Theratechnologies Inc T.TH

RE:RE:RE:RE:RE:So many questions about the patient protocol

[Wino115]

Best to prepare for what they designed it to give them --dosage and safety for part 2 to proceed, and be pleasantly surprised with all other data released if there is any.  I would hope that they would follow the examples we put up here (Prelude, SeaGen, Immu, etc.) and at least discuss some additional data around each key part of the PDC, even though we will all know it's not statistically significant. Throw us a bone, we're hungry before year end!

The more I hear PL though, I think they may also hold back the timing of results until they hear back from the FDA on any changes they both agree should be made to 1b based on the data too.  They constantly say it may change based on what they see, so I think it will change even though the sample size is so small.  Maybe they'll add a melanoma line to it since SORT1 is heavily overexpressed there.  Ideally, they wouldn't hold it back and just relase the 1a results, say they're talking with FDA based on these and will discuss 1b prior to initiation and once there's a final FDA signoff on any changes.  Gives them 2-3 chances to discuss the science and trial.

qwerty22 wrote:

Spring and summer a handful of patients were given relatively small doses. In the past couple of month a few more have been given the higher, more interesting doses. My guess is not a great deal has arisen from that limited pool of patients in terms of either efficacy or safety. I think safety is as has been described although it seems to me there could be some negatives hidden but that would assume some really weasely use of language. They could share what they know about pK, it's not useful just saying it's in line with animals. Apart from that I don't expect there is a whole lot more to share.

I guess we (I) want some PoC but if the goal here is to get a dose for the expansion groups and eventually the Ph2 then it looks like they are headed for a fairly high dose and that would be a successful outcome from part 1. It probably doesn't drive the SP up but it's enough to keep the program alive.

We'd probably stop sweating about these details if we had any sort of efficacy signal to ponder.

 

SPCEO1 wrote: Thanks Scarlett1967 for the effort you put into your response. And thanks to the others that responded as well. 

TH needs to do a better job of setting expectations around the timing of this phase 1a and how it actually will proceed. I am not sure why they failed to do so earlier and did not help investors understand that the patient protocol slide was just a best estimate of many possible permutations. It seems like something they could have easily communicated and could still communicate. 

Paul mentioned at the Q3 conference call that they would communicate with investors again about the trial after the MTD was found. Then he shared more about the trial, thankfully, at the Credit Suisse conference, but then reiterated they would not be saying anything more until the MTD had been reached. Why do you think they might want to keep a lid on information until the trial is over? I would guess that what is going on in the trial right now is messier and complicated and they don't want to just share positive info and set the wrong expectations, but they also don't want investors to focus too much on the messier data and obsess over that. So, we get nothing until it is over which allows them to carefully consider how to package the trial's results to put the best spin on it. 
 

 

scarlet1967 wrote:

I have a go at it and I could be wrong but this is my educated guess backed by the trial’s design (modified rapid dose-escalation design as described by Simon et al.), I just want to add a couple things, DLT= two cases of SAE2 or one case of SAE3 or more adverse effects at any stage during dose escalation which is why I believe these slides are not factual for instance the second slide indicates SAE2 before they switch to groups of patients but it should be two cases of SAE2 also the 28 weeks on both sides should not be there as once they are at groups of patients depending on whether there are any DLTs or not they will switch back and forward between groups of patients until more than one in groups of 6 shows DLT so they cannot know exactly how many cycles it takes in advance therefore it is impossible to estimate the duration of the trial another thing which has not been factored in is the apparently added 3 weeks or so after each cycle when they run their tests and collect data something the CMO mentioned during the CC which is my answer to the first question.

I believe as per second question although theoretically they can go to or above 745mg/m2 they would likely based on the collected PK/PD data, the relation between sortilin expression and the drug’s safety and possibly primary efficacy have to decide at what level the dose escalation stops even in case of no DLT so their MTD doesn’t cause safety issues when they are at later stages of the trial with many more patients, they have to decide how wide their therapeutic window should be considering future safety profile of the drug at the same time. From the trial’s description:

 

“Dose escalation to the next dose level will proceed following satisfactory review of safety data until the MTD is reached.”

 

 Question3, if they see DLT on 540mg/m2 they go the last safe dose which is 420mg/m2 and dose new groups of patient depending on DLT or not there will be going back and forward on groups of patients as per the trial design. Please see the below:

 

“If none of the three patients experience DLT, then the next cohort of three patients is treated at the next higher dose. If two or more of the three patients experience DLT, then three more patients are treated at the next lower dose unless six patients have already been treated at that dose. If one of three patients treated at a dose experiences DLT, then three more patients are treated at that same level. If the incidence of DLT among those six patients is one in six, then the next cohort is treated at the next higher dose.”

 

Question 4, I think considering the above exactly how many patients will be enrolled is not known factor whether it will be less than or more than 15  it depends how many cycles it takes before they get their MTD.

Question 5, they dosed one patient at the time until DLT so the initial slide shows two groups of patient on 200mg/m2 and 300mg/m2 but the second slide shows single patients had already reached those levels because none of those single patients had DLT.

Question 6, as per efficacy I don’t think we should assume the number of cycles are directly related to tumor regression because at whatever dosage the drug has to show affinity to the receptor, internalizes in to cancer cell, the enzymatic cleavage happens successfully, the PDC by passes the efflux and stabilizes the microtubules all of that has to take place in order to get a high intra cellular concentration of the docetaxel which could/should stop the cell divisions. Now all these could happen at any dose of the PDC as long as the free docetaxel released in to cancer cells is higher that docetaxel’s therapeutic window which is at most 100mg/m2, they could be at much higher levels already if the PDC functions as planned. I would like to think if the drug is tolerable patients stay on it what other choices would these late stage patients have? But again these are very sick patients so whether they outlive the trial duration or not is the question.

Now I have my own questions why the company does produces these slides which are not factual and why not elaborate more so folks understand them? It would be better not to have them but if you produce them to present it to investors why not firstly explain they are only estimates (templets) and secondly dig deeper into all the eventualities so people don’t get confused.

 

SPCEO1 wrote: I added another question - see below:

SPCEO1 wrote: Please see the two depictions of the patient protocol below which have raised a number of quesions for me. Admittedly, I may be a little slow when it comes to things like this but maybe some of you can help me out:

1.) Both protocols below indicate the  phase 1a will take 28 weeks. Was that just an unrealistic hope or do they count weeks differently since they did not update the second chart to include more weeks which clearly have been chewed up at this point?

2.) Notice we now have a whole new level on the second slide - 745 mg. If this level was found to be safe, would yet another  new level be added? How many can they add before they say it is time to stop even if no SAE's ever occur.

3.) While it appears they had no SAE's at the 420 level and that this is likely the fallback level for the MTD if SAE's are seen at the 540 level, if they had seen some at 420, could they just declare the 300 level as the MTD or would they need to go back and test some more patients. They surely could not declare it the MTD just based on one patient, right? Prehaps this is a moot point, however, as I suspect they do have multiple patients at the 420 level.

4.) Do they have to have at least 15 patients in the trial before it ends? If so, what does that mean for how long the trial might yet last? Can they knock out the extra patients very quickly?

5.) Why did the original slide have 3 patients at the 200 and 300 level but then they only apparently tested one patient each at those levels? 

6.) If one cycle equals three weeks and we would like to see at elast three cycles to see if some tumor regression can be identified, does that mean we the earliest we could likely see that from those at the 420 level would be the end of January? Does each patient get at least three cycles of treatment? Patients conitnue on the drug even after the trial ends, so is it possible the trial officially ends and then some time after that tumor regression is noticed?