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Here's a link to general info on Memantine / Namenda. In addition to being an antagonist of the NMDA glutamate receptor, it also apparently has some effects on the serotonin/5HT and ACH/nicotinic systems -
http://en.wikipedia.org/wiki/Memantine
Jerrydylan, As I understand it, in AD there are several processes going on that relate to the glutamatergic pathways, including - 1) Some degree of excitotoxicity brought on as the disease process causes cellular destruction, similar to what happens in stroke and traumatic brain injury, with a resulting disruption in the calcium ion balance (Memantine / Namenda targets this imbalance/excitotoxicity, by reducing glutamatergic activity at the NMDA receptor). And 2) - The widespread destruction of neurons reduces the overall level of neural communication in the brain generally (fewer neurons, fewer interneural connections, etc), which impairs brain functioning.
Upregulating the glutamatergic pathways with an Ampakine might theoretically be expected to worsen #1 (excitotoxicity), except for the fact that a) Ampakines are allosteric, and as such don't initiate new neural activity on their own (as an agonist would), but instead merely amplify the existing normal neural activity, and b) low impact Ampakines like CX-717 don't induce excitotoxicity at therapeutic doses. (An AMPA or NMDA direct agonist, on the other hand, would be expected to worsen the level of excitotoxicity in AD patients, and thus would probably be contraindicated). Also, an Ampakine would improve #2 above, by getting the most out of the remaining healthy neurons/neural connections.
Of course if we go a step further and use a high impact, then we would expect a much larger effect due to the upregulation of brain neurotrophins like BDNF, which are neuroprotective / neuroregenerative.
With all the pharma interest in high impacts, I think it's safe to say that no matter what ultimately becomes of Cortex as a company, the high impact approach will be fully explored by Big Pharma. One way or another, they're going to advance this technology as long and as far as it takes to see if it works. It would be that big of a breakthrough, and the scientific and financial rewards are unbelievably enormous, since the platform could apply to virtually all neurodegenerative diseases. In the end there's possibly a Nobel prize up for grabs too.
Horselover, Concerning the Euro patent challenge, I don't have the exact dates, but it seems like it's been several years since Glaxo joined the challenge, and Lilly was challenging for several years before that (losing in their first attempt). Neuro probably has more precise dates.
There was a guy over on Yahoo ("Orange45" I think) who was very knowledgeable about bio patents, though I couldn't seem to locate his posts on Yahoo with the busyant function.
It seems like it's been around 1.5-2 years since we discussed Glaxo entering the picture, and at that time there were guestimates that a resolution might take perhaps 2-5 years. Dr. Stoll discussed the topic several times back then, and basically said that there was no way to accurately estimate when a resolution would come. When the Euro patent was upheld the first time around, the news came out of the blue, and the stock moved up dramatically.
It's apparently easier to challenge patents in Europe than in the US, which is presumably why Lilly challenged there. They might conceivably try to challenge in the US someday, or perhaps go after a different patent, like the neurotrophin upregulation broad use patent.
Jerrydylan, Biotech is probably the riskiest sector of the stock market. And the neurological area is one of the riskiest subsectors of biotech. Beyond that, how about going with a tiny underfunded microcap, with a brand new unproven technology platform. Then place a massive bet on that company. Mega-high risk? You've come to the right place.
Of the bio stocks I still follow, Cortex is the riskiest. GTCB was previously tied for that spot, but with their European approval, they are now considerably safer, though still very high risk due to their small size and reliance on a risky sepsis program for Atryn.
Instead of investing in individual bio stocks, I've opted for the bio ETFs (BBH, IBB). For equity exposure I use the Vanguard Target Retirement 2045 Fund, which indexes 70/20/10% in US stocks/Intl stocks/bonds, and this rounds out my bank CDs. (Dull I know, but this is the first year I'm ahead for the year since 2003, so I guess it's working).
FWIW, I still follow some bio stocks though -
Biomarin
Cortex
Cubist
Celgene
Durect
Exelixis
Genzyme
Gilead
GTCB
Idenix
Medarex
MGI Pharma
PDLI
Pain Therapeutics
Senomyx
Teva
Vertex
Daviddal, In the Roth presentation, Dr. Stoll said they were initiating another type of AD study (an "MEG" study, see slide 25), in addition to trying to complete the PET study. I'm not familiar with what MEG is however.
What I think is most likely to happen is that Cortex won't do any deals until after getting the word from the FDA on dosing liberalization (approx Q2/May). Then Cortex and BPs will know where we stand with CX-717, and will proceed from there. In the meantime (by early '07), Cortex will have to bite the bullet and do an unfavorable PIPE.
Dr. Stoll had little choice but to roll the dice with CX-717, and essentially base the company's survival on the success of the compound. Cortex's limited resources simply couldn't support a deeper pipeline. CX-717 could have bombed out earlier, but it sailed successfully through Phase 1 and the numerous Phase 2a trials before getting into trouble. It's too early to throw in the towel, since CX-717 could still emerge as viable if the dosing restrictions are sufficiently liberalized. The way I see it, there are 3 potential scenarios, based on the degree of dose liberalization allowed by the FDA -
1) ADHD is viable - we're back in business, the stock price moves up strongly, and a large BP deal occurs.
2) ADHD isn't viable, but AD is - this seems like the most likely scenario. Cortex does a N.Amer AD/Neurodegenerative deal with a BP or Organon.
3) Neither ADHD or AD are viable - this spells serious trouble.
Objectively, #2 seems the most likely. Cortex might still get halfway decent upfronts, and the stock price could rebound considerably. One question with this scenario is whether to include ADHD in the BP deal to get a bigger deal (perhaps along with a backup compound), or to try to carve ADHD out along with the orphan indications. If Cortex can carve out ADHD, that would provide another excellent shot at ADHD with a backup like CX-701, and a nice future pharma deal/payday a few years down the road. If ADHD isn't carved out, then we have to advance a backup compound for an orphan or Sleep Related, and/or go with the non-Ampakine in-license route.
Money is the lifeblood of bio companies, even more important than good science, since with enough money one can always in-license or buy someone elses promising pipeline. A bio company can never have enough cash. Consider Celgene - riding high, but they still went out and raised a cool BILLION recently. Smart bio CEOs get the money when the getting is good. The cruel irony is that it's always easier to raise money when you don't need it.
Jerrydylan, Here's a list of the AMPA upmodulating activity going on out there, based on the various company's comp of matter patents. Glaxo reportedly teamed up with NeuroSearch several years ago for compounds (#5 below), but I haven't seen any clinical trials on the Clinical Trials.Gov site yet (I don't think trials show up there until Phase 2 however). Several years ago, Glaxo joined Lilly in challenging the Cortex/UCI broad use patent in Europe (Lilly previously challenged but was unsuccessful) -
1) CORTEX - Generally termed "Benzamides", they include Benzoylpiperidines (CX-516, CX-546), Benzoxazines (CX-614), Benzothiadiazoles, Acylbenzoxazines, Carbonylbenzoxazines, Benzofurazans (CX-717, CX-691/Org-24448). Also, Dr. Lynch was recently involved in preclinical papers on benzothiadiazines, and also on Stargazin, which is a Transmembrane AMPA Receptor Regulatory Protein (TARP), which is involved in the surface delivery and anchoring of AMPA receptors, and which may act as an AMPA upmodulator.
2) ORGANON - Org-24448 (developed by Cortex), Benzoxazepines, Benzoxathiazepines, Pyrido/Thieno-Oxazepine derivatives.
3) SERVIER - Benzothiadiazine and Thiadiazine derivatives (S-18986 for example, which is currently in a large MCI Phase 2).
4) LILLY - Biarylpropylsulfonamides (for example LY-404187, LY-503430, LY-451395 (which failed in AD Phase 2), and LY-392098).
5) NEUROSEARCH (collaborating with GLAXO) - Benzothiazine and Benzothiadiazine derivatives.
6) BOEHRINGER INGELHEIM - Napthothiazine related compounds, a preclinical paper was recently published on a compound called BIIR-777.
7) NPSP/ALLELIX - Arylpropylsulfonamides and Cyclopentanes. Allelix also appears on Lilly's Diabetes patent. Allelix also has patented some of the polynucleotide sequences which code for specific AMPA receptors, enabling Allelix to produce CNS cell lines that are useful in research.
8) EUROCELTIQUE SA / formerly "COCENSYS"(?)- Benzopyran and Benzothiopyran related compounds.
9) RETT CORP - Aminobenzenesulfonamide derivatives.
10) Sanofi-Aventis - Dipyrazoles (preclinical paper published recently).
11) Lifelike Biomatic - (Dr. Baudry's company) - They have patents attempting to cover subtherapeutic doses of just about all AMPA upmodulators when used in combination with "Nemdakines", which are NMDA receptor upmodulators. They're also trying to patent compounds resulting from the fusion of the active moieties of AMPA and NMDA upregulators into a single molecule.
12) Stargazin - Transmembrane AMPA Receptor Regulatory Proteins (TARPS). There is considerable activity going on by various research groups (see more in the Cortex section above).
Dr. Tracy may be aware of other possible AMPA upmodulating programs out there. The high level of activity and sheer number of companies/compounds now pursuing AMPA modulation is a far cry from the mid-1990s when most researchers were highly skeptical over this approach. It appears that "there's gold in them there hills", so we'll see who gets to the finish line first. Cortex could sure use a motivated BP partner with deep pockets to speed up the process.
Jerrydylan, Concerning why high impacts are taking seemingly forever to develop, some backround -
Upregulating glutamate pathways in the brain was not widely pursued years ago because just about everyone thought it would by definition lead to horrendous excitotoxicity. Overactive glutamatergic pathways were known to be associated with epileptic seizures, and with glutamate toxicity in stroke and traumatic brain injury, as cellular damage released excess calcium ions into the surrounding tissues. So it was generally believed that upregulating glutamate/AMPA pathways would almost certainly induce excitotoxicity / seizures.
Dr. Lynch was the lone voice in the wilderness - he believed that there might be a way to upregulate glutamate pathways safely, and Dr. Rogers helped him design the compounds to do it, beginning with the structure of aniracetam (a pyrrolidinone) and building from there. Over a period of years, Cortex was able to assemble its broad use patent estate and vast compound library chiefly because no one else in the pharma world believed it could work.
Cyclothiazide was also known to have the ability to upregulate AMPA activity, and Lilly got into the act with their biarylpropylsulfonamide compounds, and Servier with benzothiadiazines, both structurally related to cyclothiazide.
As it turned out, the cyclothiazide related compounds did tend to cause excitotoxicity. However, Cortex had some compounds that were able to upregulate AMPA activity without causing excitotoxicity - the "low impact" group of compounds like CX-691/Org-24448 and CX-717. No other company appears to have anything like these. Cortex also was spending a lot of time developing high impacts, but decided to advance the low impacts first clinically since they appeared far safer. Lack of money has always dogged Cortex from the beginning though, so it hasn't been possible to optimally fund both high and low impact programs over the years.
The plot thickens however, since it was found that while the low impacts upregulate AMPA activity in the hippocampus and thus improve memory/cognition, it take a high impact to significantly upregulate brain neurotrophic factors like BDNF, which are key to neuroprotection / neuroregeneration. But while the high impacts have enormous clinical potential in treating neurodegenerative diseases, they tend to be associated with excitotoxicity, and therein lies the rub.
So besides inadequate funding, there are lots of science related obstacles to overcome with the high impact approach. Not only is there excitotoxicity, but there is also the feedback loop phenomenon, which causes upregulated BDNF levels to drop back to normal after prolonged dosing with a high impact. Using intermittent burst dosing with a short acting high impact compound, we may be able to get around this feedback loop problem, but this all takes lots of time and money - something chronically in short supply at Cortex, unfortunately.
Scollins, It looks that way. The company may see the new tox data prior to the PIPE, but the FDA decision on liberalizing the dosing restrictions should come after the PIPE.
Summarizing, a likely timeline -
1) By year end/early '07 - Cortex sees new tox data.
2) By year end/early '07 - Cortex does PIPE.
3) By end of Q1-07 - Cortex submits full package of new tox data to the FDA.
4) In Q2-07 - FDA gives decision on dosing liberalization.
5) What happens then depends on the FDA's decision. If the dose is liberalized a lot, CX-717 can go into ADHD trials again, and be partnered with a BP as such. If the dose is not liberalized, or only modestly, CX-717 may still be viable for AD, and can be partnered on that basis.
Wildcards - As mentioned previously, in the next several months, instead of doing a PIPE, Cortex could raise money by doing a CX-717/N.Amer Neurodegenerative deal with Organon or a BP. Organon/the BP would have available to them the new tox data, but not the FDA's decision on dose liberalization.
Thanks Aiming. Pheew, saved from the gulag, that was a close one! My big mouth will be my undoing yet.
It looks like the Democrat's big victory isn't sitting too well with the Pharma sector, which gapped down big yesterday, and is down again today. The US is where Big Pharma makes most of its profits (by far), so some of that may be in jeopardy with Hillary and Ted Kennedy back in control. Perhaps the drug companies will now be forced to innovate more, and take a chance on new platforms instead of relying on the safer "me-too" drug approach. Well, maybe.
Concerning the timing of the financing, Dr. Stoll said cash will be approx $9-10 mil at year end. One question is whether to wait for the new tox data, or else just do the PIPE prior to that. In the R+R presentation, he said that the physical part of the new tox studies is completed and they are in data analysis. That being the case, he should have some preliminary idea of the results by year end, so perhaps he'll just wait a couple more months before pulling the trigger on the PIPE. In the recent conf call, he said that the complete package of data should be submitted to the FDA by the end of Q1-07 for their evaluation, with their decision on dosing liberalization coming after that. I doubt Stoll can afford to wait until April/May to do the financing, so I'm figuring it'll happen between now and January.
Another question is how much money to raise. Figuring the PIPE goes through at $1.50 (oh, the humanity), it'll take a jaw dropping 10 million shares to raise a paltry $15 mil.
Another approach would be to raise say only $10 mil now at $1.50, in hopes of being able to get the rest later on better terms. Pretty depressing, but the alternatives are limited - do an N.Amer Neurodegenerative deal with Organon or a BP, or sell the company outright. The Organon idea might not be so bad, particularly if Cortex is able to carve out ADHD and some orphans.
Davey, That's a good idea. I'd also like to get my post off of I-Hub before the Feds see it and put me on their "no fly" list (or worse).
Jerrydylan, Here's a summary of the May '07 Cortex $2.50 options -
$2.50 calls - open interest 719, last trade at .30 cents on 10-30-06.
$2.50 puts - open interest 1582, last trade at .75 cents on 10-30-06 (prior to the 10-30-06 trade, the last open interest figure I saw was 213, so that's a fair size jump).
The next highest open interest figures are in the Nov '06 $2.50 calls (625), the Feb '07 $2.50 calls (664), and the Feb '07 $5.00 calls (711)
These Cortex options seem very illiquid, with huge bid/ask spreads. With the stock price so low, buying the common might be a better alternative strategy, rather than going the option route, especially if things take longer than expected. Dr. Stoll estimated that they would be getting the full package of new tox data submitted to the FDA by the end of Q1-07, and with the potential for FDA dawdling, that could conceivably push the FDA decision timetable past May (plus I don't think we have the 30 day decision guarantee that the FDA gave last time).
OT - Aiming, I don't know if you still follow PTIE, but today they announced a new in-licensed program - in metastatic melanoma cancer of all things, which was a surprise. Some of the folks at PTIE apparently have past connections with Albert Einstein College (and some of PTIE's existing programs have links to there as well). The new program is an armed MAB (antibody armed with a radioactive uranium isotope). I guess PTIE needed to expand their pipeline, and they have the money from the King deal to do it. I still follow PTIE loosely, since Remoxy still looks like a quasi-sure thing (also - Durect, the inventor of the abuse resistant gel technology, will get royalties from Remoxy sales, so I follow them somewhat also).
Looks like someone recently took a fair sized position in the May '07 $2.50 puts -
http://www.amex.com/
(click on options on the left, and then type in COR about halfway down the page).
PGS, Thanks. I knew I could count on you to straighten me out :o) I remember your wisdom from the Imgnlist thread. Yes, just the thought of armed MABS and solid tumors gave me that old queasy feeling again..
Aiming, I don't know, it's extremely risky. More likely what will happen is that we'll get some modest dose liberalization, enough to make AD more palatable to BPs, but not enough to really create much hope for ADHD. That wouldn't be the end of the world, since a BP deal for AD could still be a halfway decent payday for Cortex. But ADHD appears to be the biggest prize here from a dealmaking perspective, due to the stellar Phase 2a results.
What I'd like to know is the actual human oral dose level/duration combinations that are currently allowed by the FDA, or even a fairly close ballpark figure. That would give us a much better idea how much of a dose liberalization we need to get from the FDA in order to have any hopes for ADHD. I have a feeling that the dose restrictions are fairly loose for a single dose type study (as in the AD PET scan), but far tighter for longer duration studies (since longer term dosing was where the histo finding was seen in animals).
I don't know, but from a betting/odds standpoint, to me CX-717's viability for ADHD seems like a low percentage bet. It might happen, but I suspect that at best the dose liberalization we get will still only make for iffy ADHD prospects from the BP's perspective (the dose allowed will still be on the low side).
Market_Fest, You know, we may soon be getting the mother of all buying opportunities, if the "glass half full" viewpoint turns out to be correct. Imagine that the FDA actually does liberalize the dosing restrictions considerably, enough to allow a BP a clear shot at ADHD (dosing would have to be liberalized to 500-600 mg BID range or better, one would think). If that degree of dosing liberalization came to pass, the stock would be off to the races again bigtime. That's admittedly a big "if", but combined with the unbelievably cheap entry point we'll likely get from the upcoming PIPE, one might have a once in a lifetime opportunity to make a massive bio stock killing (say $1.50 to $6 almost overnight). I don't know if I believe in the "glass half full" scenario enough to pull the trigger on such a trade, but it's fun to contemplate.
Dew, PGS, board, Any thoughts on PTIE's move into cancer? Looks like they're targeting metastatic melanoma with a MAB armed with radioactive Uranium, targeting shed melanoma antigen. In today's conf call, the CEO said there was considerable interest from other companies in this program, but PTIE had the inside track due to its previous relationships with Albert Einstein College. PTIE's pipeline has been in pain meds, but apparently their team does have considerable previous experience with setting up and running MAB trials. Metastatic melanoma looks like a tough nut, but the efficacy bar for approval is probably very low due to the severe lack of current treatment options. Targeting shed antigen should help avoid the usual difficulties MABS have in penetrating solid tumors, plus the radioactive Uranium payload reportedly has a kill distance of several millimeters. The Uranium-188 has a short halflife, with radioactivity dropping to benign levels in 5 days. Any comments welcome -
Pain Therapeutics Announces New Clinical Opportunity in Metastatic Melanoma
Wednesday November 8, 9:15 am ET
Company Gears Up for Oncology Clinical Trials in 2007
SOUTH SAN FRANCISCO, Calif., Nov. 8 /PRNewswire-FirstCall/ -- Pain Therapeutics, Inc. (Nasdaq: PTIE - News) announced today the launch of a new antibody technology that may transform how metastatic melanoma is treated, ultimately enabling clinicians to provide effective medical treatment for this rare but deadly form of skin cancer. The Company plans to initiate a clinical program in 2007.
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Historically, monoclonal antibodies have been ineffective in melanoma for technical reasons. In a new twist, scientists at Albert Einstein College of Medicine have developed a novel type of radio-labeled monoclonal antibodies that target melanoma tumor sites and deliver a short burst of lethal radiation to melanoma tumors. The specificity of this treatment ensures the destruction of the tumors without harming normal tissue. The technology, published in Proceedings of the National Academy of Science, may also have therapeutic uses outside of oncology.
Under the terms of an agreement between the Company and Albert Einstein College of Medicine (AECOM), AECOM was paid an undisclosed upfront fee and may receive milestone payments totaling approximately $3.5 million in the aggregate based on clinical and regulatory progress. AECOM will also receive a 4% royalty on net sales. In exchange, Pain Therapeutics received exclusive, worldwide commercial rights to all indications in oncology and infectious disease.
"Since the Company's inception, our business model has stayed the same," said Remi Barbier, president and chief executive officer of Pain Therapeutics. "We identify, in-license and translate scientific findings from academia into de novo therapeutics. Today's announcement is an exciting extension of our business model because we think it creates an unprecedented means to address metastatic melanoma and perhaps other difficult-to-treat diseases with new therapeutic strategies. Pain is the most common symptom in patients suffering from cancer, so for us oncology is a natural horizontal expansion of our roots in pain management."
"The survival rate is dismal for patients with metastatic melanoma," said Nadav Friedmann, Ph.D., M.D., chief medical and operating officer of Pain Therapeutics. "People with metastatic melanoma have only one goal and that's to stay alive. We think any technology that can extend survival for these patients has a bright future in clinical medicine."
"The beauty of using a radio-labeled monoclonal antibody is its ability to target tumors with specificity and to deliver an effective dose of radiation that is not subject to drug resistance," added George Ben Thornton, Ph.D., vice president of technology at Pain Therapeutics. "Since the year 2000, the FDA has approved two different radio-labeled antibodies in oncology. We think this bodes well for the future of this approach."
About The New Technology
A research team from Albert Einstein College of Medicine, led by Arturo Casadevall, M.D., Ph.D., Chairman of the Department of Microbiology & Immunology, and Ekaterina Dadachova, Ph.D., Associate Professor, Department of Nuclear Medicine, developed a novel approach to treat metastatic melanoma based on targeting melanin, a skin pigment that is released from dead melanotic tumor cells, with radio-labeled monoclonal antibodies. The antibodies seek out the released melanin and destroy human melanoma cells with a lethal dose of ionizing radiation, thus achieving a therapeutic effect. Melanin in normal, healthy tissue is not targeted because it is inside the cells and not accessible to the radio-labeled antibody.
The feasibility of this approach was tested in a proof-of-concept animal study that was published in Proceedings of the National Academy of Sciences (PNAS) in an article titled, Dead Cells in Melanoma Tumors Provide Abundant Antigen for Targeted Delivery of Ionizing Radiation by a mAb to Melanin (PNAS 2004, 101: 14865-14870). At the start of the study, mice with human melanoma cells had tumors ranging from 0.6 to 1 cm. in diameter. Tumor growth was completely inhibited in the treated group with a single dose of radio-labeled antibodies; near total tumor regression was observed in animals with smaller initial tumors. No deaths occurred among treated mice during the 30-day study. Furthermore, treated mice showed no kidney or other organ damage. In contrast, tumors continued to grow aggressively in the control group. By day 20, all the mice in the control group died except for one. A full-text copy of this publication is available on the PNAS website: http://www.pnas.org .
Pain Therapeutics cautioned, however, that this apparent success in mice must be demonstrated in human clinical trials before the therapeutic impact of the technology can be evaluated. Pilot trials involving patients with metastatic melanoma are now being planned at university centers.
Conference Call/Webcast
Pain Therapeutics will host a conference call and webcast for the investment community today at 1:30 p.m. ET to discuss this announcement. To participate in the conference call, please dial 866-770-7129 (within the U.S.) or 617-213-8067 (outside the U.S.) fifteen minutes prior to the start of the call. The call reference number is 76195346. A playback of the conference call will be available following the live event. To access the playback, please dial 888-286-8010 (within the U.S.) or 617-801-6888 (outside the U.S.) and enter reservation number 71936385. A live webcast of the conference call will also be available online at www.paintrials.com.
RBlatch, Sorry about that. I guess I needed to purge myself.
It's going to be a long wait again for new Cortex related developments. I guess we could all start speculating on when the PIPE will happen and at what price, ugh..
Q3 results. $12+ mil in cash as of end of Sept. Cortex should be able to submit new 3 month tox data to FDA by early 2007 -
>>> Cortex Reports Third Quarter Operating Results
Wednesday November 8, 8:30 am ET
IRVINE, Calif.--(BUSINESS WIRE)--Cortex Pharmaceuticals, Inc. (AMEX: COR - News) reported a net loss of $3,635,000, or $0.10 per share for the quarter ended September 30, 2006 compared with a net loss of $2,530,000, or $0.08 per share for the corresponding prior year period. For the nine months ended September 30, 2006, Cortex reported a net loss of $12,592,000, or $0.37 per share compared to a net loss of $7,867,000, or $0.24 per share for the corresponding prior year period. For both current year periods, operating expenses include non-cash stock compensation charges and amounts related to addressing the earlier clinical hold on Cortex's AMPAKINE® CX717 by the U.S. Food and Drug Administration ("FDA").
As required, Cortex adopted Statement of Financial Accounting Standards 123® -- "Share-Based Payment" ("SFAS 123R"), starting January 1, 2006. Under SFAS 123R, expenses for all share based payments to employees, including grants of stock options, are recorded in the financial statements based on their estimated fair values. Compared to the corresponding prior year periods, Cortex's total non-cash stock compensation charges increased by $673,000 and $2,488,000 for the quarter and nine months ended September 30, 2006, respectively. These stock compensation charges have no impact on Cortex's available cash or working capital.
As indicated, increased operating expenses during the current year periods also reflect amounts incurred to address the acute toxicology studies requested by the FDA related to the earlier clinical hold on CX717. As of September 30, 2006, these additional unplanned costs have added approximately $2.5 million to Cortex's research and development expenses, which amounts were partially offset by decreases in clinical development and other cost areas. Most of the expenses related to the FDA's requests were incurred during the second and third quarter of the current year period and Cortex does not anticipate the same expense level for the remainder of 2006.
As reported last month, the FDA released the clinical hold on CX717 in early October, subject to specified dose limitations. In July 2006, Cortex initiated three-month chronic toxicology trials in rats and monkeys in order to obtain additional data. The related results from these studies will be submitted to the FDA in order to determine if the current dose range limitations on CX717 can be raised to allow Cortex to initiate further clinical studies in Attention Deficit Hyperactivity Disorder ("ADHD"). Cortex anticipates that it will be able to submit the reports from these studies to the FDA in early 2007.
Decreased revenues during the current year periods reflect the winding down of the research collaboration with the Company's partner, Servier. As announced earlier, Cortex notified Servier of its intent to end the research collaboration by early December 2006.
Cortex's cash and marketable securities amounted to $12,608,000 at September 30, 2006 and $17,261,000 at December 31, 2005, with spending for the nine months ended September 30, 2006 partially offset by proceeds from the exercise of warrants to purchase shares of Cortex common stock.
Cortex Pharmaceuticals, Inc.
Cortex, located in Irvine, California, is a neuroscience company focused on novel drug therapies for neurological and psychiatric disorders. The Company is pioneering a class of proprietary pharmaceuticals called AMPAKINE compounds, which act to increase the strength of signals at connections between brain cells. The loss of these connections is thought to be responsible for memory and behavior problems in Alzheimer's disease. Many psychiatric diseases, including schizophrenia, occur as a result of imbalances in the brain's neurotransmitter system. These imbalances may be improved by using the AMPAKINE technology. Cortex has alliances with N.V. Organon for the treatment of schizophrenia and depression and with Les Laboratoires Servier for the development of AMPAKINE compounds to treat the neurodegenerative effects associated with aging and disease, including Mild Cognitive Impairment, Alzheimer's disease and anxiety disorders.
Forward-Looking Statement
Note -- This press release contains forward-looking statements concerning the Company's research and development activities. The success of such activities depends on a number of factors, including the risks that the Company's proposed products may at any time be found to be unsafe or ineffective for any or all of their proposed indications; that competitors may challenge or design around the Company's patents or develop competing technologies; and that preclinical or clinical studies may at any point be suspended or take substantially longer than anticipated to complete. As discussed in the Company's Securities and Exchange Commission filings, the Company's proposed products will require additional research, lengthy and costly preclinical and clinical testing and regulatory approval. AMPAKINE compounds are investigational drugs and have not been approved for the treatment of any disease.
Cortex Pharmaceuticals, Inc.
Condensed Statements of Operations
(in thousands, except per share data)
Three months ended Nine months ended
September 30, September 30,
------------------------ ----------------------------
2006 2005 2006 2005
----------- ------------ -------------- -------------
(Unaudited) (Unaudited) (Unaudited) (Unaudited)
Revenues $ 402 $ 625 $ 864 $ 1,971
Operating
expenses (A):
Research and
development 3,192 2,501 10,363 7,952
General and
administrative 1,014 816 3,603 2,279
----------- ------------ -------------- -------------
Total operating
expenses 4,206 3,317 13,966 10,231
----------- ------------ -------------- -------------
Loss from
operations (3,804) (2,692) (13,102) (8,260)
Interest income,
net 169 162 510 476
Change in fair
value of common
stock warrants -- -- -- (83)
----------- ------------ -------------- -------------
Net loss $ (3,635) $ (2,530) $ (12,592) $ (7,867)
=========== ============ ============== =============
Loss per share:
Basic and
diluted $ (0.10) $ (0.08) $ (0.37) $ (0.24)
Shares used in
computing per
share amounts
Basic and
diluted 34,830 32,671 34,158 32,653
(A) Operating
expenses include
the following
non-cash stock
compensation
charges:
Research and
development $ 488 $ 58 $ 1,573 $ 134
General and
administrative 243 -- 1,034 (15)
----------- ------------ -------------- -------------
$ 731 $ 58 $ 2,607 $ 119
=========== ============ ============== =============
Cortex Pharmaceuticals, Inc.
Condensed Balance Sheets
(in thousands)
September 30,
2006 December 31,
(Unaudited) 2005
------------- ------------
Assets:
Cash and cash equivalents $ 2,472 $ 2,063
Marketable securities 10,136 15,198
Other current assets 312 256
------------- ------------
12,920 17,517
Furniture, equipment and
leasehold improvements, net 448 439
Other 33 33
------------- ------------
Total assets $ 13,401 $ 17,989
============= ============
Liabilities and Stockholders' Equity:
Accounts payable and accrued expenses $ 2,185 $ 2,681
Unearned revenue -- current 23 126
Deferred rent liability 58 50
Stockholders' equity 11,135 15,132
------------- ------------
Total liabilities and stockholders'
equity $ 13,401 $ 17,989
============= ============
MORE INFORMATION AT WWW.CORTEXPHARM.COM <<<
Aiming, Lilly's compounds failed in the past, and the long period of time that has gone by since they've had anything in the clinic suggests that whatever "fix" they've come up with wasn't easy. In his 2004 SHM presentation after the failure of LY-451395, Dr. Rogers made it sound like Lilly's compounds inherently induce excitotoxicity (he also included CX-614 in that category too) - "The Lilly compounds, CX-614 - those compounds can produce very huge increases in current in the cell, which is why if you occupy all the receptors with any of those molecules, you WILL get seizures. We can completely occupy all the AMPA receptors in your brain with CX-717 - no seizures." (the low impacts like CX-717 bind at a different site).
The trick to getting the high impacts to work will include - 1) finding a compound/compound family that either doesn't induce excitotoxicity, or induces it more gradually, and at a dose level sufficiently far above the therapeutic level, thus allowing a wider therapeutic index/dosing range, and 2) perhaps using intermittent burst dosing, which could not only reduce the onset of excitotoxicity, but also would help bypass the BDNF feedback loop phenomenon.
One significant new bit of info concerning the high impact approach is that while CX-614, cyclothiazide (and apparently the Lilly compounds), all bind to the same receptor binding site (what we've previously referred to as THE high impact site), at least some benzothiadiazide compounds bind at a totally different binding site (despite their being structurally related to cyclothiazide). So this could open up the possibility for a kinder/gentler high impact (and for all we know, Cortex's high impacts could bind at still another, 3rd high impact site).
Over the last several years, xray crystallography studies have made it possible to identify the distinct binding receptor sites of the various AMPA upmodulators. The 1st high impact site was identified a few years ago, and now they've identified a 2nd high impact site. As of several years ago, researchers hadn't yet done the crystallography studies to locate the low impact site, but they know it is definitely different than the high impact site #1.
So, using a baseball analogy, we're still in the early innings when it comes to AMPA upmodulation, with several rain delays for the high impact team (excitotoxicity, feedback loop), and a technical foul on the low impact team manager (CX-717 histo finding). Some expansion teams have entered the league (Glaxo/NeuroSearch, Sanofi-Aventis), and there has been a move toward free agency (Euro patent challenge). The middle relief pitcher is warming up (CX-701), and MVP slugger Ryan Howard is walking toward the on deck circle (CX-929).
Aiming, Yes, I was going to insert a "bush blows" sequence in there, but decided not to :o)
OT - Just for laughs, here's what a genetic related patent looks like. These are nucleotide base sequences being patented by a bio company working on antisense technology -
>>> tgagaatcta atgctgccgc tgatctgaca 175620 ggaaatgggg ctcaggcagt aatgctcgct cactgctcac ctcctgctgt gtggcccagt 175680 tcctaacagg ccatgaactg gtaccagtct gtggcctggg ggctggggag tcctgcatta 175740 atgtaattaa atatgtacat ttcttgagag tgtttgttca aatatttttt cctaatagag 175800 acgtataact tagaaagtat ggaaccctct ggtcagtagc atattttatc aaaaaggcta 175860 tccgtcgtgc taaccaatgt gattaaatgt tcattttagt ctcagatatt ttgataacat 175920 aataataggg aagttatggt tattgcatgg cttttcttta ctgtattttc aataactata 175980 ttaatgggtt cagttgttac tagttttata attctgtttt attctcaatg agtcttcctg 176040 tttctcccca cgtctttcct atggttcatt tccctgcatc tttacagctc cctggaacat 176100 tctctcaaat caatcagagg cttcaaaact gggcagtctc attttgtaac ctgctctgac 176160 tcgcctctgg gaggcctccc tccccactca cagctgcctt cctgcatgat gtaaaatgaa 176220 tacagtgcca gaaagactga tccttggaac ctcttcctta cttagtttct ttatagttct 176280 gattttagaa atgaccattt tacttccagt gcccttcccc acaccagtta gctgagactc 176340 tatgcaggaa gttcccagtg atcagaactg ttcccatagc tcccaggtga ttctgacatg 176400 cacccggcat tgagcaccat ggacatggct gctgtttgtt atcctcgagc tcgcaaagca 176460 gtgtcggata ttgcttgatt gttgcacatt aatctactgc acggtccggt aggtagccac 176520 tagccacatg tggccattta gatgtaaatg aatttaaatt aaatagtatt ataagttcaa 176580 cacctcagtt gcactctctg tattcaagtg ctcagtagct acaagtggtt ggtggctacc 176640 attttgggca gtgctactat acaacatttc tatcaccaca gagagtgctg atgaataata 176700 gtactaacaa ctggaaacat tgaaatggag aggtgaagga gagaaggcag aatataagag 176760 aaacttcaaa gcattcagcg tgtctgatag gcgctgtatc ttacattatg tttggagcat 176820 agtttttgaa tttcttaatt ttcaaattcg gttgaaacag attttggtca attgaagtga 176880 aggactatgc ctgctttaat ttgcgtagct tacctttgtt tcacgtgtct cccttattac 176940 agtgtttgta gcagcatcta actcaatccc taacttcttt ttggtgcagg gaccatttaa 177000 aaacaatttg atcatagagg ttatctcctt tgcaatccat attgttttat ggaacaggtg 177060 aacagctggt gacaatagcc tcaaggtttc taatcccacc aaaggaaaat atggtgtcag 177120 taattacctt gtactatgat atttgtgaaa tccaagagag ggctagatct caggctctaa 177180 taatacatcc gtataaacat ctcagtaggg caccacggaa gagtcttagg atatcaggaa 177240 caataagagc gggagaatat cgaccttaat attctttaca cttattaaaa agtgaaaaga 177300 cagccataaa gcagaatgag ttcctgtcct ttgcagggac atggatgaag ccagaagcca 177360 tcattctcag caaactaaca caggaacaga aaaccaaaca cctcatgttc gcactcataa 177420 gtgggagttg aacaatgaga acacatggac acagggagtg gagcatcaca caacggggcc 177480 tgtcgggagt tgggggacta ggggagggag agcattagga caaataccta atgcatgtgg 177540 ggcttaaaac ctagatgacg ggttgatagg tgtagcaaac caccatggca catgtatacc 177600 tatgtaacaa acctgcacgt tctgcacata tatcccagaa ctaaaagtaa aataaatgaa 177660 aaagaaataa aaaataataa aataaaataa aataaatgaa aagtagccat tttaccagtt 177720 gagtatttac tgacttttgg tgaaaatcac tttctaagat tactagaaac cttatgaccc 177780 tcggcctcta ctcccaccac gtgcggattt tcacctccac ctactttgtc acgtcacatg 177840 cccttctgct ctttaggaca cttgtattgg gttcctcccc cacacgtaaa cagaacacac 177900 aggtctgtga atggacctca ttatgctcat ttgtctttgc caagaactat tgaaaatgat 177960 cacaaatgac tatgtaatta taattaagat tttgtacatg catacacttt atttttaaca 178020 agtttgtcct gttaaatgtc accccatttt gaatagtaac attcactggt gcaaggaaga 178080 attattaaaa tgacaattta actgatatcc ttgacaggta agccagttat tgtatttcat 178140 aattgtgatt attacaatac ctatgaagat taattaggac aatttattct ataggacttg 178200 gttatcaaaa tgatcttttt tcccatttta gtccatacat cttcagtttt aatttccttc 178260 ttccaaagaa ctctgagtct tgcccagtgt gatacttcag attttgtaaa aatataatga 178320 agaagaataa catgtatcag atcttttttt taatgtactg ggctaaaaat tataagcacc 178380 atcaaattac tagaaaattc ttttaacact ctgcttctta gttaaaaaat gattcctttt 178440 tgtgataatc ttataatttt caaagtatca ttttagaaat tttaaaaaat tattcttgtt 178500 ttcattcagt ccatttcatc agaacttaga ttttttcttc cctctacagt atgtggtctt 178560 gatgtgcttt ctccttgcaa aataaaatct ttagtttcag gatctctgtg ttctattcct 178620 tcaatttaaa atcataggaa aaataactat catttcctta tgtctgtctc caattccccc 178680 atcattttct gtgagccaat tttcttcttt ttcttctgtc tactgtaagg aactttttac 178740 tctgctctat tctctgcaat tcagggctca caatttcttt gacttctcag attatccttt 178800 gtacttgtgt ctactttttc attaaaaaaa aaaaggcttc ggtcttattt tgactttatc 178860 atctttatat tgccatattt aaaacccatc tgcttattga ttgaaccaaa cttttcatct 178920 tacttcatca tactgaatgt ataacttctg aatgacttaa aaatcatcac ataatgtgag 178980 agaattttct atcatattca ggtgactgca ttgtaagcaa tgaagttgaa gaaaaatagc 179040 ttataatgga tataatacca agaaataata agaatgagaa tctgcgtata tcatatactg 179100 ggttaacaag ctcacaaggc aaatcaccat tttattagat atttaacaaa tcatactagt 179160 actggaggaa gtatagcaga aaaaaggagt atggacattg ggattagctg ccttgctaat 179220 cttttgtcag tccctagtga catgcttttg ggttgagtca ttgttacctc cctgagctgt 179280 ttgtttataa aatgggggta aatatctcag atgtttcagt gttgtgacat ataaagcgtc 179340 ctccatagta cataataccg taagcactcc ataaggtaat tcttgtcctt ttaaaaagta 179400 tacacttttg agttcaggac acgtacactg taacctagtt gtaaccattt <<<
This was posted previously, but it's the first paper I can remember seeing by Dr. Lynch and UCI researchers on the benzothiadiazide family of AMPA upmodulators (Servier and Glaxo/NeuroSearch are involved with this general compound family, and Lilly's biarylpropylsulfonamides are more distantly related to cyclothiazide also) -
>>> 5'-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity.Phillips D, Sonnenberg J, Arai AC, Vaswani R, Krutzik PO, Kleisli T, Kessler M, Granger R, Lynch G, Richard Chamberlin A.
Department of Chemistry, University of California, Irvine, CA 92697, USA
AMPA receptors form a major subdivision of the glutamate receptor family that mediates excitatory synaptic transmission in the brain. Currents through AMPA receptors can be up- or down-regulated by compounds that allosterically modulate receptor kinetics through binding sites distinct from that for glutamate. One of those modulators is the benzothiadiazide IDRA-21 which has been reported to enhance synaptic transmission and be effective in behavioral tests, but typically requires threshold concentrations of at least 100 microM to be active in vitro. In this study, new benzothiadiazides were developed with IDRA-21 as lead compound and examined for their potency in modulating AMPA receptor kinetics. A significant increase in drug affinity was obtained by alkyl substitution at the 5'-position of IDRA-21; substitutions at other positions of the benzothiadiazide core generally did not yield a further gain in affinity and in some cases abolished drug binding. The 5'-ethyl derivative exhibited an EC(50) value in the order of 22 microM which represents about a 30-fold gain in affinity over that of IDRA-21. The EC(50) value is comparable to that of cyclothiazide, the most potent benzothiadiazide drug, but the effects on AMPA receptors differed substantially between these two compounds in that the 5'-ethyl derivative of IDRA-21 greatly increased the binding affinity for receptor agonists whereas cyclothiazide is known to reduce agonist binding. The structure--activity relationships reported here thus offer to provide new insights how receptor kinetics is linked to particular aspects of receptor--drug interactions.<<<
The benzothiadiazide binding site has been located (see paper below from Summer '06), and it is different from the previously identified site where CX-614, cyclothiazide, and aniracetam all bind (Dr. Rogers discussed that site in a SHM presentation a while back). So that makes two distinct higher impact type binding sites that we know about so far. Just speculating here, but it's likely that the low impacts CX-717 and Org-24448 bind at still another distinct site, which would represent a third binding site for AMPA upmodulators (and there may conceivably be more sites forthcoming) -
>>> Identification of a putative binding site for 5-alkyl-benzothiadiazides in the AMPA receptor dimer interface.Harpsoe K, Varming T, Gouliaev AH, Peters D, Liljefors T.
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Crystal structures of three different allosteric modulators co-crystallized with the iGluR2 ligand-binding domain are currently available. The modulators, cyclothiazide, aniracetam and CX614, bind at overlapping binding sites in the dimer interface between two iGluR2 subunits. However, pharmacological data indicate that there are one or more additional binding sites for this class of compounds. Based on differences in structure-activity relationship data we show that 5-alkyl-benzothiadiazide (5ABTD) modulators and a series of close analogs of cyclothiazide, despite having a common core structure, do not have the same binding site. In the present work, a new potential binding site for allosteric modulators has been identified in the dimer interface of the iGluR2 ligand-binding domain. By comparing different iGluR2 crystal structures including different co-crystallized agonists, this cavity is shown to be a structurally conserved part of the dimer interface. The cavity is characterized with respect to shape and potential favorable interactions with ligands and docking is used to find a reasonable binding mode for the core structure of the 5ABTDs. The extensive structure-activity data available for this series of compounds are in agreement with the proposed binding mode, supporting the conclusion that the identified cavity most likely is the binding site for the 5ABTDs. <<<
Speaking of combo treatments, here's an excerpt from a recent patent from Cephalon which among other things seeks to patent the combo use of various indole derivatives with Ampakines for the treatment of Alzheimer's. Most patents seem to try to cover every possible contingency, including the kitchen sink, but the inclusion of Ampakines at least indicates a general growing awareness of Ampakines as a potential treatment for AD. One also notes the growing use of Ampakines like CX-614 by varied researchers as a standard test "reagent" for producing neurotrophin upregulation in preclinical studies. So while Ampakines aren't quite a household word yet, within neuro research circles they now seem to be widely known -
>>> [0091] Methods for reducing or preventing the development of Alzheimer's disease comprising administering to a subject in thereof a therapeutically effective amount of a composition comprising a compound of Formula I are provided herein. In some embodiments, the method comprises administering to a mammal in need of such treatment a therapeutically effective amount of: (a) at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of Formula I; and (b) at least one agent selected from the group consisting of estrogen, risperidone, a thiobenzodiazepine, ampakine, [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate. <<<
Daviddal, There might be some clues within the Ampakine / ACHase combo use patent (link below). There seem to be all kinds of interactions between the various neurotransmitter systems -
http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsea...
At today's R+R presentation, I'd like to hear Dr. Stoll elaborate on the animal studies originally done on Org-24448/CX-691 -
1) Primates - Did Cortex originally do primate studies on Org-24448 of the type that showed the problem with CX-717, and were the doses and durations similar?
2) Rats - What doses were originally used on Org-24448 in rats? These doses were not likely anywhere near as high as those used recently in the FDA requested CX-717 studies (due to emesis, Cortex had to use a new approach and managed to get the doses much higher than was previously possible).
If the histo changes were present in the Org-24448 animal studies, would they have even been noticed? CX-717 had them in a single primate and Cortex apparently noticed something but didn't think it was a concern, or perhaps was an artifact. It took FDA scrutiny to require a further examination which confirmed its occurrence in a second species. It's very possible that if the histo finding did occur years ago with Org-24448, it went completely unnoticed.
3) Has Organon done new more rigorous animal tox studies recently, in light of the clinical hold on CX-717? If so, were they able to get the doses as high as Cortex has, and for the same duration? Has Organon shared this new info with Cortex, and if so in how much detail?
4) Concerning CX-701/other backups - have animal tox studies of the same rigor as those recently done on CX-717 been completed yet (very high level of dosing, in rats and primates, for up to 3 month duration)?
These are the type of questions that could help allay investor's platform concerns, since then the histo problem could clearly be shown to be a phenomenon that is peculiar to CX-717.
Jerrydylan, Here's one of Lilly's recent SFN presentation abstracts. For several years, Lilly has been publishing papers on their stellar results in animal models of Parkinson's. According to Lilly, their AMPA upmodulators produced better results in these animal PD models than did any other pharmacological intervention previously tried. If you look on PubMed there are numerous other Lilly papers on the subject.
I'm surprised that we haven't seen Lilly starting a human Parkinson's trial yet with one of their compounds. They might conceivably be having continued excitotoxicity problems however - their AD Phase 2 trial was stopped several years ago reportedly due to excitotox related problems. Dr. Rogers discussed Lilly's compounds at a past SHM, and it sounded like the tendency toward excitotoxicity is probably a class wide effect with Lilly's biarylpropylsulfonamides. LY-451395 for example (the compound in the AD trial that was stopped), had an extremely narrow therapeutic index, hitting MTD very suddenly at doses only modestly above its therapeutic dose. At the SHM presentation, Dr. Rogers said gravely that with Lilly's compounds, you WILL get seizures -
>>> Program#/Poster#: 76.18/HH25
Title: The ampa receptor potentiator LY450108 helps regenerate the damaged nigrostriatal pathway: mechanistic studies in the 6-OHDA model of Parkinson’s disease
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Saturday, Oct 14, 2006, 2:00 PM - 3:00 PM
Authors: *M. J. MESSENGER1, T. K. MURRAY2, W. A. MARK2, M. J. O'NEILL2;
1Eli Lilly & Co. Ltd, London, UNITED KINGDOM, 2Neurodegeneration, Eli Lilly & Co. Ltd, London, UNITED KINGDOM.
Current treatments for Parkinson’s disease (PD) relieve the symptoms of the disorder but have no effect on disease progression. Neurotrophic factors have been used as a neurorestorative treatment in PD to induce neurite outgrowth and synaptogenesis to repair the nigrostriatal tract. We have discovered a series of AMPA receptor potentiators (LY404187, LY450108, LY503430), that increase BDNF in vitro. Since BDNF can protect against neurotoxin-induced lesions of the nigrostriatal system we hypothesized that these compounds could act as a neurotrophic treatment for PD.
In the present studies we investigated the neurotrophic potential of the AMPA receptor potentiator, LY450108, after a severe 6-OHDA lesion of the nigrostriatal pathway in rats. Chronic treatment with LY450108 (0.1 and 0.5 mg/kg p.o.) produced a robust improvement in apomorphine-induced rotational behaviour and tyrosine hydroxylase immunoreactivity in the striatum, but had no effect on the number of cells in the substantia nigra. To gain insight into the mechanism of action, we carried out time-course studies (1, 3, 8 and 15 days) to evaluate the effect of LY450108 on [3H]-Mazindol ligand-binding and mRNA expression for a range of trophic factors (BDNF, NGF, NT-3), RGS2 and GAP-43 by in situ hybridization. A large increase in [3H]-Mazindol ligand-binding in the striatum and an increase in GAP43 expression in the substantia nigra occurred between eight and fifteen days following 6-OHDA in LY450108-treated rats. We also observed a transient increase in RGS2 mRNA in the striatum from two to fifteen days post-lesion. In contrast, no increase in BDNF, NGF or NT-3 gene expression was detected in the nigrostriatal pathway.
LY450108 appears to have neurotrophic properties, increasing dopaminergic innervation of striatal terminals and improving functional outcome. Modulation of AMPA receptors may provide a means of both halting the progression and perhaps reversing the degeneration in PD. <<<
Neuro, I'm not sure how we can reasonably expect the results to be significantly different this time around. For the primates, the doses will be even higher than what produced the histo finding in the original study. The only hope is that if there are more dose levels used, one could establish a more accurate level at which the histo finding begins to occur. The other hope, that a different method of tissue preparation/fixation/visualization might not show the histo finding to the same extent as before, sounds pretty flimsy to me.
Another factor would be if Cortex can start to understand what is going on on a cellular level and why, perhaps the mysterious/unknown aspect of the problem would be lessened and the FDA might loosen up the dosing restrictions. Cortex is also doing studies of the possible role that CX-717's metabolites might play, though I don't know when these might be completed. Electron microsopic studies of the affected cells are also reportedly being done.
FWIW, even with a modest dose liberalization by the FDA, I'm not expecting CX-717 to be able to realistically go ahead for ADHD. The impression one gets from Stoll's recent presentation is that they aren't even close to the dose they think they need for ADHD. If so, the best we might be able to get is a CX-717 BP deal for Alzheimer's, which at least would be something.
Money4, "IF correct, were the two doses that showed no problem not high enough to give the fda the margin of safety they felt comfortable with to allow cortex to continue using the adhd trial dose???
OR
did the fda restrict the dosing, even though at lease one of the two test doses that didn't show a problem and was high enough to give the fda the safety margin they felt comfortable with, but for which they need repeat testing to confirm the results?
OR
none of the above. ???"
The FDA must not feel comfortable with the margin of safety. They may be setting the margin higher than usual due to the somewhat mysterious/unknown nature of the histo finding.
FWIW, in the recent conf call, Dr. Stoll seemed to be hanging our hopes mainly on the fact that they're using a different method of tissue preparation/fixation/visualization this time around.
A link to the full text -
http://www.jneurosci.org/cgi/content/full/25/39/9027
Note that Dr. Rogers discussed this paper at an annual SHM, in part to explain why Lilly's problems with LY-451395 (its AD Phase 2 had been stopped) shouldn't have any bearing on CX-717's prospects.
While that may be true when it comes to excitotoxicity (which has always been the long standing theoretical knock against the AMPA upmodulation concept), if calpain activation turns out to be an additional problem (IF), the fact that CX-717 and CX-614 act at different binding sites may not matter. The key factor may instead be that both CX-717 and CX-614 act primarily via the mechanism of inhibiting receptor deactivation (as opposed to desensitization). Only time will tell, but this mystery with the CX-717 histo finding has become extremely interesting, at least from a scientific point of view.
More on the deactivation vrs desensitization topic, if anyone is interested. This is an excerpt from the 2005 paper that studied the high impact site on the AMPA receptor, and found that CX-614, cyclothiazide, and aniracetam all bind at this "high impact" site (CX-717 binds at a different site). But as we now know, in spite of binding at the same site, CX-614 activates calpain activity and cyclothiazide (CTZ) doesn't. The key difference as it relates to calpain activation might instead be in their different mechanism of action (CX-614's primarily being deactivation related, and cyclothiazide's being primarily via desensitization). Also, note that benzothiadiazides (Servier's S-18986) and biarylpropylsulfonamides (Lilly's compounds) are structurally related to cyclothiazide -
>>> Modulation of deactivation
Deactivation is the process by which the ion-conducting pore of glutamate receptors closes, allowing agonist to dissociate from the ligand-binding "clamshell." Deactivation is measured experimentally by exposing the receptor to such brief (1 ms) pulses of agonist that little receptor desensitization can occur. Desensitization is a long-lasting, agonist-bound, nonconducting state; it is measured experimentally by exposing the receptor to a prolonged (500 ms) pulse of agonist. CTZ prevents normal channel desensitization, the rearrangement of a dimer interface formed by adjacent subunits within a receptor complex that allows the ion-conducting pore to close in the continued presence of agonist (Sun et al., 2002). CTZ modulates desensitization to a far greater extent than it does deactivation, and it is more efficacious on flip isoforms. Unlike CTZ, aniracetam and CX614 slow channel deactivation (Fig. 1) and are selective for flop rather than flip splice isoforms. Modulators of deactivation can have little (aniracetam) or marked (CX614) additional effects on desensitization. <<<
Looks like Cortex is still on the Berlin exchange. One would think that Dr. Stoll may have tried to get the stock off that exchange. Other companies have apparently gotten themselves removed from there. The Berlin exchange is reportedly where naked shorting can be done more easily.
On the other hand, perhaps if a stock isn't traded there, then the PIPE financiers might be less eager to do financing deals with that company(?) In that case it would make sense for a small bio company to reluctantly stay on that exchange, in spite of the increased potential for manipulation.
Dew, board, While Dr. Cox couldn't yet provide sales/revenue estimates for Atryn in the recent conf call, I was wondering if you guys have any ballpark guestimates? Also, any estimates on the approx timeline for Atryn's approval in the US, assuming all goes well clinically? Thanks.
As discussed in the Lynch paper excerpt below, it's not clear yet why some Ampakines activate calpain activity while others don't. We were previously under the impression that this was a high impact phenomenon, but the observation that cyclothiazide and CX-546 don't activate calpain activity, while CX-614 does, indicates that there is likely more involved than just high impact vrs low impact. As the Lynch paper says, more calpain related research needs to be done on additional Ampakine compounds. Also, these studies were done using hippocampal brain slices for a maximum of 48 hours. In live animals, mega-dosed for up to 3 months, the cellular effects could be far different. Bottom line is that when it comes to AMPA upmodulation, we are still in uncharted waters -
>>> Interestingly, different classes of positive AMPA receptor modulators produced divergent effects on calpain activation. In particular, both cyclothiazide and CX546 did not activate calpain; if anything, CX546 produced a decrease in basal level of activation as evidenced by lower levels of SBDP as compared to control. Positive AMPA receptor modulators have been shown to affect AMPA receptor function through different mechanisms, with some modulators interfering with desensitization kinetics of the receptors, while others affect rates of channel opening or closing (Arai et al., 2002b). For instance, CX614 and CX546 mainly decreased the rate of deactivation of the receptor, thus prolonging the duration of AMPA receptor-mediated synaptic responses. On the other hand, cyclothiazide affects primarily desensitization kinetics, and has been shown to have little effect on AMPA receptor-mediated synaptic transmission. Our results would therefore imply that positive AMPA receptor modulators with similar effects on AMPA receptor kinetics are able to have opposite effects on calpain activation. As an antagonist of AMPA receptors completely blocked CX614-induced calpain activation, our results also indicate that AMPA receptor stimulation is necessary for ampakine-elicited calpain activation. The reasons for the decrease in calpain activation elicited by CX546 are not clear at the moment, but might be related to differential effects of various ampakines on pyramidal neurons versus inhibitory interneurons. Testing the effects of additional ampakines should provide interesting information regarding these interpretations. <<<
I should add that calpain activity is also thought to be associated with normal LTP (long term potentiation - the basis of memory formation), so it's unclear whether CX-614's activation of calpain activity is something to worry about or not. But since it's one of the few Ampakine effects we know about which could potentially cause cellular related problems (the other being excitotoxicity), it's something we need to at least consider as a possible cause of our histopathology finding.
Calpain mediates cell death and is associated with stroke, traumatic brain injury, and heart attack (does not induce these events but is associated with their cellular aftermath - the post-event cellular destruction). We know that some Ampakines like CX-614 activate calpain activity, at least in hippocampal tissue slice studies -
>>> Inhibition of calpain-mediated cell death by a novel peptide inhibitor.McCollum AT, Jafarifar F, Lynn BC, Agu RU, Stinchcomb AL, Wang S, Chen Q, Guttmann RP.
Department of Biology, Florida A and M University, Tallahassee, FL USA.
Calpains are calcium- and thiol-dependent proteases whose overactivation and degradation of various substrates have been implicated in a number of diseases and conditions such as cardiovascular dysfunction and ischemic stroke. With increasing evidence for calpain's role in cellular damage, the development of calpain inhibitors continues to be an important objective. Previously, we identified a highly specific calcium-dependent, calpain interacting peptide L-S-E-A-L, that showed homology to domains A and C of the only known endogenous inhibitor of calpains, calpastatin. This suggested that LSEAL had a calpain inhibitory function and synthetic LSEAL inhibited calpain I and II proteolysis of two calpain substrates, tau and alpha-synuclein. In the present study, we demonstrate that synthetic LSEAL is membrane permeable and is a potent inhibitor in two established models of calpain-mediated cell death using primary rat cortical neurons and SH-SY5Y neuroblastoma cells. In addition, we show that LSEAL inhibits calpain activity towards protein substrates as detected by an antibody to a calpain-specific breakdown product of spectrin. Taken together, these results suggest that LSEAL may represent a novel calpastatin mimetic with the potential for benefit in conditions of increased calpain activity such as stroke, traumatic brain injury or heart attack. <<<
Dew, Sepsis has always been a graveyard for pharma development. I wonder if reliance on this program is one of the reasons for GTCB's overall weakness?