Radioligand therapies (RLTs), in contrast to traditional treatment methods, have the potential to target cancer cells while minimising toxicity to healthy tissues, and Morgan Stanley estimates that the radiopharmaceutical market will grow from about $7 billion in 2022 to $39 billion by 2032. Pluvicto and Lutathera, two Lutetium-177 (177Lu) RLTs for metastatic castration-resistant prostate cancer (mCRPC) and neuroendocrine cancers (NETs), are prime examples, jointly generating over $479 million in Q1 2024 alone.
Big Pharma has now joined the RLT space, with recent multi-billion-dollar acquisitions further showcasing how this market is set to quickly evolve as a promising cancer precision treatment and providing more patients with access to life-saving treatments. Recent activity includes Bristol Myers Squibb (BMS) acquisition of RayzeBio for ~$4.1 billion, Lilly’s acquisition of POINT Biopharma for $1.4 billion and AstraZeneca’s acquisition of Fusion Pharmaceuticals in a deal worth up to $2.4 billion. Sanofi is now the latest pharma entering the RLT race, paying $100 million upfront deal with RadioMedix and Orano Med for the global rights of a NET-asset.This follows Novartis’ ongoing acquisition streak, which began in 2018, to the more recent planned $1 billion upfront payment to acquire Mariana Oncology. These acquisitions are now providing Big Pharma with access to RLTs using diverse radioisotopes including the alpha-particle emitter, Actinium-225 (225Ac). Examples of pipeline assets include: Fusion Pharmaceuticals’ 225Ac-PSMA-I&T and POINT Biopharma’s 225Ac-PSMA-62 for mCRPC, as well as RayzeBio’ 225Ac-DOTATE-SSTR2 for neuroendocrine cancer.
However, while there are a number of 225Ac-RLTs in development, none are currently approved, leading to uncertainty in their future and the question of whether they have a place in a field currently driven by 177Lu-RLTs. In this article, we will explore if 225Ac-RLTs are likely to change the treatment paradigm in mCRPC and NETs, or whether Pluvicto and Lutathera will continue to dominate the RLT landscape.
Advantages of 225Ac-RLT over 177Lu-RLT
Alpha-emitters such as 225Ac offer several advantages over their beta-minus emitters counterparts, such as 177Lu. For instance, the longer half-life of 225Ac of 9.9 vs 6.6 days for 177Lu facilitates more centralized manufacturing and global shipment of 225Ac-RLTs in a ready-to-use form. The longer half-life may also allow more flexible patient dose reservation and administration schedule management compared to 177Lu-RLTs.
Additionally, 225Ac’s shorter range could minimize undesired toxicity to healthy tissues, while the higher potency of 225Ac-RLTs has the potential to reduce the risk of treatment radioresistance seen with 177Lu-RLTs. As such, patients who develop resistance to the latter may benefit from 225Ac-RLTs. Moreover, alpha-emitters are better suited for smaller tumours and tumours with homogeneous expression of the target of interest (e.g. PSMA) as, unlike beta-minus emitters, they do not exhibit cross-fire effect, which can kill non-targeted cells and increase the risk of undesired toxicity to healthy tissues
But the question remains: are these combined advantages enough for 225Ac-RLTs to change the treatment paradigm and justify the big pharm’s expense to develop them?
Potential barriers to the wider use of 225Ac-RLTs
1. Assessment of 225Ac-RLTs in neuroendocrine and prostate cancer is mainly focused on the post-177Lu-RLTs setting
BMS’ leading asset 225Ac-DOTATE-SSTR2 for neuroendocrine tumours is poised to be the first 225Ac-RLT to enter the market by 2028. However, with its use limited to patients who have progressed following 177Lu-SSA therapy, approval of this 225Ac-RLT is unlikely to significantly change the treatment paradigm in neuroendocrine cancers.
Similarly, 225Ac-RLTs in the mCRPC landscape are also poised to enter the market at later lines in the treatment algorithm, at least in the near-term future. For instance, while the positive interim data from Fusion Pharmaceuticals’ Ph2 TATCIST study showed responses of 225Ac-PSMA-I&T in both treatment-naïve and Pluvicto-treated patients, Fusion Pharmaceuticals announced a Ph2/3 trial in the post-Pluvicto setting which will only initiate in 2025. Fusion’s strategy is likely aimed at positioning 225Ac-PSMA-I&T as the treatment option post-Pluvicto, especially considering that this market will grow rapidly should Pluvicto move to earlier lines of treatment (as based on the ongoing Ph3 PSMAfore study, filing expected H2 2024). This strategy is not surprising and is likely in response to the observed inherent resistance to Pluvicto (Ph3 VISION trial).
In order to pave the way to advancing 225Ac before 177Lu-RLTs, Big Pharma may explore combination therapies to enhance 225Ac-RLT potency. Combining 225Ac-PSMA-I&T and Olaparib could boost treatment potency, potentially moving Fusion Pharmaceuticals’ combination therapy to earlier lines of treatment. However, this combo is still a way from reaching the market, with Fusion Pharmaceuticals’ combination study set to initiate in H2 2024.
Novartis is also committed to bolstering its RLT portfolio with 225Ac-PSMA-617 in PSMA-positive prostate cancer with or without prior Pluvicto treatment (Ph1 study) and 225Ac-PSMA-R2 (Ph1/2 study) in heavily pre-treated PSMA-positive mCRPC patients in post- and pre-177Lu-RLTs settings. These early studies will be key to understanding the long-term potential of 225Ac-RLTs vs 177Lu-RLTs.
2. The limited availability of 225Ac and the complex production process of 225Ac-RLTs may restrict their global rollout
Producing 225Ac requires specialized equipment like cyclotrons or nuclear reactors, which require a dedicated supply chain that can potentially lead to bottlenecks. The recent 225Ac shortage, exemplified by BMS’s temporary halt in patient enrolment for the Ph3 ACTION-1 study underscores this challenge. While supply is anticipated to resume in Q1 2025, this setback highlights the importance of a stable 225Ac supply to the market entry of 225Ac-RLTs. Advanced Accelerator Applications, a Novartis company, and POINT Biopharma have already secured agreements with TerraPower to obtain 225Ac in collaboration with Isotek. However, Fusion Pharmaceuticals has gone a step further by establishing multiple strategic partnerships that may provide AstraZeneca with preferential access and pricing for 225Ac.
While recent acquisitions have provided AstraZeneca, BMS and Lilly with access to advanced state-of-the-art R&D and manufacturing facilities, optimizing scale-up, product assembly and patient delivery logistics within radioisotope decay timeframes requires extensive expertise, facilities, and coordination that even Big Pharma companies are not used to. Even Novartis experienced a Pluvicto shortage in 2023, prompting it to swiftly expand production lines at the Millburn, New Jersey site, and build new state-of-the-art RLT facilities in Indianapolis, Indiana, and California to expand its manufacturing and supply network. While Novartis may lead the charge in paving the way for future advancements, it’s important to note that currently, the company offers only two products, both relying on the same radioisotope. As such, other developers may require entirely different, and costly, R&D, manufacturing and distribution infrastructures. As such, Big pharma may seek to establish partnerships (e.g. AZ’s partnership with Nucleus Radiopharma) with CDMOs to support the development and delivery of RLT, which may also have the expertise to facilitate the regulatory hurdles associated with obtaining and using radioisotopes from different radioisotope manufacturers
3. ‘Daughter’ isotopes may induce toxicity in healthy tissues
A significant concern with 225Ac revolves around its decay chain, where several ‘daughter’ isotopes emit additional alpha and beta particles. While this can increase therapeutic effectiveness, it also poses a safety risk if these isotopes escape the targeted tumour environment. Interestingly, while Radium-223 (223Ra) shares a similar decay profile to 225Ac, the FDA (label) and European Commission (label) approvals for Xofigo (223Ra-dichloride) did not require additional dosimetry studies, thus suggesting that potential daughter isotope toxicity was not considered a significant threat. However, a study from RayzeBio showed a small fraction of free daughter isotopes from its 225Ac treatment going to the kidneys. As such, considering the multiple 225Ac-RLTs assets in development, the regulatory authorities may enforce dosimetry studies in the future to ensure the safety of 225Ac-RLTs.
Final considerations: assessment of 225Ac-RLTs beyond neuroendocrine and prostate cancer
Looking at the balance of evidence, it is clear that 225Ac-RLTs offer some advantages over 177Lu-RLTs, including a longer half-life, more centralized manufacturing, and the potential to reduce treatment resistance. However, the complexity of obtaining 225Ac limits its investigation in clinical trials, making it difficult to prove its clinical efficacy and justify the expense associated with investigating it. Therefore, innovative production methods for 225Ac are crucial to advancing its clinical trials.
Additionally, the most advanced clinical trials of 225Ac-RLTs are currently limited to 177Lu post-treatment settings, making it unlikely that the treatment paradigm in the NETs and mCRPC settings will change until 225Ac is investigated in early lines of treatment. However, recent Big Pharma acquisitions have provided access to a wider range of isotopes, targets and indications beyond PSMA and SSTR2 (e.g., AstraZeneca’s 225Ac-IGF-1R focus on solid tumours expressing IGF-1R), offering hope for the broad clinical use of 225Ac-RLTs and other RLTs, justifying these billion-dollar acquisitions. Even if 225Ac-RLTs show their therapy utility, HCPs and patients may remain skeptical of “radioactive” therapies, particularly when introduced in early treatment lines, potentially hindering their adoption and improvement in SoC. As such, it is crucial for Pharma companies to raise awareness and educate HCPs and patients to successfully implement 225Ac-RLTs in the market. Nevertheless, for 225Ac to realise its clinical potential and global commercial rollout, a robust and unconstrained supply of 225Ac will be critical, along with efficient logistics networks to deliver 225Ac-RLTs to patients in a timely manner.
Additionally, to establish RLTs as the SoC, Big Pharma must go beyond simply selling a product and focus on addressing the systemic challenges that could hinder widespread adoption. This requires a collaborative approach with healthcare systems and regulatory bodies to thoroughly identify and overcome the barriers related to integration, access, and scalability.
It is noteworthy that healthcare systems are not yet fully prepared to support the large-scale adoption of RLTs. Obstacles such as limited nuclear medicine centres and a shortage of specialized staff significantly hinder patient access to these therapies. While innovation in RLT is advancing rapidly, the readiness of healthcare infrastructure is lagging. This gap between technological advancement and healthcare readiness mirrors the early experience with CAR-T therapies, where groundbreaking innovation did not translate into immediate adoption due to similar challenges.
Big Pharma has a critical role in supporting policies, enhancing referral pathways, and optimizing funding mechanisms to accelerate the adoption of RLTs. Without proactive measures, the growing demand for these therapies could soon overwhelm healthcare systems. As such, strategic decisions must go beyond clinical development and focus on building the necessary infrastructure, collaborating with healthcare providers, and ensuring efficient patient access.
It is crucial, then, that Big Pharma companies stay ahead of this rapidly evolving market by making key strategic decisions beyond clinical development to bring the opportunity to light for these billion-dollar acquisitions. The significant investments in these therapies must be supported by a forward-thinking approach focused on the long-term strategy aimed at addressing adoption barriers, driving widespread clinical integration, and ultimately delivering better patient outcomes.
