Source- Ronny Gal Chief Strategy Novartis , Linkedin : The...

Source- Ronny Gal Chief Strategy Novartis , Linkedin

: The annual #SNMMI24 meeting took place last week and we continue to see significant advancement in the effort to develop radioligand therapies (RLT). There are couple of questions that often come up in discussing the field.Are radioligand therapy drugs just another form of Antibody-Drug Conjugates? Not quite. They share the logic of having a targeting moiety bound to a ‘payload’ but the properties of radioligands as opposed to cytotoxic agents drive different choices, thus only ~20% of the disclosed RLT molecules in the clinic are antibodies, with smaller molecules and peptides being much more dominant. Radioligands are inherently more labile (the radiation decays). Smaller molecules provide deep penetration into tumor tissue, which allows for fast binding, while also providing fast clearance through the kidneys. The hypothesis is that the deeper penetration and relatively quick decay may give RLTs below 50kDa a safety edge. This logic will be tested over the next decade as we are now seeing several validated ADC targets being adopted for RLT development by multiple companies (see graphic). The aim is that the better safety profile of RLTs could allow for their use in earlier lines of therapy. The recent results of NETTER-2 in 1L treatment for GEP-NETs provide us with one datapoint supporting this hypothesis.Another question is the choice of radioisotope – is alpha radiation ‘better’? Again, in my view, not quite. Radioisotope payloads are either beta or alpha emitters, with a 73% and 27% share in clinical trials, respectively. There is a more balanced (roughly 50:50) alpha and beta split in pre-clinical development. This should not, however, be taken as indication that alpha emitters are the future.The current thinking is that choice of radioligand will depend on the level of heterogeneity in the tumor. Beta emitters have a longer travel path (e.g., 2mm for Lutetium-177 in soft tissue) and lower energy (133 keV). They will thus have the advantage of being able to utilize the ‘crossfire effect’ of radiation to treat cells away from the binding site in the tumor to deliver a therapeutic dose. In tumors with more heterogenous expression of the target, they may prove to be the better agents. On the other hand, alpha emitters have a shorter travel path (e.g., 100μm for Actinium-225 in soft tissue) but pack more energy (5.8 MeV). That would potentially allow them to be more efficacious in tumors with uniform expression, but possibly less effective in heterogenous tumors. In addition, they would need to be more selective – as binding in healthy tissue could also lead to higher side effects. The actual balance of the two approaches will only be demonstrated in clinical trials. At Novartis we have both alpha and beta programs in development as we seek to match the isotope with target abundance and line of therapy.