What do we look at? This is all also a theranostic agent. We have these small molecules from different making, but one of the most prominent are from Uwe Haberkorn from the Heidelberg group, FAPI-46 and 74 for diagnostic agents being designed to bind to the serine protease, which is highly expressed on the cell surface of different types of tumors that we will look at. Of course we have diagnostic agents F18 and gallium 68. Then we have a lot of therapeutic agents, Y90, lutetium, terbium, actinium already out there.
Looking on the target of FAP, I guess you knew the risk that we would move out of prostate cancer a little bit because it is also expressed on prostate cancer on urologic diseases in general, but the primary target is really outside prostate cancer, I believe. So highest expression level seen here in this multi-site database on mRNA expression based in Heidelberg was in sarcoma, different sarcoma subtypes and in patients with GI cancers, hepatobiliary cancers. And there you can have patient data sets with really high expression levels and potential interesting application for theranostics.
Of course, we have an imaging biomarker for FAP expression. This is something that we were able to show in a single center dataset prospective trial that showed there is a significant association between FAPI PET and the FAP histopathologic expression level. It's not a very strong association, but it's significant. And then also FAPI PET is for different types of malignancies, has a high positive big devalue. So it's also a good diagnostic agent for different types of cancers.
And more so going into the therapeutic space, we have had some experience with Y90 FAPI treatment in patients with sarcoma, mostly sarcoma. This was a publication coming out this year, 30 patients up to 80 cycles of treatment. We saw some partial responses, 12%. We saw a lot of stable disease in this patient cohort. So disease stabilization under multiple cycles of treatment with Y90 FAPI of around 50%. Here's one of the most prominent case or more prominent cases patient with SFT, multiple metastasis after four cycles of treatment. We had a solid partial response in that patient.
And even more so, it's well-tolerated so we have few side effects, mostly hematologic side effects, some anemia, and 10% or less than 10% of platelet counts, thrombocytopenia. Otherwise, we did not find any symptomatic side effects.
Of course, this targeting is up for optimization in the future. There are different strategies you can approach. Here's one that we have approached in collaboration with telix going from a monomer binder to a dimeric binder. This then enhanced the retention of radionuclide inside the tumor. This is a really intra-patient comparison when we switched from a monomer treatment for the first cycle to a dimeric treatment on the second cycle in the same patient. We saw a significant increase of retention more than 120%. We saw significantly higher radiation dose by using the dimer of three Gray per Gigabecquerel as compared to less than half on the monomer. So this is really improving the target tumor targeting, but of course it's just one component of a radioligand. Then further down, we switched the type of radioactivity going from a pure beta emitter to beta plus Auger emitting radioisotope. That's the compound that we now chose for going into a prospective trial funded by the EU Horizon program on terbium therapy dimeric treatment.
Of course, there's more to come. We have next-generation FAP radioligands that we have seen already in the first talk by John. Different types of ligands I'd like to highlight. There's one PNT by point that has shown longer retention, much longer retention than we have seen for the dimer. This was 1.2 days in this preclinical study and then more than six days for the PNT compound. Here's an example of metastatic breast cancer. There's very interesting binders that establish even covalent binding so really irreversible high affinity binding and preclinical data at least suggests that these binds very strongly deliver very strong radiation to the FAP target, to the FAP tumor, and then leads to very good responses again in a preclinical model.
Even more so, there's also an onco FAP variant. It's a trimeric binding compound, also with very promising preclinical data showing a long retention inside tumors more than 72 hours and 96 hours tumor retention half-life and very good at least preclinical results that we might see in the future in the clinic.
And then also we've seen the ratio compound already now published in Journal of Nuclear Medicine, a trifunctional compound now explored for alpha and beta treatment and also showing these very strong tumor retentions and quite low background. So I think there's a lot to explore in the future on this concept.
Summarizing the FAP future, which is of course shining bright for different tumor entities. I think we've identified very important tumor entities, including sarcoma, hepato, and GI cancers that show high FAP expression level and are potential targets. We have prospective evidence already that the diagnostic compound really is a biomarker of FAP expression level and we have a high positive value and we have a favorable safety. We see some disease stabilization and also partial response, but we are mostly looking into the next-generation ligands to potentially improve tumor targeting.
With this, I'll leave you with the pro aspects and handing over to Lena Unterrainer now heavily battling me on the con aspects of FAP targeting. Thank you very much.
Lena Unterrainer: Okay, hello everyone. My name is Lena Unterrainer from the Technical University in Munich, and I'm glad to have the opportunity to talk within the next five minutes about the cons in the context of FAP-RLT.
Here are my disclosures.
There are currently, as we have heard, different preclinical and first small clinical studies that are investigating the potential role of FAP-based radionuclide therapy in metastatic diseases. And when we are investigating novel targets and novel radioligand therapies, the goal is of course similar tumor retention in the metastatic sides compared to our working horses. That means PSMA, radioiodine, and DOTATATE therapy. But very often, the post-therapeutic specs in the context of FAP-RLT looks like the images you can see here with no relevant tumor retention already after 48 hours.
Another example you can see here, so these serial SPECT images of patients from the FRONTIER trial revealed a rapid washout from tumor sites with under 0.5% of the injected activity remaining by 24 hours, which is quite contrary to the preclinical data on this exemplary therapeutic FAP ligand.
And when we're talking about curative potential, it of course always depends on the achievable tumor dose. And we know that our old working horse radioiodine and our now very well established RLTs, PSMA and SSTRs are curative in the context of radioiodine, or at least effective such as we know that from PSMA and SSTR. The question we have to ask here is if FAP-RLT can ever be treated as an equal to these other RLTs.
There's quite a big difference between FAP on the one side and radioiodine, PSMA, and DOTATATE on the other side as the majority of current trials on FAP-RLT are basket trials that are not only testing only one tumor entity, as you can see in this exemplary trials that are listed below. These exemplary studies are testing different FAPI ligands combined with different isotopes in different clinical scenarios so we also have here a huge heterogeneity, which makes it even more difficult to identify optimal and radioligand candidates. And we can also already state here that we are at the moment in a very early mode trial and error process with multiple publications that were often generated under compassionate use program, which also does not really lead to evidence.
And even if you know that there are some tumor entities and that FAP is higher expressed than in other tumor entities, high expression is, for example, known as in sarcomas or SFTs, the FAP expression is quite heterogeneous, also often within one tumor entity, and this makes it even more difficult to generate evidence on FAP-RLT when using basket trials.
And even if we are now having next-generation therapeutic ligands, as we have heard that, that really provide a better tumor retention compared to the first-generation in a lot of these trials, including next-generation and ligands, the uptake and thereby the absorbed doses show a high variety with a huge range of absorbed doses as you can see it here.
So at the moment, we can say that we have too many unclear factors as we are investigating FAP-RLT in very heterogeneous diseases using multiple radioligands and are labeling them with different isotopes. So that we first have to understand which ligand is optimal for which disease or which clinical scenario and what is, of course, depending on the tumor entity, the optimal isotope.
We should also not forget about the safety profile in the context of FAP-RLT. Even if many publications describe unacceptable safety profile, we should definitely not neglect any adverse events such as a significant reduction of the platelets.
And as NUCMED physicians, we should also, of course, not sit in our ivory tower as of course also other treatment options in advanced stages of, for example, soft-tissue sarcoma become more prominent while these non-radioactive treatment options might be real competitors to our FAP-RLT.
And last but not least, of course, we have to think about combination therapies that might be more effective than FAP-RLT alone.
Let me sum up. We are currently still in a trial and error situation regarding FAP therapy. You first have to identify the best radioligand combined with the best suitable isotope for the respective disease or the respective clinical scenario. And currently we have, contrary to radioiodine or PSMA, no real clinical working horse scenario with an unclear position in treatment algorithm in many tumor entities. Currently, respective data are missing and we often observe low absorbed doses in tumor lesions, especially when compared to our working horses. And additionally, we of course have to take a look at the safety profile of FAP-RLT as well as the possibility of combination therapies that might be more promising than FAP-RLT alone. Thank you very much.