Chapter 1: Targeted Radiopharmaceuticals: Clinical Development and Commercial Landscape Free

In the last five years, a few peptide-based radiopharmaceuticals have received approval from the United States Food and Drug Administration (FDA). Biotech start-ups engaged in radioconjugation have been springing up like mushrooms. Lutathera®, was the first FDA and European Medicines Agency (EMA) approved radiopharmaceutical for peptide receptor radionuclide therapy. Lutathera® is a radioactive [¹⁷⁷Lu] Lu-dodecane tetraacetic acid–tyrosine-3-octreotate (DOTA–TATE), somatostatin-targeted theragnostic for neuroendocrine tumor (NET) treatment. In 2017 it was approved by the European Medicines Agency (EMA) for gastroenteropancreatic (GEP) neuroendocrine tumors.¹  It was first developed by the German Cancer Research Center and University Hospital Heidelberg, and later licensed to the small German pharmaceutical company ABX for early clinical development.² 

In March 2022, the FDA approved Pluvicto®, [¹⁷⁷Lu]Lu–PSMA-617, a prostate specific membrane antigen (PSMA)-targeted theragnostic to treat metastatic castration-resistant prostate cancer.³  The FDA designates Pluvicto® as a breakthrough therapy. Novartis acquired Pluvicto® from Endocyte Inc. Locametz®, a kit for the preparation of ⁶⁸Ga-labelled gozetotide injections was developed at the same time for PSMA positron emission tomography (PET) imaging for prostate cancer.³  Bayer’s Xofigo® is not a radioconjugate but a straight radium-223 dichloride solution approved by the FDA for the therapy of castration-resistant prostate cancer patients with symptomatic bone metastases. Xofigo® is an alpha-emitting radiopharmaceutical and is a calcium mimic, which localizes in areas of bone mineralization (i.e. bone metastases).⁴ 

Theragnostics combines therapy and diagnosis and is a personalized approach to treating cancer. Theragnostic agents target unique properties of the cancer cell using different radionuclides for diagnostics by PET or single photon emission computed tomography (SPECT) imaging techniques and different radionuclides for treatment. The theragnostic approach is to ‘treat what you see or see what you treat’. For example, metastable technetium-99 (technetium-99m)-, indium-111-, fluorine-18-, and gallium-68-tagged somatostatin analogs are used as imaging agents for neuroendocrine tumors, and lutetium-177 coupled somatostatin analogs as therapeutic agents. Clarity Pharmaceuticals is focused on targeted copper theragnostics (TCT) with copper-64 for diagnostics and copper-67 for therapy.⁵  More than 60 radiotherapeutics have presently entered into clinical trials, among which six are already at the Phase III clinical stage.⁶  These molecules address several different cancer indications; nine of them target NET, and 18 target prostate cancer.⁷ 

Beta particle therapy involves radioisotopes emitting very small particles (electrons), for example, ¹⁷⁷Lu, ¹³¹I, and ⁹⁰Y. It radiates energy to approximately 1 cm radius, with linear energy transfer (LET) of 0.2 keV mm⁻¹, covering 10–1200 cells, including killing healthy cells and immune cells, in addition to tumor cells. Its lethality of thousands of particles kills only a single strand of the DNA. It requires lead shielding and patient sequestration and often requires an in-patient stay in the hospital for several days. The supply chain for beta-emitting radionuclides is well established.⁸ 

Alpha particle therapy, on the other hand, involves radionuclides emitting large particles (helium nuclei), such as ²²⁵Ac, ²¹²Pb, ²¹³Bi, ²²³Ra, and ²²⁷Th with a LET) of 50–230 keV µm⁻¹, tissue exposure is very narrow (100 µm range) and covers 10–120 cells i.e. it kills only tumor cells. It is highly localized and has a potency of single-atom lethality, and irreversibly kills double-strand DNA. In clinical use, patients are shielded by just a piece of paper, there is limited risk to family and doctors, and it can be done as an outpatient procedure. However, the clinical supply of ²²⁵Ac is limited, but it is getting better and stabilizing. ²²⁵Ac has a half-life of 9.92 days, while ¹⁷⁷Lu has one of 6.65 days. This means that once either isotope is attached to the therapeutic agent, companies must quickly get the drugs to hospitals and treatment centers while they are still potent.⁸ 

Which emitter is best to deploy depends on the type of cancer; the target depends on the tumor type and the volume of the tumors; for example, neuroendocrine tumors grow slowly; in this case, β emitters are good for therapy. On the other hand, ovarian cancer is a very aggressive cancer type, and in this case, the α emitters are probably the better choice (Figure 1.1).

For clinical and commercial success, radiopharmaceutical drugs must have (a) a peptide or other chemical component that binds specifically to targets that are expressed only on the cancer cells and not the healthy cells, (b) high tumor penetration and rapid clearance via the kidneys and (c) the ability to add linker–chelators to peptide binders site-specifically but without adversely affecting binding or other properties. Several companies and academic institutions are in the race to develop the best theragnostic agents. Aktis Oncology is developing radiopharmaceuticals based on miniprotein binders with excellent tumor penetration properties. Aktis has generated multiple first-in-class programs using the miniprotein platform, demonstrating its broad utility.⁹  Full-Life Technologies is developing ²²⁵Ac-FL-020, a novel PSMA-targeting radioligand therapy; the drug candidate was identified with their proprietary Clear-X technology platform.¹⁰  Bicycle Therapeutics is developing Bicycle Radionuclide Conjugates (BRC™ molecules), in which Bicycle® molecules are employed as targeting vectors for precision delivery of radioisotopes to tumors.¹¹ 

There are two antibody-based radiopharmaceutical therapy (RPT) agents: (1) ibritumomab tiuxetan conjugated to ⁹⁰yttrium yielded Zevalin® (Schering AG, Berlin, Germany)¹²  and (2) tositumomab conjugated to ¹³¹iodine yielded Bexxar® (Corixa Corp, Seattle, WA, USA). Both ⁹⁰Y–ibritumomab and ¹³¹I–tositumomab have been compared with their unlabelled antibody counterparts in randomized trials.¹³  A few RPT agents are currently on the market, and many RPTs are in clinical development (Table 1.1). The list is not exhaustive and includes only some of the agents currently in clinical development by a commercial sponsor.

Lutathera® was first granted FDA approval in January 2018, specifically for adults with somatostatin receptor-positive GEP-NETs. Lutathera®’s approval was based on results from two main studies. The first was a 229-patient randomized clinical trial where subjects with advanced somatostatin receptor-positive GEP-NETs either received a combination of Lutathera® and octreotide or octreotide alone. The study revealed that progression-free survival was longer for patients on the combination treatment containing Lutathera®. In the second study, in which 1214 patients with somatostatin receptor-positive tumors received Lutathera®, it was found that 16% of subjects with GEP-NETs reported complete or partial tumor shrinkage. Advanced Accelerator Applications was granted approval for Lutathera® after it had been under Priority Review. Lutathera® was also designated as an orphan drug, which incentivizes sponsors to develop treatments for rare diseases.¹⁴ 

In April 2024, Lutathera® was granted additional approval for use in pediatric patients of 12 years of age and up with GEP-NETs, the first FDA approval of a radiopharmaceutical for pediatric patients. Approval was based on the Neuroendocrine Tumors Therapy Pheochromocytoma and Paragangliomas (NETTER-P) trial, which measured radiation dose absorption, the incidence of adverse events, and long-term safety in adolescent patients.¹⁵ 

GEP-NETs, are tumors beginning in neuroendocrine cells that arise in gastroenteropancreatic structures, such as the pancreas, liver, and gallbladder, as well as those in the gastrointestinal (GI) tract. GEP-NETs are the most common subtype of NETs, and comprise nearly 70% of all neuroendocrine tumors.¹⁶ 

The most commonly utilized treatment methods for GEP-NETs are surgery, chemotherapy, radiation therapy, and hormone therapy. Surgeries for GEP-NETs can include resections, cryotherapy, local excisions, and more, but surgery is not always an effective option depending on tumor and carcinoma metastasis, vascular invasion, peritoneal carcinomatosis, and patient comorbidities.¹⁷  Typical chemotherapy drug regimens are less effective for GEP-NETs, with lower response rates and survival benefits in patients. More common chemotherapy drugs, like streptozocin and doxorubicin, can effectively treat high-grade aggressive neuroendocrine carcinomas but well-differentiated low-grade NETs yield limited improvement.¹⁸  Radiation therapy, often in the form of external beam radiation, is another common cancer treatment; unlike chemotherapy, it is ineffective towards well-differentiated low-grade NETs due to their slow-growing nature.¹⁹  While effective in killing off cancerous cells, radiation therapy tends to exceed its role and kills many of the patient’s healthy cells as well; this can result in acute and chronic side effects, organ damage, and even the development of secondary cancers. Finally, hormone therapy for GEP-NETs involves the usage of synthetic hormones to control carcinoma and its symptoms. High-grade tumors respond minimally to this treatment form, and cells can develop resistance to the synthetic hormones utilized.²⁰ 

Recently, a novel treatment method for GEP-NETs has emerged; peptide receptor radionuclide therapy (PRRT) involves using radiolabelled peptides to deliver targeted therapy to cancerous cells. Lutathera® is the brand name of the specific PRRT that treats GEP-NETs; in essence, it is the combination of radiation and hormone therapy, with somatostatin analogs, a synthetic hormone, allowing for the delivery of targeted radiation therapy in the body. The following sections will explore the chemical structure, mechanism of action, biodistribution, FDA approval, dosages, side effects, and challenges of Lutathera®, while also providing an in-depth overview of crucial clinical trials in Lutathera®’s journey to prominence in GEP-NET treatment.

Lutathera® is a radiopharmaceutical created using the chelating agent DOTA to bind the ¹⁷⁷Lu radioisotope of lutetium with Tyr3-octreotate, a somatostatin analog; each component of Lutathera® works to perform targeted drug delivery to ensure only affected cancerous cells are treated.

¹⁷⁷Lu (Lu-177) is a medium energy beta emitter and is produced by the irradiation of either lutetium-176 or ytterbium-176. Lu-177 is highly damaging but has a small radius of effect, allowing healthy cells to survive while targeting cancerous tissue. Its half-life of 6.7 days allows for long-distance travel throughout the body.²¹ 

DOTA, also known as dodecane tetraacetic acid or tetraxetan, is a macrocyclic chelating agent. It is often used in nuclear medicine to ligate molecules due to its thermostability and usage versatility; its cyclic structure, composed of four nitrogen atoms and four acetic acid groups, allows DOTA to maintain a high affinity and selectivity to the atoms it binds. DOTA is particularly stable when utilized with trivalent metals, such as lutetium.²²  In Lutathera®, DOTA binds the radioactive agent Lu-177 with the somatostatin analog Tyr3-octreotate to form DOTA–TATE.²³ 

Octreotide is a synthetic somatostatin analog [d-Phe–c(Cys–Tyr–d-Trp–Lys–Thr–Cys)–Thr]; when a modification replacing its third amino acid phenylalanine with tyrosine is performed, Tyr3-octreotate is formed.²⁴  This enhances the molecule’s affinity for somatostatin receptor subtype 2 (SSTR2); somatostatin receptors are overexpressed in NETs (Figure 1.2).

A greater understanding of GEP-NETs and their origin is required to describe and comprehend the pathway through which Lutathera® produces its pharmacological effects. GEP-NETs, tumors arising from neuroendocrine cells along the GI tract, are traditionally categorized on the basis of location into three groups: foregut, midgut, and hindgut.²⁵  The characteristic quality of GEP-NETs is their ability to produce, store, and secrete peptide hormones, such as somatostatin. While somatostatin does not play a major known role in the development of neuroendocrine cells into tumors, as a regulatory and inhibitory hormone, somatostatin inhibits growth and gastrointestinal hormone secretion and regulates insulin and glucagon. In the central nervous system, this cyclic peptide can serve as a neurotransmitter and influence synaptic plasticity. Somatostatin is produced throughout the body in various locations, including the pancreas, GI tract, and hypothalamic neurons.²⁶ 

Somatostatin functions by binding to six different G-protein coupled receptors (GPCRs) throughout the body, known as somatostatin receptors (SSTRs). Specifically, the binding of the ligand to the SSTR results in a decrease in calcium and cyclic AMP as well as an increase in potassium currents; this causes lower levels of hormone secretion in the targeted tissue.²⁶  Thus, somatostatin functions in tumor suppression, as its binding to SSTRs prevents the release of cell-proliferating hormones and can even induce apoptotic pathways.

GEP-NETs have been found to overexpress somatostatin receptors; SSTR2 is overexpressed in approximately 90% of patients with GEP-NETs. Lutathera® contains Tyr3-octreotate, which, as previously described, is a synthetic somatostatin analog.²⁷  The Tyr3-octreotate fulfills its role as a targeting component and identifies the tumor cell to be attacked; after the somatostatin analog binds to the SSTR, endocytosis causes internalization of the receptor–peptide complex.²⁷  The radioactive Lu-177 that is now inside the cell produces beta emissions that result in apoptotic single- and double-stranded DNA breaks, killing tumor cells.

On the basis of the results of clinical trials, the recommended median cumulative dose of ¹⁷⁷Lu–DOTA–TATE is 29.6 GBq (4 × 7.4 GBq), for patients receiving all four doses.²⁸  The radiopharmaceutical is first introduced into the body through intravenous injection, entering the bloodstream and traveling systemically. The somatostatin analog portion (Tyr3-octreotate) is drawn to the SSTR2 overexpressed on tumor cells; biodistribution studies have revealed that Lutathera® is rapidly taken up from blood.²⁹  While tumor cells internalize much of the administered Lutathera®, there is also moderate organ uptake of the radiotherapeutic among the kidneys, liver, and spleen. The kidneys’ role in filtering blood and waste as well as the presence of SSTRs in vasa recta and tubular cells results in Lutathera® uptake; amino acid infusion co-administration can mitigate radioactivity and nephrotoxicity.³⁰  The liver and spleen’s presentation of SSTRs results in Lutathera® uptake as well. Finally, bone marrow can also be exposed to radiopharmaceuticals as a result of its rich blood supply; exposure may cause hematological toxicity and associated side effects. Fractionated dosing, amino acid infusions, and post-administration monitoring can be used to manage potential complications.³¹ 

According to the results of the NETTER trial, Lutathera® is minimally metabolized and mainly excreted intact renally; high performance liquid chromatography performed on subjects’ urine samples detected a nearly 100% purity for the lutetium oxodotreotide radiochemical. 65% of the Lutathera® administered is eliminated from the body within 48 hours.²⁹ 

While Lutathera® is a groundbreaking radiotherapy for GEP-NETs, it does come with a set of challenges. Hematological toxicity, or lower levels of blood cells and bone marrow in the body, can result from use of Lutathera®.³²  Bone marrow cells also contain SSTR2, and, because Lutathera® targets this somatostatin receptor specifically, Lutathera® usage can result in anemia, thrombocytopenia, and leukopenia; this results in decreased patient immunity as well as lowered frequency and dosage of Lutathera® administration.^32,33  Kidney function can also be impaired, as the kidneys, too, express high levels of SSTR2 as well as aiding in drug excretion via glomerular filtration. Radiation damage from the prolonged exposure of the kidneys to Lutathera® can cause chronic kidney disease and nephrotoxicity; amino acid infusions, fractionated dosing, and regular kidney testing can aid in management and mitigation.³⁴  Other potential side effects of Lutathera® include diarrhea, vomiting, nausea, liver dysfunction, endocrine disruption, and secondary malignancies.³⁵ 

Treatment with Lutathera® radiation may impair kidney function. One of the most common serious side effects reported is decreased blood cell counts, along with increased liver enzymes.³⁶ 

Another PRRT also utilizing Lu-177 is Pluvicto®. Pluvicto®, also known as lutetium-177 vipivotide tetraxetan, is a targeted radioligand therapy for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).³⁷  It functions by targeting and binding to PSMA, which is overexpressed in prostate cancer cells; just like for Lutathera®, the Lu-177 component delivers beta-radiation to identified target cells, aiming to shrink tumors and cause cell apoptosis.^38,39  Locametz®, or gallium-68 gozetotide, is a diagnostic agent for PSMA-positive metastatic castration-resistant prostate cancer. Used in PET imaging, it identifies PSMA-positive lesions by binding to PSMA on prostate cancer cells and emitting positrons. Locametz® and Pluvicto® are used as a diagnostic–therapeutic pairing, with Locametz® determining suitable candidates for Pluvicto® usage.⁴⁰ 

The supply chain differs greatly from those for traditional therapeutics for radionuclide companies and raises questions regarding efficient manufacture and quality control. The upstream supply of radioisotopes can be hard to secure, and ensuring the continuity of the supply of therapeutic products while meeting regulatory guidelines has been problematic.

The forthcoming fast-growing field of nuclear medicine, particularly the supply of ²²⁵Ac, is facing a significant challenge due to supply constraints. The recent decision by RayzeBio, now a BMS company, to temporarily halt new patient enrollment in its ACTION-1 phase 3 study due to a shortage of the isotope actinium is a stark reminder of this issue.⁴¹  It underscores the urgent need for solutions to ensure a stable supply of crucial isotopes like actinium. This also leads to a race to secure the supply of ²²⁵Ac or for radiopharmaceutical companies to have manufacturing ownership to continue their clinical development and commercial success. The chemical radionuclides ²²⁹Th, ²³²Th, and ²²⁶Ra or ²²⁵Ra, are crucial to producing ²²⁵Ac, regardless of the production method used. The key contaminant of concern is ²²⁷Ac.⁴² 

Addressing the critical shortage of this highly promising isotope is poised to revolutionize the production of radionuclides. For example, RayzeBio is completing the build-out of a 63 000-square-foot manufacturing facility in Indianapolis; Telix spent up to $82M to boost isotope production with the buyout of ARTMS; Bayer recently entered a pact with Pan Tera to help supply ²²⁵Ac for clinical trial needs starting in the second half of 2024.⁴³  Aktis Oncology has announced agreements and partnerships with NorthStar Medical Radioisotopes, Niowave, and TerraPower;⁴⁴  Full-Life Technologies, a fully integrated global radiotherapeutics company, and Eckert & Ziegler announced their agreement for the supply of ²²⁵Ac.⁴⁵  Eckert & Ziegler, in conjunction with the Nuclear Physics Institute of the Czech Academy of Sciences has explored one of the most promising cyclotron-based production pathways for ²²⁵Ac.⁴⁶  NorthStar’s approach to ²²⁵Ac production utilizes non-uranium, electron accelerator-based production methods.⁴⁶  Niowave Inc. builds and operates superconducting electron accelerators to produce ²²⁵Ac and other radioisotopes. Terra Power Inc. uses a ²²⁹thorium generator.⁴⁴ 

The International Atomic Energy Authority (IAEA) scientific and technical publications provide in-depth guidance on the challenges and future developments in the production, quality control, safe handling, and regulatory aspects of Ac-225 radiopharmaceuticals for targeted alpha therapy (TAT). They provide recommendations with regard to infrastructure and training requirements, and will ensure the sustainability of the supply chain of ²²⁵Ac.⁴⁷  This will ensure the sustainability of the technology in nuclear medicine clinics.

Efforts from the FDA towards producing quality specifications for ²²⁵Ac are well underway. In 2021, the FDA–Nuclear Regulatory Commission (NRC) Workshop on Targeted Alpha Emitting Radiopharmaceuticals focussed on high energy accelerator production of ²²⁵Ac to meet clinical demand, standards development, and product quality considerations. The issue of ²²⁷Ac impurities must be assessed when accelerator produced ²²⁵Ac is used.⁴⁸  The Oncidium Foundation launched a Global “RLT-Connect” Platform in 2023 to enhance access to radiotheragnostics for cancer patients.⁴⁹  This is an excellent resource for collaborators for the future availability of industrial scale quantities of radionuclides and radiopharmaceuticals.

One of the non-oncologic utilities of radiotheragnostics is in Alzheimer’s disease, using the combination of beta-amyloid imaging and antibody therapy.⁵⁰  The amyloid antibody Lecanemab has recently been approved by the FDA, and its effectiveness has been demonstrated in clinical studies.⁵¹  Another instance is the utilization of dopamine transporter imaging in conjunction with dopaminergic therapeutics for Parkinsonian syndromes.⁵²  Novel radioligands can selectively target bacteria, enabling the differentiation between sterile inflammation and infections.⁵³ 

Over $1 billion in capital has been raised over the last five years for targeted radiopharmaceuticals. This field is moving from nuclear radiology back to nuclear medicine. At the European Association of Nuclear Medicine (EANM), Barcelona, Spain 2022,⁵⁴  Prof. Wolfgang Weber of the Technical University of Munich clearly stated that nuclear medicine is expected to grow to $15B by 2025, the total diagnostic imaging market to $540 million per year, with 180k patients on ⁶⁸Ga–DOTA–TATE and ⁶⁸Ga–PSMA, and the total therapeutic imaging market to $9.3 billion per year, with approximately 48k patients on ¹⁷⁷Lu–DOTA–TATE ($1.3B) and ¹⁷⁷Lu–PSMA ($8B).⁵⁵ 

Recent research and development and commercial successes in the renaissance of the theragnostics approach for radiopharmaceuticals have resulted in increased venture financing and acquisition, a partnership of small biotech and large pharma. Brianne Sullivan mentioned, “Over the past 5 years, there have been 86 strategic deals in the radiopharmaceuticals space, with the majority being collaboration/co-development (n = 26) and licensing-based (n = 26) agreements”.⁵⁶  As of Oct 2023, a large number of radiopharmaceutical deals happened for assets in the preclinical phase (n = 20) or pipeline assets in Phase II (n = 18). Most deals in the diagnostics space have been in neurology (54%), and most of the theragnostic deals occur in oncology (31%) therapeutic areas.⁵⁷  Based on public announcements and the company’s website information, the acquisitions of radiopharmaceuticals biotech companies from 2018 to 2023 have increased mergers and acquisitions of companies with recent radiopharmaceutical advancements.⁵⁷  Such as

• Xofigo® (once monthly injection) was the first alpha-emitter radionuclide (Ra 223 dichloride) approved by the FDA for the treatment of bone metastases in castration-resistant prostate cancer. It was developed by Algeta and later acquired by Bayer in 2013 for $2.9 billion.

• Lutathera® (once weekly injections). Lutetium-177 (a beta-emitter bound to a peptide ligand) for the treatment of solid tumors, including GEP-NETs expressing SSTR2, was developed by Advanced Accelerator Applications and later acquired by Novartis in 2017 for $3.9 billion.

• Pluvicto®, (lutetium-177, a beta-emitter chelated with a small molecule ligand) targeting PSMA was developed by Endocyte and approved by the FDA in 2022. It was acquired by Novartis for $1 billion.

• RYZ101 (actinium-225, an alpha-emitter bound to a peptide ligand), potentially clinically superior to Lutathera® for treatment of GEP-NETs, in Phase III development by RayzeBio. RayzeBio, after the initial public offering (IPO) in 2023 for its robust pipeline, was acquired by BMS for $3.1 billion.

  The acquisition of RayzeBio started a trend for financing deals based on the development pipeline of other small radiopharma biotech companies.

• Point BioPharma, developing programs for lutetium-based radiopharmaceuticals targeting PSMA and SSTR2, both in Phase III, was acquired by Eli Lilly for $1.4 billion.

• Fusion Pharmaceuticals, with a healthy pipeline and developing novel linker technology for use with alpha-emitters to reduce off-target effects on healthy tissue, was acquired by AstraZeneca for $2.5 billion.

• Mariana Oncology, developing a pipeline of peptide-based radiopharmaceuticals, was recently acquired by Novartis for $1 billion.

• Aktis Oncology, a miniproteins-based technology platform with alpha-radiation targeting, has raised more than 160 million and recently partnered to collaborate with Eli Lilly.

• Radiopharm Theragnostics Inc., with a world-class platform of radiopharmaceutical products for both diagnostic and therapeutic uses, completed a $70 million placement comprised of international and Australian institutional and industry investors.

• Telix Pharmaceuticals, which has two approved radioisotope diagnostics and a couple awaiting FDA decision for prostate cancer, one for kidney cancer, and another for glioblastoma, in a Phase III trial, is aiming to raise aims for a $202m IPO.

• Radionetics’ GPCR-targeting drug development technology has resulted in its lead candidate ⁶⁸Ga-R8760 in a Phase I study, a gallium-based radioligand conjugate with a small molecule that targets the melanocortin 2 receptor (MC2R) protein, which is highly expressed in the rare cancer adrenocortical carcinoma. Eli Lilly signed a strategic partnership with Radionetics Oncology with a $140 million upfront payment from Lilly, as well as the potential right to acquire Radionetics for $1 billion.

India is experiencing exponential growth in both diagnostic imaging and therapeutic practices. India’s nuclear medicine infrastructure includes more than 442 operating nuclear medicine centers, 359 PET-computed tomography (CT) scanners [including three PET/magnetic resonance (MR) scanners], 24 functional medical cyclotrons, and 150 high-dose radionuclide therapy facilities.⁵⁸  Fortis, Gurgaon, was the first clinical user of alpha (²²⁵Ac–²¹³Bi) therapy for prostate cancer in India.⁵⁹  indigenous production of medical radioisotopes at The Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi, has facilitated the application of PET radiometals (⁴⁴Sc, ⁶⁴Cu, ⁶⁸Ga, and ⁸⁹Zr), and its cyclotron facility developed excellent ^99mTc-based tracers, for diagnostic use in clinical applications. India has emerged at the forefront of clinical research, and it has significantly contributed to initial studies of ¹⁷⁷Lu–DOTA–TATE and ¹⁷⁷Lu–PSMA-617 in metastatic neuroendocrine tumours and prostate cancer.^60,61  The supply of radiopharmaceuticals, such as ¹⁷⁷Lu–PSMA and ¹⁷⁷Lu–DOTA–TATE by the Board of Radiation and Isotope Technology (BRIT) for treating prostate and metastatic neuroendocrine tumors has been phenomenal.

Current sources of ²²⁵Ac are primarily derived from the build-up of ²²⁹thorium through the decay of ²³³U stockpiles. The generator converts ²³³U to ²²⁹thorium and ²²⁵radium. ²²⁵Ac batches are isolated through the decay of ²²⁵Ra (half-life = 14.9 days) which is the main source. Production of ²²⁵Ac in Russia or at Oakridge National Lab and quantifying sub-particle decay were challenges in the early days.

Managing the supply chain of radionuclides and chemical agents is crucial to building, securing, and enhancing radiomanufacturing and distribution capabilities. Significant progress has been made to mitigate supply chain considerations by several biotech and pharmaceutical companies, for example, Aktis Oncology secured three sources of radionuclide suppliers that utilize varied techniques to produce high-quality actinium-225 and enhance the company’s ability to ensure just-in-time delivery of finished targeted radioconjugates to healthcare providers for administration to patients.

Significant progress has been made in the radiopharmaceuticals space. Several biotech and pharmaceutical companies are charged with anticipation and high expectations to discover and develop precision medication to treat solid tumors and imaging methodologies. The key challenges of radiopharmaceuticals that need to be addressed are preventing kidney toxicity and mitigating supply chain considerations of radionuclides, especially ²²⁵Ac. By leveraging collaboration opportunities with India’s exponentially growing nuclear medicine infrastructure and the emergence of radiotheragnostics technology, we can continue to innovate and improve patient care in oncology. Several chapters in this book will illustrate examples of research and development in radiotherapy and imaging in various disease areas.