The Story of TLX591: more compleX than what they are trying to...

The Story of TLX591: more compleX than what they are trying to Telix it!

[I shall give them all the benefit of doubt and assume they are not trying to mislead anyone]

IF you do not have time to read the long essay, here is the jist of it;
a) TLX591 as owned by Telix has never shown an OS of 42.3 in Telix trials. Its the predecessor, huJ591 (by Tagawa et al), that did, 5 to 10 years before Telix was born!
b) huJ591 survivors in that trial benefitted from life prolonging treatments that were approved during and after the trial: including an Alpha Rad-223, ARPIs, and Chemo!
c) The Tagawa study was a dose determining study like SECURE - in SECURE, the patients had failed all of the treatments that the survivors in the Tagawa study benefitted from. Very different!
d) One of Telix's TLX591 own trials (Nguyen et al, 2024) showed results that are so different from the Tagawa trial that one might be tempted to conclude that huJ591 and TLX591 are not the same drug! I believe the difference is created by confounders that disturbed the field - effectively invalidating the OS that huJ591 reported! In science - repeatability is key!
e) It would be wrong to retrospectively abandon PSA as a measure of treatment effect - just because your trial failed to show effect! In fact, the failed PSA responses in the TLX591 trial (where PSA rose by over 30%) corresponded with radiological progression (about 40% for both)! I am aware that its included in the Phase 3 trial of TLX591!

Ok, to the long write up!

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FIRSTLY: Here is what Telix say!


Ask yourself these questions:
a) If TLX591 had this OS as is being touted, why did TLX591 go back to Phase 1 in ProstACTSelect?
b) When did Telix start their TLX591 trials for them to have managed to reach 42.3 months OS!

FACTS!
1) ProstACTSelect was a Phase 1 trial of TLX591 (https://clinicaltrials.gov/study/NCT04786847), which initiated on 30th of Jan 2022! Hence, there is no way that even today, we can talk of survival of 42.3 months!
2) What happened here is that Telix are quoting data from a historical trial by Tagawa, when the drug was called J591 or huJ591 (Tagawa et al. Cancer. 2019). Although published in 2019, the trial recruited participants in 2007 to 2010 for Phase 1 (more than 5 years before Telix was founded), and Phase 2 was from 2010 to 2014. Telix was founded in 2015. Ok, maybe thats what they mean when they say "previously published'! Ok, lets give them that!

The story here is that, Telix have inherited data from the drug's previous life! No issues, except that's also complicated;
a) That trial by Tagawa was a dose determining study just like SECURE - so the person who is already claiming that TLX591 is ahead of 67Cu-Sar-bisPSMA is completely offside! Ok, he is right: the same way an older brother is actually older than his younger brother! Thats just as far as the logic goes!
b) The result being touted (42.3 months) is from a subgroup of 17 patients who received the highest dose in that study! The overall survival for the entire group was 23.6 months. No issue with that!
c) However: these survivors went on to benefit from life prolonging treatments offered by many new treatments that were approved during and after the study, including Radium-223 from Xofigo (thanks very much Dr Colin Biggin thats the Clarity COO/Former CEO who used to work for Algeta), as well as the ARPI's like Enzalutamide, and Taxanes! Some untangling is required here! These 17 patients are different from the patients in SECURE, where all of them failed everything that the 17 beneficiaries benefitted from!
d) Another interesting point here is that this group of patients that did very well, is the same group that had the highest PSA response! This is relevant in view of Telix's change of heart over PSA response (WHY are they no longer considering it useful?)!

The Tagawa Results table is at the bottom of this writeup.

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Why is the PSA no longer a good measure of treatment effect!

The Nguyen trial of TLX591 may help! First, lets look at the most important part of any research: THE METHODOLOGY!
The trial's primary objective was safety. The researchers stated in the Methods that PSA response was going to be used as one of the secondary measures for assessing disease progression!

Here it is:


So, they set out with the PSA used as one of the measures! Now, in research, you are simply not allowed to change tune just because you do not like what the data is telling you! And, I am not saying they did.

Lets go to the results!



TLX591 failed to achieve the PSA response that huJ591 got! This tells you something: either, TLX591 is NOT the same as huJ591, or huJ591 benefitted from something else! We know that huJ591 benefited!
As such - the OS of 43.2 months can not be assigned to TLX591.
As for PSA: I do not know exactly when Telix changed tune! Doing so post results is a BIG NO NO!

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Here are some extracts from the Tagawa trial with the 42.3 months OS being touted







Now to TLX591 itself!



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REFERENCES

Tagawa: Phase 1/2 Study of Fractionated Dose Lutetium-177–Labeled Anti–Prostate-Specific Membrane Antigen Monoclonal Antibody J591 (177 Lu-J591) for Metastatic Castration-Resistant Prostate Cancer https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cncr.32072

Nguyen: Lutetium-177 Labelled Anti-PSMA Monoclonal Antibody (Lu-TLX591) Therapy for Metastatic Prostate Cancer: Treatment Toxicity and Outcomes https://link.springer.com/article/10.1007/s40291-024-00699-w