From Bench to Bedside: Preclinical Best Practices in Radioligand Therapy Development

Introduction

Radioligand therapies (RLTs) combine the precision of targeted ligands with the power of radioactive payloads. With multiple drug approvals over the last 5 years, including Pluvicto, the first targeted theranostic, and Lutathera, the first approved peptide receptor radiolnuclide therapy (PRRT), radioligand therapy development has seen remarkable growth and ongoing clinical validation. Success in this area has made radioligand therapy development an extremely attractive area for drug discovery, with many sponsors investing both time and resources to advance next-generation radiopharmaceutical candidates. Radioligand therapy development, however, comes with a number of unique and complicated challenges, making the execution of preclinical best practices essential to success. The importance of a strong preclinical foundation is paramount, enhancing the translation of preclinical RLT findings from bench to bedside. 

Challenges unique to preclinical radioligand therapy development

Managing global radioligand therapy trials is complicated. With complex biological and regulatory requirements, and numerous supply chain and logistical considerations unique to this specialist nuclear medicine area, success depends on thorough forward planning and deep-rooted expertise. Success relies on careful consideration of radiochemistry, comprehensive in vitro and in vivo evaluation, biodistribution, therapeutic efficacy assessment, preclinical dosimetry, and the development of robust and regulatory-ready analytics. 

Regulation for radioligand therapy development continues to evolve alongside growing development interest, with many different countries maintaining their own approval requirements. An in-depth understanding of the regulatory frameworks for each country participating in multi-center, international clinical trials is essential to streamline radioligand development operations. Perceptive pairs regulatory expertise with the infrastructure necessary to handle such large-scale radionuclear clinical trials, allowing sponsors to navigate complex regulatory landscapes efficiently, maintaining compliance across different regions, and accelerating the path from drug development to market.

Selecting an appropriate radionuclide requires careful consideration of radiation type, emission energy, physical half-life, and production availability. The relative advantages and limitations of alpha versus beta emitters, along with their differing toxicity profiles and optimal activity levels, must be correctly aligned to achieve effective and safe radioligand performance. With all of this in mind, it is extremely important to follow preclinical best practices in radioligand therapy development.

Preclinical best practices

A robust early-phase strategy provides the scientific foundation for successful clinical translation. At Perceptive, we believe the next breakthroughs in RLT will come from strong preclinical strategies which anticipate potential challenges and bottlenecks.

Best Practice Guidelines:

• Radioligand and radionuclide selection should optimize affinity, specificity, stability, and half-life.
• Radiolabeling must achieve high specific activity, purity, and reproducibility.
• Preclinical imaging is essential to confirm target engagement and biodistribution.
• Dosimetry planning integrates animal data to project human dosing.
• Study design should include multiple models, appropriate controls, and longitudinal assessment. 
• Safety and toxicology evaluation must monitor both ligand and radiation-related effects while collecting standard endpoints.
• Translation readiness requires validation of GMP production, robustness of the supply chain, and regulatory-compliant analytics.
• Risk mitigation is used to address scaling uncertainties, supply constraints, and unexpected biodistribution challenges. 

Pharmacological safety and toxicology considerations

Characterizing potential toxicities early prevents delays in clinical translation. Imaging plays a key role in visualizing off-target effects and understanding biodistribution in vivo. Clinical markers such as complete blood counts, chemistry panels, and urinalysis should be included alongside clinical markers, producing a comprehensive evaluation of organ function and systemic toxicity. Radiation exposure should be monitored in relevant organs using quantitative imaging, with dosimetry predictive modeling providing estimates to guide safe and effective human dosing regimens. Understanding this radiation profile across tissues is essential for dose planning. Here at Perceptive, we are experts in this field, tailoring safety endpoints to each compound’s mechanism of action and route of administration to ensure preclinical safety evaluations are robust, targeted, and align with regulatory expectations.

Conclusion

Radioligand therapy development is notoriously complicated, but has the potential to deliver highly targeted treatments which improve efficacy whilst minimizing off-target effects. Perceptive tailors clinical trial design to account for radiation safety, dosimetry, and patient selection criteria specific to radioligand therapies, bolstering the success of your clinical trial. When executed effectively, early-phase studies de-risk radioligand therapy development. Moving to first-in-human studies requires the infrastructure and expertise of an expert preclinical imaging provider, while preclinical rigor reduces risk and accelerates clinical trial timelines. Developers who adopt best practices in this area will be those positioned to bring next-generation radioligand therapies to market. 

With over 15 years of experience and over 3,000 studies supported, you can count on Perceptive to drive preclinical best practices throughout your radioligand therapy development, your ally for radiochemical trial success.