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Neuro, I may be way off, but I don't think that the current running out of cash problem was an issue when they negotiated the trial agreement with the CRO. Cortex received UK regulatory approval in January, and I was guessing that they would have had the CRO agreement in place before submitting the request, and that the request would have been submitted at least a month before approval. If there is any validity to those guesses, then the CRO agreement would have been made in November / December 2008. I don't know what the standard agreement would look like, but I was also guessing that something like payment of half before the trial starts and half upon completion would be a reasonable arrangement.
Oh, I think I also mentioned CX717 incorrectly. I believe the SA trial is with CX1739, which might better define the window for when the UK regulatory application was made.
Personally, even though the settings are different for the primary application of an ampakine in RD and SA, I believe that the indications are likely going to be packaged together. That means that the likely partner would be a larger company with both a hospital and outpatient pain pharma presence (MRK, JNJ?). This would be much cleaner than trying to split them with different compounds / license agreements. Remember that the company already had partial POC in SA (opiate induced SA) from data collected during the RD trials. I'll bet that the SA trial began life as soon as they saw that in the data - maybe before if it was predicted and they were specifically collecting that data for examination of SA.
Anyway, I don't see SA as being serindipitous, and I don't think they are entering this trial unprepared.
Laker, My premise is that they would not be conducting a rushed study. They have been considering SA for quite awhile, and would have had ample time to design the trial. Plus, the metrics for an initial study could be very straight forward - for example frequency and duration of episodes - and quantities that are well established and regularly measured by sleep labs to diagnose SA. I'm arguing that it would be straight forward to design and execute a pIIa study quickly, but not in a rushed and risky manner.
I'm sure that there are other folks looking at this board (if they have not been put-off by the recent whining) who have been involved in clinical studies that can explain whay I'm way off in my assessment...
Thanks,
Karl
Neuro, Thanks for another response, and please forgive me for pressing on here. So at $20,000 per patient and 32 patients the cost to conduct the trial would be $640,000. They could probably arrange to pay a good bit of that amount after completion of the study, so I don't see a huge impact to cash. Regardless of what other posters might say, I think the Cortex folks have always been pretty conservative spenders, and I would not be surprised if they were able to arrange some other deferred payments to stretch their cash a bit further.
So, does it come down to the time it takes to complete the study? At 3 nights per patient with 32 patients and probably only one night per week for each patient, that is about 3 weeks, if they could recruit the patients and process ~6 per night. 6 patients per night sounds like a big number to me, even for a big sleep lab. Half that number seems pretty reasonable. That would imply 6 weeks - 3 weeks for 16 patients, and 2/3 of that if the patients were recruited from a population that had already spent your first night in the clinic.
Can I then guess at an upfront cost of under $400,000 and 2 - 6 weeks to complete the study? That would mean results by early April.
Thanks, again (for now the 4th time!)
Karl
I'm 0 for 2 for getting any concurrance on previous posts, but I'll try again. (What was that definition of insanity, again..?)
I suggested that the company could achieve POC in SA by conducting a small pIIa trial before signing any deal or getting additional funding. Neuro responded that he believed that a trial could be initiated, but not completed within their available funds. I still think that this is what they are trying to do, and would like to better understand why others believe they can't. To stack the deck in my favor, I'm assuming that all of the preliminary work was completed long in advance of regulatory approval - protocol written, contracts and agreements signed, IRB approval granted (pending of course regulatory approval). I think these assumptions are reasonable, given the length of time that the indication was considered, and I, for one, don't think the folks at Cortex ever sit around twiddling their thumbs. So, what are the costs to conduct and complete the study:
1. Per patient cost: This should be similar to the cost of sending a patient to a sleep lab for evaluation. They might even be able to do this on patients that are sent to the lab in one night. Get the patient to agree to participate upon or prior to his arrival; if he shows SA before 1am, wake him up and give him either a placebo or CX717; see what happens the rest of the night.
2. Administrative fee: Fixed? $50K? $100K? maybe pounds sterling? I have no clue on these costs, but I wouldn't think they would be too high.
3. Analysis fee: Fixed? Actual hours for the stataticians? How much do they make, anyway?
4. Travel by Cortex people and their time: Should be part of their normally budgetted costs whether they are doing this study or not.
Okay, what have I forgotten? What am I missing? They expected the study to complete after 1 April and before the end of June (2Q 2009). If it is just a matter of time, then I think a mid-sized to big sleep lap could get the job done in just a few weeks.
Thanks (for the 3rd time...)
Karl
gfp, To be fair, there isn't any indication that the partnering interest isn't strong. Having a lot of possible deals on the table would also drag out negotiations. The company has been about as conservative as a small biotech can be, and since Stoll is still a major player, I don't that would change. In my mind, the only way they would be keeping their burn rate as high as reported without raising funds is because they know they can get a decent deal before the cash runs out. If they thought that there was too much risk of running out of cash, then I think they would have raised money with more than 6 months to go.
I have high hopes for getting some real information from the presentation this afternoon, mostly because gfp has not posted anything since 9 Feb, and appears to have lost interest. :)
enemem,
I don't agree with your assessment on the risk of ampakines causing insomnia and invalidating their use to treat SA. In the earlier studies of ampakines effects on alertness, I think there was some occurrence of insomnia, but the majority of participants were able to sleep. Look at the DARPA study where they were allowed to nap - one of the chief complaints on this board of that study design. Certainly for some people heightened alertness could cause insomnia, but for others (like some with ADHD) the ability to focus and not have all those thoughts flying around in their head facilitates sleep. I don't know if there is a good example, but maybe an analogy could be drawn with the CNS effects of stimulants in kids with ADHD. The range of possible doses for these kids is very broad, with an even wider range of individual responses. For some stimulants never work, for others a specific dose works like a charm for years. Maybe another question is 'How many cups of coffee can you drink after dinner and still get to sleep?' I used to drink a few espressos after dinner and had no trouble sleeping. Others can't drink coffee after lunch and expect to sleep. Now I have some trouble getting to sleep after drinking several espressos, but it is the stimulant effects that are more pronounced than when I was younger that keep me awake – increased pulse and shakes – not increased alertness.
What is it that causes insomnia in most insomniacs? I've heard people talk about their inability to control thoughts and worries. Focusing exercises like counting sheep, imagining in great detail a favorite place or situation are supposed to help you fall asleep. Ampakines are described as having similar effects, as in ADHD. My expectation is that the drugs will work for most people once an individualized dose is established.
The initial reaction sounds very similar to our 7-year-old daughter's reaction to Adderall and Adderall XR. On the lowest dose of Adderall she felt angry, irritated, and sad, and had a flat affect. Prior to taking the drug she was a very happy outgoing kid. She called the pills her 'angry pills'. We discontinued use after about 2 months, and are working with her psychiatrist to find something else, and with her teacher to try alternative solutions in the classroom. Everyone agrees she is smart kid, and that her problem is not being able to focus and take her time to complete tasks. Coffee and increased one on one instruction work the best so far, but are not well suited to public school! On the plus side for Adderall, she was able to focus on her work and stay in her chair when on the drug. The cost just was not worth the benefit.
enemem,
Looking at atheroprevent's, neuro's, and your past posts, I think that RD and SA are too related to sell to separate entities, but do lend themselves to an agreement with many easily identifiable milestones.
RD
- prevention, prior to various surgeries and procedures, IV formulation
- prevention, used concurrently with oral or patch opiate pain killers, oral or patch formulation maybe extended release
-rescue, during or after various surgeries and procedures and drug overdose, IV formulation
SA
- opiate induced, similar to RD prevention, oral
- central, nightly, oral
- obstructive, nightly, oral
- mixed, nightly, oral
- muscle toning / ventilator patients, continuous drip, IV
I'm sure I've forgotten something, and I'm sorry if I've used incorrect terminology. It seems to me that these indications would have very different levels of FDA criteria for approval, and that they have a wide range of difficulty in demonstrating POC, with RD rescue probably being most difficult. But, there is probably some logical continuous path for developing all of these over time. It then makes sense for the agreement to have discrete milestones associated with the development of each of the readily identifiable indications and formulations with a single partner.
It looks like a lot money to me, even if the currency is biobucks. The great thing is that Cortex has POC in at least 2.
Neuro, thanks for the sanity check. Given your assessment, and a post by someone a couple of weeks ago (dominate??) about the new types of deals that are being made, then perhaps the most likely arrangement would be some money up front for RD, and a large, near-term payment for SA if the trial results met some predefined criteria. Since they already have some evidence that there is an effect (at least with opioid related SA), this would seem to be a desirable agreement for all parties.
Neuro,
You wrote that you believe that "The SA trial ...can begin without money, but it can't be completed without it." I'm not so sure that this is true. An SA trial would not take that long to complete, and even Cortex said that they expect to complete it in the 2nd quarter after starting this month. Sleep labs are pretty busy, and have ready access to patients with known, well documented SA. It would be pretty easy to run a small sample, placebo controlled, double blind clinical trial in just a few weeks. We do not know that their burn rate has been constant for the past few months, but if their confidence is high that the outcome of such a study would be positive, I think they could stretch out their existing resources to cover a trial.
Thanks,
Karl
Neuro, Thank you very much for posting that letter. Is this letter a typical product of the agency, or did it had a new tone of improved collaboration? Do you think it signals that the FDA is entering an era of greater transparency and predictability? If it does, I'd expect to see some other changes - stricter rules on who can sit on advisory committees, and more closely following the recommendations of the committees, fewer rejected applications, fewer applications, and faster response times. Sorry, I'm letting my imagination get away from me!!!
Mickey, I very much doubt that this study involves any Cortex compound, though I suppose it is possible. The study does not appear to match what we know about the currently available compounds. Neuro may know more. The following is from the ICARA FAQ page:
What will study participants be asked to do?
As a study participant you will be asked to:
Attend 15 study visits during an 83-week period
Receive six infusions of the investigational drug every 13 weeks for 65 weeks
Have blood tests and study-related physical and clinical exams
Participants will be randomized to investigational product or placebo (a treatment with no active ingredient). There is a 60 percent chance of receiving the investigational drug and a 40 percent chance of receiving a placebo.
I'm way out of my league, so maybe emenem or neuro could answer, but isn't it common for Parkinson's patients to have trouble with eye movement (cranial nerve 3?) and trouble swallowing (cranial nerve 12?)?
It seems to me that the company's ability to form a hypothysis on the effects of an ampakine in treating SA, and making a statement related to it in a press release shows a much greater depth of understanding on the processes affected by the compounds than I imagined.
PS Don't the processes governing eye movement and swallowing originate in the cortex?
Hmmm. Does this then have some implication in ampakine potential to treat symptoms of Parkinson's?
Sorry, I missed many earlier posts that discussed most of the points I just made. I do have questions about the "stimulation of another brain region" statement in the PR. What type of work would be required to make such a statement? Is this something they could have observed in the 'Phase I healthy volunteers', or is this more likely derived from animal studies?
Thanks.
There were several things in today's press release that I found surprising, and show that the company has been busier than I thought in assessing SA.
1. “CX1739 has been very well tolerated in Phase I healthy volunteer studies, and we are excited to be able to proceed with an efficacy study in sleep apnea,” It is nice to know that CX1739 is well along or has completed P I. It looked like this might be delayed.
2. “We anticipate starting subject enrollment in February and completing the study in the second quarter of 2009.” This is consistent with Neuro's timeframe estimate on completion at an existing sleep lab.
3. "Further analyses of these clinical studies also showed that CX717 reduced both the number and duration of apnea events caused by the opioid." In my opinion, this is the most important statement in the PR, since it implies that they already have some evidence of POC!!! Is there any other way to interpret this???
4. "Studies in animals suggest that CX1739 is approximately three times better than CX717 at reversing breathing depressed by opioids." It looks like CX1739 is ready for multiple indications.
5. "CX1739 also stimulates another brain region that regulates muscle tone in the upper airways." Wow. This means that they have been doing some additional work, but I'm not sure how they can make this statement without some difficult human studies. Isn't the extension from animal data to humans here more difficult? How would they have assessed this?
There were several things in today's press release that I found surprising, and show that the company has been busier than I thought in assessing SA.
1. “CX1739 has been very well tolerated in Phase I healthy volunteer studies, and we are excited to be able to proceed with an efficacy study in sleep apnea,” It is nice to know that CX1739 is well along or has completed P I. It looked like this might be delayed.
2. “We anticipate starting subject enrollment in February and completing the study in the second quarter of 2009.” This is consistent with Neuro's timeframe estimate on completion at an existing sleep lab.
3. "Further analyses of these clinical studies also showed that CX717 reduced both the number and duration of apnea events caused by the opioid." In my opinion, this is the most important statement in the PR, since it implies that they already have some evidence of POC!!! Is there any other way to interpret this???
4. "Studies in animals suggest that CX1739 is approximately three times better than CX717 at reversing breathing depressed by opioids." It looks like CX1739 is ready for multiple indications.
5. "CX1739 also stimulates another brain region that regulates muscle tone in the upper airways." Wow. This means that they have been doing some additional work, but I'm not sure how they can make this statement without some difficult human studies. Isn't the extension from animal data to humans here more difficult? How would they have assessed this?
Dominate,
Thanks for that post. Wow! I don't know if davidal, neuro, emenem, or others who are familiar with the effects of anti-psychotics are surprised by these results, but I sure am. It sure would be nice to have some drug that could relieve some of the symtoms of dementia without the side effects...
I always thought of SA as being "just" a quality of life issue, but according to the paper I referenced in the last post, it is much more serious than that. How much is it worth to prevent prevent brain damage in 12M to 20M people? At a buck per person per day you get close to neuro's $8B for treating 20M people.
In rummaging the web for informantion on models for sleep apnea, I found this article and paper where they used recurrent hypoxia and reoxigenation induce the effects of OSA. The paper is interesting, but this technique does not apply for testing compounds that prevent the hypoxia/reoxignation process from occurring. The Penn folks are testing a compound that reduces the damage when SA occurs.
Link to Article:
http://www.eurekalert.org/pub_releases/2008-03/uops-mbo031908.php
Link to Paper (The Journal of Neuroscience, February 27, 2008, 28(9):2168-2178; doi:10.1523/JNEUROSCI.5232-07.2008):
http://www.jneurosci.org/cgi/content/full/28/9/2168?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&titleabstract=sleep+apnea+model&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&fdate=1/1/2008&tdate=4/30/2008&resourcetype=HWCIT
Article Text:
Public release date: 19-Mar-2008
[ Print Article | E-mail Article | Close Window ]
Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Molecular biology of sleep apnea could lead to new treatments
PHILADELPHIA – Researchers at the University of Pennsylvania School of Medicine have provided, for the first time, a detailed look at the molecular pathways underlying sleep apnea, which affects more than twelve million Americans, according to the National Institutes of Health. Sleep apnea is a condition characterized by temporary breathing interruptions during sleep, in which disruptions can occur dozens or even hundreds of times a night.
The team found that in an animal model of sleep apnea poorly folded proteins accumulate in one compartment of a muscle nerve cell, which, under certain conditions, tells a cell to heal itself or destroy itself. The findings appear in a recent issue of the Journal of Neuroscience.
“Muscles relax as a normal part of sleep, causing the airway to close,” explains senior author Sigrid C. Veasey, MD, Associate Professor of Medicine, at the Penn Center for Sleep. “But in patients with sleep apnea, oxygen levels in cells drop too low, sending an arousal signal to wake by gasping for air. This happens all night long, so patients experience bad quality sleep. In addition to problems with sleepiness, subtle peripheral neural injury occurs.”
In a mouse model of sleep apnea, the researchers found that motor neurons of the jaw and face had swollen endoplasmic reticula, the part of the cell where proteins get folded properly. They surmised that misfolded proteins accumulated as the endoplasmic reticula of mice were exposed to decreased oxygen and oxygen fluctuations during sleep over eight weeks. The involvement of the endoplasmic reticula has never been shown before in explaining the physiology of sleep apnea on a cellular level, says Veasey.
But how does this work? Sensor proteins sitting on the surface of the endoplasmic reticula get activated by poorly folded proteins within. The Penn group worked with one of those proteins, called PERK. When PERK gets activated, two things can happen: The cell can take a pathway to fix itself or one that leads to self destruction. The cell makes that decision based on its initial health.
“If a patient has sleep apnea with healthy cells, the cells will take the fix-it path. Then good things happen; the cell activates another molecule called eIF-2alpha, which turns on helpful molecules like anti-oxidants that degrade the misfolded proteins,” explains Veasey.
However if cells are unhealthy to begin with, the PERK pathway can also turn on molecules that cause the cell to turn on itself and activate apoptosis or cell death. “In this event, we predict that patients with sleep apnea may lose motor neurons,” notes Veasey. “Eventually sleep apnea could continue to worsen since the few remaining neurons are already stressed when gasping for air during sleep.”
A drug called salubrinal does keep the eIF-2alpha path active, thereby preventing vulnerable cells from going down the cell-death path. But salubrinal is a double-edged sword: Just the right amount keeps the cell happy, but too much can shut down all protein synthesis, a highly toxic outcome.
The research team is now working on how to ramp up the eIF-2alpha path with changes in the mouse diet. “This paper shows which pathways are important for treating sleep apnea, but we’ll need to come up with therapies other than salubrinal,” says Veasey. “Ultimately if we can do healthy things that protect the endoplasmic reticula of cells, then sleep apnea won’t be such an insult, not only to motor neurons, but neurons involved in cognition and alertness.”
###
Co-authors are Yan Zhou, Polina Fenik, Guanxia Zhan, Ben Sanfillipo-Cohn, and Nirinjini Naidoo, all from Penn. The research was funded by the National Heart, Lung, and Blood Institute.
This release can be found at: www.pennhealth.com/news.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #3 in the nation in U.S. News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
I expect any near-term partnership to have an equity component. Say $30M - $40M, but include 10M shares to the partner. But, I think they are probably fending off buy-out offers to get to partnership discussions. - If you are willing to spend $15M for limited coverage of a single indication, why not offer 2x - 5x that for the whole kit and kaboodle?
I keep thinking about jerrydylan's comment that 'share prices do not move on their own - they are moved'. For those who track the daily trading, is there any indication that someone is intentionally keeping the share price low, or is there evidence that says the current share price is just a result of people closing their positions?
Ombowstring,
Yes, I recall Neuro's post, and I believe I responded to it. The comment is certainly true with respect to mergers, acquisition, and financing. It probably also means that the deals that any company can command now is not as rich as it was last year. But the comment is not true across the board for all company licensing and partnering agreements. Remember, there are few companies that are in Cortex's position with very positive phase 2 data, multiple families of highly promising compounds with potential in several underserviced indications.
As the news articles continually point out, the big pharmas of the world desperately need the small, innovative biotechs to refill their pipelines, and there is significant competition for proven compounds.
Maybe I'm living in fanasyland, but I see more than one company wanting what Cortex has. The COR market capitalization is at a level where a lowball buyout offer from one may gain traction. If I were one of the suitors, why would I risk losing some much needed major, longterm revenue just to save a bit of pocket change? Besides, if I expected positive results, why would I even squeeze Cortex by negotiating a deal that makes it difficult for Cortex to perform. If I were the BP, I'd be generous with the upfront and milestone payments, and negotiate hard on the sharing of revenue from eventual sales. Such a deal (with big upfronts and milestone payments) is what Cortex needs, and would allow them to bootstrap their way forward in other indications.
Sorry for the rambling, but I think some of these statements have been misinterpreted.
Thanks,
Karl
Ombowstring,
I think there is a basic difference between the way you and I interpret Varney's use of the word 'financing'. I very much believe that he was referring only to the raising of capital through means that do not involve any licensing agreements for use of their compounds or partnerships with other pharmaceutical companies. I believe that when he mentioned unfavorable terms, he was only referring to to the terms that they could negotiate in a PIPE or other methods of getting money through the capital markets. I do not interpret his comment 'terms are not too favorable' as any way related to their attempts at licensing or partnering any of their compounds.
Karl
Ombow,
I don't read this as portending bad news at all, and just confirms what the board has already concluded - a dilutive financing is unlikely, and Cortex will get their funds in some kind of deal involving CX717. I notice that there is no mention of how CX717 would be licensed - RD, ADHD, ??? My guess is that the company is being really careful not to give away the farm here, and will fight for a fairly narrow agreement unless they can get a whole lot for a broader deal.
Neuro, did you attend the SFN conference this week? It looked from the section topics and abstracts that there was a surprising amount of really interesting new material presented. I only counted 3 Ampakine related posters - all with Cortex compounds (earlier post). Maybe ememen attended.
Thanks
gfp,
Thanks, I didn't remember the CX614 designation, but remembered that CX929 has been used in studies because of its reported higher potency (than other HI compounds). I think it also was reported to have a longer half-life. I don't recall any safety concerns associated with it, only that it was replaced by the subsequent rapid development of even better compounds.
gfp,
Are you familiar with CX614? It appears to be even more potent than CX929.
Thanks
Sorry, for those who are interested, here is the meeting link.
http://www.sfn.org/am2008/index.cfm?pagename=AboutTheMeeting_main
Neuro,
Are attending the SFN meeting? I'm sure there are some interesting AD discussions this year. It looks like there are only 3 Ampakine posters, and no presentations. One was Saturday, one Sunday, and one tomorrow (abstracts below). I don't remember seeing anything about CX614 before.
Thanks,
Karl
------------------------------------------
Program#/Poster#: 35.8/E32
Title: Effects of Ampakines on hippocampal CA1 pyramidal neurons
Location: Washington Convention Center: Hall A-C
Presentation Time: Saturday, Nov 15, 2008, 4:00 PM - 5:00 PM
Authors: *D. VERBICH1, P. K.-Y. CHANG2, R. A. MCKINNEY1,2;
1Neurol. and Neurosurg., 2Pharmacol. and Therapeut., McGill Univ., Montreal, QC, Canada
Abstract: In order to improve learning deficits accompanying disease such as Alzheimer’s, schizophrenia, and attention deficit hyperactivity disorder, clinical trials using Ampakines, positive allosteric AMPA modulators, have found enhanced cognitive functions in patients. Ampakines increase AMPA-mediated transmission, the main fast glutamatergic neurotransmission in the CNS. However, the effects of Ampakines on synapse morphology have not been extensively characterized. Here, we investigate the effects of Ampakines on CA1 pyramidal neurons in mature hippocampus. We study the effects on the hippocampus due to its intimate involvement with learning and memory. Using either a Semliki Forest virus strain PD expressing membrane-targeted fluorescent proteins in neurons, or transgenic mice expressing membrane-targeted eGFP, we visualized CA1 pyramidal neurons in organotypic hippocampal slice cultures with confocal microscopy. First, we studied the effects of chronic Ampakine application on CA1 pyramidal cells by treating 3-week-old hippocampal cultures for 2-3 weeks with 250 µM of the Ampakine CX546. We acquired images with confocal microscopy, 3D reconstructed dendrites and dendritic spines on tertiary branches, and analyzed data with software co-developed by our laboratory (Imaris, Bitplane). Interestingly, we found marked decreases in total spine density of CX546-treated cultures (control, 0.75±0.06; treated, 0.15±0.01 spines/µm). The majority of spines eliminated were the large, mushroom-shaped spines, which are thought to be stable and important for memory (control, 0.18±0.03; treated, 0.01±0.01 spines/µm). The remaining spines are mostly the long-thin, plastic spines, associated with learning (control, 0.32±0.05; treated, 0.11±0.01 spines/µm). Secondly, we used time-lapse confocal imaging of fluorescent CA1 neurons to follow changes in spine motility on tertiary dendrites in response to CX546. We found no difference in spine motility after perfusion of 250 µM of CX546 compared to vehicle control perfusion. Our results are unexpected, considering the proposed function of subsets of spines with cognition; however since our experiments were not conducted using a learning paradigm such as long-term potentiation, we must address the following questions: 1) Although spines are lost with CX546 treatment, are synapses eliminated as well? 2) Is basal synaptic transmission altered after chronic CX546 treatment? 3) Since Ampakines enhance long-term potentiation, do potentiated spines respond differently to Ampakines? We are now in the process of addressing these questions in order to clarify the effects of Ampakines on synaptic plasticity.
Disclosures: D. Verbich, None; P.K. Chang, None; R.A. McKinney, None.
Support: CIHR MOP-86724
[Authors]. [Abstract Title]. Program No. XXX.XX. 2008 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2008. Online.
2008 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
--------------------------------------------
Program#/Poster#: 130.11/C59
Title: A nootropic drug Ampakine(CX-717)potently modulates synaptic AMPA receptor single channel properties
Location: Washington Convention Center: Hall A-C
Presentation Time: Sunday, Nov 16, 2008, 10:00 AM -11:00 AM
Authors: T. KARIHARAN, B. C. SHONESY, K. PARAMESHWARAN, M. DHANASEKARAN, *V. D. SUPPIRAMANIAM;
Harrison Sc Pharm., Auburn Univ., Auburn, AL
Abstract: Ampakine CX-717, a cognitive enhancer, was shown to profoundly alter the single channel properties of synaptic AMPA receptors (AMPARs). Activity dependent modulation of synaptic AMPARs in hippocampus play a key role in synaptic strengthening process required for learning and memory. Synaptosomes isolated from adult mice hippocampi were reconstituted in lipid bilayers and the modulatory effects of CX-717 on synaptic AMPARs were investigated. The AMPAR channel activity was elicited by addition of 290 nM AMPA; following which 1.0, 2.0, 4.0, 8.0 µM CX-717 were infused. The channel activity elicited by 290 nM AMPA was potentiated by
CX- 717 in a dose dependent manner. The single channel open probability, mean open time and burst duration of AMPARs increased several fold with out changing the mean close time, single channel conductance and the ability of a selective AMPAR antagonist SYM 2206 to block these channels. The addition of CX-717 also resulted in interactive channel gating of AMPARs expressing macroscopic currents. It is concluded that by profoundly modulating synaptic AMPAR activity, CX-717 can strengthen the synaptic communication required for learning and memory mechanisms.
Disclosures: T. Kariharan, Cortex pharmaceuticals Inc. Irvine, CA, C. Other Research Support (receipt of drugs, supplies, equipment or other in-kind support); B.C. Shonesy, None; K. Parameshwaran, None; M. Dhanasekaran, None; V.D. Suppiramaniam, Cortex pharmaceuticals Inc. Irvine, CA, C. Other Research Support (receipt of drugs, supplies, equipment or other in-kind support).
Support: Cortex Pharmaceuticals Inc. Irvine, CA
[Authors]. [Abstract Title]. Program No. XXX.XX. 2008 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2008. Online.
2008 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
------------------------------------------
Program#/Poster#: 754.2/BB17
Title: Ampakines enhance axonal outgrowth by cortical neurons
Location: Washington Convention Center: Hall A-C
Presentation Time: Wednesday, Nov 19, 2008, 9:00 AM -10:00 AM
Authors: *C.-Y. LIN, C. GALL;
Dept Anat & Neurobiol, UC Irvine, Irvine, CA
Abstract: There is an abundance of evidence that neurotrophic factors can support upper motor neuron survival after damage to axons in the central nervous system (CNS) and can facilitate axonal growth in vitro and in vivo. However, the question of how these effects can be harnessed to facilitate neuronal survival and axonal growth following CNS injury remains. The present studies tested if positive modulators of AMPA-type glutamate receptors (ampakines), which have been shown to increase neuronal BDNF expression in vitro and in vivo, also stimulate axonal growth. Rat cortical neurons were cultured onto a poly-L-lysine coated glass substrate in the ‘somal well of a Microfluidic Culture Platform (MCP) (Park et al., Nat. Protoc. 1:2128-36, 2006), which includes fluidic-isolation compartments (i.e., somal and axonal wells) separated by a grooved bridge region into which neurites can grow. Ampakines were applied to the MCP somal well, the axonal well, or both, and the length of neurite elongation into the bridge region was evaluated after 1-4 days of ampakine exposure. Treatments with the ampakines CX614 and CX929 significantly increased neurite outgrowth. These effects were not site- (soma vs axon) specific and were comparable across doses tested (0.1 - 10 µM for CX614 and 0.5 to 50 µM for CX929). While increases in mature BDNF protein were associated with ampakine treatment of dissociated cortical neurons, the growth promoting effects of ampakine treatment were not blocked by addition of the BDNF scavenger, TrkB-Fc. However, the Trk signaling antagonist K252a attenuated ampakine effects on neurite length most reliably after application to the somal well. These results demonstrate that ampakines enhance axonal growth and suggest that the growth response is mediated, at least in part, by increases in the signaling of multiple neurotrophins (e.g., BDNF and NGF). These results further support the possibility that ampakines might be used to facilitate reactive axonal growth following CNS damage.
Disclosures: C. Lin , Receipt of drugs, C. Other Research Support (receipt of drugs, supplies, equipment or other in-kind support); C. Gall, Receipt of drugs, C. Other Research Support (receipt of drugs, supplies, equipment or other in-kind support); patent for use of ampakines for enhancing neurotrophin expression, E. Ownership Interest (stock, stock options, patent or other intellectual property).
Support: This project is supported by the Roman Reed Spinal Cord Injury Research Fund of California
[Authors]. [Abstract Title]. Program No. XXX.XX. 2008 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2008. Online.
2008 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
150K shares
K-G
I'll cut the guy a little slack, since I'm sure he's swamped with work. The alternative is not getting a response at all, or something worse from someone else.
It was a strange comment that I, too, believe is incorrect. What I think he was trying to say is that Cortex is in a better position than other small biotech companies because of their Phase II results, and that valuation of microcaps in general inadequately accounts for their IP value and future earnings potential.
Maybe???
Maybe I'm off-base, but wouldn't a large company looking to expand their small pharmeceutical division do so by acquiring smaller companies with promising product lines? I think that they would be more inclined to buy developmental companies and depending on their existing capabilities, partner for other aspects of the business - manufacturing, distribution, as well as the development in specific indications. Just a thought.
From R&R presentation this morning:
CX-1942 5X more potent than CX-717 for RD in rats
Cash on hand: ~7M
Cash used in Operations: <$1MM/month
Budget Required to meet Key Milestones in 2009: $12-15MM
3 Phase IIs to complete in '09
http://www.wsw.com/webcast/rrshq14/cor/
I think that a few folks are just making mild adjustments to their positions based on the release of the Cortex quarterly financial report; the obvious need for more money within the 6+ months; the subsequent discussion on financing on this board; and the uncertainty in how the money will be raised.
Personally, I think the longer this drags out, the more likely we'll see an unsolicited buy-out offer from a jilted suitor.
enemem,
I suppose it could happen that way, but I don't think that Cortex wants to sell many new shares at this level, and if they only raise enough money in a partnership deal to require further financing in the near future, then the share price won't rise much. My guess is that any PIPE financing in the near term would be prior to a partnership deal, and only enough to get them to a meaningful partnership with enough money to put off the need for additional financing indefinately. Another possible scenario is to raise money through a non-RD partnership - in ADHD, by extending the existing Schering Plough agreement to more compounds, or something we have not thought of.
But if an investor wanted a large block of stock, they would either call Cortex, who already has approval to issue more shares, or go to a dark pool where large blocks are traded behind the scene and smaller blocks are assembled into larger ones. I don't know much about dark pools, but I hear that they handle large quantities of thinly traded stock. This could have already happened with COR, and we might never know.
Neuro,
Thank you for the informative post. I think there are a couple of additional things that you should that you should also consider. First, Cortex is amoung the very few small biotechs whose valuation has increased over the past year. Their 'crash' occurred last year, so while the company's share price has decreased over the past few months, the value in a partnership is significantly greater because of the recent clinical successes than just a few months ago.
Second, it is not in the interest of BP to force painful terms on the partnering company. It serves no purpose to sign a deal on terms whereby the small company does not gain sufficient resourses to live up to their side of the partnership. The same cannot be said about an acquisition, and the BP comment you mentioned about accepting their lowered valuation applies to these cases.
Finally, very few biotech products pose the kind of threat to existing product lines that Cortex's RD application does to opioid formulations. There are at least a couple of companies (I think you mentioned J&J and Cephalon.) that derive significant revenue from the sale of opioid pain medications. These revenue streams could be destroyed by the introduction of an RD risk-free opioid product line.
So, all-in-all, while the environment is horrible compared to a couple of years ago, I think Cortex should still be able to come away with a good deal.
Thanks,
Karl