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I've forgotten about cor for the last few weeks, because no news is no news, and speculation is stressful, comes at the cost of all the other things one should be thinking about, and doesn't change outcomes. I highly recommend this tactic during these down times.
That said, the tardy release of the RD-1 data is in dog-ate-the-homework territory. If we're not getting the results now because the key statistician is on vacation, then why didn't we get the results before the statistician went on vacation? These data have been in the can since mid-june, n=16. How many vacation-prone people are involved in this process? Further, if you announce "2-4 weeks" (as they did at the RD-2 unveiling) then it is implausible that you'd be blind-sided by a key individual's vacation. If cor management aren't closely following the progress of this study, then what are they doing? A vacation is not proprietary information, and at the very least could have been factored into the presented RD-1 results presentation date estimate.
At best this is bad management.
re: WINDHOVER's TOP 10 Unpartnered Projects
I assume that cor met with potential partners at this meeting, and that the tenor of these discussions would spread via word-of-mouth.
If these assumptions are correct, then trading action this week should give us some indication of whether or not RD-2 alone is convincing any potential partners.
Upon rereading what I wrote, I noticed that I more or less exactly wrote what zebra wrote. I need to get a life. This thing is going to unfold the way it will unfond, and right now the sun is shining outside.
I don't doubt that the RD indication attracts many intrested third parties, the other unknown is whether what these parties are willing to offer will be acceptable to cor. I think that this is what it really comes down to: whether or not cor and a BP can reach an agreement. Cor may be coming in with a relatively weak proof-of-concept, no share-price bounce, and hence without realistic means other than a partnership to go forward financially. I think both parties have a good idea of the size of the RD market, so there's no disagreement about that, and even if all they get is a positive RD2, it's still pretty compelling data, in part because of all the problems with experimental design and execution. If multiple BPs are competing for the partnership, then I think that cor can cut a good deal.
My point was not so much that the scenario I laid out was necessarily the case, but rather that we can't stipulate that the data will be good, let alone favorable. For the record: I don't know much of anything about pain pathways, etc.
Given that there are a number of confounding issues here that BP analysts will (I hope) factor in (arousal response as a surrogate for RD, mismatched dosages in RD2 and RD1, etc.), it still seems possible that to me that with a far-from-perfect outcome, cor can nonetheless enter into a partnership. My questions are:
On the basis of RD2 alone, is a partnership possible?
If RD-1 is ambiguous, will cor have the option of raising funds via a PIPE or other mechanisms, assuming share-price remains at or below current levels?
I've been thinking about this mush issue, and I've reached the conclusion that there is in fact a good chance that we will get erroneous results from this study, because of its design.
Leaving aside the attrition seen in RD2 due to people pulling off their masks, the problem that I see here is that in this trial two things are tested in series. My concern is that whichever test is applied first, it will contaminate results obtained with the second.
If the pain stimulus is administered under normoxia/normocapnea prior to rebreathing, my concern is that by the time subjects reach threshold for sensing the pain, they will be aroused, which will change their response to the subsequent rebreathing protocol, shifting all subjects towards a more ampakine-like response.
If the rebreathing is administered first, the arousal associated with that may sensitize subjects to the pain stimulus. It's still possible that the control group will differ from ampakines, even though both are shifted to the left.
It seems to me that this whole problem was avoidable. The right way to do this study would have been to test for efficacy first, find the effective dose, and then test for analgesia preservation at that dose, without revisiting the rebreathing protocol, since preservation of the arousal response at that dose had already been established.
The question of whether RD2 by itself is enough to secure a partnership may be what the survival of this company hinges on. To stipulate that RD1 isn't going to be mush is wishful thinking. I very much hope that RD2 alone is sufficient, but I'd like others' thoughts on the issue.
I don't think PIPEs are an option until share-price is a dollar higher, so whatever their motive, they never got the leverage. I certainly don't think they tried to arrange things for an August announcement, but since that's the way things turned out, my guess is that they want to postpone RD1 until after labor day. If that produces a more substantial bounce then they have the PIPE option, but I don't think the market is going to be convinced by the science by itself. There has to be the kind of partnership buzz that Neuro referred to to produce a share-price increase, and with a partnership in hand, it isn't obvious why they would also do a PIPE. So I don't foresee a PIPE.
Of course, if the RD-1 results were to undercut efficacy and/or analgesia preservation, then a PIPE would likely be futile too, since the terms would be so bad.
I think cor has to get a partnership deal. It is the only thing that will restore credibility to this company. Cor has established efficacy for 2 multimillion dollar indications, there are no major safety issues with the low-impacts, and yet the stock is still below a dollar. More science isn't going to change how the market views cor.
I agree with what neuro wrote about why mask-induced anxiety is not so likely to be a problem. There's another aspect: the outcome of RD-2 alerted cor to the problem, and they certainly could enquire about experiment failure rate, in light of RD-2. If the news were bad, they wouldn't wait for the analysis, since they pretty much would know the outcome based on the failure rate.
My point is that if the data were mush, they'd know already. They would have known at the time of the RD-2 results announcement.
Like everything else with cor, this isn't a binary variable: they probably have a trend to detect among those participants who didn't wash out (they could likely tolerate up to a 50% failure rate). They may have reason to believe that they have enough data for significance, so they're going ahead with the full analysis.
My hope is that they're not grasping at straws, and that their reasons for going ahead with the full analysis (and the prolonged delay) are well-founded. I think that the slow rate of progress we're seeing here is intentional. It is easy to tell people to take their time. On this view, they are slowing the process to move the announcement into September, when the news will be noticed, which, if true, reflects confidence.
I think that they will do a partnership covering all analgesia/RD indications. I think the OSA will not be part of the deal.
In your opinion, are the RD-2 results by themselves sufficient to initiate partnership discussions? Isn't everything pretty much on hold until the RD-1 results are in? Is our understanding of cross-species analgesia differences sufficiently advanced that Greer's data can be taken as strong predictors of the human-subjects trial outcome rather than suggestive preliminary data?
What happens if at 1500 mg there is no efficacy in blocking RD, and no analgesia? Wouldn't that mean that at the effective dose all analgesia would be lost? I don't mean to be a neurotic pain-in-the-ass here, but my concern is that the RD-2 data may not be as compelling as I think they were.
What it comes down to is the level of uncertainty surrounding analgesia preservation. My sense is that the main unknown here was the RD component, and that rat-to-human comparisons on the analgesia end of things would be more straight-forward, both because methods for testing analgesia maintenance are much more congruent in human and animal trials than the methods used to test for RD reversal, and because we know so much more about the physiology of pain, and the pharmacology of analgesics.
If this is the case, then there is considerably less riding on RD-1 than on RD-2.
True, but it means they have this motivator at their disposal. When you think about how little data were actually conveyed at the RD-2 presentation, it isn't at all clear to me why generating the bottom-line numbers for RD-1 is so time-consuming.
My point is that if it takes weeks and weeks (assuming that they have the data in hand) it's because they want to drag it out.
This is a study with 16 participants, with VE55 as one number they need to measure, and another number that is probably equally straight-forward as an indication of analgesia preservation. How hard is the statistical analysis of these data?
The data are in the can, and this is a simpler study. Plus, as per the earlier missive from Stoll: "We also have paid the CRO an extra incentive fee to get their personnel to work overtime to get the job done more quickly."
My sense is that they may be dragging this out to get the press release after the dog-days of August. If they can get a bigger bounce out of the announcement, they can negotiate from a stronger position.
I don't at all mean to suggest that a positive outcome is a foregone conclusion. There are too many unknowns, and a resoundingly negative outcome (no efficacy, no analgesia preservation) may do this company in as surely as an RD-2 negative result would have. That said, I think that more is known about the mapping between rodents and humans in the domain of analgesia, so if Greer saw analgesia preservation in his rats, if the people carrying out this study know their stuff, they should be able to match analgesia levels (that's the hope anyway).
I'm also not saying that they are sitting on the results. I just think that they might see it to their advantage to drag the process out a bit, and my sense is that this is something that they can probably do.
When can we expect RD-1 results?
My sense is that at least part of the problem is that the FDA has an impossible mandate. At some point, a better balance has to be struck between protecting consumer safety, and providing the ill with better access to novel treatments and drugs.
That said, the numerous reports of conflict of interest among FDA consusltants seems to indicate that there is some corruption too.
On top of that, the FDA's scope of oversight is way too broad, and their staffing is inadequate.
>>>Neurodegenerative disorders like AD, PD, HD will be the province of high-impacts
Don't you think that a low-impact might have a role in treating the symptoms of mild AZ?
>>In the past, COR had financing in place to take advantage of a short term price pop
There hasn't been a price pop. Based on your argument, a PIPE would likely follow RD-1 positive data, when there may actually be a price pop. I don't expect a PIPE, I expect a partnership on RD. I absolutely don't want them going it alone on this indication.
>>>As for iv admin of CX717- well so far we have only seen a significant effect at a high (oral) dose of 2.1g and then it still is somewhere between 20-50%.
The observation that first-exposure responses were consistently more robust than second-exposure responses suggests that there is some habituation going on here, either to the ampakine, to the opioid, or to the hypercapnea. I don't think it matters which, because the indication here is to protect against RD on a one-time basis, so these desensitization effects are irrelevant, essentially an experimental design flaw.
Further, in a clinical setting, the effective analgesic dose administered post-operatively may cause some respiratory depression in most patients, but doesn't lead to apnea, so the utility of an ampakine may be to upregulate respiratory networks to provide a better margin of safety post-operatively, rather than treat full-blown respiratory arrest.
Finally, this really was the wrong protocol to test respiratory depression. What was shown here was that ampakines reduced opioid-induced depression of chemosensory feedback.
Considering how bass-ackwards this whole thing was, the fact that statistical significance was obtained from an n of 7 really does lead me to think that this compound works.
It's more of a question for clinicians, but that's always looked like a logical next step, considering the fatalities that occur with some regularity among those chronically taking opiates for intractable pain.
If Cephalon partners with cor, my guess is this is the primary reason.
If they developed tolerance to the opiate, you'd expect to see a steeper slope to H in the opiates only group. A tolerance to the ampakine would be a flatter amp+opioids slope. Another possibility is that the chemosensory response itself desensitized. If this were the case then both H curves would be flatter, resulting in a smaller difference between amp+opioid vs opioid alone. It would be useful to see the data
>>is VE55 the appropriate one or should H slope be used?
For RD neither should be used, but that's another story...
VE55 and H are interchangeable: H is the slope of the line (respiratory frequency X PCO2)and VE55 is the respiratory frequency at 55 mm HG PCO2. Given that the response is linear (over the range they're operating), it means that you'd get the same result.
n=16 double-blind crossover design with 7 day washout in between.
Worst-case: no efficacy, no analgesia.
I think there's a decent chance that efficacy will be there, because they got significance with n=7. This is consistent with a robust effect, so I expect there to be some effect at 1500. Further, in this second study, efficacy is a bonus, since it's established that there's good efficacy at 2100 mg. The only thing that matters is analgesia, and even partial preservation of analgesia will warrant further development, given the dearth of alternatives.
They showed nothing pertaining to the lower dosages. This may be because the data were terrrible, but it is also possible that there were problems with the fentanyl administration, or with the rebreathing protocol.
From a scientific standpoint this looks pretty clean. I don't think that the big boys are holding back, I think they're not paying attention yet. A partnership will bring the attention. That partnership is coming, since these compounds offer a substantial advantage to any BP interested in developing analgesics for severe chronic pain. If the RD-1 study shows a trend in the E50 data, and robust preservation of analgesia, we're good to go.
I'd be surprised (based on the animal data) if analgesia were lost.
What doesn't fit with this though, is why volume is so low going into this event. At ~.90/share, I'd expect there to be heavier volume, since the upside and downside risks are roughly equal, and the animal data are good.
I think there's room for some ambiguity. Right now RD is the wall for anybody developing analgesics, and the only thing available to doctors now (in the context of opioids) is naloxone. If we get ok efficacy, then ampakines are an alternative to naloxone, and cannot have a worse anti-analgesia profile. BPs will recognize that a. this was a far-from-perfect trial design; b. there are other ampakines in the pipeline, with wiggle-room via better formulations, more accurate dosages, etc.
There's an aphorism in The Ginger Man: "Dear God give me one break that's not my neck"
Nothing matters here but how potential partners perceive the results of the RD trials. Of course, the more ambiguous the results the harder to infer BP reaction, but if the data look good, then short-term share-price fluctuations are background noise. This stock will go up eventually, and this increase will be independent of regulatory or scientific binary events (pace RD-1).
I hope for all of us that we're not disappointed tomorrow.
What is an 8K? What are these generally used for?
I've been seeing the potential humor in a negative result too. I can laugh at it now, but the next time I'll laugh about it is in about 10 years. Comedy is tragedy plus time (Woody Allen more or less).
Even on very good news, I don't expect this stock to break 2 bucks. On good news, I expect it to go somewhere around $1.50
If I had bought a big chunk @ 0.60 or less, I'd be selling into this as a hedge against a negative outcome.
My hunch is that the news will be positive with enough ambiguity that there won't be that much of a rally. We'll have to wait for RD-1, and then a partnership announcement.
I hope that 2100 mg isn't the effective dose. I wouldn't be surprised if the market interpreted that negatively.
I'd be very surprised if Stoll announced a negative result.
So how do you all think the market will react if the only effective dose is 2100 mg? Glass-half-full? Glass-half-empty?
I think you are right. We'll see.
I agree. There is some wiggle-room with analgesia.More important is a robust arousal response, as a surrogate for RD.
I still think it's nuts that this trial's outcome depends on ampakines' effect on a behavior other than the one that's supposedly being tested.
It's possible also that (as neuro pointed out), the higher dose was given to establish a new highest dosage.
I think that it is quite possible (given the extremely potent opioid being used, and hence the difficulty of getting functionally matching dosages for every subject) that cor will fail to reach statistical significance, not because of ampakine's lack of efficacy, but because of the variability of the control (opiates-only) group.
What I mean is that it is possible that for all ampakine-exposed subjects, there will be a robust arousal response, but in the control group, while there will be a number of subjects who do show a blunted/absent arousal response, there will be others who don't loose the arousal response, muddying the analysis. This would be the kind of glass-half-full outcome whose significance can be shaped by spin, both positive and negative.
The nice thing is that the n of the control group is 3X the size of each ampakine condition, hence the likelihood of the main effect being lost due to control group variability is mitigated.
I agree with all the posts regarding analgesia not being all-or-none. There are plenty of first-principles reasons for why it's likely that analgesia will be conserved. All this aside, we're still dealing with probabilities, not certainties, and my point was just that knowing that the effective dosage is low (or high) may justify changing those probabilities.
I have to say, I feel pretty good. It's hard me to believe that Stoll would present a negative result at a business conference at this juncture for him personally, and for the company.
One thing I'll be looking at is the effective dose in RD 2. If it's at the low end of the dosages administered, the likelihood of preserving analgesia is higher.
If the effective dose is higher than the 1500 mg administered in RD 1, then only a negative result in RD 1 will be unambiguous. Preservation of analgesia @ 1500 mg does not rule out that at the higher effective dose (2100 mg if that were the case) analgesia is compromised.
I don't think this is such a big problem though, since the arousal response rather than RD is what is being tested here. Still, I think an effective dose at or below 1500 mg is a reason for more optimism.
If the news is good in a week, will this matter?
What we don't know is how good the good news will be. In the best case, they'll be presenting unambiguously positive results, but it is also possible that they will be putting the best possible spin on something more ambiguous.
This does sound good. Let's see how the market reacts.
Does this look like the venue for their RD data? Wouldn't they present those results separately?
be glad you're an opsimath. I'm an oopsimath.
I like the points you and neuro make. There are no leaks, there is no information, and neither TA, nor the low volume being traded can tell us anything. Since mysery loves company, here are some nice verses from the Rime of the Ancient Mariner:
Down dropt the breeze, the sails dropt down,
'Twas sad as sad could be ;
And we did speak only to break
The silence of the sea !
All in a hot and copper sky,
The bloody Sun, at noon,
Right up above the mast did stand,
No bigger than the Moon.
Day after day, day after day,
We stuck, nor breath nor motion ;
As idle as a painted ship
Upon a painted ocean.
With a nice quote in the beginning in Latin, by a certain T. Burnet:
I can easily believe, that there are more invisible than visible Beings in the universe. But who shall describe for us their families? and their ranks and relationships and distinguishing features and functions? What they do? where they live? The human mind has always circled around a knowledge of these things, never attaining it. I do not doubt, however, that it is sometimes beneficial to contemplate, in thought, as in a Picture, the image of a greater and better world; lest the intellect, habituated to the trivia of daily life, may contract itself too much, and wholly sink into trifles. But at the same time we must be vigilant for truth, and maintain proportion, that we may distinguish certain from uncertain, day from night.
-- T. Burnet, Archaeol. Phil. p. 68 (1692)
I think you're missing the obvious here. Nobody's touching this stock: 20K traded. Those who are holding can only sell at considerable loss, and this is because nobody's buying going into this binary event, even at these prices. When you consider the back-of-the-envelope valuation calculations that zebra04 put up a while back, and plug in some of our estimates of a positive outcome (me at 0.6, neuro at 0.7), this stock looks like a pretty good deal. Insofar as anybody is doing these calculations, I'd say that the market is displaying considerably more pessimism about the outcome of this trial than this board.
My sense is that this glassy calm leading into a binary event is unusual, and almost never happens if there is even guarded optimism. On the flip side, at least there's no evidence of stock manipulation going on, given the many more lucrative targets available now.
Here's my take on this letter:
"Bob, We know that the DSMB(Data Safety Monitoring Board) and the CRO are very busy crunching the data...from the standpoint of Cortex, we need to now wait until we can see results which are sufficiently complete ....The first study to be completed and analyzed will be the Parexel dose ranging study. Roger"
For whatever reason, we're going to have to wait. The company seems to intend to release the study results as they get them, rather than simultaneously. I have no experience in clinical trials, so I don't know how time-consuming the data-analysis might be. There is no advantage for them to sit on bad news if that's what they have. At least there's no press release friday evening. In fairness, this is around the very earliest we could be getting results, so the fact that we haven't heard anything yet is probably meaningless.
I'm worried sick though.