Theratechnologies Inc T.TH

Dose escalation

[jfm1330]

I went back to the KOL presentation to determine at what dose Thera likely is right now in the dose escalation trial. Marsolais said it take three to four weeks for every cycle. It was annouced on March 23 that they injected the first patient of the trial at 30 mg/m2. So taking that date as the starting point it gives this assuming a full four weeks for every cycle, which is likely not the case, especially in the first two or three cycles. Anyways, it gives this

March 23: 30 mg/m2

April 20: 60 mg/m2

May 18: 120 mg/m2

June 15: 200.4  (on June 21, Marsolais said they were close to the MTD of docetaxel of 230 mg/m2. So this is in line with what he said then)

July 13: 300.6 mg/m2

So it gives July 13 for the first dose well above the MTD of free docetaxel. Again, Marsolais said three to four weeks per cycle, so more than three weeks, but in some cases, probably in the first cycles, with one patient, less than four weeks. So this dose of 300 mg/m2 has been likely given somewhere between July 5 and July 15. Likely in the middle of that interval. So it is easy to understand why Marsolais willing to say in the last CC that they will surely have a MTD of TH1902 that is higher than the MTD of free docetaxel. Also, he probably already had the dosing of free docetaxel over time in the blood after the injection of the 300 mg/m2 dose. So he knew the level of free docetaxel this dose was generating. If the number was as low as expected, it confirmed to him that toxicity at that dose was very unlikely.

The next step will be 420 mg/m2 on August 10. This will be close to two times the MTD of free docetaxel.

Then, if they get there, it would be 558.6 mg/m2 on September 7, and 742 mg/m2 on October 5. This would be a bit higherthan three times the MTD of free docetaxel, which is what they saw on rats in the preclinical.

So we are sure to have a significantly higher MTD of docetaxel with TH1902. At this stage the only question to answer is how much higher will it be. The higher it will be, obviously, the better it will bode for efficacy. This helps understanding why they are so confident with TH1902 anf the SORT1 approach in general. Why they hire people to coordonate preclinical and clinical work. It also allows to understand why they were willing to write in their last press release, and say through the CEO in their last CC that they believe that They have developed a targeted peptide-drug conjugate that may potentially transform the way cancer is treated. These are their words, not mine, and this is a very bold statement coming from them. I can't figure how they can be more positive than that without releassing real good results. After such a statement, coming out in a few months with negative results would be an absolute surprise. But again with this company at this time, it is a matter of credibility and they obviously don't have much with the market. So this statement went by like it was never made. Even here, I have been the only one underlining it. So we will have to wait for the real results. It will either be a shocker for many, or a big disapointment for me.

[Wino115]

In the pre clinical graphs at the webcast CM said they stopped some of the dosing because they proved their point, but that they could have continued dosing longer or higher.  Do you think they can go beyond the 3x docetaxel?  Do you think they will or will they max the dose at the 750ish level on your opinion?  

[qwerty22]

They can stop at the final dose and just declare they haven't reached MTD. That's something that happens often enough to be normal in cancer dose escalation. You would do that if you have signs of efficacy. You might also use some of the rational JFM is talking about. Normal docetaxel is your guide here. While 100mg/m2 is the usual dose it still has efficacy at 60mg/m2 and this is the dose

[qwerty22]

The other way to think about this is in regard to therapeutic window. You want your drug to have a wide therapeutic window. Simplistically the bottom end of the window is defined by the lowest dose where you have meaningful efficacy. The top of the window is defined by the dose where unacceptable toxicities begin. So if you get to dose 4 and you have your 1st meaningful clinical response and then

[SPCEO1]

Thanks for sorting out the dosage situation - that is very helpful.  I think the credibility issue is real, of course, but I think another factor is just that their cancer drug is their first effort in the area, so the claim likely seems a bit fantastic to many. I think all of us here who are paying attention know it is possible that TH-1902 could turn out to be a very, very important drug

[qwerty22]

There is very good reason when a company says it's drug is transformative to let that statement go in one ear and straight out the other. Surely every company thinks it's drug can be transformative until the data says it isn't. All of the indications th1902 might be tested in have a list of approved drugs. Some of those lists might be short and some of the drugs on that list will

[jeffm34]

TH1902 doesn't need to be transformative to be successful anyways.  Even if it's only as effective as Docetaxel alone but has less risk of side effects like neutropenia, it will still be an attractive drug to use over current therapy.  

[qwerty22]

It's that and bypassing resistance. Presumably these patients are failing treatment because of resistance. If they get the drug inside the cell and it stays in the cell then the freed docetaxel will do it's thing in most cases.

[scarlet1967]

I couldn't agree more, all these speculations re dose escalation based on educated presumptions are not going to move the valuation. It's getting repetitive with many focusing on the same old subjects, their assessment could very well turn out to be completely, partially or not at all correct. As per the clip you posted well educated investors will do their deep analysis to identify

[longterm56]

[scarlet1967]

"But what will we be discussing on this board for the next 3-4 months?" My take is absent "promotional" efforts from the company it will be same o same discussions, dose escalation, reading between lines, more scientific analysis and me and few more complaining about investor engagement. It all depends on that re-engineering plan stops with LSA or it's more to it. I believe

[Wino115]

Perhaps we can discuss raising money to send a large bag of "Fiery Hot Cheetos" to each of the analysts.  My kids love them.  I can't eat more than a few before my mouth is on fire.  It's a fine reward for their excellent analysis. It may spur some creativity and urgency.......Not.

[stockman75]

Jfm thanks for this great information/analysis. From a scientific perspective how would you explain a scenario where they have such large MTD dosage and NOT have very good efficacy (for sortllin expressing cancers)? Thanks

[jfm1330]

The only explaination would be that docetaxel is not efficacious against certain type of cancers, but it is hard to imagine it would not work against every cancers. That's why the scientific logic leads to think that if the MTD is high, efficacy should be there.

[jfm1330]

Reaching a high MTD is important because it would be a good predictor of efficacy, but it would be more than that. It would point to the demonstration of the proof of concept, which is the ability of TH19P01 to concentrate a cytotoxic drug in the cancer cells. If you can establish that proof, it opens the doors to a wide array of othe PDC combination with other cytotoxic agents. So the key here is

[qwerty22]

... or if it's not bypassing resistance so chemo resistant cells are pumping the drug out as fast as Sortilin is moving it in. .... or if the docetaxel is not efficiently being released from the PDC inside the cell so it doesn't become active. .... or if the PDC is not able to get to the cells in the first place, that's to say it doesn't efficiently penetrate the tumour

[palinc2000]

Qwerty I really  appreciate  your measured ,tempered take ,,,Your posts on the science do not sound like pronouncements  like  others ,,,,,,,,,,, I think your posts accurately  reflect the risks involved in the oncology platform,,,and that lack of toxicity is not a guarantee for efficacy,,,Its a necessary pre requisite but not a predictor of final results in humans,,,I

[juniper88]

There are other mechanisms of resistance.  The 2 I am most concerned about are resistance to apoptosis and resitance to DNA repair, because I don't believe that TH-1902 specifically overcomes those.   About efficacy, I just wanted to share our experience with Taxol.  My wife has had a total of 11 cycles of Carboplatin/Taxol.  Many cancers have a blood test for a

[Wino115]

Glad to hear a positive update. as someone stated earlier, let's not forget that the platform (re, peptide TH19P01) is more important than the attached drug in proving the science.  Any sign of efficacy shows the PDC tool works.  Then you can attach something better than a 30 year old  chemo agent to overcome some of these potential obstacles in future trials.

[qwerty22]

All strength to your wife! You are right about multiple different mechanisms of resistance, and certainly some of those mechanisms th1902 just can't overcome. I think people are grounded about cancer drug efficacy. They expect there will be some cohorts that a drug just can't help and some where it will. They just have to focus on maximizing the later. This is from a paper on breast

[qwerty22]

For me the biggest unknown is Sortilin. The scientific literature is seductive but it's pretty shallow when it comes to it's role in cancer, so there's a lot of PROMISE for Sortilin as a cancer target but no direct evidence for that. It's THTX's job to prove that. I wouldn't take that as a super negative statement. I took a little look at Padcev's history. That's

[jfm1330]

Based on my estimation, we are now at least two weeks after the 300.6 mg/m2 dose and no news of toxicity. Instead we have the ATM news with a credible US broker. To me the likely plan is to raise money when the stock price will sharply rise on good news. Remember the rise after the approval of Trogarzo. We saw a lot of volume over a months and a half. If we see a similar raise this time, between

[jfm1330]

Another thing that is not taken into account here, even though I repeated it many times, and I will do it one more time because it is very important to understand. They do blood sampling after every injection of TH1902 to monitor the levels in the blood of free docetaxel and TH1902, over time. So they already know how much free docetaxel is generated by a given dose of TH1902, they also know the

[SPCEO1]

Things seem to be moving in the right direction on safety. I think the fact that Marolais said they will not have preliminary info on phase 1a until Q4 tells us they are pretty confident of not getting a safety signal that causes them to stop the phase 1a from proceeding to its conclusion. And that is likely because of the testing they have done that you reference. So it is all about efficacy at

[jfm1330]

That will depend on the quality of the results if they are good. In other words, how good will it be. If results are at the level of a real breakthrough therapy, a game changer in cancer treatment like they claim it has the potential to achieve as a best case scenario, then this thing will promote itself. The news of these results will make headlines. If the results are good, but kind of mildly

[qwerty22]

It's tempting to think the two things are linked. Cantor want to know they aren't getting on a train that's about to come off the rails. Thtx need to get the market moving. BUT WE MUST AVOID CONFIRMATION BIAS! :)

[SPCEO1]

Unfortunately, we are all humans here, no robots. We are are all stuck with some degree of confirmation bias. But since we seem to have different views here, we can at least challenge it among one another when we think we are seeing it. And we see it all the time.

[jfm1330]

The only way they see very low free docetaxel and the PDC is not working as planned is if the linker would not be cleaved at all inside the cancer cells. If TH1902 stays in the bloodstream long enough because it is not internalized by sortilin, the linker would be cleaved and free docetaxel would be released in the bloodstream and they would see higher concentrations of it. The curve would be

[qwerty22]

... assuming it penetrates the tumours efficiently and get's to the receptors.  ... and assuming the heterogeneity of the tumours doesn't have an effect of "masking" an efficacy signal. Saying "only" is a very dangerous thing in science.

[palinc2000]

Even a non science guy like me knows that no one on earth  can predict any outcome with certainty in Phase 1 first in human clinical trials,,,,But of course JMF pretends to have you ON IGNORE and never directly adresses your chalenges Coward is the first word that comes to mind but the more I think about it and based on an oipinion  from a great  world known scientist  friend

[qwerty22]

Months ago I wrote a post that said I saw things moving in the opposite direction for a THTX-led (1), regulator supported (2), market supported (3), straightforward NASH Ph3 (4). I said those 4 pieces needed to be in place to get the outcome the company was presenting. Well they delivered the regulators (2). There is zero evidence the market cares one way or the other about NASH (3). The

[jfm1330]

So we will have another fireside chat with the CEO on August 11, and at that time they should be at twice the MTD of free docetaxel, either well into it or just starting it. So to see Levesque willing to participate in such a public event at that point is a very good sign that they are still on the right track. I will repeat myself, because it is very important to clearly understand the actual

[Wino115]

I fully appreciate the implications of what you are saying.  Unfortunately between Ed Nash stuffing his face with Cheetos, all his questions will probe quarterly doctor visits for Trogarzo and the NASH strategy.  I hope he includes the cancer analyst Scarlet quoted below.  If I were PL, I would beg him to include that guy and have some oncology pointers for him to ask.  

[palinc2000]

It does not make sense that the cancer analyst is not included in the fireside chat..I think Paul can call the shots on this analysts attendance...... if he so desires........Does he?IDK

[Wino115]

If he wants to start building that audience he certainly should.  If things go right, that analyst will be a hero in Canada for understanding their cancer pipeline before anyone else.  Doug Loe still doesn't even know they've already started Phase 1....!

[palinc2000]

I know but I dont think Paul will want to ho in a deep dive Q&A with a cancer analyst unless he feels very bery very confident....Has he reached that stage? 

[Bucknelly21]

Paul seems extremely confident to me I think he has to be honest

[qwerty22]

They mostly remain pretty contained with their statements so it's not too difficult to stay honest. They've essentially said nothing about the on going trial. This board has a tendency to take those contained statements and blow them up with all sorts of hidden meaning. Just think how much has been read into that nothing! (I'm not saying I'm not guilty too)  

[palinc2000]

The board has gone from speculating on the oncology platform to fantasising..... Reminder ..... This is only a few months in  Phase 1 in first in human testing and ZIP has so far been reported .... I also witnessed big smile in Beliveau and Paul and Marsolais but this reminds me of Spceo reporting more than 2 years ago after a phone call with Dubuc and Tanguay that he had not learned

[qwerty22]

I wouldn't mind hearing some of the parameters around the type of partnership they are after in NASH but do we know 100% it's with Ed Nash? They've flogged that horse to death already. All the blurb is leading with cancer so you'd expect that to be front and centre. Force Ed Nash to engage with that.

[jfm1330]

In the last KOL presentation in June, Marsolais said that they expect to reach a toxic dose at the end of the summer or begining of the fall (time: 41:45). So based on my calculations here, based on Thera's plan for dose escalation, it means that they expect a MTD of two to three times the MTD of docetaxel injected alone, so between 500 and 800 mg/m2 of TH1902. After MTD is reached, he said

[jfm1330]

I need to requote myself to put the record straight here... So much bad faith... I even gave the exact time of the quote by Marsolais to make it easier for any interested person to hear it, but despite that some idiots are telling the opposite of the truth.  SPCEO, do me a favor, don't quote idiots like that. I only read two lines and I saw the bad faith is still there, as always since

[qwerty22]

"We might reach docetaxel toxic dose the end of the summer beginning of Fall" NOT th1902 toxic dose.And not MTD. You're being sloppy and he isn't.

[palinc2000]

My confidence level in Qwerty  is much much higher than in JFM..... I posted once that JFM is a frustrated scientist who never got the recognition HE thought he deserved Qwerty on the other hand is at Peace with himself and fact based scientist...The smile o meter is purely and only an invention of JFM Beliveau and Marsolais were smiling 2 months ago during the Kol event and that is almost

[PWIB123]

No need to make it personal everyone.  The reality is no one knows anything for certain.  The benefit of the debate is to understand the risk around different potential scenarios, which are only best guesses based on one's understanding or lack of understanding of some small intentional or unintentional detail.  Those Execs aren't inerrant either and could easily

[qwerty22]

I continued listening to the rest of the event. If you were to re-interpret every "might" , "could" or "if" statement as "expect" then we are sitting on a goldmine. "might" implicitly includes "might not". We might not reach MTD at the end of the summer, dose 7 might not be all that toxic. I'm not expecting "we did not reach

[realitycheck4u]

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[scarlet1967]

Listen "dude" and listen carefully as I am not going to say it again to you, you want to make a return on your freaking investment so does everyone else if you think they have done an ok job to make sure valuation is fair good for you the difference is you came from your dark side  after bashing the company for a good while to the other side versus many here have been waiting

[realitycheck4u]

This post has been removed in accordance with Community Policy

[Lee430]

THIS IS NOW WAY TO TOXIC FOR ME, GOOD LUCK TO EVERYONE AND THANK YOU ALL FOR THE GREAT INSIGHT.

[jfm1330]

So, in theory, we are into another cycle at a higher dose of TH1902 now, this is equivalent 2.4 times the MTD of docetaxel alone. It seems that the previous dose, at almost two times the MTD was of docetaxel alone, was not toxic enough to be the MTD of TH1902. All this is very good, in theory, still it is not a proof of concept. 

[SPCEO1]

A couplle fo questions about this: 1.) When I counted out the 28 week estimate for the phase 1a length, it suggested it would end in the first week of October but you have them starting the highest dose then. What accounts for that difference or how did you come up with the first week of October being the last step of the trial? 2.) If the trial had reacched a MTD already, I thought we had

[realitycheck4u]

This post has been removed in accordance with Community Policy

[qwerty22]

1) I think 2.4x is about the highest scheduled dose so dosing last dose about now and finishing that cycle early Oct. Seems to fit. If there has been any DLTs then the schedule gets thrown off as they re-dose at the same level before moving on. You're early Oct assumes no DLTs 2) MTD will get announced with all the rest of the data, just because they haven't said something yet doesn't

[SPCEO1]

I don't have a Smile-O-Meter. I think that was Palin or JFM. But, hopefully, we see a lot of smiling! I am just worried that few others than ourselves will even notice. THTX must be concerned by the loss of analysts over time and the very low trading volume seen on some days recently. While there is good reason for things to be moving forward on both of those fronts, they nevertheless seem to

[SPCEO1]

We are two trading days away from the KOL NASH event and we have barely traded more than 10,000 shares of THTX. Clearly, the event is meant to create a postiive tone around THTX's NASH program but we see no trend toward investors pre-positioning ahead of that event. That is really odd in my view. I know the market is much more broken that I can imagine but this lack of interest is still

[Lee430]

Kinda appears like the alarm bells are on mute, Go figure it looks like there is an app for smile-o-meter.

[jfm1330]

Here is my full original post describing how everything is supposed to go assuming one full month per cycle. It is based on one slide they showed in the KOL presentation. The fact is, I think some cycle could have been shorter than a full month, especially at the begining. Remember that Marsolais said in the KOL presentation that they expect to reach the MTD at the end of the summer or the

[SPCEO1]

Great info - thanks!

[qwerty22]

He didn't make any projection about reaching MTD, that is not possible without a time machine, I'd like to see the exact quote. I also don't think Christian works by making the sorts of assumptions JFM makes. He might have made a projection about reaching the last scheduled dose based on the speed at which doses were escalating at the time, that's a different thing. I just don'

[SPCEO1]

My best recollection is that Christian did say something like JFM has indicated during the cancer KOL. But I could be wrong as that was a few months back and my mind may be playing tricks on me. 

[scarlet1967]

“1 If ≥2 patients in a dose cohort experience an emergent DLT by Day 21 of the first treatment cycle, dose escalation will stop, and the prior dose level will be declared as the MTD. MTD is defined as highest dose level at which ≤1 of 6 patients in a cohort develop an emergent dose-limiting toxicity; 2As indicated; TNBC, triple-negative breast cancer; 3RP2D is defined as one dose level below the

[qwerty22]

I'm not saying similar toxicities described here will happen with th1902 (if I was forced to guess I'd probably say they won't). But the company making public statements assuming they won't happen makes no sense. https://www.annalsofoncology.org/article/S0923-7534(19)36547-0/fulltext (particularly lesson 1)