Webinar Notes (10/3/26)

A few points from the webinar presentation: TLX591-Tx ProstACT Global Phase 3 study (NCT06520345) Part 1 results: Safety and dosimetry)

·        Part 1 Safety & Dosimetry study in combination with standards of care (Abiraterone, Enzalutamide and Docetaxel) completed meeting the FDA requirements of n=10+ for each allows for approval by the FDA to proceed to Part 2 with no adverse drug-drug interactions observed indicating FDA approval to proceed is likely.

·        Of 57 patients screened for eligibility, 36 were eligible. A question as to whether this indicates a limitation on the eligibility of patients in market was confirmed but we don’t have any indication what % of the market this may preclude. Follow up needed.

·        Team highlighted the low radiation exposure and advantages to small molecule (less exposure outside of target areas and safer exit via Liver and Fecal extraction Vs Kidneys and urinary).

Comments

It is important that TLX591 is able to be administered along side standard of care for Part 2 of the Phase 3 study because they cannot for ethical reasons run a placebo randomised trial where some patients have no care while others have TLX591 (can’t deny standard of care).

For context there are a little over 3m in the US that have prostate cancer and of these most are just having on going monitoring or local therapies (surgery). About 1m have androgen deprivation therapy (ADT) which is hormone therapy and involves androgen receptor pathway inhibitors (ARPI’s) of which Abiraterone (very old but still in use) and Enzalutamide (about 10 years in market) are the market leaders and are used for metastatic (mCRPC) and non-metastatic (nmCRPC) prostate cancer. Ultimately ADT treatments become ineffective and the next step is chemotherapy of which Doxetaxel is the market leader and has been around for decades mainly for the use for metastatic cancer of which there are around 100k patients.

Hence the Part 2 study will need to show improved patient outcomes compared to the existing standards of care. They will do this with a much larger 490 patient study where TLX591 in combination with standard of care treatments will be compared to outcomes with just the standard of care (Abiraterone/Enzalutamide/Doxetaxel).

I am unclear on what patient categories they are seeking approval for. It could be initially for the mCRPC patient cohort of ~100k or include nmCRPC which would be ~1m. Note depending on pricing, the mCRPC alone can be a very attractive market.

Disc: I own RL

@Tom73 great summary. I recorded the webinar (as it clashed with my morning run!) and am just siting down to watch it now.

My top level reading is that this is a positive hurdle cleared, as it appears to me that it should lead to FDA approval of US patient enrolment in Part 2.

But overall, it doesn't really tell us anything about the Phase 3 Primary Endpoint: that the combination treatment leads to better radiographic progression-free survival than SoC alone. By my reckoning we have 3-4 years to wait for that!

@Tom73 I've now listened to the webinar including the Q&A, and have a couple of additional thoughts, relating to some of the questions you asked.

1) Target eligibility

Based on the design of ProstACT, $TLX appear to be shooting for a label indication of treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have progressed after treatment with a novel androgen-receptor pathway inhibitor.

Again, based on the trial design, it would seem to be for a combination therapy together with the existing SoC, per thoses tested in the trial, which cover the regimes both in US and outside the US.

Of course, once (if!) approved and launched, it would presumably make sense for them to conduct a monotherapy trial, which was not open to them at this stage on ethical grounds. (This is a few years down the track, and I don't have the clinical background to know if that is a reasonable prospect!)

Base on some work by my BA, the addressible market is probably about 75,000 globally and 25,000 in the US. This is lower than your 100,000 estimate because of the proportion of patients who might be judged to not tolerate radioligand therapy.

But the prize is large, with the global TAM for this market of the order of US$10-15bn. So even if TLX-591 only gets a 10% market share, that makes it a blockbuster. (But... we are getting WAY ahead of ourselves!)

2) Ineligible patients screened out

A couple of the analysts in the webinar zoomed in on the 18/57 (32%) of patients screened out as ineligible. It was explained as follows:

All the 57 patients meeting the intake criteria were then subject to a baseline, independent radiology review. Only patients expressing a high PSMA positivity were selected. This makes sense because TLX-591-Tx works by binding to PMSA-prodicing cancer cells. The strong the PSMA expression, the better the radioligan binds to the cancer and the more likely the drug is to be effective.

So if the 18/57 (32%) is representative of the wider patient population, then it possibly gives an indication of TAM-reduction we might expect.

I use the language "possibly gives an indication" with care.

What we don't know is how different patient characteristics might correlate with treatemnt efficact in the final dataset. For example, are there significantly diffferent outcomes depending on the degree of PMSA positivity or other factors?

Circling back to the TAM, this does indicate to my that only a portion of the "75,000" maximum potential will end up being covered, in the success case, by the registered label.

However, again, that just the potential first label indication. Who know what other studies to expand the label might be conducted over time.

3) When might we get a preliminary glimpse of efficacy

The trial has a long way to run. Hopefully, at some time this year, the FDA will approve the enrolment of US patients into part 2, and it seems likely that European approvals should follow that. This is important to ultimately getting the drug approved in these major markets. Furthermore, the more participating centres, the sooner the trial completes.

But what about efficacy? Management gave an indication of when we might expect a preliminary (i.e. early) indicator of efficacy.

Davod Cade, the CMO said:

"That [i.e. efficacy] will be first gauged as an exploratory endpoint from Part 1, progression-free survival and radiographic progression-free survival are exploratory endpoints. And we anticipate that they will probably be available later in the year, second half of 2026. Obviously, that's a time to event, which is guided by how the patients perform. And so longer for each patient is better, and that obviously pushes that out."

Who knows what the signal will be, but it is a potential early SP catalyst.

Overall Conclusion

Apart of the eligibility attrition flagged by @Tom73 this looks to be an overall positive update, insofar as it can be without any efficacy reading, for which it is too early.

However, I don't view the eligibility attrition as bad news per se. And that's because it is implicit in the nature of this treatment that it is going to be most effective in patients with high PSMA positivity, and I think it is right to focus the trail design on the patient cohort most likely to deliver a statistically significant, positive benefit over SoC-alone.

i.e., I'd rather get approval to serve 75% of a $US10-15bn TAM, than a failed attempt to serve 100% of the same TAM.

Disc: Held

Thanks @mikebrisy for covering the Q&A more fully, I got interrupted at one point so missed the eligibility attrition follow up. While efficacy is the most important issue, which is yet to be disclosed as you note, I wanted to drill down on the TAM analysis because I think the PSMA-positive criteria is a very big issue.

PSMA Requirements

Firstly on PSMA-positive, almost all mCRPC patients have PSMA, so are PSMA-positive (95% PSMA expression for mCRPC). So to for nmCRPC patients (90% PSMA expression for nmCRPC) with a high PSA (over 2ng/ml) increasing the chance. But there may be no distinction between the two, with a view that nmCRPC is just mCRPC that hasn’t been diagnosed due to testing limitations (Is Nonmetastatic Castration-Resistant Prostate Cancer a Valid Disease Category?). Hence, I think we can assume PSMA is going to be high with mCRPC, so presumably this is a good initial target cohort for TLX591

Secondly, we need to understand how positive PSMA needs to be for TLX591 use. Which comes down to the eligibility attrition we saw in the Part 1 of the Phase 3. 32% (18/57) were not eligible, but we have no idea if that sample group was representative of the CRPC population, metastatic or non-metastatic. I suspect they would have pre-screened their screen based on some criteria, so it is highly unlikely it is a representative sample – probably highly skewed to those more likely to meet the PSMA requirements.

So the PSMA requirements could form a very limiting factor on eligibility. 

If the number of PC patients actually undertaking PSMA-PET imaging is any indication then it doesn’t look good. In the US in 2024 only 77.6 per 1000 PC patients had scans (US PET for PC), lets assume only the 1m CRPC patients not the whole 3m PC patients population are offered this then we can probably triple the use of PET imaging for the relevant cohorts, but that is still only 23%.

So, it could be as low as 23% of the CRPC population, not 68% (100-32%). Just don’t know. We can probably get some indication based on an analysis of TLX’s market opportunity for it’s diagnostics and then assume a subset of those would be eligible – analysis for another time.

Market Size & Addressability

The market size figure for treatment of prostate cancer of US$15b is around most of the estimates I have seen (US$13-17b is a range most land). Xtandi (Enzalutamide) is the market leader with ~US$6b in 2023 (Top 10 Cancer Drugs in 2024) and is used in around 25% of CRPC cases. The high proportion of market value than use is due to it still being on patent, costs ~US$15k a month in the US.

So this is probably as good as it gets and only if you have full access to the CRPC market, but I would like to show the path Xtandi took to market. It had 3 different approvals as I show below. The patient population figures are US and based on analysis I did around a year ago when I put this together (noting @mikebrisy your different numbers), but the point is the different clinical groupings and the big distinction between mCRPC and nmCRPC.

First approval was for post chemo (ie post treatment with Doxetaxel) treated mCRPC patients – basically those who had no more options. The next was for the rest of the mCRPC population, it is unclear if TLX will get approval for these separately or together, either way we are talking about ~10% of the current Xtandi eligible patient population. So that US$6b revenue opportunity is probably ~US$0.6b, if that is the first approval. Then the eligibility % will need to be factored in, so it could be as low as 23% of that ~US$0.14b…

The last approve was done post-acquisition by Pfizer of Medivation the original developer for US$16b in 2016. So there is certainly value in a company with PC treatments, but it isn’t until this last approval is received that you start to get a sufficiently large market that loosing a solid chunk due to eligibility constraints still lets you get to a block buster. Pfizer purchased late in the Phase 3 for the final approval and were obviously banking on it being approved.

So, we need the efficacy read, an indication on how much eligibility is impacting market size and to better understand the patient cohorts they are seeking approval for and when. Maybe then we can have a stab at the eligible TAM and value.

I suspect it will be some time before we get these answers.

Disc: I own RL

@Tom73 you make a lot of great points. Particularly in that we don’t even know how many don’t make the pre-screen, as well as how they define high PSMA positivity.

I agree with you that it’s pretty much impossible to do a good job risking the potential success case revenues until we see the full efficacy data, and even then, until we see the label.

One thing we can be sure of (and need to be aware) is that you can’t accuse management of not being promotional enough!

Great to have a fellow StrawPerson who can add so much to this topic.

What do you guys make of the current amount sold short (14% as of 4 days ago).

Even with the heavy shorting it is still up from that recent low of approx $8.

Wow @Schwerms, I didn’t realised shorts were so high, and up from 12% to 14% since the results came out on 20 February. It’s been building over the last 3 years but took off after price falls post July last year.

Generally I ignore shorts, unless I am looking for a short squeeze on a company I think could give an upside surprise. For TLX my guess is that it may be part of a pairing trade with CU6 the other side. Alternatively, it could just be a momentum trade which seems to happen a bit with shorts.

Either way, I don’t see it as “smart money doing something smart”, they are just more big money looking for something to invest in out of a limited field of options. No change to the fundamental view on the business which is high risk for both long and short investors.

So I'll admit to being quite conflicted when it comes to $TLX @mikebrisy & @topowl. I do like the strategy and possible treatment products (yet to be approved of course) for kidney, prostate & brain and I believe the current missed approval was overreacted to by shareholders (so my time to buy as I had been watching an entry price for some time). The conflicted comes from personal experience and use of their isotope solution using Gallium 68 for my own PSMA PET Scan at iMed. Unfortunately, it was a failure in my case and the best summary stated inconclusive!!

On the other hand, another PSMA PET solution using F18 DCFPyL via Qscan worked great when recently undertaken before my prostatectomy.

I'll put it down to "horses for courses" (I think the stats say approx 15% have no postive reaction to Gallium 68 type solutions, or so my Urologist said) as I do like the $TLX story, so hopefully I don't get to trial any more of their products, but if I do, that they actually work for me!!

That said, my Urologist was pretty sure Qscan would get an outcome, which they did, but also to be fair to iMed and Gallium 68, Qscan knew that solution did not work, so they went with the more onerous 2.5 injection of F18 and got the desired result.

Anyway, still bought $TLX in SM portfolio, but will continue to watch closely as a shareholder, not a patient!!