RE:RE:RE:RE:RE:RE:RE:Quick Summary Very, very helpful - thanks! I have no experience with a cancer drug going through trials so all the nomenclature and procedures are new to me.
If I understand you correctly, there is almost nothing that you would see in the phase 1a that would convince you of anything related to efficacy. Is that correct? So we should just stop talking about it regarding the phase 1a altogether as there is almost no realistic scenario where we can see it? Now, I asked Paul once if there was no scenario where we could see efficacy in phase 1a and he indicated there was such a scenario possible. Maybe he was just putting a sales job on me but he seemed to think there was a way to see it in phase 1a. My understanding of what he said and how he said it made it seem to me like a hint that TH may have indeed seen something positive in th e phase 1a with regard to efficacy. Now, he left himself plenty of room to deny that he was hinting about anything as well. But it was clear that he did not think it was impossible to see efficacy in phase 1a. What defintition of efficacy he may have been referring to is also something that I do not know.
Also, even with no efficacy data from phase 1a, there is a whole lot of relevant info they could share with us that would be helpful as JFM pointed out. But if they share some good info, they may also be ethically required to share some bad info. So, I suppose it is possible we may get neither, at least until any financing is completed.
qwerty22 wrote: 1) I wouldn't talk about it in this way. There won't be a placebo arm and drug arm and there won't be stat sig to calculate between those arms. What happens is there will be an ORR and PFS number that will be agreed upon in advance as the target but with wiggle room depending on the toxicity profile. Sometimes analysts come out with what they think the ORR target is for a particular cancer target population, sometimes the company gives advance info based on their discussions with the fda, sometimes you are guessing based on the recent experience of other drugs. Rather than stat sig I think about clinical utility. Based on the larger Ph2 is this a drug clinicians will quick go for because it's benign and/or has a high success rate or is this a drug of last resort because it's toxic and/or has a low success rate. You might increase it's hit rate by preselecting for responders using a biomarkers thus improving it's utility but reducing it's target market. This is the efficacy that supports approval but I don't think it comes thru statistical analysis per se. it comes from whether the drug passes a risk/reward analysis. After that it's value comes from how it fits into the treatment options for the indication.
2) I'd really put 1a and maybe even 1b into this category. I think a way to thinking about this is proving anti-tumour activity. This goes all the way from the first proof of efficacy thru to deciding on which cancer indications to chase. It's really saying that a response I see in a patient has a very high chance that it's coming from the anti-tumour activity of the drug. That's why I don't particularly like one patient having stable disease for upto 12 months. I think within a cohort of 12 or so patients you might 'naturally' see that in untreated patients so being able to clearly say it's a drug effect is difficult. Rather than putting that into 3) I'd rather say it's just not enough. I think anti-tumour activity can look weak or strong. It looks strong when you can imagine extrapolating it into a larger cohort and it hit those clinical utility targets It's weak when it's the odd response that doesn't hit that target.
3) I don't really think there is a third category. If they are trying to sell you this then it's because they've failed to reach 2. I guess the odd hint is good if you have nothing very early on but it's never going to grab the attention of new people and it won't have a long shelf life. They need to quickly prove they have 2. The difficulty is you end up trying to sell 'noise' as efficacy. We probably should stop talking about CYDY but this is what I thought they were doing with their cancer data.
I think the thing I don't like about what you have been saying is that I think there is no rationale for separating signs of efficacy into something that meets a certain scientific criteria and others data that doesn't. It all has to hit a minimum. It's hard to strictly say what that threshold looks like until we see what they are trying to sell us. At the moment they are selling us nothing. It seems reasonable to think nothing has passed that minimum threshold yet.
Having said all that there is some subjectivity here. I think these are noisy clinical circumstances and it's about judging whether an observation stand out above that noise. When we finally get some detail we can make some judgements. But clearer signals will convince more people.
SPCEO1 wrote: One thing I am trying to get better at is stating precisely things around the question of efficacy because I think how it has been often loosely talked about by speed typing people like myself has contributed to what some of us actually mean. For me, there are three categories odf efficacy that we are talking about and I am going to name them so we can use that going forward.
1.) Efficacy - This will be understood as something we should not expect to see until phase 2 and is statistically significant signs of a favorable effect of TH-1902 on cancerous tumors.
2.) Preliminary signs of efficacy - This is what we might see, but probably will not in any scientifically defined way in phase 1a, but will more likely see in phase Ib. It is not statistically significant, since there will not be enough patients to make that claim, so it is only a preliminary observation of an actual favorable effect of TH-1902 on cancerous tumors. It will probably be seen on more than one patient in a similar cancer type.
3.) Hopeful signs of efficacy - This is what we may see in phase 1a. It is likely just a marginal indication that TH-1902 is active and just starting to do its thing against a cancerous tumors in just one patient with a dertain type of cancer.
Do those seem like a better way to generally define what we are talking about here when we speak of efficacy?
So, I am expecting a Hopeful sign of Efficacy in phase 1a. Everything the company has said and done recently points to this from my perspective. I believe the company already knows they have a very good shot at seeing preliminary signs of efficacy in phase 1b and, if so, the chances of seeing efficacy in phase 2 is pretty high. So, I am feeling pretty good about how things are shaping up even though the company will not address directly the things JFM mentioned. I fully expect there to be some nastier data points in just about any phase 1a trial so I am not overly concerned since the weight of the evidence we have points to an overall good outcome. Unless THTX management is made up lying, theiving rattlesnakes. They will certainly not tell the whole truth at times but that is not lying. But they have lied at times as well, so that has to be taken into account. But I have not seen them steal anything other than an awful lot of our time and they do not appear to me to be rattlesnakes. So, yes, there will be some bad news mixed in at some point but the overall picture looks pretty good to me. Actually, very good as the drug is safe (the main objective of the 1a was to prove safety and its safety is in line with the pre-clincial work according to the CMO). The company is and has been taking actions with financial consequences that appear to confirm they believe what they were selling today as well. Clearly there was some ugliness to the phase 1a but we may never hear much about it and we certainly will never get all the dirt on it. But all that matters is that they win this round and advance to the next one and it is pretty apparent TH-1902 has won round 1a.
qwerty22 wrote: The drug if it's going to work has to have an efficacious dose, at the moment hopes rest on 300mg/mm2. My guesstimate is once they have enrolled the last 6 patients they will have 13 evaluable patients that have recieved 1 or more doses above 300. I've seen companies report responders from those sorts of numbers. I think Sutro and bcyc both did that. But you are right, not having efficacy at that point is very possible and doesn't stop them moving to 1b. It seemed pretty clear to me that not only is it possible efficacy emerges only during 1b but that is exactly what they were signalling today. The efficacy could come from 1a patients that continue after the start of 1b but it seems like what they are preparing us for is efficacy not being part of the end of 1a update.
MAC7824 wrote: First time poster, long time reader. Invested in THTX (formally THERF) since 2014. I appreciate all of the insight from the posters as it has been very helpful to keep my attention on this company since THTX has done a very poor job of communicating.
I totally agree with this post, JFM. One sense I have gotten from this board is that we have been hopeful for "preliminary signs of efficacy" from Phase 1a for around 6 months now. Around that time, I spent time researching how many other companies going through a Phase 1a with a FDA fast-track designation actually release "preliminary signs of efficacy" for a trial focused on safety, and found it was incredibly rare for a company to do so. Additionally, I do not agree with this board trying to glean bits of truth from management regarding preliminary signs of efficacy, as one of the primary jobs of externally facing employees (CEO, CFO, etc.) of THTX is to act as a salesman of the company. Every company tries to sound optimistic during their earnings calls, and that is their job to do so. I think it is foolish to expect that a company that is new to the oncology scene would be the rare exception to release any signs of efficacy prior to the Phase 1b being totally finished. The wise company would hold off on releasing any data until it is absolutely bullet-proof, and I expect THTX to do that.
Having said that, I am still optimistic that THTX is on-to something in oncology. As I have read on this board previously, there are MANY companies that do not make it passed Phase 1a safety trials in oncology, and I think that should be celebrated. I anticipate there will be a small price bump in the stock price once the Phase 1a PR is sent out. I do not, however, based on today's call, believe that this board should hold out any hope for efficacy data prior to the end of Phase 1b, and anticipate THTX will shift it's tone from focusing on pre-clinical efficacy to potential future avenues now that TH1902 is deemed as safe. I also agree with JFM's point regarding the explanation around repeatedly missing timelines. Based on the evidence we have thus far, what expectation is there that the Phase 1b will not be delayed significantly? My approach to THTX's timelines over the last eight years has been to listen to it, and add at least 3 months (and sometimes 6 months) to each timeline they provide, which has been more in-line with reality.
Thank you all for the posts and I will go back to just reading now!