2.3 Radiopharmaceuticals space heats up as BMS and Lilly join the fray

The use of radiation in medicine began with the work of the great pioneers Marie Curie, her husband Pierre, and Henri Becquerel. In the 1940s, Samuel Hertz, Samuel Seidlin, and William Beierwaltes established radioactive iodine (I-131) as a treatment for overactive thyroid and thyroid cancer. 

The effects of radiation are not cell-specific – it is inherently damaging to all cells, so the focus of current development efforts is on delivering a targeted dose of radiation, by attaching a radioisotope to an agent, be it a small molecule, a peptide, or an antibody, that can recognise and bind a protein expressed on the surface of a cancer cell. 

Over two decades ago, the approvals of Zevalin (ibritumomab tiuxetan) and Bexxar (tositumomab), CD20-targeting antibodies labelled with Yttrium-90 or Indium-111 and with  I-131, respectively, kicked-started the modern era of radiopharmaceutical development. Neither was a commercial success, however, as the naked antibody Rituxan (rituximab), which also targets CD20, dominated the market for CD20-positive lymphomas. Although perhaps not quite as potent as its radioactive rivals, Rituxan was far easier to handle and administer. It was also far easier to make.

Radiopharmaceuticals production is complicated. At a minimum, these constructs involve a radioisotope, a chelator that binds it, and a linker that connects these to the tumor targeting agent. Moreover, because the radioisotopes used in medicine typically have half-lives of seven to ten days, they cannot be stockpiled – manufacturing is unavoidably on a just-in-time basis. This has led to supply chain problems and product shortages, which can have very serious consequences for patients.

Optimising a radiopharmaceutical’s residence time in a patient’s blood is a key parameter. Too long in the circulation can expose off-target tissues to excessive radiation. Rapid elimination via the kidneys is also problematic, as patients’ tumors may not receive sufficient drug to have a significant impact, while the kidneys may be exposed to too much.

Ratio Therapeutics adds in an additional molecule, an albumin binder, to enable it to ‘tune’ the pharmacokinetic (PK) profile of the drug. Novartis has invested heavily in this modality by acquiring Advanced Accelerator Applications and Endocyte, which gave it ownership of the gastroenteropancreatic neuroendocrine tumor drug Lutathera (lutetium 177 dotatate), and the prostate cancer drug Pluvicto (lutetium-177 vipivotide tetraxetan), respectively. More recently, Eli Lilly & Bristol Myers Squibb have entered the fray, by acquiring Point Biopharma and Rayzebio, respectively. The field is definitely hotting up.

Companies mentioned in this episode: 

Abdera Therapeutics, Advanced Accelerator Applications, Algeta, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Eli Lilly, Endocyte, Noria Therapeutics, Novartis, Peptidream, Point Biopharma, Ratio Therapeutics, Rayzebio

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