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You've got that from a horse's mouth?
2 questions:
1. Does anyone still think that the SA data are still being analyzed?
2. If corx has the results, aren't they legally required to divulge them?
I hope you're right. Corx isn't negotiating from a position of strength, so I think the deal will be more a life-support kind of thing, allowing the company to stay in business perhaps, but not driving up share-price. I hope I'm wrong.
FWIW, a big, authoritative review on OSA:
Physiol Rev. 2010 Jan;90(1):47-112.
Pathophysiology of sleep apnea.
Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP.
The first 40 pages are directly relevant, and give a sense of the complexity and heterogeneity of the condition.
What you write makes sense. My guess is the buyer has a direct interest in ADHD drug development. What are the candidate companies?
What's your guess as to the share-price at sale?
The article has little to do with my hunch. We're in a dog-that-didn't-bark situation: corx's survival appeared to hinge on them for once meeting their deadlines for the IND and for SA completion. Instead, they've blown past their projected completion dates; even for a company that has had a really lousy track record for meeting its self-imposed deadlines, this has been shocking, particularly because the time they gave themselves was more than sufficient for the tasks at hand. We went through something similar with the Biovail announcement. In the recent past, when corx has completely failed to account for why it had missed some rather specific near-term, self-imposed deadlines, a deal near completion was the cause. That's what I think is happening here.
Unfortunately, there is no guarantee the deal will happen. If it doesn't, we're screwed.
Meanwhile, it appears that the pattern of propping up share-price by day's end buys continues.
My hunch is that corx has committed to negotiations regarding the outlicensing of CX1739 for any and all indications, but up-front for ADHD. As suggested in Varney's email on the subject, the delay in IND submission could be accounted for by such negotiations. Likewise, the silence on SA is consistent with an across-indications outlicensing of the compound.
If corx has the preclinical data to convince a counterparty that CX1739 has no toxicity problems, and if they can also provide animal data to confirm that the pharmacological profiles of CX717 and CX1739 are qualitatively the same, then an ADHD outlicencing shouldn't be a hard sell, since CX717 has already shown good efficacy in ADHD.
I think they are closing in on a deal with a company primarily interested in CX1739 in the treatment of ADHD, but are negotiating a deal for the molecule rather than the indication. My guess is that such a deal would raise $10-$15M.
What are the candidate companies for ADHD drug development?
That also always struck me as a total no-brainer. Hindsight only makes things worse though.
I really don't see a way forward. In the spring, the general idea was that corx would get SA results by summer/early fall, and have an ADHD IND submitted by then. Neither of these things have happened, and this slippage(if you can call it that) leaves corx with no discernible ways to raise funds going forward. At this share-price, a PIPE or a reverse split are pretty pointless, and with the money they have left, it's not obvious to me that they can bring anything forward for an outlicencing deal.
It could be that they are in negotiations to outlicence the whole low-impact platform, but if they have a company interested in that, why wouldn't that company just buy them outright?
I know that one way or another this whole ridiculous thing will go forward. I don't have any idea how they are going to do it, but I am pretty sure that we won't all be sitting here waiting in the of spring 2011. Something's going to give.
elaborate?
You need someone who knows SA to identify the features of the data that need to be quantified (apnea duration, frequency, associated sleep phase, BP, etc.). when these variables are extracted from the data, statistical analyses can be performed by someone who is ignorant of SA, but knows her way around SAS or R or whatever. If / when a trend in a subgroup is identified the SA expert can look at the data and assess whether what is found is clinically meaningful.
With 2.5 years lead time, you'd want to hope that corx would have lined up the SA consultants to make sense of the data. There are plenty of statisticians who can handle the data analysis. The SA experts would not be responsible for the data mining itself, but rather would interpret the results of the statistical analysis.
If the dataset was complete by early/late September, there is just no way that they are still figuring out what it all means. Nobody is that incompetent when the company's livelihood is riding on it.
There's just no way this is a data analysis bottleneck.
If the only thing delaying announcement of the SA outcome is their own difficulty in analyzing the data, corx would throw what little they have left onto the fire to get this done. Corx has very little money, and even less time.
SoCal is chock-ablock with competent biomedical statisticians, so even if they couldn't think their way through the analysis, there are plenty of people who could in their neck of the woods.
Something else is up. Either they came very close to getting a good result, but some of the data were contaminated, or they are closing in on some kind of deal (this would also explain the lack of IND), or they have just flat-out lost it.
I don't see how you can do data mining with n=20. It would be trivial to write a program which would select every possible arbitrary subgroup and test for significance; they could work backwards from there, and the whole exercise would take a few days.
It's not that the data are hard to analyze. Not with n=20, and certainly not so hard as to take 6-8 weeks. Either they've brought people back in to get better data, or there is something brewing.
This whole thread about a corx buyout is plausible, and in the big picture a good thing, but does it have any bearing on the delay in SA results?
If they've got the data, can they sit on it because of ongoing negotiations? My impression has been that if you've got the results of a trial, you have to divulge them. Insofar as corx is bound by this standard, it would suggest that a merger/buyout can't account for the absence of news.
I agree. My only hunch on all this is that when they went to the data, they found that some of it was bad (i.e., contaminated by artifact or some other extraneous situation rather than data going in the wrong direction), and that they have gone back to recruiting patients.
My other hunch is that they've all finally lost it and are on a massive ampa-jack bender.
looks like I misoverestimated them with my end of November date.
There goes that idea...
Time to hack off the other arm then
A broad enough high impact deal might generate enough funds to bring low-impacts to the clinic.
I think we're at the point in this movie where it's time to decide just how to cut the arm off, and give up on moving the rock.
Unless they can get ~$50M they're staying stuck.
Another way forward is the reverse of the one I've been proposing for some time now: a very broad out-licensing of the high impacts, to fund development of the low-impacts.
If the Servier trial establishes an effective dosage range that is far from the dosage range that induces seizures, such a deal could happen.
The advantage of relinquishing high-impact IP to develop low-impact IP is that the low-impacts are closer to the clinic, and hence could generate profits sooner. Also, seizure risk is much lower, so low impacts have a better chance of getting FDA approval.
I don't know how they'll get there, but I think that somehow corx will find its way to profitability. Unfortunately, it is going to be still more difficult to get there without wiping out current stock-holders in the process.
Because of the low share-price, it would be relatively low-risk to manipulate the share-price upwards and then sell into the momentum trading.
Despite the happy psychics at Yahoo, were still at 0+0=0 here.
Below "Daily chart, last 10 days" and "Two year chart" I see data for Coresite Realty Corp, listed on the NYSE as COR. FWIW, they're tanking.
Does anyone know why the BB displays the charts of an unrelated company? It's cold comfort to see that the new cor is tanking about as badly as the old cor did, but it's a bit confusing to somebody who is trying to find out more about corx here.
It would be so spectacularly great if I was wrong about everything. This is the clearest example of "it's better to be happy than right" that I can think of right now. I very much hope that the buying is a portent of good news.
We haven't seen volume like this for a long time.
Here are the Society for Neuroscience abstracts that come up with "ampakine" as a search term:
Partial rescue of social deficits in the BTBR T+tf/J mouse model of autism by AMPA receptor modulator CX546
Location: Halls B-H
Presentation Time: Monday, Nov 15, 2010, 1:00 PM - 2:00 PM
Authors: *J. L. SILVERMAN, S. M. TURNER, J. N. CRAWLEY;
Lab. of Behavioral Neurosci., NIH, Natl. Inst. of Mental Hlth., BETHESDA, MD
Abstract: Animal models provide translational research tools for discovering treatments for autism spectrum disorders. BTBR T+tf/J (BTBR) is an inbred strain of mice that displays behavioral phenotypes with face validity to all three of the diagnostic symptoms of autism, including well-replicated social deficits, unusual patterns of vocalization, and high levels of repetitive self-grooming (McFarlane et al., 2007; Yang et al., 2007; Scattoni et al., 2008; Wöhr et al., 2010). We previously reported reductions in repetitive self-grooming in BTBR treated with the prototypic mGluR5 antagonist MPEP (Silverman et al., 2010). The present study tested an ampakine, CX546, that was previously reported to restore respiratory function in the Mecp2 mutant mouse model of Rett syndrome (Ogier et al., 2007), and to improve prepulse inhibition in mGluR5 knockout mice (Lipina et al., 2007). Ampakines modulate glutamatergic AMPA receptors and have been reported to elevate BDNF, rescue long-term potentiation deficits, and improve cognitive functions in rodent models of neuropsychiatric disorders (Lauterborn et al., 2003, 2007; Ren et al., 2006; Jourdi et al., 2009; Ng et al., 2009; Simmons et al. 2009; Damgaard et al., 2010). Adult male mice of the low sociability strain BTBR and the high sociability control strain C57BL/6J (B6) received an intraperitoneal injection of CX546 (25, 50, 75, or 100 mg/kg) or 25% ß-cyclodextrin vehicle, at an injection volume of 10 ml/kg, thirty minutes prior to sociability testing in our automated three-chambered social approach apparatus. In this task, sociability is defined as the subject mouse spending more time with a novel mouse than with a novel non-social object. On subsequent days, the same treatments were administered to BTBR and B6 for scoring of self-grooming and open field locomotion. Preliminary data indicate that acute administration of CX546 improved sociability in BTBR at the highest dose tested, while having no effect on sociability in B6. High doses of CX546 also increased time spent sniffing the novel mouse versus novel object, although vehicle alone elevated novel mouse sniff time in BTBR, presenting a confound potentially related to the vehicle. CX546 and vehicle had no effect on general exploratory locomotion during either the sociability phase or the habituation phase of the social approach task. CX546 and vehicle had no effect on novel open field exploratory locomotion in BTBR or B6, indicating the absence of sedation or hyperactivity. High repetitive self-grooming in BTBR was not reduced by CX546 or vehicle. Our findings suggest that modulation of AMPA receptors may improve components of sociability in a mouse model of autism.
Title: Amplitude-specific AMPA receptor modulator protects against excitotoxicity in hippocampus and is well tolerated with respect to stable GluR subunit levels after prolonged treatment
Location: Halls B-H
Presentation Time: Tuesday, Nov 16, 2010, 9:00 AM -10:00 AM
Authors: J. M. COOPER1, M. G. VARGA2, Q. BROWN2, J. HWANG1,2, C. N. QUACH3, G. A. ROGERS3, *B. A. BAHR1,2;
1Biotech. Res. and Training Ctr., Univ. of North Carolina, Pembroke, Pembroke, NC; 2Dept. of Pharmaceut. Sci. and the Neurosciences Program, Univ. of Connecticut, Storrs, CT; 3Cortex Pharmaceuticals Inc., Irvine, CA
Abstract: Ampakines are positive modulators of glutamatergic signaling that can enhance repair responses through the AMPA receptor-MAPK axis. The potent Ampakine 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691) enhances EPSP amplitude in hippocampal CA1 with an EC50 of 3 µM, as compared to its half-width EC50 of >500 µM. Single application of CX691 at 0.5 µM caused prolonged activation of the ERK MAPK pathway in hippocampal slice cultures, as indicated by increased pERK2 for more than 5 hours. As an evaluation of AMPA receptor maintenance, daily infusions of 1 µM CX691 into slice cultures were found to have no effect on GluR subunit levels, as well as no evidence of spectrin breakdown or GFAP induction over a 20-day period. Neuroprotection was tested in the hippocampal slice model consisting of a 17-min excitotoxin exposure to produce cytoskeletal and synaptic deterioration. When 0.5 µM CX691 was added to the slices immediately after excitotoxin washout, calpain-medicated cytoskeletal damage was reduced both early (1 h) after the excitotoxic insult as well as 20 h later. CX691’s neuroprotective action also promoted the maintenance of pre- and postsynaptic proteins and protected against cell death. The level of protection found in the present study appears to be as much as 200 times more potent than previous reports that used the Ampakine CX516 (Bahr et al. 2002, Exp Neurol 174:37-47; Kanju et al. 2008, Exp Neurol 214:55-61). These results show that long-term AMPA receptor modulation can be beneficial to reduce excitotoxic vulnerability without producing common tolerance issues of receptor down-regulation. Potent Ampakines may be effective for treating neurodegenerative disorders by enhancing MAPK and related trophic factor pathways.
Title: Ampakines as proneurogenic modulators in murine subventricular zone cell cultures
Location: Halls B-H
Presentation Time: Wednesday, Nov 17, 2010, 9:00 AM -10:00 AM
Authors: *C. S. SCHITINE1, F. AGASSE2, S. XAPELLI2, A. P. SILVA3, R. A. M. REIS1, F. G. DE MELLO1, J. O. MALVA2;
1Carlos Chagas Filho Biophysics Inst., Federal Univ. of Rio De Janeiro, Rio de Janeiro, Brazil; 2Neuroprotection and Neurogenesis in Brain Repair, Ctr. for Neurocience of Coimbra, Univ. of Coimbra, Coimbra, Portugal; 3Fac. of Med., Inst. of Biomed. Res. on Light and Image (IBILI), Univ. of Coimbra, Coimbra, Portugal
Abstract: Neurogenesis is a constitutive process that persists in two restricted niches in the adult mammalian brain, the subventricular zone (SVZ) and the hippocampal dendate gyrus subgranular zone. Neural stem cells from SVZ generate neuroblasts that migrate throughout the SVZ and along the rostral migratory stream to the olfatory bulb where they differentiate into interneurons.
AMPAkines are positive modulators of the ionotropic AMPA subtype of glutamate receptors, potentiating excitatory signals and enhancing cognitive properties including hippocampal-dependent memory. AMPAkines effects are presumably mediated as a result of an increase in the synaptic efficiency of excited neuronal circuits. As neurogenesis has been described to sustain hippocampal-dependent memory and learning, it is reasonable to speculate that AMPA and AMPAkines may positively regulate neurogenesis. Here, we examine the putative pro-neurogenic effects of an excitatory stimulation, through AMPA and AMPAkines treatment in SVZ cell cultures derived from postnatal mice.
AMPA and CX546 treatment triggered an increase in proliferation, evaluated in cultures through the BrdU incorporation protocol after 48h. However, while AMPA enhanced cell death levels, CX546 did not cause toxicity on the SVZ cultures revealed by the TUNEL assay. AMPA and AMPAkines stimulated neuronal differentiation evaluated by the numbers of NeuN mature neurons 7 days after treatment. Moreover AMPA and AMPAkine treatment increased the numbers of functional neurons, evaluated by single cell calcium imaging.
JNK is one of the signaling pathways activated mediating axonogenesis. Immunodetection of the phosphorylated form of the JNK signaling pathway after 6 hour treatment with 1 µM AMPA or 5 µM AMPAkine CX546 promoted an increase in the number and in the total length of the ramifications per neurosphere, indicating that CX546 can induce neuronal maturation.
Altogether, this work demonstrates that AMPA and AMPAkines CX546 are positive modulators of neurogenesis in SVZ cell cultures. Considering that modulating stem cell dynamic and neurogenesis is envisaged as a way to replace dead cells in the diseased brain, AMPAkines may prove to be an importante tool in future stem cell-based therapies.
Title: BDNF and BDNF upregulation restores synaptic plasticity in middle-aged ovariectomized rats
Location: Halls B-H
Presentation Time: Wednesday, Nov 17, 2010, 2:00 PM - 3:00 PM
Authors: *E. A. KRAMAR, L. Y. CHEN, J. C. LAUTERBORN, D. A. SIMMONS, C. M. GALL, G. LYNCH;
Univ. California, IRVINE, CA
Abstract: Ovariectomy leads to major impairments in long-term potentiation (LTP), an observation that helps explain the memory problems that sometimes accompany low levels of circulating estrogen in humans. Stabilization of hippocampal LTP depends on remodeling of the dendritic spine actin cytoskeleton and we have shown that acute estrogen infusion restores activity-induced F-actin assembly and LTP in hippocampal slices from middle-aged ovariectomized (OVX) rats. The present studies further characterized estrogen effects on actin-regulatory systems and then tested if BDNF, which is known to facilitate both actin remodeling and LTP, can restore LTP in OVX rats. We previously reported that estrogen activates the GTPase RhoA which is known to signal to filamentous (F-) actin. Here we show that estrogen infusion leads to increases in spine levels of the phosphorylated cofilin; increases in phosphorylation of this RhoA effector is consistent with the conclusion that estrogen elicits signaling through a RhoA-to-cofilin signaling cascade. We then tested if another known Rho-GTPase activator, brain-derived neurotrophic factor (BDNF), could, like estrogen, correct impairments of activity-induced F-actin assembly and LTP in OVX rats. A 60 min infusion of BDNF (2nM) normalized LTP in slices prepared from 8-month old OVX rats without causing detectable changes to baseline transmission. A comparable result was obtained with 4 days of daily injections with the short-half life AMPA receptor modulator (ampakine) CX929 in tests conducted 18 hrs after the last injection. Consistent with our previous report, ovariectomy eliminated the actin polymerization that normally occurs within spines after LTP induction. BDNF infusion, and in vivo ampakine treatments which were verified to increase endogenous BDNF expression, rescued both activity-induced actin polymerization and LTP. These results provide the first evidence that minimally invasive drug treatments that increase BDNF protein content can restore spine cytoskeletal reorganization in the presence of depressed estrogen levels and, in association with this, restore LTP.
Long story short:
1.ampakines provide some symptom improvement in an animal model of autism.
2. Ampakines protect against excitotoxicity in vitro.
3. Ampakines have been identified as potentially improving outcomes in stem cell therapy.
4. Ampakines match the effect of BDNF in restoring LTP in estrogen-poor rats, further evidence that ampakines provide the therapeutic benefits associated with BDNF.
I can't think of another class of compounds with nearly the promise of ampakines. This company may go under, but I very much hope that one way or other, these drugs reach patients.
I think you're right. The analogy is bad though, because the 10-speed probably still works, and it didn't cost $60K.
PS Davidal, I've been thoroughly enjoying your posts.
What are corx's options going forward? My sense is that a PIPE isn't possible, nor a reverse split. Do they have any mechanism to bring capital in? If they get negative/weak SA results, lack the wherewithal to do an ADHD trial, can't find someone to pay for the trial, and hence don't even submit an IND, do they have any option other than liquidation?
I think your conjecture is right, but it doesn't change the fact that we are in Jesus-on-a-tortilla territory here. If you have to trim a dataset to get a hint of concept, then you don't have a very compelling story. Under the circumstances, there isn't much else they can do, but if they have to study the data, it seems likely that the data aren't very compelling.
Something tells me that they will have sorted out what it all means around 4:30 PM on friday.
If this letter is legit, I'm expecting a friday night special.
Actually, if it is legit, and they're sitting on a negative result for release on friday after the close, that's pushing up on the edges of what's legal, I think.
I wonder if the low volume we're seeing is that there are only sellers and no buyers. Is there any way to find out about this?
You're assuming they have all the data. The truth is, we don't know anything, because the information we are getting from corx is essentially meaningless.
Right now they're trapped, and they're wasting the patent life of their IP.
Unfortunately, I am sure they've thought of all this, and found it to be impracticable. I've been proposing this for 1.5 years.
My bet is that corx gets approached with buy-out offers regularly, but at this share-price, they are reluctant to sell. They lack the funds to get the kind of data that would attract the kind of partnerships that would boost share-price.
Maybe a semi-buyout would work: sell all the low-impacts at ~60% of the going buyout price, then focus on the high-impacts. They need to buy 2-5 years of operating expenses.
A new Lynch abstract:
Brief Ampakine Treatments Slow the Progression of Huntington's Disease Phenotypes in R6/2 Mice.
Simmons DA, Mehta RA, Lauterborn JC, Gall CM, Lynch G
Neurobiol Dis. 2010 Oct 23;
Daily, systemic injections of a positive AMPA-type glutamate receptor modulator (ampakine) have been shown to reduce synaptic plasticity defects in rodent models of aging and early-stage Huntington's Disease (HD). Here we report that long-term ampakine treatment markedly slows the progression of striatal neuropathology and locomotor dysfunction in the R6/2 HD mouse model. Remarkably, these effects were produced by an ampakine, CX929, with a short half-life. Injected once daily for 4-7 weeks, the compound increased protein levels of brain-derived neurotrophic factor (BDNF) in neocortex and striatum of R6/2 but not wild-type mice. Moreover, ampakine treatments prevented the decrease in total striatal area, blocked the loss of striatal DARPP-32 immunoreactivity and reduced the area of intranuclear huntingtin aggregates in R6/2 striatum by 36%. The CX929 treatments also markedly improved motor performance of R6/2 mice on several measures (rotarod, vertical pole descent) but did not influence body weight or lifespan. These findings describe a minimally invasive, pharmacologically plausible strategy for treatment of HD and, potentially, other neuropathological diseases.
Given how slow and unpredictable getting the data together has proven to be this far, it wouldn't make a lot of sense on MV's part to give a date for when the last data point would be collected. We've been waiting 5 months for a handful of subjects to enroll and complete.
Regarding the signal, if the signal were really clear and obvious, it would have made sense to unblind the trial and take what they could get. They may have seen a trend in the data, but what people see in their data -- particularly when there is a lot riding on it -- isn't always validated by statistical analysis.
FWIW I'm not expecting news by 11/1. When we get SA news, I expect it to be bad or weak. The trial design was weak, and the disastrous execution of the study (1.5 years overdue) will put the fear of god in potential partners.
SA is an extremely complicated condition. The focus here has been on the size of the market, and the money that can be made. If nothing else, corx's trial makes clear how hard it is to carry out a study in a population this heterogeneous, with all kinds of comorbidity. Good data will at best be hint-of-concept (how much can you read into 1 night's sleep?); a more robust trial would be daunting prospect even for a company with deep pockets. Because the pharma sector appears to be focused on short-term profits, I don't think corx will have an easy time finding a partner even if they get good data.
The only way that they can make money with SA is by targeting patients who use opioids chronically for pain management. This population has high SA rates, and is likely to be more clinically homogeneous (at least wrt the cause of their SA).
Finally, I hope I'm wrong, but I don't think the study will provide a positive result.
In addition, we will likely see cuts in NIH funding in the new congress.
I've come to the conclusion that the NIH should play a VC role, funding microcaps to get drugs to late stage, and sharing the profits from successful drugs. There are conflict-of-interest issues that would need to be adressed, but the current system is inefficient: almost all of the basic research that NIH funds doesn't reach patients, because the commercialization mechanism is broken.
That actually sounds believable. The problem is, if the new POC study isn't as robust as the original trial, then they may end up saving money on the trial only to get inconclusive results due to the weaker trial design.
How likely is it that they can get a partner to sign on to foot the bill for the trial prior to an IND submission? What does this do to the up-fronts etc? In order to get the trial done, they may have to defer a decent up-front again.
This company is trapped by its undercapitalization. All the counterparties are going to continue to take advantage of this situation.
After having been jerked around repeatedly in the partnering process, and reaching a point where their capitalization leads them to loose leverage, and having established a perfectly viable ADHD trial protocol, I really have to wonder why corx management is deferring to a potential partner.
On the up-side, it could be that the counterparty wants to inlicence the compound for all indications, and awaits the SA data before moving forward with their offer. This begs two questions: 1. why hold up the IND filing since the ADHD experimental paradigm is fine anyway (how many ways are there to skin this cat)? 2. Why not get the SA trial done, once and for all? If the data are in the can, what's holding it up (n=20, yes/no question)?
On the downside, there may be a problem with the compound for ADHD. The longer this drags on, the more I believe this. The fact that corx management says the compound is problem-free doesn't reassure me. Stoll said the exact same thing about cx-717.
Similarly, the longer this drags on, the more I suspect that the SA data are negative. If you have a robust effect, the statistics are simple. If you're digging around for a trend, the statistics get complicated and time-consuming.
For once, management should be held to their deadline. If they said end of October, it should be end of October. Such a precise date is only plausible if the data are in the can, and all that's left is the analysis. If they were still rooting around London looking for people who snore, they shouldn't have said anything.
It's worth pointing out that once again, in one of their rare communications to the outside world, corx presented a timeline for study completion, etc. that they once again failed to meet.
We don't even know whether all the SA data have been collected. Nor does anyone have the foggiest idea of where corx is at with the IND.
Does anybody have any idea what these people are actually doing?