Theratechnologies Inc T.TH

Any comments on this from Leede's Doug Loe?

[SPCEO1]

Thera provided an update on its Phase I solid tumor testing with TH-1902, indicating that it has likely identified a maximum (barely) tolerable dose that is at or above 420 mg per square meter of body surface area, and this observation motivated the decision to shift all future patient dosing to a lower level of 300 mg/m2. Thera indicated that this represents a 1.5x elevated dosing level over that commonly used for docetaxel itself in solid tumor chemotherapy, but in our review of the literature, it is far higher than that (docetaxel as a monotherapy tends to be administered initially in most tumor types at 75-to-100 mg/m2). Accordingly, we believe that dosing at or above 300 mg/m2 still reflects favorably on the tumor targeting pharmacology that conjugation to sortilin receptor-binding peptides confers in TH-1902. As stated above, the concept of incorporating sortilin biochemistry into TH-1902 for targeted chemotherapy still seems reasonable to us and we are optimistic that justification for us to ascribe formal market value to this program will be forthcoming.

[Wino115]

I belive one of our science experts once discussed how to convert what the PDC level attached means in relation to the normal IV administration levels.  Revolved around the fact the peptide has two units attached and there's some sort of molecular weight conversion  you have to do to make it an apples-to-apples conversion. I think Loe is not doing that so it's not the proper

[qwerty22]

It does sound like he's mis-understanding that but given he doesn't state his own multiple it's hard to say. It could just be that he thinks by picking 100mg/mm2 that THTX are at the cautious end of this equivalent estimate. Does it say what he thinks the multiple is anywhere else in the report?

[SPCEO1]

He did not make any further comments of note about cancer in the report. 

[qwerty22]

Just to clarify. This paper from THTX's scientists  https://onlinelibrary.wiley.com/doi/10.1111/cas.15086 states " Note that 35 mg/kg TH1902 and 15 mg/kg docetaxel contain equimolar amounts of docetaxel.  " When you do the calculations ther is 100mg of docetaxel in 233.33mg of th1902 So 300mg is exactly 1.5x higher than a 100mg dose of docetaxel. So

[Wino115]

On the AEs, in reading a lot of trial PRs, I noticed that certain types of cancer seem to have uniquely located AE issues.  I don't know how much of it is that the metasticism tend to move first to those areas or organs (like eye or brain or lymph nodes) or that the target tends to pop up in those organs.  But I recall one of them (maybe pancreatic) seems to all have issues around

[SPCEO1]

Someone I know who has a friend who is a doctor sent this to me and I thought I would share it in case it helped: TH1902 contains 2 dox molecules per peptide.  It’s weight contribution to 1902 is 43% (2x800/3700x100). Therefore, 300 mg of TH1902 is 129 mg of Dox.  Approved dose of dox is 70-100 mg/m2.  So 1902 delivers about 1.5 fold more dox per cycle.  Does this mean more

[qwerty22]

That's an interesting perspective. There is a certain rationale to this drug. For the drug to be successful that rationale has to be realized. If the drug fails on any of a number of steps to deliver the bomb to tumour cells then that rationale falls apart. If the drug is adequate on all these fronts then they might have a successful drug. I think what your friend is pointing out is the

[jfm1330]

You need to compare apples with apples. The MTD of docetaxel alone is 100 mg/m2. In TH1902 terms, it's 230 mg/m2. So if the MTD of TH1902 ends up being 300 mg/m2, it would mean the MTD of TH1902 would be 1.3 times the MTD of docetaxel alone. That's only 30% higher on a MTD basis, and a much narrower therapeutic window than hoped for. All that without a proof of concept. Even if they end

[qwerty22]

Clearly yesterday was not intended to be a full report on the dose escalation phase. It was an update on where they are at and where they are at is dosing 6 patients at 300 to nail down the dose for the next phase. You've said it many times before (oh no I'm doing it now!) the 1a report comes when they reach the end of dose escalation. That's now 6 more patients away at 300 or 3

[qwerty22]

One way I understand the process is that you can see some of the negative facts like AE become 'hard data' fairly instantaneously. Where as the positive data like tumour response develop over time. That development over time comes both from the fact that tumours respond over time but also from the fact that there is a practical time element to their collect. I think this is how it goes, a

[Wino115]

I wouldn't disagree with your overall view that they didn't give enough info to really understand the situation other than that 450 was a lot.  But I think there's other issues to balance out your view. For one, the preclinical work looking at tumor burden and sustained effect was all done at equi-molar doses of docetaxol and TH1902 (15 and 35).  So all those charts in the

[jfm1330]

Sorry. Since yesterday comparisons with preclinical data are worthless. In preclinical they established on mice a MTD of TH1902 that is three times the MTD of docetaxel alone. So a MTD of 690 mg/m2. Now we know it will likely be 300 mg/m2. So 3x to 1.3x the MTD. So take your efficacy data on mice and reduce them by the same amount. Also, as said many times, we have no hints at some efficacy signs

[jfm1330]

Correction. So you lost most of the theoretically widened therapeutic window based on preclinical data, and got nothing at this point on proof of concept.

[Wino115]

Sorry JFM, I believe you are wrong on this.  Take a look at this chart in the January IP.  This is a 1 for 1 comparison of TH1902 vs. docetaxol.  So your argument would be the OPPOSITE -- it will be 30 to 50% BETTER since the RP2D will be higher than what this chart shows, not lower as you state. These charts showing tumor suppresion and progression free survival are equimolar, not

[jfm1330]

Sorry Wino, you still base you thinking on preclinical data that we now know is irrelevant. We know that because the only thing we know for sure is that they are testing 300 mg/m2 as the MTD. They decided that 420 mg/m2 was not tolerable, so it cannot be the maximun tolerable dose. OK. So follow me. In the preclinical data, Thera stated that for TH1902 they reached an equivalent MTD of three

[juniper88]

JFM, you are mixing safety with efficacy. Just because MTD (safety) is higher in mice it doesn't mean that efficacy will be lower in humans. Perhaps humans have more sortilin receptors than mice in normal cells. You are right about the fact that we are still in the dark about many things. For example, what where the safety issues. Were they similar to using normal taxol or were the problems in

[jfm1330]

Sorry. I am not mixing up anything. I just point out that the data on animal model and cancer patients on the only thing we know, MTD, is very different, and it would be foolish to think that efficacy will be the same as in animal models with their minuscule xenograft tumors genetically homogenous and known to be very high on sortilin expression, in comparison with big genetically heterogenous

[juniper88]

Where we disagree is that 300 mg/m2 is a negative. 1a seems to have proven that up to a 300 mg/m2 can be safely and yes that is less than in mice. But so what? It says nothing about efficacy. Like Christian I believe this is a good dose, as long as the pdc technology actually works. And the news we just got about the safety aspect just doesn't tell us whether or not the taxol is actually

[scarlet1967]

No point to argue with him, he simply ignores all the other pieces of the technology and falsely link everything to the MTD. Why would the company add more patients to phase1b if their therapeutic window had no chance showing efficacy? Why would Chinese companies be interested? Are all those scientists absolutely clueless? 

[SABBOBCAT]

I think JFM is adding some caution into the overall optimisim on this board and appreciate the thought and insight.   

[scarlet1967]

“Docetaxel was shown to be greater than 98% plasma protein bound independent of concentration at 37 °C and pH 7.4.”   https://en.m.wikipedia.org/wiki/Docetaxel I am not trying to be optimistic but realistic. Fact is a very small portion of docetaxel enter the cells, the point Juniper was making. Now they haven’t shared the PK/PD data so we don’t know but they do or at least

[JayjayUSA12007]

Concur with scarlet1967. "I am not trying to be optimistic but realistic. Fact is a very small portion of docetaxel enter the cells, the point Juniper was making" The whole point of SORT+ technology is how concentrated docetaxel could be delivered to the cell. The MTD could be 1.5x or 3x as long as docetaxel could be internalized into cancerous cells multiple times the existing

[jfm1330]

300 mg/m2 is only a 30% higher MTD. Puting aside efficacy and proof of concept, without PK/PD data, and "cancer sortilin load" it is hard to understand what it could mean. Add to that the enormous delay in finishing phase Ia. To me it is a black box at this point with only negative output. To give publicly the likely MTD without any context is problematic. Also, no explainations about

[jfm1330]

One thing I forgot to say about the siRNA option is that logically you invest in research about that only if you have a proof of concept with TH1902, otherwise it would be very aggressive for a small company. Also, imagine that they hire somebody well qualified for that job, but in a few months they end uo without a proof concept and release that person. Ethically it does not make sense. So this

[Lee430]

Could it be that Thera is simply holding back as much info as they are allowed to until they have the new IR hire in place and have developed a plan to maximize the impact?

[SPCEO1]

I suspect you are right about the hiring of the siRNA specialist is a clear indication they must have seen proof of concept. And I would submit that the reason they have not shared that info with us yet is because that is the kind of thing you save to announce just before the next, hopefully non-odious, necessary share offering. For a small biotech, it is all about the next fundraising and

[qwerty22]

I think you have to think there are a number of factors that go into how and when you release the info. Financing is one consideration for sure. Doing it the right way is another. To me the right way is when things become hard data points and when you can put enough facts together to tell a supportable story. We just aren't at that point yet.

[jfm1330]

Since I did not see any answers to my rather gloomy take on TH1902, I will provide something a little positive that escaped me on first reading of the press release yesterday. In this PR, the company states this: Once MTD has been established, the study protocol allows for immediate initiation of enrollment of a larger open label basket trial. The basket trial will further assess the safety and

[qwerty22]

It doesn't say anywhere they are only going to look at screened patients in the basket trial. That's wrong of you. What they did say in the CC is they are dropping two cancers because their research suggests Sortilin expression is lower in those cancers. A follow on comment suggested WHEN they have the appropriate screening tool they may be able to return to those cancers. The obvious

[juniper88]

I have another thought why the FDA wanted all comers for the safety portion of the trial. What happens when TH1902 works really well and tumors shrink significantly? Obviously, now sortilin expression will be much lower. So, having screened out lower sortilin expressing patients would tell you nothing of the safety for the patients that have a good response.

[scarlet1967]

        It is also worth mentioning the receptors cycle back across the cell membrane  to the surface of the cells so my take is if their PDC finds those same receptors it will have another shot/shots to internalize into cancer cells.   SORT1+ TechnologyTM Platform (ENG)     It is also worth mentioning the receptors cycle

[scarlet1967]

  6bf36423-4892-48b9-876b-1f45778d127b If you go to page 16, you see based on an abstract published in 2017  TH1904(Doxorubicin) was accumulated in cancer cell at about 8000 ng/g of tissue versus about 1000 ng/g Doxorubicin alone.(Ovarian tumor) Looking at the abstract the reason is bypassing the efflux so what really matters is whether the PDC manages to stay put inside the

[qwerty22]

I think basically he's pointing to the facts that Wino, Juniper and others have made. That if SORT1 can vacuum up more of the drug than would passively enter the cell in it's naked docetaxel form then 300 is still potentially a very potent dose. I think that's what the sentence starting "Accordingly" is referring to.  He seems pretty forthright about the tolerability

[SPCEO1]

That was all he really said about TH-1902. This analyst's financial analysis capabilites have been historically weak so Iusually do not focus on his earnings models. He was low on his Egrifta sales estimate and high on Trogarzo for 2021. He is projecting $79.8 million in revenues for 2022 and $89.6 in 2023.