Lantheus Holdings Stock

Lantheus Holdings, Inc. (Lantheus) operates as a radiopharmaceutical-focused company.

The company is delivering life-changing science to enable clinicians to Find, Fight and Follow disease to deliver better patient outcomes. The company classifies its products in three categories: Radiopharmaceutical Oncology, Precision Diagnostics, and Strategic Partnerships and Other Revenue. The company’s Radiopharmaceutical Oncology diagnostics and therapeutic candidates help healthcare professionals (‘HCPs’) Find, Fight and Follow cancer, with a focus in prostate cancer. The company’s leading Precision Diagnostic products assist HCPs to Find and Follow diseases, with a focus in cardiology. The company’s Strategic Partnerships focus on enabling precision medicine through the use of biomarkers, digital solutions and pharma solutions platforms.

The company’s 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. The company’s 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 throughout the healthcare system.

The company produces and markets its products throughout the United States (the ‘United States’ or the ‘U.S.’), selling primarily to hospitals, independent diagnostic testing facilities, and radiopharmacies. The company sells its 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.

Strategic Agreements with Perspective Therapeutics

On January 9, 2024, the company entered into multiple strategic agreements with Perspective, a radiopharmaceutical company that is pursuing advanced treatment applications for cancers throughout the body. Under the agreements, the company obtained an option to exclusively license Perspective’s Pb212-VMT-Alpha-NET, a clinical stage alpha therapy in development for the treatment of neuroendocrine tumors, and an option to co-develop certain early-stage therapeutic candidates targeting prostate cancer using Perspective’s innovative platform technology. In addition, Perspective agreed to acquire the assets and associated lease of the company’s radiopharmaceutical manufacturing facility in Somerset, New Jersey. Following satisfaction of the closing conditions, on January 22, 2024, the company’s subsidiary, Lantheus Alpha, held approximately 10.74% of Perspective’s common stock.

Exclusive License for PNT2002 & PNT2003

On December 20, 2022, the company announced the closing of a set of strategic collaborations with POINT, in which the company was granted a license to exclusive worldwide rights (excluding Japan, South Korea, China (including Hong Kong, Macau and Taiwan), Singapore and Indonesia) to co-develop and commercialize POINT’s PNT2002 and PNT2003 product candidates. PNT2002 is a PSMA-targeted radiopharmaceutical therapy in development for the treatment of metastatic castration-resistant prostate cancer (‘mCRPC’). PNT2003 is a somatostatin receptor (‘SSTR’) therapy with non-carrier added lutetium-177, which is in registration to treat patients with SSTR-positive neuroendocrine tumors.

On December 27, 2023, Eli Lilly and Company announced the completion of its acquisition of POINT.

PNT2002

With respect to PNT2002, POINT is generally responsible for funding and development activities required for FDA approval, including generating all clinical and nonclinical data, analysis and other information; and the company is responsible for preparing for and seeking regulatory approval, as well as performing and funding all future development and commercialization following such approval. POINT will be responsible for all manufacturing of PNT2002, subject to certain exceptions described in the license and collaboration agreement between Lantheus Two and POINT, dated November 11, 2022 (the ‘PNT2002 License Agreement’).

In April 2023, the company announced with POINT that the FDA had granted Fast Track designation for PNT2002. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and address unmet needs.

On December 18, 2023, the company announced positive topline results from SPLASH. SPLASH is designed to evaluate the efficacy and safety of PNT2002 in patients with mCRPC who have progressed following treatment with an androgen receptor pathway inhibitor (‘ARPI’).

The open-label study randomized 412 patients with PSMA-expressing mCRPC who had progressed on ARPI therapy and either refused or were not eligible for chemotherapy, in a 2:1 randomization ratio. At the time of the analysis, 84.6% of patients who experienced progressive disease in the control arm subsequently crossed over to receive PNT2002. SPLASH was conducted across the United States, Canada, Europe, and the United Kingdom. Eighty percent of SPLASH patients resided in North America and approximately ten percent of all participants were Black or African American.

During 2023, the company worked on establishing an Expanded Access Program, (‘EAP’), for PNT2002. EAPs, which are also referred to as compassionate use programs, provide a potential pathway for patients with serious or life-threatening conditions to gain access to an investigational drug for treatment outside of a clinical trial. The company expects to enroll the first patient in the EAP for PNT2002 during the first quarter of 2024.

PNT2003

With respect to PNT2003, POINT is responsible for curating all data, analysis and other information necessary for regulatory approval, and supporting the company in the preparation of regulatory filings. The company is responsible for preparing for and seeking regulatory approval of all such applications, as well as performing and funding all future development and commercialization of PNT2003 following such approval. POINT will be responsible for all manufacturing of PNT2003, subject to certain exceptions described in the license and collaboration agreement between Lantheus Three and POINT, dated November 11, 2022 (the ‘PNT2003 License Agreement’).

On January 11, 2024, the company announced that its ANDA for Lutetium Lu 177 Dotatate (177Lu-PNT2003) had been accepted for filing by the FDA. On January 26, 2024, the company was sued in the District Court for the District of Delaware by Advanced Accelerator Applications USA, Inc. and Advanced Accelerator Applications SA, each a Novartis entity, for patent infringement in response to the company’s ANDA filing. Based on the most recent update to the FDA’s online paragraph IV database listings, the company is the first applicant to have filed a substantially complete ANDA for Lutetium Lu 177 Dotatate containing a Paragraph IV certification under the provisions of the Hatch-Waxman Act. As the first applicant, the company will be eligible for 180 days of generic marketing exclusivity in the U.S.

Under the Hatch-Waxman Act, any company submitting an ANDA must make certain certifications with respect to the patent status of the drug for which it is seeking approval. In the event that such applicant plans to challenge the validity or enforceability of an existing listed patent or asserts that the proposed product does not infringe an existing listed patent, it files a ‘Paragraph IV’ certification. The company filed a Paragraph IV certification in connection with PNT2003. In the case of ANDAs, the Hatch-Waxman Act provides for a potential 180-day period of generic exclusivity for the first company to submit an ANDA with a Paragraph IV certification. This filing triggers a regulatory process in which the FDA is required to delay the final approval of subsequently filed ANDAs containing Paragraph IV certifications until 180 days after the first commercial marketing. When litigation is brought by the patent holder in response to a Paragraph IV certification (like the Novartis entities did for the company’s ANDA for PNT2003), the FDA generally may not approve the ANDA until the earlier of 30 months or a court decision finding the patent invalid, not infringed or unenforceable. The submission of the company’s ANDA for PNT2003 could result in protracted and expensive patent litigation and the outcome of such litigation is uncertain.

Acquisition of Cerveau

On February 6, 2023, the company acquired Cerveau. Cerveau holds the rights under a license agreement to develop and commercialize MK-6240, an investigational second-generation F 18-labeled PET imaging agent that targets Tau tangles in Alzheimer’s disease.

Portfolio of Commercial Products

Radiopharmaceutical Oncology

The company’s commercial product in the company’s Radiopharmaceutical Oncology category includes 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’). 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. Piflufolastat F 18 is approved under the name PYLCLARI in Europe and licensed by the company to Curium.

Precision Diagnostics

The company’s commercial products in its Precision Diagnostics category include the following:

DEFINITY is an injectable ultrasound enhancing agent with perflutren-containing lipid microspheres, or microbubbles, that is used in echocardiography exams. The company offers two formulations of DEFINITY, one of which requires refrigerated storage (branded DEFINITY) and one which allows both storage and shipment at room temperature and provides clinicians an additional choice for greater utility of this formulation in broader clinical settings (branded DEFINITY RT). The indication for both formulations in the U.S. is for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. The company is the leading worldwide provider of ultrasound enhancing agents for use in echocardiography.

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 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.

Xenon-133 (‘Xenon’) is a radiopharmaceutical gas that is inhaled and used to assess pulmonary function and also to image cerebral blood flow. The company’s Xenon is manufactured by a third party as a bi-product of Mo-99 production and is processed and finished by the company.

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. Included in CARDIOLITE revenues are branded CARDIOLITE and generic sestamibi revenues.

Strategic Partnerships and Other Revenue

The company’s commercial products in its 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. In 2011, Progenics licensed methylnaltrexone (MNTX) along with products containing MNTX, including both approved forms of RELISTOR, to Salix Pharmaceuticals, Inc., a Bausch Health company (‘Bausch’) and on August 2, 2023, the company sold the right to the RELISTOR net sales royalties under that license agreement and retained the rights to future sales-based milestone payments.

Automated Bone Scan Index (‘aBSI’) automatically calculates the disease burden of prostate cancer by detecting and classifying bone scan tracer uptakes as metastatic or benign lesions using an artificial neural network. aBSI is FDA cleared and CE marked. The software is used as one of the correlative objectives of the DORA trial, an open-labeled, randomized, Phase 3 study of docetaxel versus docetaxel in combination with radium-223 (Ra-223) in subjects with mCRPC. aBSI is also approved in Japan and part of the JSMO guidelines (Japanese Society of Medical Oncology) in the support of clinicians with patient treatment selection. The Japanese non-exclusive rights to aBSI have been transferred and sold to FUJIFILM Toyama Chemical Co. Ltd. (‘FUJIFILM’) under the name BONENAVI.

aPROMISE, which is commercialized as PYLARIFY AI in the U.S., is artificial intelligence medical device software that is designed to allow HCPs and researchers to perform standardized quantitative assessment of PSMA PET/CT images in prostate cancer, including those images obtained by using PYLARIFY.

Radiopharmaceutical Oncology

Continued Growth of PYLARIFY

PYLARIFY is the leading radiopharmaceutical 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 scan that enables the scan reader to detect and locate the disease.

PYLARIFY is manufactured on a diverse, F 18 distributor supply network of PMFs, ensuring convenient and reliable supply. 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 PMF manufacturing PYLARIFY is deemed by the FDA to be a separate manufacturing site, each is separately approved by the FDA. As of December 31, 2023, the company had activated 54 PMF manufacturing sites in its PMF network. These additional sites provide geographic breadth, out-the-door time flexibility and added optionality within the company’s existing PMF network. Overall, the company has achieved broad national distribution of PYLARIFY with customers in 47 of 50 states, the District of Columbia and Puerto Rico.

In addition to the company’s network of commercial PMFs, the company works with academic medical centers in the U.S. that have radioisotope-producing cyclotrons and that have expressed an interest in manufacturing PYLARIFY. For this initiative, the company enters into a fee-for-service arrangement under which the academic medical center manufactures F 18 on its cyclotron and completes the manufacturing process for PYLARIFY. PYLARIFY can then be used by the academic medical center itself, and in some cases distributed to other customers under separate purchase agreements.

The company’s Healthcare Procedure Coding System (‘HCPCS’) code, which enables streamlined billing, went into effect as of January 1, 2022. In addition, effective January 1, 2022, the Centers for Medicare and Medicaid Services (‘CMS’) granted TPT Status in the hospital outpatient setting for PYLARIFY, enabling traditional Medicare to provide an incremental payment for PET/CT scans performed with PYLARIFY in that setting. TPT Status for PYLARIFY is expected to expire on December 31, 2024.

In July 2023, CMS proposed possible changes to its regulations covering payment for diagnostic radiopharmaceuticals. This included, for the first time since 2008, options for separate payment for diagnostics instead of the current packaged payment following expiration of TPT Status. The company, along with numerous industry organizations, submitted comments to CMS. In completing its 2023 rulemaking for the 2024 payment calendar year, CMS recognized the challenges of patient access to diagnostic radiopharmaceuticals and requested feedback on various payment alternatives that could provide separate reimbursement for these items, but the agency did not adopt any of these proposals in the final rule, while stating that it would continue to evaluate this issue in subsequent rulemaking. The company plans to submit additional comments to CMS in connection with its 2024 rulemaking for the 2025 payment calendar year.

The company’s continued growth of PYLARIFY will depend on its ability to clinically and commercially differentiate PYLARIFY from other products on the market and to maintain PYLARIFY as the leading PSMA PET imaging agent in a competitive marketplace. PYLARIFY’s competition is primarily two Gallium-68 (‘Ga-68’)-based PSMA imaging agents, a fluorine-18-based PSMA imaging agent, and other non-PSMA-based imaging agents commonly referred to as conventional imaging. Continued growth and revenue contribution from PYLARIFY will also depend on the company’s ability to differentiate PYLARIFY in light of the potential loss of TPT Status, including through flexible and dependable access to PYLARIFY nationally, a best in class customer experience and through long-term strategic contracts.

The company actively pursues patents in connection with PYLARIFY, both in the U.S. and internationally. In the U.S. for PYLARIFY, the company has five Orange Book-listed patents, including composition of matter patents, the last of which expires in 2037. Outside of the U.S., the company has, and is pursuing, additional PYLARIFY patents to obtain similar patent protection as in the U.S.

Precision Diagnostics

Continued Growth of DEFINITY

DEFINITY is the leading ultrasound enhancing agent in the U.S. and is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. Numerous patient conditions can decrease the quality of images of the left ventricle, the primary pumping chamber of the heart. The term DEFINITY includes its activated and non-activated forms and the two formulations it is commercially available in; one that requires refrigerated storage and one that the company has branded as DEFINITY RT that may be stored at room temperature.

DEFINITY is a clear, colorless, sterile liquid that, upon activation in a VIALMIX or VIALMIX RFID, medical devices 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.

Since its launch in 2001, DEFINITY has been used in imaging procedures in more than 25 million studies throughout the world. The company estimates that, as of December 31, 2023, DEFINITY had over 80% share of the U.S. segment for ultrasound enhancing agents in echocardiography procedures. DEFINITY competes with two other FDA-approved ultrasound enhancing agents, as well as echocardiography without the use of ultrasound enhancing agents and non-echocardiography imaging modalities. DEFINITY and the other FDA-approved ultrasound enhancing agents 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.

The company continues to actively pursue additional patents in connection with DEFINITY and DEFINITY RT, both in the U.S. and internationally. In the U.S. for DEFINITY, the company has six Orange Book-listed method-of-use patents, one of which expires in 2035 and five of which expire in 2037, as well as additional manufacturing patents that are not Orange Book-listed expiring in 2037. In the U.S. for DEFINITY RT, the company has eight Orange Book-listed patents, including two composition of matter patents which expire in 2035. The Orange Book-listed patents include a patent on the use of VIALMIX RFID (see below), which expires in 2037; the company has submitted additional VIALMIX RFID patent applications in major markets throughout the world.

As noted above, DEFINITY is activated through the use of medical devices branded as VIALMIX and VIALMIX RFID. 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. The RFID tag, which is affixed to the vial label, enables the DEFINITY vial to be appropriately activated with the VIALMIX RFID activation device.

To manufacture DEFINITY that requires refrigeration, historically, the company has relied on Jubilant HollisterStier (‘JHS’) as a significant supplier. The company constructed a specialized in-house manufacturing facility at the company’s North Billerica campus for purposes of producing this formulation of DEFINITY and, potentially, other sterile vial products. On February 22, 2022, the company received FDA approval of the company’s supplemental new drug application (‘sNDA’), authorizing commercial manufacturing of this formulation of DEFINITY at the company’s new facility.

TechneLite

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 sourced in the company’s supply chain in nuclear research reactors located in Belgium, South Africa and Australia from enriched uranium. The TechneLite generator is a self-contained system that houses a vertical glass column at its core that contains Mo-99, which degrades to Tc-99m. During the company’s manufacturing process, Mo-99 is added to the column within the generator where it is adsorbed onto alumina powder. The column is sterilized, enclosed in a lead shield and further sealed in a cylindrical plastic container, which is then immediately shipped to the company’s radiopharmacy customers. 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 the company’s TechneLite generator is the medical radioisotope that can be attached to a number of imaging agents, including the company’s 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. The sterile saline is pulled through the generator where it attracts Tc-99m resulting from the radioactive decay of Mo-99 within the generator column. The Tc-99m-containing radioactive saline is then pulled into a vacuum vial and subsequently combined by a radiopharmacist with the applicable imaging agent, which allows the preparation of individual patient-specific radiolabeled imaging agent doses. When administered, the imaging agent binds to specific tissues or organs for a period of time, enabling the Tc-99m to illuminate the functional health of the imaged tissues or organs in a diagnostic image. The company’s ability to produce and market TechneLite is highly dependent on the company’s supply of Mo-99.

TechneLite is marketed primarily in the U.S., Canada, 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., the company has supply contracts with large radiopharmacy groups, including PharmaLogic Holdings Corp (‘PharmaLogic’), Cardinal Health (‘Cardinal’), RLS (USA) Inc. (previously GE Healthcare) (‘RLS’) and United Pharmacy Partners (‘UPPI’). The company also supplies generators on a purchase order basis to other customers.

TechneLite has patent protection in the U.S. and various foreign countries on certain component technology until 2029, and the company is pursuing additional patent protection in the U.S. and world-wide on other component technology that, if granted, would expire in 2040.

Strategic Partnerships and Other Revenue

The company continues to seek ways to further increase the overall value of the company’s portfolio of products and product candidates. The company is evaluating a number of different opportunities to collaborate, in-license or acquire additional products, product candidates, businesses and technologies to drive the company’s future growth. In particular, the company is focused on radiopharmaceutical therapeutic and diagnostic product opportunities in oncology and other strategic areas that complement the company’s existing portfolio. The company’s Pharma Solutions business focuses on advancing innovative imaging biomarker solutions, such as MK-6240, through collaborations with pharmaceutical companies and academic centers. The company’s Digital Solutions business focuses on developing and commercializing 510(k) cleared and CE marked digital applications to enhance the performance of imaging agents; the company’s Digital Solutions portfolio includes aBSI, aPROMISE and PYLARIFY AI.

Oncology

As the company continues to pursue expanding strategic partnerships, the company’s Pharma Solutions activities in oncology include:

Prostate Cancer – The company collaborate with pharmaceutical companies developing therapies and diagnostics in prostate cancer.

In July 2023, Curium (the company’s licensee that is developing and commercializing piflufolastat F 18 in Europe) announced that it received marketing authorization for piflufolastat F 18, under the name PYLCLARI, from the European Commission. In addition, the company previously entered into an agreement with Curium to add PYLARIFY to its U.S. ECLIPSE trial, a multi-center, open-label, randomized Phase 3 trial comparing the safety and efficacy of Curium’s PSMA-targeted therapeutic versus hormone therapy in patients mCRPC. PYLARIFY will be used to determine PSMA-avidity as part of patient selection.

The company has also entered into several other separate agreements, including with RefleXion Medical, Inc., POINT and Regeneron Pharmaceuticals, Inc., under which the company supplies PYLARIFY in connection with their clinical trials and 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 with PCCTC is to integrate the company’s artificial intelligence (‘AI’) platform into PCCTC studies to advance the development and validation of novel AI-enabled biomarkers.

Immuno-Oncology - The company entered 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, to develop NM-01, a novel technetium-99m SPECT imaging agent under development to assess PD-L1 expression in cancer cells. In connection with the collaboration, NanoMab recently completed a Phase 2 clinical trial at King’s College London. The Phase 2 clinical trial was an open-label, single-arm trial in non-small cell lung cancer patients. The primary endpoint was the assessment of PD-L1 expression in primary tumor and metastatic lesions by NM-01 compared to immunohistochemistry. Other objectives were aimed at quantifying intra- and inter-tumoral heterogeneity of PD-L1 expression by NM-01, as well as establishing correlations with other diagnostic procedures. The company expects results from the clinical trial to be presented at an upcoming medical congress.

Pan-Oncology - In collaboration with Ratio Therapeutics LLC (‘Ratio’) (previously Noria Therapeutics, Inc.), the company is developing LNTH-1363S, a novel copper-64 labeled PET imaging agent, targeting fibroblast activation protein alpha. This diagnostic agent candidate could have broad potential applicability and use in oncology and also in inflammatory diseases. Recently, in collaboration with Ratio, the company completed a Phase 1 study for LNTH-1363S to evaluate the pharmacokinetics, biodistribution and radiation dosimetry in adult healthy volunteers. The company plans to initiate a Phase 1/2a study in patients in 2024.

Microbubble Franchise

In addition, the company continues to seek to optimize its microbubble platform through new collaborations. Some of the company’s microbubble collaborations are with the following parties: (i) Cerevast Medical, Inc. (‘Cerevast’), in which the company’s 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 the company’s microbubbles in combination with SonoCloud, a proprietary implantable device in development for the treatment of recurrent glioblastoma; (iii) Insightec Ltd. (‘Insightec’), which will use the company’s 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; (iv) Allegheny Health Network (‘AHN’), which will use the company’s microbubbles in combination with AHN’s ultrasound-assisted non-viral gene transfer technology for the development of a proposed treatment of xerostomia; and (v) SonoThera, Inc. (‘SonoThera’), who will use the company’s microbubbles in combination with their ultrasound-guided, non-viral, gene therapy platform and treatments.

In March 2012, the company 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 the company’s behalf three confirmatory clinical trials in pursuit of cardiac, liver and kidney imaging indications, as well as one small pharmacokinetic study. In November 2022, the company announced the approval of the company’s Import Drug License application with the National Medical Products Administration (‘NMPA’) for the use of DEFINITY in patients with suboptimal conventional echocardiography and to better identify the left ventricular endocardial border. Double-Crane is responsible for obtaining adequate coding, coverage and payment and commercializing DEFINITY in China under a local brand name. Double-Crane is also in the process of analyzing the clinical results relating to liver and kidney indications and will also work with the company to prepare an Import Drug License application for those indications, as appropriate.

MK-6240

MK-6240 is an investigational clinical stage F 18-labeled PET imaging development candidate designed to detect Tau protein in the form of neurofibrillary tangles in the brains of patients with known or suspected Alzheimer’s disease. MK-6240 is being used as a biomarker in more than 90 active clinical trials for Alzheimer’s disease therapeutic candidates. Research revenue related to MK-6240 is derived from the use of MK-6240 in those clinical trials and includes milestone and dose-related payments.

RELISTOR

On August 2, 2023, the company sold its right to its RELISTOR net sales royalties under the company’s license agreement with Bausch; the company retained the rights to future sales-based milestone payments.

aBSI

aBSI automatically calculates the disease burden of prostate cancer by detecting and classifying bone scan tracer uptakes as metastatic or benign lesions using an artificial neural network. The cloud based aBSI was made available for clinical use in the U.S. on August 5, 2019. In February 2020, Progenics received European Conformity Marking (‘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

PYLARIFY AI is artificial intelligence medical device software that is 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. PYLARIFY AI has demonstrated improved consistency, accuracy and efficiency in quantitative assessment of PSMA PET/CT. The technology analyzes the PET/CT image to segment anatomical regions, including 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. The company’s subsidiary, EXINI, was granted 510(k) clearance by the FDA in the U.S. and received a CE marking in Europe for aPROMISE. The company commercially launched aPROMISE under the name PYLARIFY AI in the U.S. in November 2021 and the FDA granted the company an additional 510(k) clearance during the second quarter of 2022.

[18F] flurpiridaz

GE Healthcare Agreement – In 2017, the company entered into a definitive, exclusive Collaboration and License Agreement with GE Healthcare for the continued Phase 3 development and worldwide commercialization of flurpiridaz, a fluorine 18-based PET MPI agent designed to assess blood flow to the heart in patients suspected of coronary artery disease (‘CAD’). Under the company’s agreement, GE Healthcare will complete the development of flurpiridaz, pursue worldwide regulatory approvals, and, if successful, lead a worldwide launch and commercialization of the agent, with the company collaborating on both development and commercialization through a joint steering committee. The company also have retained 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. GE Healthcare recently announced that it had filed an NDA with the FDA for flurpiridaz. Assuming regulatory approval, the company anticipates commercialization by GE Healthcare beginning in the second half of 2024.

Clinical Development Candidates

In addition to the company’s commercial products and strategic partnerships with third parties, the company has ongoing clinical development programs, including, among others, the following:

PNT2002 is an investigational PSMA-targeted radiopharmaceutical therapy for the treatment of mCRPC. On December 18, 2023, the company announced positive topline results from SPLASH, the Phase 3 registrational trial for PNT2002 designed to evaluate superiority to the standard of care in mCRPC pre-chemotherapy patients who have failed one androgen receptor pathway inhibitor.

PNT2003 is an investigational SSTR therapy with non-carrier added lutetium-177, which is in registration to treat patients with SSTR-positive neuroendocrine tumors. On January 11, 2024, the company announced that its ANDA for PNT2003 was accepted for filing by the FDA. On January 26, 2024, the company was sued in the United States District Court for the District of Delaware by Advanced Accelerator Applications USA, Inc. and Advanced Accelerator Applications SA, each a Novartis entity, for patent infringement in response to the filing of the company’s ANDA and Paragraph IV certification, consistent with the process established by the Hatch-Waxman Act.

MK-6240 is an investigational second-generation F 18-labeled PET imaging agent that targets Tau tangles in Alzheimer’s disease. MK-6240 is currently being used in more than 90 active clinical trials for several Alzheimer’s disease therapeutic candidates being developed.

LNTH-1363S is an investigational fibroblast activation protein, alpha targeted, copper-64 labeled PET imaging agent candidate that could have broad potential imaging applicability and use in oncology. Recently, the company completed a Phase 1 study for LNTH-1363S to evaluate the pharmacokinetics, biodistribution and radiation dosimetry in adult healthy volunteers.

1095 (also known as 131 I-MIP-1095) is an investigational 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. The company enrolled the last patient in the company’s ARROW Phase 2 study during the second quarter of 2022. Patients in this study will be followed for one year after their first treatment for all efficacy endpoints and survival and safety data will be collected for an additional year.

Distribution, Marketing and Sales

With respect to the company’s medical devices:

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. The company launched aPROMISE under the name PYLARIFY AI in the U.S.

PYLARIFY sales are generated in the U.S. through an internal PYLARIFY sales team, as well as a sales team at some of the company’s PMF partners. Sales of DEFINITY are generated in the U.S. through an internal DEFINITY sales team. While a small portion of the company’s nuclear imaging product sales in the U.S. are generated through the company’s internal sales force to hospitals and clinics that maintain their own in-house radiopharmaceutical preparation capabilities, the company primarily sell the company’s nuclear imaging products, including TechneLite, NEUROLITE, Xenon, and CARDIOLITE, to large radiopharmacy chains. The company has licensed RELISTOR to Bausch, and while the company has sold the right to the company’s RELISTOR net sales royalties under its license agreement, the company has retained the rights to future sales-based milestone payments generated by Bausch.

Supply Relationships

For the year ended December 31, 2023, the company’s 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 9.3% of the company’s total purchases.

Manufacturing and Supply Arrangements

DEFINITY, CARDIOLITE and NEUROLITE

In February 2022, the company entered into a Manufacturing and Supply Agreement with JHS, for the manufacture of DEFINITY, CARDIOLITE, NEUROLITE and evacuation vials, the latter being an ancillary component for the company’s TechneLite generators. The agreement expires on December 31, 2027, and can be renewed upon mutual consent.

Intellectual Property

Trademarks, Service Marks and Trade Names

The company owns various trademarks, service marks and trade names, including, among others, PYLARIFY, DEFINITY and Find Fight and Follow. The company has generally registered these trademarks, as well as others, in the U.S. and/or numerous foreign jurisdictions.

Patents

PYLARIFY - The company actively pursues patents in connection with PYLARIFY, both in the U.S. and internationally. In the U.S. for PYLARIFY, the company has five Orange Book-listed patents, including composition of matter patents, the last of which expire in 2037. Outside of the U.S., the company has, and is pursuing, additional PYLARIFY patents to obtain similar patent protection as in the U.S.

DEFINITY - The company continues to actively pursue additional patents in connection with DEFINITY and DEFINITY RT, both in the U.S. and internationally. In the U.S. for DEFINITY, the company has six Orange Book-listed method-of-use patents, one of which expires in 2035 and five of which expire in 2037, as well as additional manufacturing patents that are not Orange Book-listed expiring in 2037. In the U.S. for DEFINITY RT, the company has eight Orange Book-listed patents, including two composition of matter patents which expire in 2035. Outside of the U.S., the company is 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; additional VIALMIX RFID patent applications have been submitted in major markets throughout the world.

TechneLite - The company owns patents in the U.S. and various foreign countries on certain component technology expiring in 2029, and the company is 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, the company has a substantial amount of valuable and defensible proprietary intellectual property associated with the product.

PYLARIFY AI – The U.S. Patents and pending patent applications worldwide relating to automated medical image analysis, have expiration ranging from 2037 to 2041.

Other Nuclear Products - Neither CARDIOLITE nor NEUROLITE is covered any longer by patent protection in either the U.S. or the rest of the world. The company has patent protection in the U.S. that expires in October 2035 for an improved container for Xenon, and is pursuing similar patent protection outside the U.S.

aBSI - The company owns 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. in 2028. Further, the company owns a U.S. patent and have patent applications that are pending in the U.S. and worldwide relating to aBSI improvements, which have expiration ranging from 2040 to 2041.

flurpiridaz - The company owns 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.

PNT2002 - The company exclusively licenses granted U.S. patents and pending U.S. patent applications as well as pending patent applications in jurisdictions outside of the U.S. directed to formulations, use and manufacturing of PNT2002. The granted U.S. patents expire in 2041.

PNT2003 - The company exclusively licenses pending U.S. patent applications as well as pending patent applications in jurisdictions outside of the U.S. directed to formulations, use and manufacturing of PNT2003 which, if granted, would expire in 2041.

MK-6240 - The company exclusively licenses patents directed to composition of matter and methods of use of MK-6240 which expire in 2035.

1095 - The company owns patents relating to 1095, with the composition of matter patent as well as radiolabeled forms patent in the U.S. and Europe expiring in 2027. Additional U.S. patents that the company owns for stable compositions and radiolabeling processes expire, respectively, in 2030 and 2031.

LNTH-1363S - The company exclusively licenses patent applications directed to compositions of matter and methods of use of LNTH-1363S. If granted, the last patent will expire in 2043.

NM-01- The company exclusively licenses in the field of imaging, patents and applications directed to compositions of matter of NM-01. The granted U.S. patents expire in 2037.

1404 - The company owns patents relating to composition of matter, as well as technetium-99 labeled forms of 1404 expiring in the U.S. from 2029 to 2030, and expiring worldwide in 2029.

Regulatory Matters

The company is 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. Nuclear Regulatory Commission (‘NRC’), the U.S. Department of Health and Human Services (‘HHS’), Health Canada, the European Medicines Agency (‘EMA’), the U.K. Medicines and Healthcare Products Regulatory Agency (‘MHRA’), the NMPA and various state and provincial boards of pharmacy, state and provincial controlled substance agencies, state and provincial health departments and/or comparable state and provincial agencies, as well as foreign agencies, and certain accrediting bodies depending upon the type of operations and location of product distribution, manufacturing and sale.

Any drug products for which the company receives 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.

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 the company distributes pursuant to the FDCA and FDA’s implementing regulations.

Because the company’s operations include the manufacture and distribution of medical radioisotopes and other medical products, the company is subject to regulation by the NRC and the departments of health of each state in which the company operates and the applicable state boards of pharmacy.

The company is neither a ‘covered entity’ nor ‘business associate’ subject directly to regulation under HIPAA (Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act), HIPAA’s criminal provisions can apply to entities other than ‘covered entities’ or ‘business associates’ in certain circumstances.

The company is subject to various federal and foreign laws that govern the company’s international business practices with respect to payments to government officials. Those laws include the Foreign Corrupt Practices Act (‘FCPA’) which prohibits U.S. companies and their representatives from paying, offering to pay, promising, or authorizing the payment of anything of value to any foreign government official, government staff member, political party, or political candidate for the purpose of obtaining or retaining business or to otherwise obtain favorable treatment or influence a person working in an official capacity.

Those laws also include the U.K. Bribery Act (‘Bribery Act’) which proscribes giving and receiving bribes in the public and private sectors, bribing a foreign public official, and failing to have adequate procedures to prevent employees and other agents from giving bribes.

Research and Development

For the year ended December 31, 2023, the company invested $77.7 million in research and development.

Competition

For PYLARIFY, the company’s principal competitors are Telix Pharmaceuticals Limited, Novartis AG, and Blue Earth Diagonstics Ltd. (‘Blue Earth’), a subsidiary of Bracco Diagnostics Inc. (‘Bracco’).

For DEFINITY, the company’s competitors include GE Healthcare (GE Healthcare Limited) and Bracco.

For a number of the company’s SPECT radiopharmaceutical commercial products, the company’s competitors include Curium, GE Healthcare, Bracco and Jubilant Life Sciences, an affiliate of JHS and Jubilant Radiopharma, and potentially BWXT Medical.

History

Lantheus Holdings, Inc. was founded in 1956. The company was incorporated in 1999.