The use of theranostics has accelerated radiopharmaceutical development. Theranostics is the combination of diagnosis and therapy with the same targeting molecule, labeled with a diagnostics-therapeutic radionuclide pair. Ideally, you want to bring your new radiopharmaceutical candidate to patients as fast as possible. You can use Phase 0 imaging studies to achieve this. To understand how Phase 0 imaging studies accelerate your radiopharmaceutical development it is important to know what steps you need to take to complete one successfully.
First-in-human microdosing study with radiopharmaceuticals.
You start with selecting a radionuclide and labeling method that match the pharmacokinetics of your targeting agent. Once you succeed to label the compound, you can test your compound in preclinical experiments.
Preclinical experiments consist of in vitro and in vivo models. With a proof-of-concept in a simple rodent model, you can continue to test your (new) radiopharmaceutical in humans. For example, with a new radiopharmaceutical for a certain type of tumor, you need to show the proof-of-principle in a rodent model with an induced tumor. For a microdosing study you don’t need to perform extensive animal studies in sophisticated animal models with spontaneous (orthotopic) tumor models. Moreover, you don’t need to perform large animal studies before starting your first-in-human study.
Requirements for a Phase 0 study.
After you provided proof-of-concept in a preclinical animal model, you can start the translation of your new radiopharmaceutical for clinical use. In other words, you need to produce a clinical grade radiopharmaceutical for in human use. This means that you need to manufacture your radiopharmaceutical under GMP-conditions in a GMP hot lab facility. However, this doesn’t mean that you always need to produce the targeting agent/precursor (antibody/peptide/small molecule) under full GMP. Namely, you can use GLP-grade material and label this in a hot lab under GMP-conditions. The final product will then be GMP-grade. This process saves you significant time and resources.
To start your Phase 0 imaging study, you also need to perform a toxicity study. In contrast to studies with therapeutics, the requirements for toxicity studies for radiopharmaceutical development are limited. In this case, for imaging studies, you can use low doses of your targeting agent. This allows you to conduct your trial under the microdosing principle.
When you administer a dose of your radiopharmaceutical that is lower than 100 microgram (or 30 nanomoles for large proteins) your study will fall under microdosing according to the FDA and EMA. This means that you only need to do a single dose extended toxicity study. This toxicity study is more time efficient and cost effective. At the same time, you need to manufacture less drug product for your toxicity studies, as the dose is lower, you need less animals and you don’t need large animals. This, of course, also reduces your costs significantly.
Before you can start in human studies, you also need to calculate the radiation burden to the patient. You can use the (biodistribution) data from your preclinical experiments to estimate the radiation dose to patients. When you have combined all the information in a submission package for the authorities and have obtained approval, you can start with your study.
The advantages of Phase 0 imaging studies with your radiopharmaceutical.
When you perform a Phase 0 study, you can test your radiopharmaceutical in your target population. Unlike classical Phase 1 studies in healthy volunteers, this will give you disease targeting information of your radiopharmaceutical. Moreover, you will obtain the biodistribution and pharmacokinetics of your compound. In short, you will obtain much more relevant data from a Phase 0 imaging study.
The imaging study will also give you an indication that you can use a therapeutic radionuclide to treat the disease of interest. When you perform dosimetry on the imaging data, you can calculate the dose to, for example, the tumor and healthy tissues. With this information you can then design your theranostic pairing.
So, how does it accelerate your radiopharmaceutical to patients and the market? With the information from your Phase 0 study, you can more effectively design your Phase 1 and 2 study to investigate the diagnostic performance of your radiopharmaceutical.