enroll approximately 100 patients with known or suspected neuroblastoma.

The FDA has granted an Orphan Drug designation for the use of LMI 1195 in the management indication.

For the years ended December 31, 2021, 2020 and 2019, we invested $45.0 million, $32.8 million and $20.0 million in research and development (“R&D”), respectively, primarily related to our clinical development candidates.

In addition to our clinical development group, our R&D team also includes our Medical Affairs and Medical Information functions, which educate physicians on the scientific aspects of our commercial products and the approved indications.

See Part I, Item 1A.

“Risk Factors” for information regarding certain risks associated with our strategic partnerships and clinical development programs.

Distribution, Marketing and Sales

The following table sets forth certain key market information for each of our commercial pharmaceutical products:

The following table sets forth certain key market information for each of our commercial pharmaceutical products within each product category:

Product Approved Markets

DEFINITY Australia, Canada, European Union, European Economic Area, India, Israel, Mexico, New Zealand, Singapore, South Korea, Taiwan, United States

Precision Diagnostics

DEFINITY (or LUMINITY) Australia, Canada, European Union, European Economic Area, India, Israel, Mexico, New Zealand, Singapore, South Korea, Taiwan, United States

TechneLite Australia, Brazil, Canada, Colombia, Costa Rica, New Zealand, Panama, South Korea, Taiwan, United States

NEUROLITE Australia, Austria, Belgium, Canada, Costa Rica, Denmark, France, Germany, Hong Kong, Italy, Japan, Luxembourg, New Zealand, Philippines, Slovenia, South Korea, Spain, Taiwan, Thailand, United States

RELISTOR (Solution for Injection 12 mg/0.6 mL vial) Austria, Belgium, Bulgaria, Canada, Switzerland, Cypress, Czechia, Germany, Denmark, Estonia, Greece, Spain, Finland, France, Croatia, Hungary, Ireland, Iceland, Italy, Liechtenstein, Lithuania, Luxembourg, Latvia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Sweden, Slovenia, Slovakia, United Kingdom, United States

RELISTOR (Solution for Injection in pre-filled syringe 8mg and pre-filled syringe 12 mg) Austria, Belgium, Bulgaria, Canada, Cypress, Czechia, Germany, Denmark, Estonia, Greece, Spain, Finland, France, Croatia, Hungary, Ireland, Iceland, Italy, Liechtenstein, Lithuania, Luxembourg, Latvia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Sweden, Slovenia, Slovakia, United Kingdom, United States

RELISTOR (methylnaltrexone bromide) Oral Tablet 140 mg United States

Xenon Canada, United States

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Thallium Australia, Canada, Colombia, New Zealand, Pakistan, Panama, South Korea, Taiwan, United States

Radiopharmaceutical Oncology

PYLARIFY United States

AZEDRA United States

QUADRAMET United States

and Canada, our sales team of approximately 80 employees is split into separate sales teams for each of DEFINITY, AZEDRA and our radiopharmaceutical products.

We are also beginning to assemble a sales and commercial team for PyL in anticipation of potential FDA approval and a commercial launch later in 2021.

We sell a majority of our radiopharmaceutical products in the U.S.

to five radiopharmacy groups—namely Cardinal, RLS, UPPI, Jubilant Radiopharma and PharmaLogic.

Our contractual distribution and other arrangements with these radiopharmacy groups are as follows:

• Cardinal maintains approximately 131 radiopharmacies that are typically located in large, densely populated urban areas in the U.S.

We estimate that Cardinal’s radiopharmacies distributed approximately 44% of the aggregate U.S.

SPECT doses sold in the first half of 2020.

Our supply agreement with Cardinal relating to TechneLite, Xenon, NEUROLITE and other products has been extended until December 31, 2022.

The agreement specifies pricing levels and requirements to purchase minimum percentages of certain products during certain periods.

The agreement may be terminated upon the occurrence of specified events, including a material breach by the other party and certain force majeure events.

• RLS maintains approximately 31 radiopharmacies in the U.S.

that purchase our TechneLite generators.

RLS purchased these radiopharmacies from GE Healthcare in the third quarter of 2020.

We estimate that RLS distributed approximately 8% of the aggregate U.S.

SPECT doses sold in the first half of 2020.

We currently have an agreement with RLS for the distribution of TechneLite, Xenon and Gallium.

The agreement provides that RLS will purchase a minimum percentage of TechneLite generators as well as certain other products from us.

Our agreement, which has been extended until December 31, 2021, may be terminated by either party upon the occurrence of specified events including a material breach by either party, bankruptcy by either party, certain irresolvable regulatory changes or economic circumstances, or force majeure events.

• UPPI is a cooperative purchasing group (roughly analogous to a group purchasing organization) of approximately 52 independently owned or smaller chain radiopharmacies located in the U.S.

UPPI’s radiopharmacies are typically broadly dispersed geographically, with some urban presence and a substantial number of radiopharmacies located in suburban and rural areas of the country.

We estimate that these independent radiopharmacies, together with approximately 13 unaffiliated, independent radiopharmacies, distributed approximately 19% of the aggregate U.S.

SPECT doses sold in the first half of 2020.

We currently have an agreement with UPPI for the distribution of TechneLite, Xenon and certain other products to radiopharmacies or families of radiopharmacies within the UPPI cooperative purchasing group.

The agreement contains specified pricing levels based upon specified purchase amounts for UPPI.

We are entitled to terminate the UPPI agreement upon 60 days written notice.

The UPPI agreement has been extended until December 31, 2023.

• Jubilant Radiopharma maintains approximately 48 radiopharmacies in the U.S.

that purchase a range of our products.

We estimate that Jubilant Radiopharma distributed approximately 13% of the aggregate U.S.

SPECT doses sold in the first half of 2020.

We currently have an agreement with Jubilant Radiopharma for the distribution of TechneLite, Xenon, NEUROLITE and other products.

The agreement specifies pricing levels and volume and percentage purchase requirements.

The agreement has been extended until June 30, 2021 and may be terminated upon the occurrence of specified events, including a material breach by the other party.

• PharmaLogic maintains approximately 27 radiopharmacies in the U.S.

that purchase a range of our products.

We estimate that PharmaLogic distributed approximately 4% of the aggregate U.S.

SPECT doses sold in the first half of 2020.

Our written supply agreement with PharmaLogic relating to TechneLite, Xenon, Cardiolite and other products has been extended until December 31, 2021.

The agreement specifies pricing levels and requirements to purchase minimum percentages of certain products during certain periods.

The agreement may be terminated upon the occurrence of specified events, including a material breach by the other party and certain force majeure events.

In addition to the distribution arrangements for our radiopharmaceutical products described above, we also sell certain of our radiopharmaceutical products to independent radiopharmacies and directly to hospitals and clinics that maintain in-house radiopharmaceutical capabilities and operations.

In the latter case, this represents a small percentage of overall sales because the majority of hospitals and clinics do not maintain these in-house capabilities.

In Canada, we operate some direct distribution activities and also rely on third party distributors.

In Europe, Australia, Asia-Pacific and Latin America, we utilize third party distributor relationships to market, sell and distribute our products, either on a country-by-country basis or on a multi-country regional basis.

In March 2012, we entered into a development and distribution arrangement with Double-Crane for DEFINITY in China, Hong Kong and Macau.

With Double-Crane’s support, we are currently pursuing Chinese regulatory approval required to commercialize DEFINITY.

In July 2013, we submitted a clinical trial application to the NMPA seeking an Import Drug License.

After a very extensive waiting period caused by a large number of drugs seeking NMPA regulatory approval, in February 2016, the NMPA approved our clinical trial application.

Double-Crane has conducted on our behalf three confirmatory clinical trials in pursuit of cardiac, liver and kidney imaging indications, as well as one small pharmacokinetic study.

In March 2020, we filed an Import Drug License application with the NMPA for the use of DEFINITY for the echocardiography indication.

We believe this is an important milestone in our efforts to commercialize DEFINITY in China.

For the diagnostic portion of our business, we have some modest seasonality as patients may seek to schedule diagnostic imaging procedures less frequently during the summer vacation months and over the year-end holidays.

Strategic Partnerships and Other Revenue

RELISTOR (methylnaltrexone bromide) Oral Tablet 140 mg United States

With respect to our other products:

• Progenics received CE marking for the standalone workstation model of aBSI, meeting the quality standards set by the European Economic Area.

In September 2020, the FDA granted 510(k) clearance for the use of aBSI as software-as-a-medical device on a GE Healthcare imaging system.

• EXINI was granted 510(k) clearance by the FDA in the U.S.

and received CE marking in Europe for aPROMISE.

We launched aPROMISE under the name PYLARIFY AI in the U.S.

Sales of our microbubble ultrasound enhancing agent, DEFINITY, are generated in the U.S.

through a DEFINITY direct sales team.

While a small portion of our nuclear imaging product sales in the U.S.

are generated through our direct sales force to hospitals and clinics that maintain their own in-house radiopharmaceutical preparation capabilities, we primarily sell our nuclear imaging products, including TechneLite, NEUROLITE, Xenon, and Cardiolite, to commercial radiopharmacies as described below.

PYLARIFY sales are generated in the U.S.

through a PYLARIFY direct sales team and a sales team at some of our PMF partners.

PYLARIFY AI sales leads are generated in the U.S.

through a direct sales team with sales generated through distributors and other strategic partners.

AZEDRA sales are generated in the U.S.

through an AZEDRA direct sales team.

We have licensed RELISTOR to Bausch, and we collect quarterly royalties based on sales generated by Bausch.

As noted above, in the U.S., we have supply contracts with large radiopharmacy groups, and we sell a majority of our radiopharmaceutical products in our precision diagnostics category to five of these groups—namely Cardinal, Jubilant Radiopharma, formerly known as Triad Isotopes, Inc.

(“Jubilant Radiopharma”), PharmaLogic, RLS and UPPI.

Our contractual arrangements with these radiopharmacy customers generally specify pricing levels and requirements to purchase minimum percentages of certain products during certain periods.

The agreements are generally multi-year arrangements that may be terminated upon the occurrence of specified events, including a material breach by the other party and certain force majeure events.

We have some modest seasonality for our products as patients may seek to schedule diagnostic imaging and other procedures less frequently during the summer vacation months and over the year-end holidays.

No customer accounted for greater than 10% of revenues for the year ended December 31, 2021.

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• For DEFINITY, our competitors currently include GE Healthcare and Bracco.

• For a number of our radiopharmaceutical commercial products, our competitors currently include Curium, GE Healthcare, Bracco and Jubilant Life Sciences, an affiliate of JHS and Jubilant Radiopharma, as well as other competitors, including NorthStar Medical Radioisotopes.

• For PyL, if and when it is approved by the FDA, it will compete with Bracco’s Axumin (fluciclovine F 18).

We also may face competition from Telix Pharmaceuticals Limited, which also has a PSMA-targeted prostate cancer PET diagnostic imaging agent currently under review with the FDA.

• For RELISTOR, our principal competitors include Nektar Therapeutics, in collaboration with AstraZeneca PLC;

• For a number of our SPECT radiopharmaceutical commercial products, our competitors currently include Curium, GE Healthcare, Bracco and Jubilant Life Sciences, an affiliate of JHS and Jubilant Radiopharma, as well as other competitors, including NorthStar and potentially BWXT Medical.

• For PYLARIFY, our competitors currently include Telix Pharmaceuticals Limited’s Illuccix (gallium-68 PSMA-11 injection), a PSMA PET imaging agent approved by the FDA for commercialization in December 2021, and Bracco’s Axumin (fluciclovine F 18), a PET imaging agent.

In addition, the University of California, San Francisco and the University of California, Los Angeles have approved NDAs for a gallium-68 PSMA-11 injection for PSMA PET imaging, which we believe will primarily be used within their hospital systems.

We also face potential competition from Novartis AG, which has a gallium-68 PSMA-11 kit for PET imaging currently under review with the FDA, and Bracco, which has an F 18 PSMA PET imaging agent in late stage clinical development;

we believe that one or both of the Novartis and Bracco PSMA agents could be approved by the FDA for commercialization later in 2022 or in 2023.

• For RELISTOR, our principal competitors include RedHill Biopharma Inc.;

Cubist Pharmaceuticals, a subsidiary of Merck & Co., Inc.;

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for malignant, recurrent, and/or unresectable pheochromocytoma and paraganglioma.

The markets into which any of our product candidates would be launched, if approved, are also highly competitive and continually evolving.

• For 1095, our principal competitors in the field of mCRPC for radiopharmaceutical therapeutics may include Novartis AG;

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and Bayer HealthCare Pharmaceuticals Inc., each of which have product candidates in development.

We cannot anticipate the actions of our current or future competitors in the same or competing diagnostic modalities, such as significant price reductions on products that are comparable to our own, development of new products that are more cost-effective or have superior performance than our current products or the introduction of generic versions after our proprietary products lose their patent protection.

In addition, distributors of our products could attempt to shift end-users to competing diagnostic modalities and

products, or bundle the sale of a portfolio of products, to the detriment of our specific products.

• For LMI 1195, our principal competitors may include GE Healthcare’s iobenguane 123 injection.

• For flurpiridaz, our principal competitors may include rubidium generators from Bracco and Jubilant Radiopharma.

We cannot anticipate the actions of our current or future competitors in the same or competing diagnostic modalities, such as significant price reductions on products that are comparable to our own, development of new products or other technologies that are more cost-effective or have superior performance than our current products or the introduction of generic versions after our proprietary products lose their patent protection.

In addition, distributors of our products could attempt to shift end-users to competing diagnostic

modalities and products, or bundle the sale of a portfolio of products, to the detriment of our specific products.

Our current or future products could be rendered obsolete or uneconomical as a result of these activities.

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Due to the specialized nature of our products and the limited, and sometimes intermittent, supply of raw materials available in the market, we have established relationships with several key suppliers.

For the year ended December 31, 2020, our largest suppliers of raw materials and supplies were Institute for Radioelements (“IRE”), ANSTO and NTP, which, in the aggregate, accounted for approximately 23% of our total purchases.

For the year ended December 31, 2021, our largest suppliers of raw materials and supplies were Institute for Radioelements (“IRE”), the Australian Nuclear Science and Technology Organisation (“ANSTO”) and NTP Radioisotopes (“NTP”), which, in the aggregate, accounted for approximately 21% of our total purchases.

Molybdenum-99

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With a 66-hour half-life, Mo-99 decays into, among other things, Tc-99m, another radioisotope with a half-life of six hours.

Tc-99m is the isotope that is attached to radiopharmaceuticals, including our own Cardiolite and NEUROLITE, during the labeling process and is the most common radioisotope used for medical diagnostic imaging purposes.

Tc-99m is the isotope that is attached to radiopharmaceuticals, including our own NEUROLITE and Cardiolite, during the labeling process and is the most common radioisotope used for medical diagnostic imaging purposes.

We currently purchase finished Mo-99 from three of the four main processing sites in the world, namely IRE in Belgium, NTP in South Africa and ANSTO in Australia.

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The IRE Agreement allows for termination upon the occurrence of certain events, including failure by IRE to provide our required amount of Mo-99, material breach of any provision by either party, bankruptcy by either party or force majeure events.

The IRE Agreement expires on December 31, 2022, and is renewable by LMI on a year-to-year basis thereafter.

Our agreement with NTP (the “NTP Agreement”), with NTP acting for itself and on behalf of its subcontractor ANSTO, specifies LMI’s percentage purchase requirements and unit pricing, and provides for the supply of Mo-99 derived from LEU targets from NTP and ANSTO.

The IRE Agreement expires on December 31, 2023, and automatically renews on an annual basis thereafter, subject to prior notice of non-renewal by either party.

Our agreement with NTP (the “NTP Agreement”), with NTP acting for itself and on behalf of its subcontractor ANSTO, specifies our percentage purchase requirements and unit pricing, and provides for the supply of Mo-99 derived from LEU targets from NTP and ANSTO.

The NTP Agreement allows for termination upon the occurrence of certain events, including failure by NTP to provide our required amount of Mo-99, material breach of any provision by either party, bankruptcy by either party or force majeure events.

The NTP Agreement expires on December 31, 2021.

Despite our globally diverse Mo-99 suppliers, we still face challenges in our Mo-99 supply chain.

The NTP Agreement expires on March 31, 2022, and we are actively negotiating an extension.

Despite our globally diverse Mo-99 suppliers, we still face supplier and logistical challenges in our Mo-99 supply chain.

The NTP processing facility had periodic outages in 2017, 2018 and 2019.

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Because of the COVID-19 pandemic, we experienced challenges receiving regularly scheduled orders of Mo-99 from our global suppliers, particularly in the second quarter of 2020.

We continue to manage these various supply chain challenges, but depending on reactor and processor schedules and operations, at times we have not been able to fill some or all of the demand for our TechneLite generators on certain manufacturing days.

We continue to manage these various supply chain challenges.

Depending on reactor and processor schedules and operations, at times we have not been able to fill some or all of the demand for our TechneLite generators on certain manufacturing days.

A prolonged disruption of service from one of our three Mo-99 processing sites or one of their main Mo-99-producing reactors could have a substantial negative effect on our business, results of operations, financial condition and cash flows.

We are also pursuing additional sources of Mo-99 from potential new producers to further augment our current supply.

In November 2014, we entered into a strategic arrangement with SHINE for the future supply of Mo-99.

Under the terms of the supply agreement, SHINE will provide Mo-99 produced using its proprietary LEU-solution technology for use in our TechneLite generators once SHINE’s facility becomes operational and receives all necessary regulatory approvals, which SHINE now estimates will occur in 2022.

However, we cannot assure you that SHINE or any other possible additional sources of Mo-99 will result in commercial quantities of Mo-99 for our business, or that these new suppliers together with our current suppliers will be able to deliver a sufficient quantity of Mo-99 to meet our needs.

To augment our current supply of Mo-99, we entered into a strategic arrangement with SHINE Medical Technologies LLC (“SHINE”) for the future supply of Mo-99.

Under the terms of the supply agreement, entered into in November 2014, SHINE will provide Mo-99 produced using its proprietary LEU-solution technology for use in our TechneLite generators once SHINE’s facility becomes operational and receives all necessary regulatory approvals, which SHINE now estimates will occur in 2023.

The term of this arrangement provides for three years of supply of Mo-99.

However, we cannot assure you that our arrangement with SHINE will

result in commercial quantities of Mo-99 for our business, or that SHINE together with our current suppliers will be able to deliver a sufficient quantity of Mo-99 to meet our needs.

Xenon is a by-product of the Mo-99 production process.

Under a strategic agreement we entered into in 2015, we receive from IRE bulk unprocessed Xenon, which we process and finish for our customers at our North Billerica, Massachusetts manufacturing facility.

That contract runs through June 30, 2022, and is subject to further extension.

Under a strategic agreement entered into in 2021, we receive from IRE bulk unprocessed Xenon, which we process and finish for our customers at our North Billerica, Massachusetts manufacturing facility.

That contract runs through December 31, 2023, with auto-renewal provisions and terminable upon notice of non-renewal.

Until we can qualify an additional source of bulk unprocessed Xenon, we will rely on IRE as a sole source provider.

Iodine 131 is also a by-product of the Mo-99 production process, and it is the active radioisotope ingredient in both AZEDRA and 1095.

We receive Iodine 131 from IsoSolutions Marketing & Management Inc., which sources the isotope from IRE in Belgium.

We receive Iodine 131 from IRE in Belgium and we are in the process of securing a secondary source.

We use Iodine 131 at our Somerset facility to manufacture and produce AZEDRA.

We also rely on Center for Probe Development and Commercialization (CPDC) for our clinical supply requirements for 1095.

We also rely on Center for Probe Development and Commercialization (“CPDC”) in Canada for our clinical supply requirements for 1095.

CPDC sources Iodine 131 from IRE in Belgium and NTP in South Africa.

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We maintain manufacturing operations at our North Billerica, Massachusetts facility.

We manufacture TechneLite on a highly automated production line, Thallium and Gallium and certain radiochemicals using our cyclotron technology, and we process and finish Xenon and QUADRAMET using our hot cell infrastructure.

We also operate a manufacturing facility at Somerset, NJ for AZEDRA that may also provide manufacturing support for 1095 in the future.

We manufacture TechneLite on a highly automated production line, Thallium and Gallium and certain radiochemicals using our cyclotron technology, and we process and finish Xenon on a hot cell line.

We also operate a manufacturing facility at Somerset, NJ, using a hot cell line for AZEDRA.

During 2021, we increased the manufacturing staff at our Somerset facility to help maintain an adequate supply of AZEDRA.

We also began constructing an additional manufacturing suite at Somerset which, if approved by the FDA, could provide redundancy for AZEDRA manufacturing as well as increased overall future capacity for 1095, if approved by the FDA or other iodine-based products.

We have constructed a specialized in-house manufacturing facility at our North Billerica campus for purposes of producing DEFINITY and, potentially, other sterile vial products.

On February 22, 2022, we received FDA approval of our sNDA, authorizing commercial manufacturing of DEFINITY at our new facility.

DEFINITY manufactured at this facility became commercially available on February 23, 2022.

We manufacture, finish and distribute our radiopharmaceutical products on a just-in-time basis, and supply our customers with these products either by next day delivery services or by either ground or air custom logistics.

We believe that our substantial capital investments in our highly automated generator production line, our cyclotrons and our other manufacturing assets, and our extensive experience in complying with the stringent regulatory requirements for the handling of nuclear materials and operations in a highly regulated environment, create significant and sustainable competitive advantages for us.

We believe that our substantial capital investments in our highly automated generator production line, our cyclotrons and our other manufacturing assets, which we have made over the years, and our extensive experience in complying with the stringent regulatory requirements for the handling of nuclear materials and operations in a highly regulated environment, create significant and sustainable competitive advantages for us.

In addition to our in-house manufacturing capabilities, a substantial portion of our products are manufactured by third party contract manufacturing organizations, and in certain instances, we rely on them for sole source manufacturing.

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After the final products are manufactured, they are sent back to us for final quality control testing, and then we ship them to our customers.

We have expertise in the design, development and validation of complex manufacturing systems and processes, and our strong execution and quality control culture supports the just-in-time manufacturing model at our North Billerica, Massachusetts facility.

PyL and flurpiridaz F 18 will require the creation of a field-based network of specialized PMFs with radioisotope-producing cyclotrons.

The radioisotope used in both PyL and flurpiridaz F 18 is fluorine-18, or F 18, which has a 110 minute half-life, requiring that these products be manufactured and distributed rapidly to end-users.

After being made on a cyclotron at a PMF, the F 18 is then combined with certain chemical ingredients in specially designed chemistry synthesis boxes to manufacture either PyL or flurpiridaz F 18.

PyL or flurpiridaz F 18 is next transferred to a radiopharmacist who prepares and dispenses patient-specific doses from the final product.

Because each of the PMFs manufacturing these products will be deemed by the FDA to be a separate manufacturing site, each will have to be approved by the FDA, and we can give no assurance that the FDA will do this in accordance with the planned roll-out schedule for the products.

In our PyL NDA, we included a limited number of PMFs for approval, and we intend to add in a sequenced manner, using FDA site approval processes, additional PMFs to our manufacturing network in the months following FDA product approval with the goal of having broad availability for the U.S.

population within six months of product approval.

We are also in the final stages of an extensive, multi-year effort to add specialized manufacturing capabilities at our North Billerica, Massachusetts facility.

This project should not only deliver efficiencies and supply chain redundancy for our current portfolio but should also afford us increased flexibility as we consider additional external opportunities.

We currently expect to make use of this in-house manufacturing capability in late 2021.

However, we can give no assurance that we will be successful in these efforts or that we will be able to successfully manufacture any additional commercial products at our North Billerica, Massachusetts facility.

The commercial manufacture of PYLARIFY required us to create a field-based network of specialized PMFs with radioisotope-producing cyclotrons.

The radioisotope used in PYLARIFY is F 18, which has a 110 minute half-life, requiring that this agent be manufactured and distributed rapidly to end-users.

After being made on a cyclotron at a PMF, the F 18 is then combined with certain chemical ingredients in specially designed chemistry synthesis boxes to manufacture PYLARIFY.

The finished PYLARIFY is then quality control tested and transferred to a radiopharmacist who prepares and dispenses patient-specific doses from the final product.

Because each of the PMFs manufacturing PYLARIFY is deemed by the FDA to be a separate manufacturing site, each requires separate FDA approval, and we can give no assurance that the FDA will continue to approve PMFs in accordance with our planned roll-out schedule for PYLARIFY, particularly given ongoing challenges of the COVID-19 pandemic.

Flurpiridaz F 18, if approved by the FDA, will have a manufacturing and PMF approval process similar to PYLARIFY.

Manufacturing and Supply Arrangements

We currently have the following technology transfer and manufacturing and supply agreements in place for some of our major products:

• DEFINITY —In February 2012, we entered into a Manufacturing and Supply Agreement with JHS, for the manufacture of DEFINITY.

Under the agreement, JHS manufactured DEFINITY for us for an initial term of five years.

In September 2016, we extended the agreement through January 2022.

The agreement contains automatic renewals for additional one-year periods thereafter.

• DEFINITY, Cardiolite and NEUROLITE —In February 2022, we entered into a new Manufacturing and Supply Agreement with JHS, for the manufacture of DEFINITY, Cardiolite, NEUROLITE and evacuation vials.

The new agreement, which superseded all of our prior agreements with JHS for those products, expires on December 31, 2027 and can be renewed upon mutual consent.

The agreement allows for termination upon the occurrence of certain events such as a material breach or default by either party, or bankruptcy by either party.

The agreement also requires us to place orders for a minimum percentage of our requirements for DEFINITY with JHS.

Based on our current projections, we believe that we will have sufficient supply of DEFINITY from JHS to meet expected demand.

On May 3, 2016, we entered into a Manufacturing and Supply Agreement with SBL to perform technology transfer and process development services to manufacture and supply DEFINITY RT.

There are no minimum purchase requirements under this agreement, which has an initial term of five years from the date of first commercial sale and is renewable at our option for an additional five years.

This agreement allows for termination upon the occurrence of certain events, including material breach or bankruptcy of either party.

We believe DEFINITY RT will become commercially available later in 2021, although that timing cannot be assured.

• Cardiolite —In May 2012, we entered into a Manufacturing and Supply Agreement with JHS for the manufacture of Cardiolite products.

In the third quarter of 2016, we completed the technology transfer process and received FDA approval to manufacture Cardiolite at JHS.

Under the agreement, JHS has agreed to manufacture products for an initial term of five years from the effective date.

That agreement has now been extended until December 31, 2021, and can be further extended for two additional one-year periods thereafter so long as the parties, using good faith, reasonable efforts, agree to new pricing for the upcoming additional term.

The agreement allows for termination upon the occurrence of specified events, including material breach or bankruptcy by either party.

The agreement requires us to place orders for 100% of our requirements for Cardiolite products with JHS during such term.

Based on our current projections, we believe that we will have sufficient supply of Cardiolite products from JHS to meet expected demand.

• NEUROLITE —In May 2012, we entered into a Manufacturing and Supply Agreement with JHS for the manufacture of NEUROLITE, and in January 2015, the FDA granted approval to manufacture NEUROLITE at JHS.

Under the agreement, JHS agreed to manufacture NEUROLITE for an initial term of five years from the effective date.

The agreement allows for termination upon the occurrence of specified events, including material breach or bankruptcy by either party.

The agreement also requires us to place orders for 100% of our requirements for NEUROLITE during such term.

Based on our current projections, we believe that we will have sufficient supply of NEUROLITE from JHS to meet expected demand.

See Part I, Item 1A.

“Risk Factors” for information regarding certain risks associated with our manufacturing relationships.

Strategic Activities

In addition to integrating the new assets and programs resulting from the Progenics Acquisition, we continue to seek ways to further expand our portfolio of products and product candidates and how best to optimize the value of our current assets, evaluating a number of different opportunities to collaborate with others or to acquire or in-license additional products, product candidates, businesses and technologies to drive our future growth.

As the Progenics Acquisition indicates, we are particularly interested in expanding our presence in oncology, in both radiotherapeutics and diagnostics.

In May 2019, we commenced an initiative to build out our Pharma Services capabilities by entering into a strategic collaboration and license agreement with NanoMab Technology Limited (“NanoMab”), a privately-held biopharmaceutical company focusing on the development of next generation radiopharmaceuticals for cancer precision medicine.

We believe this collaboration will provide the first broadly-available PD-L1 imaging biomarker research tool to pharmaceutical companies and academic centers conducting clinical trials on immuno-oncology treatments, including combination therapies.

We have also expanded our Pharma Services offering to include PyL for pharmaceutical companies developing PSMA-targeted therapies and have entered into PyL clinical supply agreements with each of Regeneron, Bayer and POINT BioPharma for use of PyL in drug development programs.

We can give no assurance as to when or if any of these Pharma Services collaborations will be successful or accretive to earnings.

In addition, as described above, we continue to expand our microbubble franchise.

In October 2020, we announced a strategic collaboration with Insightec which will use our microbubbles in connection with Insightec’s transcranial guided focused ultrasound device for the treatment of glioblastoma as well as other neurodegenerative conditions.

Glioblastoma is a lethal and devastating form of brain cancer with median survival of 15 months after diagnosis.

Previously, we announced a strategic commercial supply agreement with CarThera for the use of our microbubbles in combination with SonoCloud, a proprietary implantable device in development for the treatment of recurrent glioblastoma.

We also previously announced a strategic development and commercial collaboration with Cerevast in which our microbubbles will be used in connection with Cerevast’s ocular ultrasound device to improve blood flow in occluded retinal veins in the eye.

Retinal vein occlusion is one of the most common causes of vision loss worldwide.

The agreement also requires us to order from JHS a specified minimum percentage of our requirements for DEFINITY and fixed quantities of Cardiolite and NEUROLITE each year during the contract term.

Based on our current projections, we believe that we will have sufficient supply of DEFINITY from JHS and our in-house manufacturing facility and sufficient supply of Cardiolite and NEUROLITE products from JHS to meet expected demand.

• PYLARIFY —The commercial manufacture of PYLARIFY required us to create a field-based network of specialized PMFs with radioisotope-producing cyclotrons.

In preparation for our commercial launch, we entered into commercial supply agreements with different radiopharmacy networks.

Under our supply agreements, the PMF manufactures the radioisotope F 18 on a cyclotron, and then combines the F 18 with certain chemical ingredients in specially designed chemistry synthesis boxes to manufacture PYLARIFY.

The finished PYLARIFY is then quality control tested and transferred to the PMF’s radiopharmacist who prepares and dispenses patient-specific doses from the final product.

Our agreements with our PMF networks allow for the termination upon the occurrence of specified events, including material breach or bankruptcy by either party, and have various termination dates generally terminating in 2025 and subject to renewal provisions.

See Part I, Item 1A.

“Risk Factors” for information regarding certain risks associated with our strategic activities.

“Risk Factors” for information regarding certain risks associated with our manufacturing and supply relationships.

Intellectual Property

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We review third party proprietary rights, including patents and patent applications, as available, in an effort to develop an effective intellectual property strategy, avoid infringement of third party proprietary rights, identify licensing opportunities and monitor the intellectual property owned by others.

Our ability to enforce and protect our intellectual property rights may be limited in certain countries outside the U.S., which could make it easier for competitors to capture market position in those countries by utilizing technologies that are similar to those developed or licensed by us.

Our ability to enforce, defend and protect our intellectual property rights may be limited in certain countries outside the U.S., which could make it easier for competitors to capture market position in those countries by utilizing technologies that are similar to those developed or licensed by us.

Competitors also may harm our sales by designing products that mirror the capabilities of our products or technology without infringing our intellectual property rights.

If we do not obtain sufficient protection for our intellectual property, or if we are unable to effectively enforce our intellectual property rights, our competitiveness could be impaired, which would limit our growth and future revenue.

If we do not obtain sufficient protection for our intellectual property, or if we are unable to effectively enforce or defend our intellectual property rights, our competitiveness could be impaired, which would limit our growth and future revenue.

Trademarks, Service Marks and Trade Names

We own various trademarks, service marks and trade names, including, among others, DEFINITY, DEFINITY RT, TechneLite, Cardiolite, NEUROLITE, VIALMIX, VIALMIX RFID, QUADRAMET, Luminity, PyL, AZEDRA, AZEDRA Service Connection, RELISTOR, Lantheus, Lantheus Medical Imaging, Progenics, Progenics Pharmaceuticals, Molecular Insight, EXINI, PyL Research Access Program and Find, Fight and Follow.

We own various trademarks, service marks and trade names, including, among others, AZEDRA, AZEDRA Service Connection, Cardiolite, DEFINITY, DEFINITY RT, EXINI, Find, Fight and Follow, Find > Fight > Follow, Lantheus, Lantheus Medical Imaging, LUMINITY, Molecular Insight, NEUROLITE, Progenics, Progenics Pharmaceuticals, PYLARIFY, PYLARIFY AI, TechneLite, VIALMIX and VIALMIX RFID.

We have registered these trademarks, as well as others, in the U.S.

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We also rely upon trade secrets and contracts to protect our proprietary information.

As of December 31, 2020, our patent portfolio included a total of 107 issued U.S.

patents, 804 issued foreign patents, 49 pending U.S.

patent applications and 239 pending foreign applications, owned or exclusively licensed.

We have patent protection on certain of our commercial products and on all of our clinical development candidates.

We typically seek patent protection in major markets around the world, including, among others, the U.S., Canada, Western Europe, Asia, and Latin America.

We typically seek patent protection in major markets around the world, including, among others, the U.S., Canada, Western Europe, Asia, Central America and South America.

All patent terms described below are presented without giving effect to any applicable patent term adjustments or regulatory extensions.

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and internationally.

for DEFINITY we own a total of four Orange Book-listed method of use patents, one of which expires in 2035 and three of which expire in 2037, as well as additional manufacturing patents that are not Orange Book-listed expiring in 2021, 2023 and 2037.

for DEFINITY RT, we own a total of five Orange Book-listed patents, including a composition of matter patent which expires in 2035.

for DEFINITY RT, we have five Orange Book-listed patents, including a composition of matter patent which expires in 2035.

Outside of the U.S., we are currently pursuing additional DEFINITY and DEFINITY RT patents to obtain similar patent protection as in the U.S.

The Orange Book-listed patents include a patent on the use of VIALMIX RFID which expires in 2037;

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Even though our longest duration Orange Book-listed DEFINITY patent extends until March 2037, because our Orange Book-listed composition of matter patent expired in June 2019, we may face generic DEFINITY challengers in the near to intermediate term.

Under the Hatch-Waxman Act, the FDA can approve Abbreviated New Drug Applications (“ANDAs”) for generic versions of drugs if the ANDA applicant demonstrates, among other things, that (i) its generic candidate is the same as the innovator product by establishing bioequivalence and providing relevant chemistry, manufacturing and product data, and (ii) either the marketing of that generic candidate does not infringe the Orange Book-listed patent(s) or the Orange Book-listed patent(s) is invalid.

Similarly, the FDA can approve a Section 505(b)(2) NDA from an applicant that relies on some of the information required for marketing approval to come from studies which the applicant does not own or have a legal right of reference.

With respect to the Orange Book-listed patent(s) covering an innovator product, the ANDA applicant or the Section 505(b)(2) applicant (if relying on studies related to the innovator product) (together, the “Applicant”) must give a notice (a “Notice”) to the innovator of its certification that its generic candidate will not infringe the innovator’s Orange Book-listed patent(s) or that the Orange Book-listed patent(s) is invalid.

As of the date of filing of this Annual Report on Form 10-K, we have not received any Notice from an ANDA applicant.

If we were to (i) receive any such Notice in the future, (ii) bring a patent infringement suit against the ANDA applicant within 45 days of receiving that Notice, and (iii) successfully obtain the full 30 month stay, then the ANDA applicant would be precluded from commercializing a generic version of DEFINITY prior to the expiration of that 30 month stay period and, potentially, thereafter, depending on how the patent dispute is resolved.

If we received a Notice some number of months in the future and the full 30 month stay was obtained, the commercialization date would roll forward in the future by the same calculation.

We can give no assurance that we would have grounds to file a patent infringement suit, that we would obtain the full 30 month stay, that we would be successful on the merits asserting that an Applicant infringes our Orange Book-listed patent, or that we would be successful defending the validity or enforceability of our Orange Book-listed patent in court or in a USPTO adversarial proceeding.

As of the date of filing of this Annual Report on Form 10-K, we have not received any Notice from an Applicant.

If we received a Notice some number of months in the future and the full 30-month stay were obtained, the commercialization date would roll forward in the future by the same number of months.

In the event a 505(b)(2) applicant does not rely on studies related to the innovator product, the 30-month stay would not apply, but additional clinical studies may be required.

TechneLite - We currently own patents in the U.S.

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PYLARIFY - We actively pursue patents in connection with PYLARIFY, both in the U.S.

and internationally.

for PYLARIFY, we have four Orange Book-listed patents, including composition of matter patents which expire in 2030 and 2037.

Outside of the U.S., we are currently pursuing additional PYLARIFY patents to obtain similar patent protection as in the U.S.

PYLARIFY AI - U.S.

Patents and pending patent applications worldwide relating to automated medical image analysis, have expiration ranges from 2037 to 2041.

Other Nuclear Products - Neither Cardiolite nor NEUROLITE is covered any longer by patent protection in either the U.S.

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In addition, we own pending applications worldwide for manufacturing improvements, and the resulting compositions which, if issued, would expire in 2035.

PyL - The PyL patent family was licensed from the Johns Hopkins University (“JHU”).

Patent protection for composition of matter patents, radiolabeled forms of the compound, and methods of use in the U.S.

expire in 2029 and 2030.

Corresponding patents issued or pending worldwide, all expire in 2029.

Process improvement patent applications are pending worldwide and, if issued, would expire in 2037.

flurpiridaz F 18 - We own patents and patent applications in numerous jurisdictions covering composition, use, formulation and manufacturing, including in the U.S.

a composition of matter patent expiring in 2026, a formulation patent expiring in 2032, a method of use patent expiring in 2028, and manufacturing-related patents expiring in 2031 and 2033, and various patent applications, some of which, if granted, will expire in 2033.

aBSI - We own patents relating to automated detection of bone cancer metastases.

The patents on this technology expire in the U.S.

in 2032 and outside of the U.S.

Patent applications are pending in the U.S.

and worldwide relating to aBSI improvements which, if issued, will expire in 2040.

1095 - We own patents relating to 1095 that expire from 2027 to 2031, with the composition of matter as well as radiolabeled forms in the U.S.

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a composition of matter patent expiring in 2030, a method of use patent expiring in 2027, and manufacturing-related patents expiring in 2031 and 2032, and patent applications which, if granted, will expire in 2027 and in 2031.

flurpiridaz F 18 - We own patents and patent applications in numerous jurisdictions covering composition, use, formulation and manufacturing, including in the U.S.

1404 - We own patents relating to composition of matter, as well as technetium-99 labeled forms of 1404 expiring in the U.S.

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In-licensed patents relating to reagents for radiolabeling expire in the U.S.

aBSI - We own patents relating to automated detection of bone cancer metastases.

The patents on this technology expire in the U.S.

in 2032 and outside of the U.S.

Patent applications are pending in the U.S.

and worldwide relating to aBSI improvements which, if issued will expire in 2040.

PSMA-AI – U.S.

Patents and pending patent applications worldwide relating to automated medical image analysis, have expiration ranges from 2037 to 2040.

PSMA Antibody TTC – We own and in-license composition of matter patents on PSMA antibodies expiring in the U.S.

PSMA TTC - We own and in-license composition of matter patents on PSMA antibodies expiring in the U.S.

in 2022 and 2023 and outside of the U.S.

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In addition, we license third party technologies and other intellectual property rights that are incorporated into some elements of our drug discovery and development efforts.

Some of these licenses are material to our business – for example, the licenses of the patent rights on RELISTOR from Wyeth LLC and on the PyL patent family from JHU.

Some of these licenses are material to our business – for example, the licenses on the PYLARIFY patent family from Johns Hopkins University (“JHU”) and on the patent rights on RELISTOR from Wyeth LLC.

See Part I, Item 1A.

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Food and Drug Laws

The development, manufacture and commercialization of our agents and products are subject to comprehensive governmental regulation both within and outside the U.S.

The development, manufacture and commercialization of our products are subject to comprehensive governmental regulation both within and outside the U.S.

A number of factors substantially increase the time, difficulty and costs incurred in obtaining and maintaining the approval to market newly developed and existing products.

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Governmental regulatory actions can result in the seizure or recall of products, suspension or revocation of the authority necessary for their production and sale as well as other civil or criminal sanctions.

Our activities related to the development, manufacture, packaging or repackaging of our pharmaceutical and medical device products subject us to a wide variety of laws and regulations.

Our activities related to the development, manufacture, packaging or repackaging of our products subject us to a wide variety of laws and regulations.

We are required to register for permits and/or licenses with, seek approvals from and comply with operating and security standards of, the FDA, the U.S.

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In addition, if a product that has Orphan Drug designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to Orphan Drug exclusivity, which means the FDA may not approve any other application to market the same drug for the same indication for a period of seven years, except in limited circumstances, such as a showing of clinical superiority over the product with orphan exclusivity or where the manufacturer is unable to assure sufficient product quantity.

Under Section 529 of the FDCA, companies that develop new drugs for the prevention and treatment of certain rare pediatric diseases may be eligible for a rare pediatric disease priority review voucher for a subsequent human drug application.

The voucher is only granted if the drug is approved for the rare pediatric disease, but once granted, the voucher can either be used by the recipient or sold to a third party, typically a large pharmaceutical or related company that seeks priority review for an unrelated drug it expects will generate substantial revenue.

Any drug products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, complying with certain electronic records and signature requirements, and complying with FDA promotion and advertising requirements.

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Manufacturers must establish validated systems to ensure that products meet specifications and regulatory standards, and test each product batch or lot prior to its release.

In addition, manufacturers of commercial PET products, including radiopharmacies, hospitals and academic medical centers, are required to submit either an NDA or ANDA in order to produce PET drugs for clinical use, or produce the drugs under an IND.

In addition, manufacturers of commercial PET products such as PYLARIFY, including radiopharmacies, hospitals and academic medical centers, are required to submit either an NDA or ANDA in order to produce PET drugs for clinical use, or produce the drugs under an IND.

The FDA also regulates the preclinical and clinical testing, design, manufacture, safety, efficacy, labeling, storage, record keeping, sales and distribution, post-market adverse event reporting, import/export and advertising and promotion of any medical devices that we distribute pursuant to the FDCA and FDA’s implementing regulations.

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Currently, medical devices comprise only a small portion of our revenues.

The FDA may withdraw marketing authorization for a pharmaceutical or medical device product if compliance with regulatory standards is not maintained or if problems occur after the product reaches the market.

The FDA may withdraw marketing authorization for a product if compliance with regulatory standards is not maintained or if problems occur after the product reaches the market.

Later discovery of previously-unknown problems with a product may result in restrictions on the product or even complete withdrawal of the product from the market.

Further, the failure to maintain compliance with regulatory requirements may result in administrative or judicial actions, such as fines, civil monetary penalties, warning letters, holds on clinical studies, product recalls or seizures, product detention or refusal to permit the import or export of pharmaceuticals or medical device products, refusal to approve pending applications or supplements, restrictions on marketing or manufacturing, injunctions, or civil or criminal penalties.

Further, the failure to maintain compliance with regulatory requirements may result in administrative or judicial actions, such as fines, civil monetary penalties, warning letters, holds on clinical studies, product recalls or seizures, product detention or refusal to permit the import or export of products, refusal to approve pending applications or supplements, restrictions on marketing or manufacturing, injunctions, or civil or criminal penalties.

Regulations are subject to change as a result of legislative, administrative or judicial action, which may also increase our costs or reduce sales or otherwise adversely impact our products.

For example, on April 16, 2021 in the case Genus Medical Technologies LLC v.

Food and Drug Administration, the U.S.

Court of Appeals for the D.C.

Circuit held that a product (other than a combination product) that meets the definitions of both “drug” and “device” under the FDCA must be regulated as a device.

On August 9, 2021, the FDA announced that, as part of its implementation of this court decision, the FDA intended to regulate products that meet both the device and drug definition as devices, except where Congress intended a different classification.

The FDA further indicated that it intended to bring previously classified products into line with the court decision and would reexamine whether individual imaging agents meet the device definition.

In connection with its announcement, the FDA requested comments from the industry on five topics:

categories of products implicated by the court decision;

the transition process;

the transition timing;

user fee transitions;

and determining drug or device status.

We submitted comments to the FDA in response to its request for comments.

While we question whether the FDA has authority to make this change, we believe that pre-existing law already establishes that a broad spectrum of imaging agents have already been established by Congress to be “drugs”, and do not believe that any of our imaging agents meets the definition of a “device” under the FDCA.

We can give no assurance that the FDA will agree with our position.

In addition, if the FDA determines that one or more of our imaging agents meet the definition of a “device”, we do not know when such reclassification would be effective, how any transition rules would be formulated or applied, and whether or not the legal framework provided by the Hatch-Waxman Act described below would be preserved for some time after such reclassification.

A reclassification of one or more of our imaging agents as a “device” could have a material adverse effect on our business, results of operations, financial condition and cash flows.

Because our operations include the manufacture and distribution of medical radioisotopes and other medical products, we are subject to regulation by the NRC and the departments of health of each state in which we operate and the applicable state boards of pharmacy.

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Drug laws also are in effect in many of the non-U.S.

markets in which we conduct business.

markets in which we or our partners conduct business.

These laws range from comprehensive drug approval requirements to requests for product data or certifications.

In addition, inspection of and controls over manufacturing, as well as monitoring of adverse events, are components of most of these regulatory systems.

Most of our business is subject to varying degrees of governmental regulation in the countries in which we operate, and the general trend is toward increasingly stringent regulation.

Most of our business is subject to varying degrees of governmental regulation in the countries in which we or our partners operate, and the general trend is toward increasingly stringent regulation.

The exercise of broad regulatory powers by the FDA continues to result in increases in the amount of testing and documentation required for approval or clearance of new drugs and devices, all of which add to the expense of product introduction.

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and (2) statutory protection, known as exclusivity, against the FDA’s acceptance or approval of certain competitor applications.

Patent term extension can compensate for time lost during product development and the regulatory review process by returning up to five years of patent life for a patent that covers a new product or its use.

law, patent term extension can compensate for time lost during product development and the regulatory review process by returning up to five years of patent life for a patent that covers a new product or its use.

This period is generally one-half the time between the effective date of an IND and the submission date of an NDA, plus the time between the submission date of an NDA and the approval of that application.

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The three-year exclusivity does not prohibit the FDA, with limited exceptions, from approving generic drugs containing the same active ingredient but without the new innovation.

Reimbursement

The successful commercialization of our products is also subject to the availability of appropriate third-party coding, coverage and payment for our customers.

Third-party payors in the U.S.

include commercial payors, including managed care providers, and State and Federal healthcare programs, such as Medicare and Medicaid.

The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product.

Coverage of a product does not ensure there will be an appropriate reimbursement amount for such product and the process to ensure appropriate reimbursement is outside our control.

For commercial payors, coverage and reimbursement of our products vary from commercial payor to commercial payor.

Many commercial payors, such as managed care providers, manage access to products, and may use medical policies (which may include specific coverage requirements such as prior authorization, re-authorization and achieving performance metrics under value-based contracts) to control utilization.

Exclusion from or restriction in coverage can reduce product use.

For government payors, we participate, as required, in the Federal Supply Schedule (FSS) and the PHS 340b program, which each require discounts for participation and may be subject to change.

For Medicare, reimbursement to customers for our products is generally established through the rulemaking process or in discussion with Medicare Administrative Contractors (MACs).

We have ongoing conversations with third-party payors to advocate for appropriate coding, coverage and payment for our portfolio of products, but we can give no assurance that adequate coding, coverage and payment can be obtained from such commercial or government payors.

Medicare Outpatient Pass-Through Payment Status

Part B of the Medicare program generally reimburses medical services and supplies, including drugs, provided to beneficiaries by physicians and other qualified healthcare professionals.

Generally, drugs furnished “incident to” a physician’s service in the hospital outpatient setting of care are reimbursed at Average Sales Price (“ASP”) plus a certain additional percent, unless the product is treated as a “supply” in the performance of the procedure and “packaged” and paid as part of bundled payment for the procedure.

Novel drugs, however, may apply for “pass-through status” in which case they are provided a separate payment at ASP plus a certain additional percent for two to three years, regardless of whether they would ordinarily be packaged.

PYLARIFY has received pass-through status effective January 1, 2022 through December 31, 2024, thereby providing separate reimbursement to customers using PYLARIFY in the hospital outpatient setting during this specified period.

The reimbursement rate for PYLARIFY is based on the wholesale acquisition cost (WAC) plus three percent until CMS can establish an ASP for the product, which could take six months.

Once CMS establishes an ASP, the add-on percentage applicable to PYLARIFY will likely vary.

PYLARIFY has been assigned Healthcare Common Procedure Coding System code A9595 (piflufolastat F 18, diagnostic, 1 millicurie) for identification in claims and can be used by both public and commercial payors.

Under existing Medicare Part B payment policy, non-pass-through diagnostic radiopharmaceuticals are not separately paid and are instead packaged into payment for the underlying procedure.

Therapeutic radiopharmaceuticals, however, continue to be eligible for separate payment even after expiration of pass-through status.

We plan to continue our advocacy efforts with CMS and private insurers so that PYLARIFY customers will have appropriate and adequate reimbursement following the expiration of pass-through status, although we can give no assurances that we will be successful in those efforts.

Healthcare Reform and Other Laws Affecting Payment

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and state governments continue to propose and pass legislation that may affect the availability and cost of healthcare.

For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, the Healthcare Reform Act, substantially changes the way in which healthcare is financed by both governmental and private insurers and has a significant impact on the pharmaceutical industry.

For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively, the “Healthcare Reform Act”), substantially changes the way in which healthcare is financed by both governmental and private insurers and has a significant impact on the pharmaceutical industry.

The Healthcare Reform Act contains a number of provisions that affect coverage, reimbursement and/or delivery of drug products and the medical imaging procedures in which our drug products are used.

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• increasing drug rebates paid to state Medicaid programs under the Medicaid Drug Rebate Program for brand name prescription drugs and extending those rebates to Medicaid managed care organizations;

• expanding access to the 340B program by allowing additional covered entities to participate in the program;

• imposing a non-deductible annual fee on pharmaceutical manufacturers or importers who sell brand name prescription drugs to specified federal government programs.

The Healthcare Reform Act also amended the federal self-referral laws, requiring referring physicians to inform patients under certain circumstances that the patients may obtain services, including MRI, computed tomography (“CT”), PET and certain other diagnostic imaging services, from a provider other than that physician, another physician in his or her group practice, or another individual under direct supervision of the physician or another physician in the group practice.

The Healthcare Reform Act also amended the federal self-referral laws, requiring referring physicians to inform patients under certain circumstances that the patients may obtain services, including PET, CT, MRI and certain other diagnostic imaging services, from a provider other than that physician, another physician in his or her group practice, or another individual under direct supervision of the physician or another physician in the group practice.

The referring physician must provide each patient with a written list of other suppliers who furnish those services in the area in which the patient resides.

These requirements could have the effect of shifting where certain diagnostic medical imaging procedures are performed.

The Healthcare Reform Act has been subject to political and judicial challenges.

For example, tax reform legislation was enacted at the end of 2017 that effectively eliminated the “individual mandate” to maintain health insurance coverage by eliminating the tax penalty for individuals who do not maintain sufficient health insurance coverage beginning in 2019.

In December 2018, a federal district court judge, in a challenge brought by a number of state attorneys general, found the Healthcare Reform Act unconstitutional in its entirety because once Congress repealed the “individual mandate” provision, there was no longer a basis to rely on Congressional taxing authority to support enactment of the law.

In December 2019, a federal appeals court agreed that the individual mandate provision was unconstitutional, but remanded the case back to the district court to assess more carefully whether any provisions of the Healthcare Reform Act were severable and could survive.

In November 2020, the U.S.

Supreme Court heard an appeal of the federal appeals court decision, but has not opined on the constitutionality of the individual mandate or the severability of the remaining aspects of the Healthcare Reform Act.

Pending resolution of this case, the Healthcare Reform Act is still operational.

Recently, there has been considerable public and government scrutiny of pharmaceutical pricing and proposals to address the perceived high cost of pharmaceuticals.

For example, in May 2018, President Trump and the Secretary of the Department of Health and Human Services released a “blueprint” to lower prescription drug prices and out-of-pocket costs.

Certain proposals in the blueprint, and related drug pricing measures proposed since the blueprint, could cause significant operational and reimbursement changes for the pharmaceutical industry.

As an example, legislation passed in 2019 revised how certain prices reported by manufacturers under the Medicaid Drug Rebate Program are calculated, a revision that the Congressional Budget Office has estimated will save the federal government approximately $3.0 billion in the next ten years.

As another example, in November 2020, CMS issued an interim final rule that announced a new “most favored nation” payment model for certain Medicare Part B drugs, which would reduce the Medicare payment amount for such drugs to the lowest price that drug manufacturers receive in other similar countries.

(Multiple federal courts have issued temporary injunctions blocking implementation of this final rule).

The Healthcare Reform Act has been subject to political and judicial challenges, but it has generally withstood such challenges, and the main provisions of the Healthcare Reform Act remain in effect.

Recently, there has been considerable public and government scrutiny of pharmaceutical pricing and proposals to address the perceived high cost of pharmaceuticals at both the federal and state levels.

Efforts by government officials or legislators to implement measures to regulate prices or payment for pharmaceutical products could limit our flexibility in establishing prices for our products or otherwise adversely affect our business if implemented.

Changes could occur at the federal level or state level and may be adopted by statute, rule, or sub-regulatory policies.

For instance, Congress is currently considering the Build Back Better Act, which contains many drug pricing provisions that could adversely affect our business, including but not limited to authorization for Medicare to directly negotiate pricing for high-cost drugs, and inflation penalties for Part B and D drugs with price increases greater than the rate of inflation.

To be clear, changes could occur at the federal level or state level and may be adopted by statute, rule, or sub-regulatory policies.

Recent state legislative efforts seek to address drug costs and generally have focused on increasing transparency around drug costs or limiting drug prices.

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The Budget Control Act, as amended by the Bipartisan Budget Act of 2019, resulted in the imposition of 2% reductions in Medicare (but not Medicaid) payments to providers beginning in 2013 and will remain in effect through fiscal year 2030 unless additional Congressional action is taken.

The Coronavirus Aid, Relief, and Economic Security (CARES) Act suspended the 2% payment adjustment for dates of service from May 1 through December 31, 2020, and the Consolidated Appropriations Act 2021 subsequently extended this suspension until March 31, 2021.

The Coronavirus Aid, Relief, and Economic Security (CARES) Act suspended the 2% payment adjustment for dates of service from May 1 through December 31, 2020, the Consolidated Appropriations Act 2021 subsequently extended this suspension until March 31, 2021, and Congress further extended the suspension through March 31, 2022.

Any significant spending reductions affecting Medicare, Medicaid or other publicly funded or subsidized health programs that may be implemented and/or any significant taxes or fees that may be imposed on us could have an adverse impact on our business results of operations, financial condition and cash flows.

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We are subject to various federal, state and local laws targeting fraud and abuse in the healthcare industry, including anti-kickback and false claims laws.

Patient assistance programs, if not properly implemented, can implicate these laws.

Violations of fraud and abuse laws may be punishable by criminal or civil sanctions, including fines and civil monetary penalties, and/or exclusion from federal health care programs (including Medicare and Medicaid).

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See Part I, Item 1A.

“Risk Factors” for information regarding certain risks related to regulatory matters.

“Risk Factors” for information regarding certain risks related to reimbursement and regulation.

Environmental Matters

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We store low level radioactive waste at our facilities until the materials are below regulatory limits, as allowed by our licenses and permits.

As of December 31, 2020, we currently estimate the D&D cost of all of our manufacturing sites (including our Puerto Rico radiopharmacy which we sold on January 29, 2021) to be approximately $26.9 million.

As of December 31, 2021, we currently estimate the D&D cost of all of our manufacturing sites (excluding our Puerto Rico radiopharmacy, which we sold on January 29, 2021) to be approximately $26.4 million.

As of December 31, 2021 and 2020, we have a liability recorded associated with the fair value of the asset retirement obligations of $20.8 million and $14.0 million, respectively.

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None of our employees are represented by a collective bargaining agreement, and we believe that our relationship with our employees is good.

During 2021, we hired additional employees to assist us with the commercialization of PYLARIFY, including in sales, marketing, reimbursement, quality and medical affairs.

In addition, we hired a Chief Human Resources Officer to help us attract, develop and retain leading and diverse talent in business-critical roles.

Diversity, Inclusion, Ethics and Compliance

We believe that supporting our local community and instilling a diverse, inclusive, ethical and compliant culture will make us an employer of choice, maintain good standing with the regulatory authorities and customers and benefit stockholders in the long run.

We have a female CEO, 50% of our Vice Presidents and above are women, and approximately 44% of our employees are women.

We continue to strive to improve our diversity and inclusion with a strategic emphasis beyond gender and we require recruiters working with us to present candidates in the spirit of diversity and inclusion.

We believe that supporting our local community and instilling a diverse, inclusive, ethical and compliant culture makes us an employer of choice, allows us to maintain good standing with the regulatory authorities and our customers, and benefits our stockholders in the long run.

We have a female Chief Executive Officer, over half of our Vice Presidents and above are women, and approximately 46% of our employees are women.

We continue to strive to improve our diversity and inclusion with a strategic emphasis beyond gender, and we require recruiters working with us to present diversity candidates.

We are committed to promoting a culture of ethics and compliance.

Our Code of Conduct and Ethics reflects the Company’s commitment to corporate integrity and the underlying business practices and principles of behavior that support this commitment.

Our Code of Conduct and Ethics reflects our commitment to corporate integrity and the underlying business practices and principles of behavior that support this commitment.

Each year our employees complete mandatory training that includes anti-bribery/anti-corruption rules, insider trading prohibitions, confidentiality obligations, as well as specialized training in healthcare industry marketing practices.

We also have a formal Ethics and Compliance Committee that develops, implements and overseas our ethics and compliance programs.

We have a formal Ethics and Compliance Committee that develops, implements and oversees our ethics and compliance programs.

We also have a Supplier Code of Conduct, and we seek to do business with minority-owned, female-owned and other diverse businesses and organizations (including those owned or operated by veterans and disabled veterans) that appropriately reflect the communities in which we operate and the customer base we serve.

Compensation and Benefits

We seek to provide pay, benefits, and services that are competitive to market and create incentives to attract and retain employees.

Our compensation package includes market-competitive pay, cash bonuses and restricted stock and other equity grants to certain levels of employees, health care and retirement benefits, paid time off and family leave, among others.

Our compensation package includes, among other things, market-competitive pay, cash bonuses, healthcare and defined contribution plan benefits, paid time off and family leave, and restricted stock and other equity grants to certain levels of employees.

We are focused on pay equity and regularly assess pay among similar roles and responsibilities throughout our organization and in comparison to our peer group.

Communication and Engagement

We believe that our success depends on employees understanding how their work contributes to the Company’s overall strategy.

We believe that our success depends on employees understanding how their work contributes to our overall strategy.

To this end, we utilize a variety of channels to facilitate open and direct communication, including:

(i) quarterly town hall meetings with our executive team;

(i) quarterly town hall meetings for our entire company;

(ii) regular ongoing update communications;

(iii) employee engagement surveys;

and (iv) an externally administered whistleblower hotline and website that is prominently advertised to our employees, and a whistleblower’s anonymity is protected, if so requested.

and (iii) an externally administered whistleblower hotline and website that is prominently advertised to our employees, and a whistleblower’s anonymity is protected, if so requested.

We also established various employee recognition award programs to recognize and reward employees for specific outstanding accomplishments and to foster a positive employee relations climate.

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We work to promote an environment of awareness and shared responsibility for safety and regulatory compliance throughout the Company, in order to minimize risks of injury, exposure, or business impact.

With respect to the COVID-19 pandemic, we operate a “Pandemic Response Team” to implement and oversee appropriate precautions to minimize the spread of COVID-19 in our teams and communities.

With respect to the COVID-19 pandemic, we operated a “Pandemic Response Team” to implement and oversee appropriate precautions to minimize the spread of COVID-19 in our teams and communities.

We continue to have all non-critical employees and contractors work-remotely and avoid non-essential work-related travel.

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In January 2008, Avista Capital Partners, L.P., Avista Capital Partners (Offshore), L.P.

and ACP-Lantern Co-Invest, LLC (collectively “Avista”) formed Lantheus Holdings and acquired our medical imaging business from BMS.

On June 30, 2015, we completed an initial public offering (“IPO”) of our common stock.

We completed our acquisition of Progenics Pharmaceuticals, Inc.

on June 19, 2020.

and ACP-Lantern Co-Invest, LLC formed Lantheus Holdings and acquired our medical imaging business from BMS.

On June 30, 2015, we completed an initial public offering of our common stock.

We completed our acquisition of Progenics on June 19, 2020 (the “Progenics Acquisition”).

Our common stock is traded on the NASDAQ Global Market under the symbol “LNTH”.

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Our global Internet site is www.lantheus.com.

We routinely make available important information, including copies of our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act, as soon as reasonably practicable after those reports are electronically filed with, or furnished to, the SEC, free of charge on our website at www.investor.lantheus.com.

We recognize our website as a key channel of distribution to reach public investors and as a means of disclosing material non-public information to comply with our disclosure obligations under SEC Regulation FD.

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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