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Beta-emitting RLTs have a long history of clinical success dating back to the approval of Zevalin and Bexxar in the early s, later followed by Lutathera and Pluvicto. Alpha radioligand therapeutics ARTs offer the potential for even greater success. New company formations, promising clinical trial data, and progression for many radioligand therapy products, as well as an inflow of investor capital, are contributing to this expanding field. Future growth will be fueled by further efficacy and safety data from ART clinical trials and real-world results, but challenges remain. Radionuclide supply, manufacturing, and distribution are key obstacles for growth of the field. New models of delivery are needed, along with cross-disciplinary training of specialized practitioners, to ensure patient access and avoid challenges faced by early RLT candidates such as Zevalin and Bexxar. Understanding of the history of radiation medicine is critical to inform what may be important to the success of ART—most past projections were inaccurate and it is important to analyze the reasons for this. Practical considerations in how radiation medicine is delivered and administered are important to understand in order to inform future approaches. Alpha radioligand therapeutics ARTs have been gaining increasing attention as a rapidly advancing experimental modality that holds promise for delivering high doses of lethal radioactivity specifically to cancer cells. The combination of the high energy and short tissue range typical of alpha-emitting isotopes enables effective killing of the targeted tumor while sparing the surrounding normal tissue. ARTs offer the potential to overcome resistance to beta-emitting radioligand therapies, which have already entered the market, or chemotherapy drugs. The promise of alpha has led to growth in new clinical trials and new company formations fueled by risk-tolerant investors. In this chapter, we explore the history of the targeted radioligand therapy commercial landscape, including the approval and performance of key drug candidates that have shaped the current and future directions of the field. We provide an overview of the current market and its potential, as well as challenges faced in therapeutic and isotope availabilities and barriers for the delivery of ARTs at commercial scale. As diagnostics applications flourished, the ability of X-rays to selectively kill rapidly dividing cells did not go unnoticed. The clinical usefulness of radiation to treat cancer was observed in , when Grubbe used X-rays from an improvised X-ray tube to treat patients with breast cancer and later lymphoma 1 , 2. Later, in , Marie and Pierre Curie identified and purified radium in the form of radioactive mineral salts isolated from radioactive pitchblende in their laboratory in Paris. In the following year, they shared the Nobel Prize in Chemistry with fellow scientist A. Henri Becquerel for their ground-breaking investigations of radioactivity, following the first observations that tumor-forming cells were destroyed faster than healthy cells when exposed to alpha-emitting radium 3. Early in its development, X-ray based radiation medicine struggled against its limits: directionality and localization, collateral damage. Therefore, many cancer physicians instead turned their attention to surgical techniques and other approaches 4. Nevertheless, ongoing innovation in external beam radiation and brachytherapy has been a hugely important development in cancer treatment, discussed in detail below. An array of approaches to achieve this effect has since been deployed in oncology, building on huge advances in cell and molecular biology over the past 50 years. This culminated many years later with the exciting possibility of being able to selectively direct a radioactive warhead to a target highly expressed uniquely on a cancer cell to engender selective cell killing. Great progress has been achieved through radiation-centric approaches in the fields of diagnostics, nuclear medicine, and targeted therapies. Millions of lives have been saved as a result of faster and accurate diagnosis and treatment of injuries and diseases that would not have been possible without nuclear medicine, with significantly improved delivery of care. Modern-day EBRT has proven to be hugely successful for its target indications. Brachytherapy comes in the form of seeds, ribbons or wires placed within the body, in or near the tumor site. High-dose-rate brachytherapy temporarily introduces iridium isotopes close to the tumor site to deliver a higher dose of radiation over a shorter period of time and overcomes limitations of early brachytherapy approaches Evidence-based medicine indicates that brachytherapy may be superior to EBRT in terms of efficacy and safety in several patient groups 15 , A significant reason for this decline is the development of more technologically sophisticated treatments, including robot-assisted surgery and proton therapy, as well as more advanced forms of non-invasive EBRT such as IMRT and SBRT 20 — 26 ; Figure 1. Falling rates of brachytherapy administration in the US in favor of EBRT have also been attributed in part to financial considerations—a shift partly facilitated by hospital reimbursement policies that favor newer approaches. Brachytherapy is more labor- and cost-intensive for hospitals—some studies have shown that the total cost and staff time devoted to brachytherapy are double those of EBRT In addition, the reimbursement levels set for EBRT are nearly double those for brachytherapy 22 , Figure 1. Radiation modality by stage and diagnosis year for prostate cancer based on NCDB data for the period — Figure adapted with permission from 23 , ACS. Although EBRT and brachytherapy remain two of the most efficient tools for eliminating isolated and discrete cancer, their application in treatment of more advanced and systemic disease is limited. In parallel to their development, nuclear medicine pioneers such as Saul Hertz experimented with the therapeutic applications of metabolically targeted radionuclides, such as iodine in thyroid cancer. Further major advances in this area occurred after the development of peptide receptor radionuclide therapy PRRT in the late s by Mark Kaminski, Richard Wahl and colleagues at the University of Michigan 28 , In this approach, an engineered peptide or antibody aimed at a specific marker found in abundance on cancer cells would carry a radioactive atom capable of delivering a lethal dose of radiation to the tumor—creating a magic bullet against cancer. Further developments in antibody conjugate technologies led to the launch of monocloncal antibody mAb -targeted radiotherapeutics in the early s. Zevalin yttriumlabeled anti-CD20 mAb and its competitor Bexxar iodinelabeled anti-CD20 mAb were the first pioneers to appear on the market within this new class, approved for treatment-resistant slow-growing lymphoma. Despite the efficacy, better response rate compared to Rituxan, and an acceptable safety profile, Zevalin failed to meet forecasts Figure 2. Issues cited with the slow uptake include high price, complicated prescribing, administration and monitoring process, and preference for familiar tools and processes and non-radioactive competitors amongst physicians Table 1. Figure 2. Annual revenue for Zevalin over the period —, reflecting a steady decline and failure to meet forecasts. Source: Biogen and Spectrum financial reports. Table 1. Reasons cited for the commercial challenges of Zevalin and Bexxar, highlighting market-driven forces that contributed to declining sales and discontinuation of the drugs. The compound was also targeted at the CD20 antigen and delivered a powerful local dose of gamma and beta radiation. The drug was developed in the late s by Coulter Pharmaceutical and acquired in by Corixa 36 , who attracted significant investment for the manufacturing and marketing of the drug. The drug was granted orphan drug designation in , and fast-track designation was added in Approval was delayed in the US, however, by a series of FDA requests for information, and was granted 4 years after the new drug application was filed in June Bexxar sales failed to meet expectations following the delay by the FDA. In , only 75 patients received Bexxar On 20 February , GSK announced that the manufacture of Bexxar would be voluntarily discontinued, due a projected decline in sales and the availability of alternative treatments. Issues cited more widely included clinical trial strategy and issues with the FDA, complicated patient referral process, supply chain issues, reimbursement, and emergence of non-radioactive competitors. Survival was worse in I-tositumomab arms of the study, and although not statistically significant, the results highlighted potential harms such as severe allergic reactions at the time of infusion and cytopenia Zevalin and Bexxar, as first-in-class targeted radiotherapeutics, shared some common commercial penetration issues Table 1. However, as one dose is usually enough, the cost of the drugs was actually similar to a full 4-months regimen of chemotherapy and Rituxan. The radioactivity of the treatments made some oncologists worry that it might prevent them from giving other treatments later. Prescribing the drugs also requires oncologists to coordinate care with the hospitals that administer it—to get either drug, patients first receive a low-radiation diagnostic dose, then imaging scans, then a high-radiation therapeutic dose, which comes a week after the first dose. Other more familiar and thoroughly tested drugs were also preferred as first-line treatment, leading physicians to prescribe such drugs even when Zevalin and Bexxar might have worked better. Financial incentives were also at play—as Zevalin and Bexxar were radioactive, they were administered in hospitals by nuclear medicine experts following a referral by hematologists, who were likely to lose revenue in some markets. As a result, referral rates were lower than they could have been based on the product labels. This led to the use of Zevalin and Bexxar as last resort treatments only. While beta-emitters Zevalin and Bexxar traversed along their respective journeys, the development of targeted radionuclide therapies using different alpha-emitters was also in progress. The first alpha emitter to appear on the market was metabolically targeted, analogous to I for thyroid cancer. Once injected into the blood, its active moiety radium mimics calcium and selectively targets bone due to natural tropism, with high specificity for areas of bone metastases. Approval was also received from the EMA in Xofigo had very high commercial promise due to its high efficacy and targeting specificity, and its potential to treat late-stage prostate cancer patients with few other options. Firstly, the prostate cancer market evolved rapidly with many non-radioactive competitors. In the trial, the combination caused more fractures and deaths than abiraterone acetate alone The resulting negative perceptions of the drug, the challenges to extend its use to earlier stages of prostate cancer, and the difficulties in combining with other emerging important prostate cancer medicines, made Xofigo subject to the increasing competition provided by new therapies. Xofigo may face additional commercial threats from the recently approved targeted radioligand therapy LuPSMA Pluvicto , which has the potential for utility in a broader population of metastatic prostate cancer patients; unlike Xofigo, LuPSMA use is not restricted to patients with metastases predominantly in bone. Figure 3. Annual revenue for Xofigo over the period — Source: Bayer annual reports. Following the failed trial and fast-changing nature of the prostate cancer market, analyst sales estimates fell. In , Xofigo suffered a double-digit sales decline that continued for several years Figure 3 , exacerbated by COVID restrictions Despite the challenges, Xofigo remains an approved therapy for the treatment of prostate cancer and Ra-chloride is undergoing further evaluation in several ongoing trials; the commercial performance of Xofigo has far exceeded those of the beta-emitters Zevalin and Bexxar Since the approvals of Zevalin, Bexxar and Xofigo, momentum has continued in the field. Promising proof-of-concept signals from small compassionate-use case series, investigator-led clinical trials, and improvements in tumor-targeting technologies resulted in more refined and optimized targeted RLTs. The drug has also show potential in off-label use in other neuroendocrine tumors e. If successful, these trials could significantly increase the patient pool eligible for Lu-PSMA As Lutathera becomes accessible to more hospitals and clinics, the number of patients qualifying for the treatment is projected to increase. Table 2. Lutathera revenue and estimated number of doses and treatments for the period — Figure 4. Lutathera sales and projected sales for the period — Source: The two additional trials in progress are expected to drive a 2—3x increase in currently modeled sales if successful, indicating the blockbuster potential of Pluvicto Figure 5 ; Figure 5. Pluvicto sales projections. Based on estimates from The company has also continued to increase its exposure to radiopharmaceuticals—for example by participation in the Series A financing of Aktis Oncology and the in-licensing of a other targeting agents from SOFIE Biosciences. The subsequent approvals and early robust market uptakes of the two lutetium-based drugs coupled with lofty future projections suggest better market readiness for RLTs than at the time of the launches of Zevalin and Bexxar two decades ago. This commercial success has in turn sparked the interest of investors and other large pharmaceutical companies looking to address unmet needs in cancer. Several developments facilitated further expansion of the RLT concept for oncology. These included improved drug targeting; the increased availability of Lu and growing investment in production of alpha emitters; advances in new processes for efficient manufacturing of RLTs and increasing production capacity; and compelling clinical data. As a result, momentum has continued to build in the nuclear medicine field, with the potential to elevate the profile of the entire sector. If the industry is able to effectively manage historical challenges, there is significant opportunity for a new and promising wave of RLTs to significantly change oncology treatment paradigms—particularly if alpha emitters are effectively utilized. With this momentum, new company formation has grown since , and pharma giants such as Bayer and Novartis continue to build early stage pipelines that expand into other targets and radioisotopes—with increasing focus on alpha-emitters. Hard data and future potential attracted significant capital. Private companies have also experienced positive market reception. Analysis indicates that at least 11 companies working in the ART space have raised significant amounts of capital during the period — Much of the focus of this new investment has been on targeted alpha approaches as investors seek out opportunities with differentiated clinical efficacy potential. Investment has also continued into companies pursuing beta-based approaches which have a different risk profile given the existence of two approved products and a more established supply chain. This is a reflection of increased public and private funding and clinical progression for many RLT products between and , as well as increasing cancer prevalence. Other opportunities and drivers for further growth in the RLT market include the aging population, increased awareness and understanding of radiotherapy isotopes, product innovation and development, and improvements to isotope production and infrastructure for clinical use. Beta-emitting isotopes currently dominate research efforts, as they have done since the inception of RLT In September , of ongoing registered radionuclide therapy clinical trials, were focused on beta-emitters and 28 on alpha-emitters This has been driven mostly by the availability of isotopes such as lutetium and the market is expected to evolve to reflect a shift to alpha emitter therapeutics. In comparison, beta emitters were projected to exhibit a CAGR of only Despite the advances in RLT and the positive outlook of the projected commercial landscape, challenges in the commercial penetration and uptake remain. Primarily, radionuclide supply, manufacturing and distribution, in particular for alpha-emitting radionuclides, are key obstacles for growth of the field. Effective delivery of RLT requires carefully orchestrated manufacturing, transport and preparation of radiopharmaceuticals, and necessitates dedicated infrastructure and mechanisms for waste disposal. The existing model for manufacturing, transporting and preparing radioligand therapy is suitable for administering the therapy to a limited number of people per week, and so there is a need to develop different models for larger patient populations. Additional challenges include the failure by physicians to adopt and rigorously evaluate this treatment modality, which may be explained in part by the multidisciplinary nature of the treatment and financial incentive challenges, as experienced by Zevalin and Bexxar Public perception and fear of radioactivity, as well as the perceived complexity of the treatment, may also be a difficulty, but one that can be overcome with better communication of risk—benefit profiles and increasing positive data around side effects and effectiveness. Radioligand therapy RLT is a growing market despite the challenges faced. Assuming that the early ground-breaking results obtained with ART continue to be borne out in rigorous clinical trials, the growth of ART is also likely to accelerate over the use of EBRT. Alpha particles are helium nuclei that are emitted from the nucleus of a radioactive atom. The amount of energy deposited per path length traveled linear energy transfer or LET is approximately 1, times greater than beta particles, leading to substantially more damage along the path of travel 59 , 61 , The combination of high energy and a short tissue range ensures the deposition of a large amount of energy within a short radius, leading to the effective killing of the targeted tumor with sparing of the surrounding normal tissue. This occurs due to direct DNA damage from alpha particle collisions with DNA, leading to severe DNA double-strand breaks, which are difficult to repair and trigger cell death. This is a key advantage of alpha-emitters as double-strand breaks are harder for a cell to survive than the single-stranded breaks induced by beta radiation 59 , 61 , Each of these requirements is explored in more detail below. A shorter half-life means the radioisotopes must be isolated closer to the time and site of treatment, whereas a longer half-life means the radioisotope can be produced in a specialized, central location and subsequently delivered to hospitals and clinics, provided that the daughters can be stable in the complexes during delivery. The 9. In addition, care must be taken to ensure the quality of the product is not compromised by prolonged storage periods, which can occur due to radiolysis from the targeting ligand—these characteristics may limit the deployment of Ac therapeutics. Lead Pb , with a shorter but still manageable half-life of This allows for delivery of up to 10 times more dose per unit of administered activity and provides the possibility for the synthesis of complex radiopharmaceuticals with minimum loss of radioactivity during preparation For a radiopharmaceutical to be used successfully, it must manifest sufficient stability in vivo to retain its targeting properties, and in the case of metal isotopes an appropriate chelator needs to be identified that matches the physical properties of the isotope to link the isotopes to targeting ligands 68 , With target in mind, the half-life of the isotope should also be compatible with the characteristics and half-life of the vector molecule 64 , Isotopes with longer half-lives are often complexed with long-lived antibodies: while the targeting is adequate, the long circulation times of antibodies may increase the risk of non-specific toxicity and off-target effects, e. Many isotopes emit alpha particles but some leave behind toxic by-products or decay before they reach a cell. Issues arising when using Ac for therapy, for example, as mentioned above, include unwanted toxicity from recoiled daughter radionuclides without a targeting ligand Upon the emission of an alpha particle, the radioactive daughter nuclides experience a recoil energy of about — keV, which is sufficient to allow the daughter nuclide to break free from the targeting agent. Further, the different chemical properties of the daughter radionuclide can make re-association with the chelator unlikely. When these factors are taken into account, despite that many different alpha-emitting radionuclides have been identified, only a few have desirable characteristics that render them suitable for clinical application 66 , Of the alpha-emitting radionuclides that have been identified as suitable for therapeutic use, several candidates have now been complexed to ligands such as PSMA inhibitors for evaluation in preclinical and clinical studies for cancer such as mCRPC Following these early evaluations, four of the most promising isotopes emerging within the ART field are Ac, At, Pb, and thorium Th —although Bi has been used with positive results in select malignancies, we are not aware of large scale commercial efforts with this isotope. Medical isotope shortages are a concern globally due to limited source material and challenging production processes. Although many isotopes are produced in nature, extracting a significant amount of purified material demands an accelerator or nuclear reactor and the facilities and expertise to chemically separate out the desired isotope from many others created during production. Other strategies include generators, where a parent isotope decays to the desired radionuclide that is then extracted, and cyclotrons that accelerate and bombard a target using variety of particles, including protons, alpha particles, lithium, and carbon ions. For the four isotopes identified as most suitable for therapeutic use, the availability and ease of production are therefore a key factor to consider for their use. Below is a state-of-play for each, including current and potential future availability and production methods. Despite being a straightforward method of production, the number of accelerators capable of a 28 MeV alpha-beam limits the availability of At, and current quantities are inadequate for widespread clinical use The main production route of Pb is through the use of radium Ra -based generators from which Pb is obtained by elution. The short half-life of Pb and the relatively long separation times of the methods above reduced its applicability to date. However, several companies such as ARTBIO recently started to innovate such production processes and made significant process toward scaling up the supply of Pb through sustainable methods While the specific production and purification methods of Pb are under development, there is good availability of the potential parent radionuclide Th, which provides good confidence in the ability of these approaches to ultimately scale to accommodate commercial therapeutic volumes. Future production methods in development for the production of Ac include neutron, proton and deuteron irradiation of Ra targets, and high-energy proton irradiation of Th targets. Large-scale production of Ac by cyclotron proton irradiation of Ra has also shown promise Table 3. Overview of current and potential production methods for four key alpha-emitting isotopes. Table 4. Summary of current and potential future capacity for key Ac production facilities. Since it can be produced in virtually unlimited amounts with current technology, Th has attracted attention as a viable radionuclide for several forms of systemic radionuclide therapy 80 , Although production of most alpha-emitting isotopes remains limited, many industry experts assume that capacity will increase as clinical evidence supporting the benefits of ARTs grows over time. In addition, technology development continues in the public and private sectors For example, Table 3 shows current and anticipated production methods for therapeutic alpha-emitter systems. Location of the different facilities will also be important for the scale-up of isotope production for clinical and commercial use, as ART is delivered as a just-in-time therapy. For the widespread treatment of patients in the future, facilities will be needed in each continent to ensure broad access. Growing radioisotopes demand will require sustained efforts from the health and energy sectors to ensure consistent supply and delivery particularly as there can be additional logistical difficulties in post-production processing and distribution to hospitals The efficacy of Ac was demonstrated in early first-in-human patient studies for mCRPC—one of which was conducted under a collaboration between the Joint Research Center in Karlsruhe and University Hospital Heidelberg in Two patients in highly challenging clinical situations showed a positive response to Ac-PSMA therapy—both experienced a complete response with prostate-specific antigen decline and no hematologic toxicity, with manageable xerostomia as the only notable side effect While the clinical application of Ac-PSMA was further developed with the collaboration of JRC and hospitals in Heidelberg, Pretoria and Munich, the remarkable potential of Ac also gained worldwide interest due to its use in a growing number of studies for patients with late mCRPC 86 , Consequently, an increasing number of novel Ac-labeled compounds are currently under development. We last counted 16 active clinical programs in clinicaltrials. However, as noted above, Ac faces major production challenges due to scarce availability of source material and the infancy of alternative production methods. The total global annual Ac production volume is approximately 66 GBq, which is inadequate for current and future demand from researchers and for the development of new agents 75 ; Figure 6. Estimates of current demand for Ac are less than GBq per year and it is estimated to grow by about — GBq per year for each Ac-based therapy that is approved for clinical use. Should efforts to develop Bi-based therapies also increase, Ac demand may be even higher Figure 6. Projected Ac demand versus current Ac production via Th production from U legacy waste and potential future production. Current Ac production is estimated to be 55—65 GBq per year, which is inadequate even for current demand from researchers. Demand is projected to increase by — GBq per year for each Ac-based therapy that is approved for clinical use. Should efforts to develop Bi-based therapies also increase, Ac demand may be even higher, highlighting the importance of new production methods to increase Ac supply to meet increasing demand. However, it should be noted that estimates of both demand and future production capacity vary widely. Private and public efforts to increase Ac supply for medical research and clinical use are ongoing. For example, in , the International Atomic Energy Agency convened a meeting to discuss a global strategy to meet the rising demand for Ac. The resulting report described potential production routes via multiple sources, including proton cyclotrons, linear accelerators, and nuclear waste. The US Department of Energy is also supporting many initiatives to increase production quantities to meet market demand for trials and experimental drugs and is currently leading the Tri-Lab Research Effort to Provide Accelerator-Produced Actinium for Radioimmunotherapy. Private companies such as TerraPower, a leading nuclear innovation company founded by Bill Gates and like-minded visionaries, are also contributing to efforts to increase production. While others are working to ramp up production of Ac by using a linear accelerator or cyclotron, TerraPower has been working since to increase the global supply of Ac from Th decay, and hopes to harvest the equivalent of , to , doses a year times the number of doses currently available globally from US Department of Energy U legacy wastes A delay is expected before production capacity can meet demand. Table 4 provides examples of current and potential sources of Ac production going forward. Although new production facilities have been set up or are under construction through efforts such as those of the US Department of Energy, new processes for supply expansion have not been fully developed, have only been demonstrated at small scale, or do not currently produce any commercially available quantities. It appears that the shift and rush to Ac has happened more quickly than with the beta emitter Lu: in that case, the supply has grown at a rate commensurate with the demand without creating long-term major shortages There is also significant concern in the sector that the rush to use Ac before full investigation of the stability of its chelated state and how its long-half life may result in potential toxicity was premature. In addition, the disconnect between supply and demand of Ac is slowing down academic research and is driving academic and industrial stakeholders to consider alternative isotopes such as Pb, which has a more favorable decay profile. There are a number of considerations when selecting an appropriate isotope for use in ART. Once an isotope—molecule combination has been matched to the target disease and its clinical profile, logistics and supply chains must also be built to match. Currently, it appears that several companies may have chosen the isotope first, based on logistics, rather than the approach proposed here. Developers face additional challenges in this space as guidelines and protocols vary between countries, adding complexity to an international delivery solution The scale at which models are implemented may vary, with certain benefits and challenges associated with implementation at a localized or centralized level. A localized model, where manufacturing and administration facilities are co-located, could be beneficial for many reasons. Such a structure may reduce geographical access challenges compared to a centralized model where people are required to travel significant distances, or where isotope choice is limited due to the need to transport therapeutic doses over long distances, even across countries, for treatment. In the early days of RLT, physicians experimented locally in these ways. A localized model may garner support by physicians as it could provide facilities with their own generators and production stations, improving treatment autonomy and the ease of referrals. Localized models of delivery and care may also alleviate the challenges posed by financial incentives and reimbursement that contributed to the issues experienced by Zevalin and Bexxar. The regulatory framework for such a model is not well-developed for pharmaceuticals while there is significant experience in radioactive diagnostics: current frameworks would have to be adjusted while the purveyors of such models may also have to develop processes with different requirements and features to enable such models. Quality assurance and quality controls are fundamental parts of the currently accepted GMP standards: manufacturers are expected to adhere to such standards and ensure them in every country where they supply therapies. A localized model creates challenges to such approaches as each individual hospital could be considered a manufacturing site, each with their own approaches and facilities out of the management of the originator companies. Regulators may have to inspect hundreds or thousands of individual sites, raising fears that patients may receive therapeutic doses with varying characteristics across different hospitals. In addition, several post-launch processes may become increasingly difficult: data collection pertaining to real-world use of the therapies; pharmacovigilance processes; product liability assignments; and others. In spite of this, it is worth remembering that distributed manufacturing models are routinely used in the nuclear medicine industry for diagnostic radionuclides such as 68 Ga and 99 m Tc, which have even shorter half -lives than Pb and can be produced with generators close to the point of use. It is therefore likely that a regulatory framework can be achieved for an analogous concept in the ART setting. A centralized model fits within the existing regulatory framework, enabling consistent quality controls across manufacturing sites of a given manufacturer. Such facilities could offer advantages such as improved manufacturing infrastructure for high-volume production, streamlined influx of source material, more uniform rules for developers and better regulatory and quality control. In a centralized model, it should also be easier to assemble and train teams with the relevant manufacturing expertise in this budding new area. Centralized models do, however, create supply chain risk. A manufacturing network with few facilities and low supply chain redundancy may lead to radionuclide shortages and disrupt patient treatment. For example, in May , Novartis was forced to halt production of both Lutathera and Pluvicto at facilities in Italy, the US and Canada due to quality issues. The disruption led to shortages in Europe and Asia, but these areas were also supplied from another facility in Zaragoza, Spain. Looking to the future, a middle ground may be the best option in the form of a distributed model, with a moderate number of manufacturing facilities supported by an integrated supply network. This may overcome challenges that prevent rapid scale up on a local level, while addressing challenges such as long patient travel, isotope transport times, supply chain security, and regulatory consistency. In this model, although not every country or state in the US may have its own production and manufacturing facility, multiple sites could ensure that therapies are more accessible, reducing patient travel and therapy transport times. Such a network may also be more resilient to supply chain shocks, and render regulatory compliance more manageable than in the localized model. A network of 10—15 sites per region may be sufficiently redundant for a resilient supply chain and it should be manageable from a regulatory perspective. Distributed networks are known to be far more stable and productive than centralized alternatives, and the redundancy that would be introduced will be essential for effective and stable therapeutic supply in the future. Taking the internet as example, network redundancy provides multiple paths for traffic, so that data can keep flowing even in the event of a failure. Put simply, more redundancy equals more reliability. Currently, the unexpected closing of one reactor or one specialized laboratory could already lead to worldwide problems in the supply of medical radionuclides and therapeutics. Other reactors or manufacturing sites may not always absorb the increased demand. This phenomenon was eminently on display during the productions issues of Novartis described above 90 , Alpha radioligand therapeutics ARTs offer great promise for the treatment of cancer that is reflected in high expectations for patient impact and financial returns. It is encouraging to see this reflected by the rapid growth of ART-focused companies and expanding clinical pipelines within the field. Future growth will be fueled by further efficacy and safety data from ART clinical trials and real-world results—with expanded investigations of earlier stages of cancer. Thorough investigations of the fundamentals of ART coupled with combination therapies with other modalities, particularly immunotherapeutics, provide fertile ground for academic and industrial researchers alike. Sustained efforts to increase the availability of isotopes by establishing more manufacturing facilities and new methods of production are key to successful growth of the field. Such advances will need to keep pace with each other to avoid situations such as the current expected imbalance between supply and demand of Ac. Cross-disciplinary training of specialized practitioners to overcome the referral challenges to adoption will also need to be supplemented with an adjustment of financial incentives that puts patients first. New delivery models must also be developed and implemented to provide equal and resilient patient access. This innovation will require that regulatory frameworks evolve at the speed of the rest of the field in order to balance the needs of all stakeholders. Both authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. British Medicine Journal. Obituary: E. Br Med J. 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Preclinical and clinical status of PSMA-targeted alpha therapy for metastatic castration-resistant prostate cancer. Targeted alpha therapy: progress in radionuclide production, radiochemistry and applications. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Commercial and business aspects of alpha radioligand therapeutics. Taylor 2. Introduction Alpha radioligand therapeutics ARTs have been gaining increasing attention as a rapidly advancing experimental modality that holds promise for delivering high doses of lethal radioactivity specifically to cancer cells. Modern day applications Great progress has been achieved through radiation-centric approaches in the fields of diagnostics, nuclear medicine, and targeted therapies.

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