RE:RE:RE:RE:RE:RE:RE:RE:RE:10 questions from RBC January 8The probability they are giving to both protocols is zero atm while other phase 1,2 ,3 biotech trials get credit for their programs.
Wino115 wrote: Makes sense as we've all heard similar issues from the likes of Steven Harrison the NASH investigator and KOL. His discussion at the conference THTX presented at was insightful and made it clear the guidelines from 3-4 years ago will be modified in many ways -- endpoints, data needs, trial designs and powering, lipids, diabetic effects, etc...Maybe with more clarity there we'll see more combo drugs too. There's only a few now and I have felt given the safety profile of F8 and it's upstream MOA that it would make a nice addition to some of these other more fibrotic agents. Maybe with Novo Nordisk -- any combo would help the credibility of Egrifta in NASH so I'm all for that as long as the other partner pays for it.
I think your analysis sort of encapsultates where the RBC and other analysts are (or were?). It will be interesting to see if they are willing to put pen to paper and make a more robust case for the drug "totality case" regardless of limited biopsy data. I think the Doug Loe guy could do service to the scientific arguments and data and Cannacord should too. But since I don' think CMO or CEO actually explain the science all that well for NASH themselves, I'm not sure we'll see a really new convincing case. A conference call with Grinspoon to really dig in to it and hear it at that level along with a Loomba or some other KOL that can place the science within the context of the industry experience in trials so far is what they would need and I doubt they'll do that. At some point someone in THTX will just have to learn that science inside and out and understand the full industry issues and put together a comprehensive case for their trial and approach. We've heard it in a jumbled way in their calls but it's either been regurgitation of the limited data or Grinspoon wondering why we don't understand the science and genomics graphs he's showing us.
It will never change the mind of the more traditional minded NASH analysts (which many of the US guys seem to be too from the conferences they recently did). They all just want the simple answer with simple consistent data so they can place the project, drug and company valuation. It explains a lot of the discount, but the laziness explains a lot too. Hopefully these 3 analysts will flesh out the case and give some probabilities around it and at least attempt to value it properly with some comps in there. Same for the cancer project.
qwerty22 wrote: Another way to look at this.
Loomba is AHEAD of the regulator. Loomba wants to take the regulators to where his science tells him things should be. That may happen (maybe it should happen) soon, in 6 months, 12 months, before THTX trial readout. The analyst don't want to be ahead of the regulators, they want to be in step with the regulators in their analysis and advise to clients. If the regulators eventually move towards Loomba position and the analysts follow then maybe THTX looks more promising to them. Clearly this is not a full description of reality because THTX wouldn't have a Ph3 in hand if this was completely true but this is the perception of the situation. Does any of that make sense.
Is THTX getting a Ph3 a sign that the FDA are not so fixated of biopsy data?
qwerty22 wrote:
WRT NASH I'm just saying what I always say. Thtx doesn't have enough biopsy data in its target population for Ph3. If the markets are fixated on that aspect then it's a big weakness. Assuming the RBC guy isn't playing games and isn't an idiot then my best explanation is he can't get past the lack of biopsy data. As Wino said recently if that's the case, and there is no interim data readout, then he remains on the sidelines thru the whole of the Ph3. I'm not trying to excuse the fact that he doesn't take that piece of info and use it in a better way.
It'll be interesting to see how the 3 companies supporting the financing will report all this. How they weave the weakness of not having robust biopsy data into a positive narrative. That might shed more light on the markets general attitude.
Just as an aside my wife was listening to a podcast yesterday on visceral adiposity in Lupus. It's amazing how it is a factor in so much chronic disease. It's clear to me that Egrifta is at its heart an anti-visceral adiposity drug there is a wealth of data to support that idea, hopefully Grinspoon's heart fat study is going to further confirm that. I'm sure that's a big part of the NASH story for Egrifta. It doesn't rely on biopsy data to come to this conclusion and until we get robust biopsy data people need to understand the relevance of that. But right now, my opinion, all the market cares about is biopsy data and they don't see very much of that in thtx's case so they don't seem to need to do a deep dive into all the other thing they do have.
qwerty22 wrote:
RECIST is the standardized protocol/rules of cancer studies, it's mentioned on thtx's clinicaltrials page. The wiki entry is a great place to start but there are many good guides to understand RECIST. I think it's worth getting familiar with it and familiar with how other companies report it because there are right and wrong ways to report this data and any company that starts to stray from reporting the data in the standard way are maybe trying to hide something.
https://en.wikipedia.org/wiki/Response_evaluation_criteria_in_solid_tumors
The four categories of response are.
- Complete response (CR): Disappearance of all target lesions
- Partial response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD
- Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
- Progressive disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions
Overall Response Rate (ORR) is the total % of CR+PR group. What is recorded is the best response hit at any particular time point. So if a patient had their tumours measured 4 times and it went over time SD, PR, CR,PD then that patient gets catorgorized CR because that is the best response they hit.
Duration of Response (DOR) is the (mean) time from when the patient had their maximal response to the point their cancer re-started progressing. This can take time because it relies on time to pass to get an result but you can get reading like % with response at 6 months or 12 months to give some indication of the depth of response. Again using Sutro as an example they are reporting a number of durable responses hitting 6 and 12 months in their population.
Overall Survival is what it suggests, the time from initiation on trial to death. Obviously this might take a long time if people stay alive but they can report this in different ways so they might say % survival at 6 or12 months for example.
So if you read the literature one concern with chemo (and now also with ADCs) is in late line setting they don't give extended disease control so patients may respond but then relapse quickly. We have to watch for that with our PDC. Immunotherapeutics tend to give reverse outcomes, they often work in a limited number of patients but when they do they often give much longer benefits.
Clearly part of the reason to chase a PDC is to avoid toxicity. That paper was describe the present landscape of late treatment TNBC, toxicity of chemo is horrible, women have to come off drug early and this is contributing to the poor DOR. Fix toxicity and you might fix part of the DOR problem with chemo/ADCs. Again this is to some extent what Sutro have done, it allows some women to keep taking the drug for 1year+ and that helps maintain disease control. Let's start off by hoping for this from THTX's drug.
That paper I linked to just described how bad the drug landscape looks in the initial pop in TNBC that THTX is chasing. It just shows how low the bar is. I haven't looked deeply at all the indications THTX is chasing but they all look similarly dire.
SPCEO1 wrote: Since amny of us are not familiar with oncology, could yo give us a brief explanation of ORR, DOR and OS. Also, what is the toxicities issue?
I am also not sure what you meant when you were referring to the biopsy in NASH as a weakness. All NASH trials involve biopsies, so it is a weakness shared by all NASH companies.
qwerty22 wrote: I see cancer as data driven, it's hard to ignore ORR or DOR, they should speak loadly, I guess you could ignore them if you want to focus on corporate competence.
Here's a meta-analysis of mTNBC lots of numbers to pick out of that but my summary of the present tested drugs.
https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-019-1210-4#Tab1
10-20% ORR
4-6months DOR
12-18months OS
50-66% grade 3+ toxicities
This is what the drug needs to beat to look promising. Sutro is doing that but in Ovarian and the SP over the past 12-18 months looks great even with a drug related death.
I actually also see NASH as data driven and in that case very focused on the biopsy endpoints as the foundation for a program. I still think collectively we are under-estimating the importance of that weakness at least to the perception of the program.
scarlet1967 wrote: Most of questions are relevant but it seems there are so much pending doubts regarding company's ability to execute so even when they produce good results it won't be factored in by the market, I believe the problem is the failed IR and inability to convince the investors of course the recent deal wasn't helpful at all.
But if company can address these questions in a convincing manner going forward it will definitely help the valuation imo, therefore they need to have a serious discussions re changing their failed strategy.