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Nah... that movie was entertaining!
Makes more sense anyway, although I feel that you're making the most negative assumption possible, as usual. You're assuming similar efficacy, which may not be true. From the Theratechnologies PR regarding P3 trial results:
"At the end of the treatment period using ibalizumab with optimized background regimen (OBR), the proportion of study participants with undetectable viral load (HIV-1 <50 copies/mL) was 43% (mean viral load reduction of 3.1 log10) and 53% of patients had a viral load lower than 400 copies/mL."
Source: http://www.eatg.org/news/phase-iii-trial-results-for-ibalizumab-announced/
It seems like almost half of the patients who could be stolen from PRO 140 by Ibalizumab will likely still be "failing" their regimen.
Preliminary results from PRO 140 sound much stronger than that, much closer to 100% as opposed to ~50%. Granted, we don't have complete trial data yet for PRO 140, that's obvious. But if the numbers we DO have hold up, and I'm a patient who qualifies for PRO 140, I'm opting for the one batting nearer to 1.000 than .500. Come to think of it, I'd pick that if I were the doctor too.
From the protocol for the combo trial, on clinicaltrials.gov. Bold type is mine:
"Study population includes treatment-experienced HIV-infected patients with CCR5-tropic virus who demonstrates evidence of HIV-1 replication despite ongoing antiretroviral therapy with documented genotypic or phenotypic resistance to ART drugs within three drug classes (or within two or more drug classes with limited treatment options).The options may be limited as a result of drug antiviral class cross-resistance or documented treatment intolerance."
Why in the world would the FDA limit labeling to resistance to four, or even all five, classes of HAART after agreeing to this trial protocol, as you suggest is "likely"? Your "small market" argument makes sense as is, even if not everyone agrees completely on the final impact of that market. Why are you making such unsubstantiated claims? You lose credibility when you make things up.
I suppose that talk of explicit violence is probably frowned upon by the Terms of Service. Nevermind the literary reference... it's fair enough that some may not have caught it, and the post would then have seemed pretty extreme. I'll choose less violent allusions in the future, but only if other posters tee them up for me so nicely again.
Either way, I hope we get good news soon to help out the share price and the share holders. Same thing as before, just nicer words.
That's interesting. I've never heard any indication (from you or any other source) suggesting that Ibalizumab would target mono. In fact, I'm prety sure that you've expressly stated the opposite any number of times. The conversation I've always heard about the next generation of monthly injections was that it was simply about convenience and compliance. Any references for the assertion that they'll likely target a monotherapy labeling?
Ha, hope I'm as close with my prediction (hope?) for when we get some good news from ENDV!
Edit: I see that I should have read ahead, and I would know that misiu already responded... I'll leave my post anyway.
They don't technically need FDA approval to unblind the data from the first 30 patients - but they may need FDA agreement to include the additional patients they've enrolled. I believe they're having discussions with the FDA to ensure that they're all on the same page with unblinding the data and including (or not) the additional patients to avoid any costly procedural missteps. I believe they'll have the data in hand long before the meeting in October, as my understanding is that meeting is intended to discuss BTD and a BLA, which would both require having the data in hand to discuss.
All of that is my speculation, except for the bit about not needing FDA approval to unblind the 30 patients that were agreed upon in the original protocol.
Misiu or any others with deep experience, please feel free to chime in if I missed anything here.
Ha, glad you enjoyed my hot take on the match. Nobody has offered me a show yet... but I'm not saying no to offers.
For the other poll, I'm going with sometime in the next 2-4 weeks. While I'd love to say that I have complete faith that they have something blockbuster coming, the reality is that it's hard to keep the lights on when you're paying the bills by diluting with very, very cheap shares. They've got to put something out there to turn the momentum. Hopefully it's something really good!
While I'd love to see McGregor knock Mayweather out (not that either of them are model human beings...), that's about 100:1 odds in my book. That "crazy in his eyes" is probably going to get him killed against a guy who has made an all-time great career out of defense and countering. McGregor's defense gets super lazy when he swings - his hands barely come up to defend counters. I bet Mayweather dances with him for 5-7 rounds, McGregor gets tired/impatient, and Mayweather takes advantage of the bad defense to end his career with some emphasis. I'm calling Mayweather by KO in 8.
And to the point about the fix... the only thing that drives Mayweather more than money is his ego. He wouldn't throw the fight for the keys to Fort Knox!
Still, I'm rooting for a meteor to hit the arena.
Your train of thought about how long it takes to sign off on a budget, etc, makes sense, but...
My wife works in budgeting/finance for a public university. Let's just say that you might be surprised.
All speculative either way, I suppose.
Regarding the trial protocol...
For reference, here's a trial where the protocol evidences an explicitly negotiated open-label arm (not blinded) after the blinded period. This is admittedly a less-complex protocol due to lack of crossover, etc, but this is what it might look like if they had agreed in advance with the FDA to allowing some element of the trial to be open. This is essentially what the FDA would be agreeing to with PFS and OS if they unblinded the PFS data now - the OS would be considered open label since SOMEONE has access to the full data set. This was clearly never agreed to in the original protocol for DCVax-L, thus why it is not simple to make that change.
https://clinicaltrials.gov/ct2/show/NCT02483078?term=pro+140&draw=1&rank=3
Appreciate the welcome, might have been my first post here. Honestly not sure, been around for a little bit.
And apologies, you're correct. I misread your post as a quote from an article, not a quote from a comment on an article. Laziness on my part, sure, but it was late and I wanted to go to bed! Either way, it doesn't change the fact that the statement showed a fundamental misunderstanding of double blind trial protocol, and is not a compelling argument in any way. The only way that they could unblind the data for PFS but not fix the OS data would be if they negotiated a protocol change with the FDA prior to unblinding. Otherwise, it's all one trial and one data set. When you unblind for the primary endpoint, you're de facto unblinding for all endpoints that were intended to be tested using double blind protocol. Having an independent assessor or statistician view the data doesn't change that - in fact, double blind trials using independent assessors blind the assessors. However, the intent of a double blind isn't just to blind the physicians and statisticians to prevent bias. Patients are also blinded, as it is suspected that patients may respond differently if they think they've been given a brand new drug vs. a placebo or an old drug. The FDA very well may reject the continuation of an unblinded data set for OS on these grounds. Even though only the independent assessor in this hypothetical case would have the full data set, the blind has still been compromised, therefore they can't be SURE who knows what. That's the whole point of an effective double blind.
After a quick google search, since it seems you may want something more than my word, here's a peer-reviewed, journal-published article on reporting methods for clinical trials, with a focus on blinded studies. It's not 100% the paper I would provide to answer the question directly, but I don't have the time to spend reading papers to find the perfect one. It discusses blinding protocol, including who is blinded and why, and references the above-mentioned placebo effect. Nowhere in the paper does it suggest that a trial can still be considered blinded if an independent assessor (which is a common methodology) breaks the blind.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1800311/
Now, an argument could be made that they could petition the FDA for the protocol change since OS is a rather objective outcome (you're either dead or alive), and thus less subject to bias than something like PFS, where the failure to have an effective method of delineation has been discussed ad nauseum. Plus, the crossover option for patients in the placebo group who have a PFS event muddies the water a bit, although the official protocol on clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT00045968?term=dcvax&rank=2) makes no allowance for unblinding the data based on crossover. I doubt that it would be easy to convince the FDA to allow such a protocol change, and it would likely take months at the glacial pace the FDA moves. That doesn't seem like a logical use of time and effort for the company, given that most believe they're a) close to out of money, and; b) relatively near closing the trial anyway.
In summary, that's why I believe that it is incorrect that they could "easily have an independent statistician report the data" without compromising the OS data. Could they continue to "monitor" OS? Sure, but it wouldn't count towards the data assessment post-unblinding. And OS appears to be an extremely critical secondary outcome measurement here, so I can't imagine the company would do anything to compromise what they likely view as their ace in the hole at this point.
This isn't compelling in the least, particularly since the author hasn't even done the (very basic) due diligence to understand the definition of PFS used in the trial protocol. That smacks of a cheap hit piece. Also, it makes perfect sense that they would continue to keep the trial blinded for as long as they can if they're getting positive feedback re: OS, which even fully blinded, can be roughly analyzed. They cannot, as sentiment mentioned earlier, unblind the data for PFS without fixing the data in place for OS, denying the OS results the benefit of patients who may be living the longest. The author clearly either doesn't know or doesn't care anything for double blind procedures and how they work. Based on the laziness with which the author treated the definition of PFS, I'm guessing they simply don't care.
I used to have faith in SA, but I've realized that many of their PRs and articles on the OTC biotechs I follow are at best lazy, and at worst demonstrably false. I can point to one only several days ago on another company where the author conflated two different studies - without even acknowledging or perhaps realizing that there were two studies - and made positive news sound horrible. I now consider it "journalism" on par with The Onion.
Thanks for pointing this out, that's important.
For those following along at home, steadyhand didn't say that the entire P1 trial was 3 patients. He correctly stated that the first cohort was three patients, and that no side effects were noted and some efficacy was noted. As BoredLawyer points out here, the entire P1 trial is for up to 18 patients. Phase 1 trials typically don't even assess efficacy to any great degree - rather, they are intended to assess the safety of a prospective drug through the use of increasing doses of the compound in a number of cohorts of patients. This is standard stuff. Biotech 101.
The real point was that in the lowest dose that the FDA agreed to - meaning that there are several higher doses that the FDA agreed to - not only were no side effects noted, but some efficacy was noted. That's a good thing. It takes some mental gymnastics to spin anything that we currently know about the P1 trial in a negative light.
Ah, thanks for digging that up. Using that timeline, a PR wouldn't reasonably be expected for full enrollment until mid-November at the earliest. Hopefully they'd learned their lesson on overly aggressive timelines at this point though, and were maybe erring conservatively. Either way, they may still be able to PR a significant chunk of the trial being enrolled in the next month or so, if it makes sense for them to do so.
No problem.
You're right, I can't answer that question directly. We do know from the PR on May 17, 2017 that they had dosed the first patient in GvHD P2, and I believe they gave an estimated timeline during one of the calls they've held. That may be more accurate than what's on clinicaltrials.gov, but I can't seem to locate my notes...
Good question.
The P2 GvHD trial is a 60-patient, double blind study with nearly all endpoints at 100 days post-treatment. There are two minor "other outcomes" that are measured at 365 days post-treatment, but all key data will be available to be unblinded at 100 days. Clinicaltrials.gov lists December 2017 as the estimated primary completion date. If you assume that means December 31, and you assume enrollment is on pace to meet that goal (a large assumption, no doubt), then we could reasonably expect a PR regarding completion of enrollment in roughly one month - sometime in mid or late September. Data would obviously not be available until sometime in early 2018.
Wouldn't that be a nice thing to layer on to combo PE's? And remember - many biotech buyouts occur after P2, meaning that potential buyers may see real value in positive P2 results. Not to say that this will be the case here, but it would be naive not to consider the possibility when viewing valuations if a deal were to happen six months from now.
Exactly... news comes after the ticker change. No sense PR'ing for a ticker you're not going to trade under.
And thank you for the explanation of P1 trial structure and purpose. Most people don't seem to understand the difference in trial phases.
Anyone on the board attending the meeting in person? It would be very interesting to get reports of firsthand discussions outside of the voting sessions.
Update: Jodie Cain confirmed that there will be no dial in or webcast. I didn't receive the email from her personally, but it was forwarded to me.
Right you are, thanks for the response. I haven't seen a dial-in or webcast anywhere for it, so we may be out of luck unless we're in person. Anyone have information to the contrary?
On another note to the board at large, I wouldn't hold your breath for anything significant out of this meeting. This is a standard, annual, corporate governance requirement, that likely will not have any juicy information for shareholders. Information like that would come out through a PR or investor call. While I suppose that it's possible that they could PR after hours today or tomorrow morning, I don't see the need or benefit. The purpose of this meeting is simply not to brief or update anyone, as much as I would like for it to be.
I believe it's Friday, but I don't have the details on hand. I haven't seen an agenda.
Incredibly transparent, isn't it? Not to say that they're not right to a degree - without news, it will continue to fall. But this thing is all about news... not dilution, not (apologies to technicians here) charts, not hearsay... nothing but news. Let's hope that comes soon.
To the post earlier asking about what filings you might expect to see prior to an acquisition, either as the acquirer or (hopefully) the acquired, the answer is none. You'd likely just see a PR about a material definitive agreement, unless it was a hostile takeover attempt.
This shouldn't be shocking to anyone. Nothing he has said previously about AEPP or it's principals is true - why start now?
I do appreciate you looking for yourself, confirming, and reporting back to the board. Thank you for that!
Agreed on both counts, but the FDA has broad authority to approve as it sees fit. Just outlining a way that it could possibly go.
And true with Rexista. Seems the FDA could/should have more control over it than that though. That went way off the rails...
I'm sure that you're correct here about typical label expansion procedures. The one bit of speculation I may have here is that the FDA may consider expanding the label to instances of fewer classes of drug resistance based on two things:
1) The safety profile appears stellar, so that's not much of a concern barring new developments.
2) While the combo market described by the trial participant criteria is very small, it's possible that addressing instances of drug resistance earlier (i.e. before multiple classes fail and patients live with an elevated viral load for prolonged periods of time) would keep more patients from progressing to multi-tropism. Ibalizumbab would still be there if they were to progress, but I would think that overall treatment goal should be inhibiting disease progression as early and effectively as possible. Testing could be ongoing as a post-approval P4.
Maybe that's wishful thinking on my part, and it doesn't change that the real money is in mono, but it seems to me that the FDA would have the incentive to expand the labeling without requiring additional trials pre-approval. The safety data appears to support that at the moment, as well. Then again, and not to rub salt in the wound since it's my wound as well, but that's along the lines of what we thought about Rexista! Just never know with the FDA.
I think that it absolutely does, but it's a different patient set, a different treatment regimen, and I'm not a doctor. I don't think it's unreasonable to draw that conclusion though, particularly since the rebounders witnessed in the P2 trials occurred well before 25 weeks. Personally, I take it as a significant feather in the cap, and think that overall risk to mono and the company stepped down quite a bit yesterday.
That's just my opinion though. And failing the treatment regimen or not, combo is not mono, so it's definitely not 100% apples to apples.
To answer your last question first - yes, that is the protocol for the trial. While personally I suspect that the benefit could be quite obvious to a casual observer, I am not well-versed enough in HIV itself to know that with any certainty. I think your point is that if the drug works that well, it may not be so "blind" as we think, and they may have a good idea of what the data will look like when it comes back, thus impacting financing decisions now. I suspect that is the case to some degree, and the results from the open label arm probably reinforce that for them.
Also, I do think it's possible for the PE data to not be outstanding but the 25-week data great. I don't expect it, but it's possible. That said, I think stellar 25-week data - which is what we've seen thus far - evidences the efficacy enough that less conclusive PE data may not be as meaningful as it otherwise would be.
As for the dilution to come, I think we all agree that cash will be raised, but we're unsure of amounts and terms. Plug different numbers in for those, as well as SP, and you get different expected returns for buy in points both before and after the raise. Many here are of the opinion that they'd rather not miss the chance on the biggest upside, while you (and others, no doubt) are on the side of being willing to miss the biggest upside for the safest return. It's all good - different strokes for different folks. As long as we have all the facts right, that's all that matters.
I don't think so. My thought on this stock for a while now has been that the majority of folks who want in at this level, before news that seriously impacts risk (positively or negatively), are already in. And conversely, the majority of those who don't want in right now, aren't. Shares just aren't trading on any consequential level. And honestly, the news that has come out hasn't been impactful enough to change most investors' paradigms or thought processes. I think they're just feeding shareholders a few PR's to keep them in the loop, since most were expecting PE's from combo by now. I think you'll see significant movement in share price when they release combo PE's, one way or another.
Plus, as has been referenced more times than I can count, of course they're going to raise money in the future. They're a clinical stage, pre-revenue biotech. That's how they fund operations. And of course they're trying to do it at a better share price based on exciting news. The only way that doesn't happen is if they sell or partner pretty much immediately. If anyone is taken aback by the prospect that the firm may be trying to use exciting news to raise money, they're probably chasing the wrong tail to begin with.
Only disagreeing with your last point - no need to close the trial (in fact, they haven't to our knowledge) in order to disclose results from the 24-week extension arm since that one is open label. They're free to share information on that, when and if they so choose. The one-week efficacy primary endpoint is the only thing they need to close the trial and unblind the data for, to my knowledge. They weren't "forced" to do anything in that regard.
Could even be 11/11. We have no way of knowing for certain if another one or two has completed it, but based on previous CC's, it can't be much more than that. 12 or 13 (as you referenced) tops, at this point.
What you are misstating or misunderstanding is due to an apparent conflation of the one-week efficacy portion of the trial, and the 24-week open label extension.
According to today's PR, 33 patients have finished one-week efficacy at this point. However, this data is still blinded as far as we know. The company has given no indication that they have efficacy data at one week, much less what that data might say.
Also from today's PR, we know for sure that 11 patients have finished the 24-week open label extension, and the company is claiming zero detectable viral load for those patients at 25 weeks (total - 1 week for the trial vs. placebo, and 24 more for open label extension). They have access to this data because it is an open label arm of the trial. We do not know for sure that only 11 patients have finished the complete 25-week trial, although based on information provided in Jan/Feb, we can deduce that they can't have many (if any) more patients completed at this time. That data appears to be extremely good at this point, but it is a secondary endpoint, and unrelated to the one-week double blind arm of the trial which is providing the primary endpoint data.
All clear?
I agree - I don't see where they give any indication of number of patients through the 25 weeks outside of the 11 they reference. It certainly can't be 25, although I'm not used to thinking that Pearsby's statements are overly optimistic!
I think your assessment is likely correct based on the CC and the calendar. It would be nice to know for sure though. I have a hard time believing that not one of the patients who finished the 25 weeks to date has no detectable viral load, but that would be amazing. It would simply surpass my expectations greatly, and I'm willing to be surprised.
That's fair, you're on record multiple times (not just this morning) as thinking they'll be able to get the money, but you have also mentioned the possibility of bankruptcy multiple times over the last week or two. I also think your question about how/why they're going about it is fair, but maybe it's just part of the finance game I (we?) don't understand fully. For example, if they believe that the trial is going to give them a huge momentum boost soon, but they need to raise $1.5mm to get there, maybe upmarket isn't an option. Larger finance firms are probably going to want to do minimum deal sizes. I have a buddy in a small venture capital firm in California who has told me before that they won't even look at anything with less than a $10mm investment. While that VC obviously has some money to throw around, I can assure you that it's not a major, upmarket financier. That's completely anecdotal, but maybe that's why they've remained in the smaller, darker corners of financing while they're pushing towards major events? Don't know, just a theory on how/why that could be, without being a negative to CYDY. Who knows what they may have lined up post-combo PE, if they feel the need to raise a chunk of money to carry things for a while? You never know, they could also have more significant transactions (buyout or partnership) lined up contingent upon combo results and this meeting with the FDA. Not saying it's likely, but not impossible, and would explain the lack of apparent effort towards attracting major financing.
I guess when uncertainty is involved, there are always (at least) two potential sides to a story. Believe it or not, I'm naturally skeptical and pessimist, so it surprises me that my inclination is to see the positive side of everything here. It could also be confirmation bias - I'm already invested, therefore I'm interpreting facts in such a way to support my previously made decision. That said, I, along with the group of folks I loosely invest with, have tried hard to make ourselves see the downside on this, and none of us can. That's not to say there's not risk - there's always risk - I just can't find the "other shoe" in the verifiable information we've received from the firm to date.
If, as I suspect, the placebo/drug split was only altered by the patients enrolled after the first 30, then you still have the agreed-upon 30-patient double blind trial with integrity intact. If the FDA doesn't allow the additional patients, fine... the company just gives them the data from the 30 patients under agreed-upon protocol. And that's the only departure from previous protocol language that we have noted this morning. Over-enrolling trials is de rigueur, and I wouldn't consider that to be a protocol change. Asking the FDA to allow to allow data in addition to what was agreed upon is one thing; asking the FDA to accept data that is not what was agreed upon INSTEAD of the data they asked for is another thing. Discussing this with the FDA prior to unblinding the trial seems responsible, since tainting this trial would be very, very bad. Again, this is why the idea that the company changed the exclusion criteria, without discussing with the FDA, to allow patients who had previously used Maraviroc rings very false for me. I don't believe that the FDA would accept that for a pivotal trial, which would make it wildly irresponsible for management to do so. Speculation on my part, but it's at least logical. It would be nice for the company to provide more clarity, but I don't think they owe it to anyone to disclose anything prior to discussing with the FDA. The trial is still in progress, after all.
As for a second phase III for mono, I agree that it's common in many drugs, but I think that it's highly unlikely here unless we witness a significant change in the safety profile of the drug. What incentive would the FDA have to massively delay bringing a drug to market that has such a (to date) clean safety profile when SOC is so toxic? Especially if it works, which it appears to, and you agree that it appears to work. I think it's more more likely that the FDA would consider accelerated approval prior to the completion of the mono trial, and require that the trials continue after the accelerated approval. Again, certainly speculation on my part, but I believe that it's a far more logical outcome given what we currently know about the drug.
I do agree that combo alone may have limited commercial viability depending on the labeling, but I disagree that derisking of mono is so far off. Again, the mono trial is open label. Potential buyers or partners will not have to wait until the end of next year to see data. It's possible that nobody would bite until mono is approved and (nearly) completely derisked, but I don't believe that it will take that long before someone bites when you can see the data for the trial real time as long as you sign an NDA.
I don't blame you for being cautious - I've noted before that you appear to have a different risk appetite than many here, and that's perfectly fine. I actually don't even disagree with your approach to try to time an entry after the last big dilution, although there you're making assumptions regarding share price and money raised that could go either way. Nothing wrong with that approach though, and I understand that you're willing to miss out on the biggest upside to reduce your risk to an acceptable (to you) level. I do think that you reach very hard to see the negative in any situation, no matter how much of a stretch, rather than considering much more benign and plausible explanations. It's also beyond me how you could honestly think that they may not be able to raise money to keep the lights on at this point, which you've referenced repeatedly, although I agree that funds can be raised at either very beneficial or very painful levels.
I know that you're just fishing, but that's pretty baseless speculation. Significant changes to qualification criteria would have to go through the FDA ahead of time, or the trial would pretty much be invalidated. If you - or anyone else - believes that there is a non zero chance that this occurred, then you (and anyone else who thinks that) should be running from this company as fast as humanly possible, because that would be unforgivable management ineptitude and would be unbelievably costly at best.
I agree that as it appears that timelines are moving further out, additional clarity on finances would be nice. I have no doubt that they can raise money, however. It's a matter of terms, in my mind. Publishing some solid data could obviously help that cause.
In the end, no new evidence has been presented to change my belief in the science, and the science will carry the day in my opinion. Everything else just dictates the ultimate value of a share.
Right - we're discussing only the first, one-week arm where PRO-140 is compared to placebo in a double blind protocol. Misiu and myself both believe that the protocol specified 50/50 vs placebo in the first arm, but now we don't see that in the protocol.
I'm with misiu on this one - I read and re-read that protocol many times, and it was 50/50. I just read it again, and the split is not specified.
My speculation is that when they began adding patients over 30 (not knowing what the final enrollment would be), they gave everyone PRO-140. It would be difficult to effectively randomize for a near 50/50 split while maintaining full blindness when you're adding patients ad hoc. That said, I'm surprised that clinicaltrials.gov doesn't have a marker that the language has been updated. I'm very interested to hear what misiu finds out on that front.
This could very well be one of the discussions that the company is having with the FDA prior to analyzing data. If they gave all additional patients PRO-140, then that portion of the trial would by definition not be double blind, and they would have to advocate for the inclusion of that data. As long as they don't unblind the trial though, they can simply exclude the additional patients and the integrity of the double blind trial would be intact.
All speculation and deduction on my part, excluding that I'm sure that the protocol was 50/50.
Completely standard language - this is in the filings of every small company without a fully built out system of internal controls, an audit committee, etc. Hard to have dual control, three lines of defense, etc, when you're a ~5-person company. It's a routine disclosure that they have to make as a public company lacking those things, and presents zero additional concern over and above the general attention one should pay to the finances of any small company.