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Just rambling here, but concerning the Narcolepsy "orphan / back door" approach to approval (the modafinil/Cephalon route), there are several things that bother me about this approach as a potential road to approval -
Will the new/improved hyper-cautious FDA fall for this a second time? Years ago they allowed modafinil to slip through via the orphan Narcolepsy indication, and then watched as its off-label use (and misuse) exploded. Schools are now inundated with the stuff (along with Ritalin/methylphenidate and amphetamine based ADHD drugs). The way they recently shot down modafinil's latest attempt at label expansion (into ADHD) was particularly telling (the extremely lame skin rash excuse).
The FDA has gotten so much flak over ADHD/CNS drugs in the past few years, with weird side effects and black label warnings, etc, that it just seems like they want to stonewall anything and everything CNS related. I wonder how much of a factor that could be with CX-717 right now. CX-717 didn't have any FDA problems at all until showing those phenomenal ADHD results, and then wham, the FDA pounced immediately. I can't help thinking the FDA has overreacted into a general circle-the-wagons mode, especially with CNS and ADHD. Plus the FDA is currently going through a major restructuring of the CNS division, dividing it into separate Psychiatric and Neurological sub-divisions. So general disarray at the FDA could be a large part of CX-717's current troubles.
Moosedogger, Good points. The main rationale for the non-Ampakine in-license is based on the notion that once CX-717 and the N.Amer Neurodegenerative rights are gone, there won't be much for Cortex to do indication-wise or compound-wise for some time. There actually could be a considerable amount left indication-wise, though compound-wise it's true that it will take probably 18 months or so to get CX-701 up to where CX-717 is now (assuming we're able to keep CX-701), and of course the high impacts are considerably farther back than that.
Indication-wise, at a minimum Cortex should be able to carve out the various orphan indications (Frag-X, Huntington's, post-ECT, etc). There's a reasonably good chance that the Sleep Related indications (including orphan Narcolepsy and non-orphans like Excessive Daytime Sleepiness, Shift Work, etc) can also be carved out. There's also the possibility of doing an ADHD-only BP deal, and retaining all the N.Amer Neurodegenerative rights.
So the key rationale for the non-Ampakine in-license idea mainly boils down to not having any compounds ready to go. In a presentation a while back, Dr. Stoll said that the prospect of sitting around for several years waiting to get another compound up to speed is very unattractive from a CEO's perspective. So bringing in another company's late stage orphan program does make some sense. Originally he was talking about a Phase 3 program, now it sounds more like a Phase 2 program.
An alternate approach would be to just sit tight while CX-701 gets through Phase 1, then move it into Phase 2a for Narcolepsy/Sleep Related. Or if Cortex does an ADHD-only deal, retaining the N.Amer Neurodegenerative rights, we could move CX-701 into a Phase 2a in AD or MCI. The time lag waiting for CX-701 is still there however, and waiting for a high impact will take even longer, so that's the dilemma.
The other possible approaches I can think of are - 1) to forgo the BP deal and take CX-717 into Phase 2b in ADHD ourselves, or 2) do an ADHD-only deal with someone like Shire and try to carve out the co-use of CX-717 (very unlikely Shire would go along with that though).
Based on Dr. Stoll's presentation comments, it sounds like they're definitely moving toward the non-Ampakine in-license direction.
As bad as things have seemed at times, 2007 has the potential to be a watershed year for Cortex. First though, we need to get through a difficult period - probably a PIPE sometime in the next 3 months, and getting the primate studies done and dosing restrictions lifted. Once past those obstacles, the path is then wide open for a good BP deal and a nice move up in the shareprice.
Of course complicating the picture in 2007 to some extent will be the non-Ampakine in-license activity. Other factors are the Org-24448 Schizo results, which one would expect to be published before too long.
One thing I've learned in bio investing is patience, and patience is a lot easier with a diversified portfolio.
Alertmeipp, It actually hasn't been established yet if the FDA requested the new 3 month tox trial. It sounds like Cortex and/or their consultants decided to start it on their own in the Summer, figuring (correctly it turned out) that the FDA might want still more data in the Fall (and a 3 month primate study was the obvious place to start). Whether this new 3 month data will be enough for the FDA to lift the dosing restrictions is another question - has Cortex gotten that in writing? Also, assuming a 3 week dosing duration is still currently allowed, at what dose level is it allowed? Obviously something like 200 mg BID for 3 weeks isn't going to cut it.
Then there's the question of Phase 2b type 3 month studies. Approval for this duration is likely out of the question without first getting the new 3 month primate data. And the FDA would have to approve not only the 3 month duration but also the desired dosing level (again, approving the longer duration but only at lower dose levels isn't going to help us).
Much of this should hopefully be clarified in tomorrow's conf call.
Thanks Neuro. Assuming it was seen in the primate, the lack of any 3 month tox data at all in primates is the obvious glaring hole in Cortex's animal tox data.
Something I've been curious about is why do the acute studies in rats and primates, and the longer 3 month studies in rats and dogs? There are several possible explanantions I can come up with -
1) Primates are expensive, so having done one study with them already, Cortex switched to the cheaper dog model for the 3 month studies.
2) Switching to dogs results in total tox data in 3 species rather than only 2, which might be seen as a plus.
3) Another scenario has some sinister overtones (just speculating here) - that having noticed a histo "finding" in the original acute primate data (Cortex noticed it but apprently the FDA didn't, since they allowed the Phase 2a trials to proceed based on that very same acute animal data), Cortex decided to switch from primates to dogs for the 3 month studies (thus eliminating the chance for a repeat of the primate "finding"). Not saying this was their rationale, but I suppose it's a possibility.
Neuro, Just wondering - do you remember if Dr. Stoll ever said specifically that the histo finding was seen in primates (the original short term acute studies)? We've basically been assuming that (primates), but I don't recall Cortex actually saying it. I suppose a histo finding in the rats could have theoretically also led to a clinical hold. Thanks.
Daviddal, Dr. Stoll may not give much additional info on the nature of the original histo finding, though I'd like a confirmation that it was seen in primates (I don't remember this being officially revealed, unless I missed it).
Some topics for the conf call include -
1) Details of the dose level restrictions.
2) Are there dosing duration restrictions also (specifically, is 3 week dosing allowed and at what dose?).
3) Did the new acute data that Cortex sent to the FDA appear clean (no apparent repeat of the histo finding)?
4) Was the current 3 month tox study in primates requested by the FDA, or was it a preemptive "just in case" suggestion by Cortex's consultants?
5) Is there any assurance from the FDA that getting clean 3 month primate tox data will remove the dosing restrictions?
6) Likewise, can we reasonably expect clean 3 month primate tox data to allow future 3 month human trials to proceed?
Meixatech, Cancer vaccines, antisense, gene therapy - these ultra high risk areas have scorched investors for years, so there's a lot of skepticism. I once followed the cancer sector, but with history seemingly against the vaccine companies, I avoided them.
Within cancer, I figured that MABs were a good general area - at least there's been a long history of success with naked MABs. Armed MABs was very cool science that seemed promising, but it hasn't really panned out yet (MABs armed with toxins or radioactive materials). Then there are the various improved taxane programs, the "kindler/gentler" anthracyclines, etc. Some of these may yet be successful. I finally gave up on the cancer sector however, except for some low risk plays like MGI (palliative treatment of chemo side effects, whoopee).
Dew is the gunslinger to ask. The only advice I'd give is to diversify.
OT - Thanks to Dew's thread for this article on statin anti-cholesterol drugs - major side effects -
>>> The depletion of the essential nutrient coenzyme Q10 (CoQ10) by the increasingly popular cholesterol lowering drugs, HMG-CoA reductase inhibitors (statins) has grown from a level of concern to one of alarm. With ever higher statin potencies and dosages, and with a steadily shrinking target LDL cholesterol, the prevalence and severity of CoQ10 deficiency is increasing noticeably to the physicians in the trenches of front line patient care. An estimated 36 million Americans are now candidates for statin drug therapy.
CoQ10 serves as the coenzyme for mitochondrial enzyme complexes I, II and III and is essential for mitochondrial ATP production. CoQ10 is also a clinically relevant fat-soluble antioxidant and is the only fat soluble antioxidant that is known to be synthesized de novo. It is found normally in the diet, predominantly in organ meats and is biosynthesized in all cells with peak capabilities in late teens and early twenties with a gradual age-related decline in blood and tissue CoQ10 levels after the age of 30 years.
Statin-induced CoQ10 depletion has been documented in 15 animal studies in six different animal species and has been shown to correlate with decreased ATP production, increased ischemia reperfusion injury, skeletal muscle injury and increased mortality.
There are 15 published trials on statin-induced CoQ10 depletion in humans. Of these 15 trials, nine were controlled trials, eight of which documented significant CoQ10 depletion. Statin-induced CoQ10 depletion has been shown to be associated with a fall in left ventricular function, an elevation of lactate to pyruvate ratio and an enhancement of LDL cholesterol oxidation. The current data on diastolic dysfunction further confirms the clinical importance of this drug-nutrient interaction.
Statin-induced CoQ10 depletion is well documented in animal and human studies with detrimental cardiac consequences in both animal models and human trials. Furthermore, this drug-induced nutrient deficiency is dose-related and more notable in settings of pre-existing CoQ10 deficiency such as in the elderly and in heart failure. Finally, statin-induced CoQ10 deficiency is completely preventable with supplemental CoQ10 with no adverse impact on the cholesterol lowering or anti-inflammatory properties of the statin drugs.
We are currently in the midst of a congestive heart failure epidemic in the United States, the cause or causes of which are unclear. As physicians, it is our duty to be absolutely certain that we are not inadvertently doing harm to our patients by creating a wide-spread deficiency of a nutrient critically important for normal heart function.
"Ubiquinone (CoQ10) is a popular heart medication. Until 2001, it was only available by prescription in Japan. The public is hardly aware that an increasingly popular class of cardiovascular drugs called statins (HMG-CoA reductase inhibitors) interfere with the body’s synthesis of CoQ10.
Top selling statin drugs, such as Lipitor and Zocor, earn their makers in excess $20 billion per year. These drugs lower the endogenous production of cholesterol and are often touted as “life saving” by cardiologists and the Media.
Are the statin drugs really good for us, or are cardiologists mistaken? How can drugs that lower the body’s production of CoQ10 benefit heart patients? Are the health benefits attributed to CoQ10 supplementation hype or is it that there is something fundamentally wrong with the thinking and science being used by those who market statin drugs?
COQ10 BASICS
Coenzyme Q10 is a vitamin-like fat-soluble antioxidant found everywhere in the body; the highest concentrations have been measured in vital organs such as the heart and pancreas. At age 20, the heart has a higher CoQ10 level than other major organs. At age 80 this is no longer true, with the heart levels cut by more than half. More than 35 controlled clinical trials in Japan, Europe and the U.S. have proven that CoQ10 therapy is highly effective in treatment of congestive heart failure, angina and ischemic heart disease, and myocardial infarction. It is now believed that CoQ10 is the key nutrient for generating 95 percent of the total energy required by the human body.
A healthy, youthful human body can make its own CoQ10. Endogenous production or biosynthesis of CoQ10 has 17 steps, requiring at least seven vitamins (vitamin B2 - riboflavin, vitamin B3 - niacinamide, vitamin B6, folic acid, vitamin B12, vitamin C, and pantothenic acid) and several trace elements.
The pharmaceutical giant Merck has known for more than 15 years that statin drugs interfere with CoQ10 biosynthesis; leading to low serum levels which cause muscles to atrophy. The following claim from one of two 1990 Merck patents (4,933,165) is to add CoQ10 to statin drugs in order to overcome statin induced myopathy:
1. A pharmaceutical composition comprising a pharmaceutical carrier and an effective antihypercholesterolemic amount of an HMG-CoA reductase inhibitor and an amount of Coenzyme Q.sub.10 effective to counteract HMG-CoA reductase inhibitor-associated skeletal muscle myopathy.
This invention has never been implemented, probably because the entire world supply of CoQ10 is limited and current production would only supply one-sixth of the world’s statin users..
VARIOUS HEALTH BENEFITS ATTRIBUTED TO COQ10
The CoQ10 science has accelerated from its discovery in 1957 until the present day and appears excellent.
For all you gunslingers out there, here's an interesting investment idea - Uranium -
>>> Myra Saefong's Commodities Corner
Uranium's poised for more powerful gains
By Myra P. Saefong, MarketWatch
Last Update: 10:16 AM ET Oct 20, 2006
SAN FRANCISCO (MarketWatch) -- As the world seeks alternatives to oil as a source of energy, uranium has been on a tear, scoring a gain of around 700% in six years as interest in nuclear power has revived.
"Uranium's performance has been in a league of its own," said Scott Wright, an analyst at financial-services company, Zeal LLC.
Uranium has been one of the best-performing commodities in this bull market, he said. Spot prices are trading at around $56 a pound, an eight-fold increase from as low as $7 back in 2000. See the latest uranium prices.
"And the way fundamentals look today, there could be a lot more room to run," said Wright.
Crude and gold prices have seen strong gains, but they pale in comparison to uranium. Over the last six years, crude futures are up around 90% and gold futures prices have more than doubled.
The biggest reason for uranium's rise? Simply put: supply scarcity.
Short on supply
Uranium, a radioactive heavy metal that's the basic material for nuclear technology, is actually more common than silver, according to the U.S. Energy Dept.
But the market for it is suffering from a supply and demand squeeze. "For more than 10 years, the nuclear-power industry has consumed more uranium than has been mined," said Lawrence Roulston, editor of Resource Opportunities, an independent investment newsletter.
World consumption was pegged at 171 million pounds last year and global supplies were estimated at about 102.5 million pounds, according to Sean Brodrick, contributing editor of MoneyandMarkets.com.
The difference of more than 60 million pounds has been met mostly by using highly-enriched uranium from Russia's nuclear weapons that were being decommissioned, he said. But "we are fast reaching the end-game on that source."
In fact, the end to the above-ground supply will come before there is time to develop significant new mine supplies, said Roulston.
Exacerbating the problem, now that nuclear energy is in vogue again, the growing pipeline of reactors coming online in the next decade will substantially add to the overall demand for uranium, said Wright.
"As stockpiles dwindle, people are starting to see the writing on the wall that there will likely be several decades of mined supply deficits for this metal," he said.
A key fuel
Uranium is the key fuel for nuclear energy which remains the proven alternative to oil and coal for creating electricity.
"Nuclear energy has become a very acceptable alternative to the fossil fuels that power the globe today and uranium is the commodity poised to shoulder this drive," said Wright.
'For more than 10 years, the nuclear-power industry has consumed more uranium than has been mined.'
— Lawrence Roulston, Resource Opportunities
"Unlike many of the alternate energy plays out there, nuclear energy is proven to work on a mass scale," he said, pointing out that 16% of the world's electricity is generated from it.
Nuclear power is "getting cheaper and safer," said Brodrick, and operating a nuclear plant produces zero greenhouse gases, compared with the average coal plant's release of 3.7 million tons of carbon dioxide every year. Read his recent report on nuclear energy.
In addition, nuclear energy offers a means for countries to take control of their own destiny. "Right now, OPEC has us over a barrel," Brodrick said, referring to the Organization of the Petroleum Exporting Countries, whose members produce about 43% of the world's crude oil.
While nuclear power can't replace oil, it can "be a much larger part of our energy picture," he said.
The U.S. was once the world's largest producer of uranium and uranium mines in the nation are gearing up again, he said.
Countries boost spending
The U.S. gets about 20% of its power from 103 nuclear power plants that produced 780.4 million megawatts last year -- that makes it the world's largest generator of nuclear power, said Brodrick.
Worldwide, there are 442 nuclear reactors in operation, with a total of around 250 under construction, planned or proposed, according to data from the World Nuclear Association.
It's estimated that this year, over 170 million pounds of uranium will be required to operate these reactors, said Wright.
Canada has an $18 billion plan to upgrade nuclear plants and build new ones, according to Brodrick. And so far, the U.S. has earmarked $13 billion in new subsidies for nuclear power, "but I expect that to rise -- substantially too," he said.
Russia's President Vladimir Putin has targeted nuclear power's share of Russia's energy use to increase from 15% to 25% by 2030, he said. To get there, Russia would need to add 40,000 megawatts of nuclear energy each and every year, "building at least 40 new nuclear reactors by 203," Brodrick said.
"Governments around the world ... are realizing they can't meet their growing energy needs through fossil fuels alone, and are embarking on very ambitious nuclear programs," he said.
Uniquely lacking a trading forum
So, it's obvious uranium can offer a unique investment opportunity. There's just one problem: you can't just buy the product -- the commodity doesn't trade on any futures exchange like oil and gold trade on the New York Mercantile Exchange.
"Unlike many of the major metals, uranium has never been traded in the formal futures markets, nor has it existed on any kind of tradable commodities exchange," said Wright.
It is, however, actually "traded," or exchanged, through long-term contract prices negotiated directly between the buyer and seller, he said.
Uranium producers buy uranium on the spot market "because their production is falling short of their own projections, and they are locked into contracts to deliver a certain amount of uranium to their customers," Brodrick explained.
'For the average investor, the best way to take advantage of this run in uranium is to invest or speculate in the stocks of the companies that will bring uranium to market today and tomorrow.'
— Scott Wright, Zeal LLC
And, of course, there are "strict rules about buying, selling and moving uranium," said Roulston. "The metal itself is pretty much off-limits to most investors."
Rest assured, there is an alternative way to invest in this alternative energy fuel.
"For the average investor, the best way to take advantage of this run in uranium is to invest or speculate in the stocks of the companies that will bring uranium to market today and tomorrow," said Wright.
There are about 300 exploration/development companies, "a few of which will be successful and generate big payoffs for investors," said Roulston.
"The unique sector of stocks, the majority of which trade on the TSX Venture Exchange, has soared in recent years," said Wright. And "any publicly-traded company staking a claim on or near a potential uranium deposit has watched its stock go through the roof."
Saskatchewan-based Cameco Corp. (CCJCameco Corporation
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CCJ ) is the world's biggest uranium producer and "if you want to buy one of the big names in the business, it's a good choice," said Brodrick. The company's net income jumped 358% in the latest quarter, compared to a year earlier thanks to surging uranium prices, he said.
The biggest movers, however, will be in the small- and mid-cap companies, he said.
Winners among the uranium miners and producers will include those companies using realistic near-term production plans and utilizing deposits discovered previously, and exploration companies that make new discoveries that are large, high-grade and in favorable locations, Roulston said.
Traders can also invest in a mutual fund or exchange-traded fund that holds uranium, Brodrick said. There are a few of these but none are listed primarily on the U.S. exchanges. Brodrick is expecting a U.S.-based uranium ETF to eventually be launched.
For now, there's Uranium Participation Corp. (CA:U: news, chart, profile) , a Canadian fund that buys physical uranium, he said. Its common shares trade on the Toronto Stock Exchange under the symbol "U" and on the Pink Sheets in the U.S. under "URPTF."
Myra P. Saefong is a reporter for MarketWatch in San Francisco <<<
Aiming, I think it's safe to say that the repeat tox trials at lower doses were clean (hence the partial lift of the clinical hold at the lower doses). However for the higher doses, we'll have to wait to hear from Dr. Stoll. All we know is that the FDA won't allow dosing beyond a certain dose level. That would suggest that either 1) there's still some question over the repeat high dose acute data (the results were ambiguous), or 2) the repeat high dose results looked clean but they now want additional longer term (3 month) primate data just to be on the safe side. Remember, Cortex didn't perform any long term tox studies in primates (those original studies were in rats and dogs, and the FDA didn't originally request new 3 month studies, only new short term/acute studies). With the histo finding presumably being seen in the short term primate data, getting some longer term primate data only seems prudent.
Alertmeipp, No, what that means is at doses higher than the current FDA allowed levels, but we don't know what those levels are. They could be 200 mg BID, 400 mg BID, 600 mg BID, etc. - we have no idea what they are. The only clue we have is that the AD PET scan study dose is OK, which as I recall had a single 1000 mg dose (if I remember correctly). BID dose limits we don't know. Dosing duration we don't know. Dose/duration combinations we don't know.
Alertmeipp, Neuro would be the one to ask about "Top 10" since it looks like he was on the selection committee for that conference.
BTW, just guessing here, but I think there's a pretty fair chance that 800 mg BID for 3 weeks is beyond what is currently allowed by the FDA's dosing restrictions. That dose was at the highest end of BID dosing in the Phase 1, where Cortex stopped dose escalations and called it MTD. Single dose MTD was 1600 mg. Further speculation on the dosing restriction topic is really somewhat pointless without having some additional info from Stoll, since we currently have next to nothing to go on.
Alertmeipp, That's right, the press release didn't say anything about dosing duration one way or the other, so we are left completely in the dark. We have no idea if we or a BP could even replicate the trial protocol of the successful ADHD Phase 2a. Can we do a 800 mg BID study for 3 weeks? Who knows. How about 500 mg BID for 3 weeks? Who knows. How about a 1000 mg once/day study for 3 weeks? Again, who knows. It's time for Dr. Stoll to shed some light on the situation.
OT - The way out of Iraq -
Since it's a slow day, here's a potential solution to our Iraq problem that's being bandied about - 1) Divide Iraq into 3 separate areas (Shiite, Sunni, Kurds), each to be governed autonomously, then - 2) the US declares victory and leaves. Of course the region will inevitably descend into civil war, but the US will have a) successfully extricated itself, avoiding the 5-10 additional years we're going to be stuck there otherwise, b) saved face (sort of) by avoiding a pure cut/run, and c) we won't have to worry about Iraq becoming a nuclear power for many years, which was the point of the whole excercise in the first place. This seems like a cynical solution until one considers that there's going to be a civil war once we leave anyway, even if we stay for 10 more years.
Then we can get on with the next task at hand - bombing the hell out of the Iranian nuclear sites. Ah, the joys of being the global policeman...
Alertmeipp, While the hold was technically "lifted", all we know for sure is that the AD PET scan trial can resume (the only trial that was still ongoing at the time of the hold), and that's about it. We investors have no idea what the upper limit is on dosing, or what the allowed dosing duration is (1 day, 1 week, 1 month, etc). For all we know, the dosing regimen used in the successful ADHD Phase 2a trial isn't allowed under the current dosing restrictions (800 mg BID for 3 weeks). If that's the case, then from a BP deal perspective, having the hold "lifted" doesn't mean much.
Beyond that, what a BP partner really needs to know is if 3 month dosing is allowed. Under the current dosing restictions, 3 month dosing in humans is probably not allowed at any dose level. So, calling the clinical hold "lifted" is not really an accurate description of the situation. It made for a nice press release headline, for about 20 seconds, until one reads that there is a dosing restriction, the extent of which is totally unknown to us investors.
The way I see it, Dr. Stoll has to give us at least some idea of the extent of the dosing restrictions. We've been largely left in the dark about the nature of the histo "finding" for over 6 months. If he does the same thing with the dosing restrictions, then uncertainty will reign and the share price will continue to erode. That might not matter so much if the company didn't need to raise money soon, but the company's own guidance is for cash levels to drop under $10 mil by year end. So investors need to know where we stand.
Concerning the dosing restrictions, I still think it probably has to do with the lack of 3 month monkey tox data (the original 3 month studies being in rats and dogs). This deficiency would be especially glaring if the histo "finding" was seen in the acute monkey study.
Seeing the histo problem in the original acute monkey data, the FDA asked to see that acute monkey study repeated, which Cortex did. Now they want to see longer term 3 month data in monkeys, which wasn't part of their original request. Luckily, Cortex's consultants recommended getting the 3 month monkey study started back in the summer, figuring correctly that this might be the FDA's next request.
In trying to read the current tea leaves, one related question is whether the acute tox data from the repeated studies was - 1) totally clean, 2) ambiguous in some way, or 3) clearly not clean. We can almost certainly rule out #3, since if the histo problem was clearly repeated in the new data, we'd be looking at the "CX-717 is toast" scenario, which would have been a material event. It's possible that the repeated study data was ambiguous in some way, leading to the FDA's decision to place dosing limits on CX-717 pending further monkey data. It's also possible that the repeated study data was totally clean, but that the FDA is being extremely cautious and wants to see the additional 3 month monkey data anyway (particularly since they know the next logical step in CX-717's development will be 3 month human trials).
Call it a semi-educated guess/intuition, but I think CX-717 will get the dosing restrictions lifted once the new 3 month monkey data is delivered to the FDA. However, this delay has thrown a wrench into the BP deal timetable, most likely making a PIPE necessary, and thrown off the non-Ampakine in-license plans. All in all, the FDA has wreaked some havoc, but if CX-717 gets a clean bill of health, it'll have been worth it.
Thanks Neuro. Well, if they've pushed the timetable estimate for the BP deal back even more, to 1H-07, then I don't see how a PIPE is realistically going to be avoided (barring some unexpected event in the next several months that sends the stock price skyward and triggers a large amount of warrant excercising - something like blowout great Schizo results, or a final Euro patent victory).
Your discussion with Dr. Karran sounded interesting. I'm not sure I followed your last comment though, ie - did Karran not seem to disagree with Lilly's position that they don't need Cortex's IP, or did he not seem to disagree with your comments that a partnership would be good for Lilly? Thanks for all your insights Neuro.
(BTW, it looks like I just used up the last of my 15 free daily I-Hub posts, so will see you guys later).
Meixatech, Yes, the BDNF upregulation aspect of high impact Ampakines could be ideal for stroke/TBI. However the downside is a high impact's inherent tendency to stimulate excitotoxicity/calcium imbalance at the synapse, which would be undesirable. Hopefully, by combining a short term "burst" dosing approach, with an ultra-short acting compound (of the safest compound family), the approach might end up being successful. As Neuro has said, TBI/Stroke has been a pharma graveyard for years, but perhaps the high impact Ampakine approach could be the exception.
BTW, I really thought PARS had a decent chance with their cannabinoid approach, but luckily I bailed out of the stock a week or so before the bad news. That near death experience contributed to my decision to go back to following biotech as a hobby :o)
Aiming, Dr. Baudry is a prominent researcher and was apparently a colleague of Dr. Lynch's, but rumors were that they had a falling out a while back. Based on the activities of Lifelike Biomatic, that would make sense.
The AMPA/NMDA receptor combo approach makes sense, although AMPA upregulation by itself already indirectly upregulates NMDA activity, since the NMDA receptor is directly downstream of the AMPA receptor. Some of an AMPA upregulator's activity might in fact already be due to its downstream effect at the NMDA receptor (in Schizophrenia for example). An advantage of stimulating the NMDA receptor via upstream stimulation of the AMPA receptor alone (via an Ampakine) is that the downstream activity should have more allosteric/activity dependent characteristics, compared to a direct NMDA agonist/partial agonist.
The Lifelike approach of stimulating both AMPA and NMDA receptors a little bit independently (at what would be otherwise sub-therapeutic levels), has been shown to have an additive/synergistic effect. Lifelike is apparently trying to patent this sub-threshold concept (sub-therapeutic doses in combination), as well as the fusion approach (combining elements of AMPA and NMDA upregulators into a single compound). However, Lifelike's approach brings into play a whole new set of potential side effects. Theoretically it's a cool idea, but in practice we'll have to see what happens.
The rapidly expanding amount of research activity involving AMPA upmodulation is a sign that Cortex is likely onto something really big, especially with the high impacts. Everyone was extremely skeptical 10 years ago, but now they're all jumping on the bandwagon.
Another Baudry paper, this one combining CX-546 and an ACHase inhibitor, and various other combinations. BTW, Cortex has a use patent covering AMPA upmodulators when used in combination with ACHase inhibitors. Baudry's company Lifelike Biomatic appears to be trying to circumvent some of Cortex's broad patents by various approaches - 1) by using sub-therapeutic doses of AMPA modulators combined with NMDA modulators ("Nemdakines") to achieve a synergistic effect, as well as 2) structurally fusing an AMPA upregulator moiety with an NMDA modulator moiety into a single molecule. Clever ideas, if they work -
>>> Program#/Poster#: 39.10/D22
Title: Positive modulators of AMPA but not NMDA receptors potentiate the effects of cholinesterase inhibitors on LTP
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Saturday, Oct 14, 2006, 2:00 PM - 3:00 PM
Authors: *M. M. CHOU, X. XIE, T. W. BERGER, M. BAUDRY;
Neuroscience Program, Univ So California, Los Angeles, CA.
LTP induction requires activation of both AMPA and NMDA receptors and positive modulators of both classes of receptors have been shown to facilitate LTP induction. Acetylcholinesterase inhibitors (AChEI) increase cell excitability and there is substantial evidence that they improve learning and memory although their effects on LTP induction have not been studied extensively. In the present study, we tested potential synergistic interactions between positive modulators of AMPA receptors or NMDA receptors and AChEIs on LTP induction in field CA1 of acute hippocampal slices from young male rats. The positive AMPA receptor modulators, CX-546 and piracetam, and the positive NMDA modulator, D-serine, were used at concentrations that were ineffective to facilitate LTP induction. Similarly, several AChEIs, rivastigmine, donepezil and galantamine, were used at concentrations that produced no or minimum effects on LTP induction. The combination of CX-546 or piracetam but not of D-serine with any of the AChEIs resulted in marked enhancement of LTP. This effect was completely blocked by atropine, a muscarinic receptor blocker. The analysis of the effects of the compounds alone and of the various combinations of modulators and AChEIs on short-term potentiation (STP), LTP and burst responses indicated that, despite the fact that the inhibitors act on the same target, they each produce a distinct pattern of effects. The marked synergy observed on LTP induction suggests that some of these combinations might provide new avenues for the treatment of patients with cognitive impairment. <<<
A Servier paper from SFN comparing S-18986 with an ACHase inhibitor. There may be a typo in this abstract though, since they have the lower dose as effective while the higher dose wasn't. Too much wine perhaps -
>>> Program#/Poster#: 273.20/LL30
Title: S 18986 and donepezil totally reversed the age-induced contextual memory deficits in C57BL/6 mice
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Sunday, Oct 15, 2006, 4:00 PM - 5:00 PM
Authors: D. BERACOCHEA1, J. PHILIPPIN1, K. BERNARD2, *P. MORAIN2;
1Université de Bordeaux-UFR biologie, CNRS UMR-5106 - Lab. de Neurosciences Cognitives, 33405 Talence, FRANCE, 2Neuropsychiatrie, Institut de Recherches Internationales Servier, 92415 Courbevoie Ced, FRANCE.
Our study purported to probe the effects of S 18986, a new positive allosteric modulator of AMPA-type receptors in a mouse model of contextual memory deficits induced by ageing. S 18986 was compared to donepezil, an cholinesterase inhibitor with beneficial memory effects in minor forms of Alzheimer’s disease.
Mice (14-15 month-old) underwent a behavioral task designed to study simultaneously the retrieval of stable (spatial) and flexible (contextual and serial) information (Celerier et al, 2004). The task involved the learning of two consecutive spatial discriminations in a four hole-board apparatus; these were performed on two different floors (white versus black) and the rewarded holes (one baited hole per discrimination) were diagonally opposite. Memory testing, performed on independent groups, occurred 24 hrs after the acquisition phase. During the test, mice were placed either on the floor of the 1rst or of the 2nd discrimination.
Mice underwent a chronic (9 days) per os administration of either donepezil (at 0.3 mg/kg) or S 18986 (at 0.1-0.3 and 1.0 mg/kg). They were compared to placebo-treated mice under similar conditions and to young (5 month old) mice. The two last administrations were given one hour before the acquisition (day 8) and test (day 9) phases. Placebo-treated mice exhibited a severe memory deficit in the remembering of the first discrimination as opposed to 5 month-old mice. The deficit in aged mice was evidenced by a significant fall of head-dips into the previously baited hole, and by an increase of interference. Both donepezil at 0.3 mg/kg and S 18986 at 0.1 mg/kg significantly reversed the memory impairments observed in 14 month-old mice; the other S 18986 doses had no effect. The memory-enhancing effects of both donepezil and S 18986 resulted from a lower rate of interference. Thus, S 18986 emerges as having effective beneficial impact on contextual memory processes among aged mice. <<<
A Boehringer Ingelheim SFN paper -
>>> Program#/Poster#: 267.2/GG19
Title: Effects of the positive allosteric AMPA receptor modulator BIIR 777: In vitro and in vivo studies
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Sunday, Oct 15, 2006, 2:00 PM - 3:00 PM
Authors: *T. WEISER1, K. WINTER2, K. KLINDER3, T. OSUGI4, A. CECI1;
1CNS Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, GERMANY, 2Quality Operations, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, GERMANY, 3Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, GERMANY, 4R&D Project Management, Boehringer Ingelheim US, Rigdefield, CT.
Positive modulation of AMPA-receptor mediated neurotransmission is a promising approach for the treatment of disorders affecting learning and memory. Here we describe the effects of BIIR 777, a novel and selective AMPA receptor modulator. In patch-clamp experiments using rat cortical neurons, or cells transfected with human GluR1/2, BIIR 777 significantly reduced desensitisation at concentrations >1 µM without affecting agonist potency. Investigating selectivity in >65 binding assays showed that the compound was highly selective. In anaesthetised rats, the excitatory local effect of AMPA on electrical activity of CA1 pyramidal hippocampal neurons was significantly increased in response to iontophoretic coadministration with BIIR 777. The systemic administration of BIIR 777 increased firing frequencies of pyramidal neurons in the CA1 region of the hippocampus, as well as in prefrontal cortex (CG3; at doses of 0.1 to 0.3 mg/kg i.v.). Pharmakokinetic investigations showed that BIIR 777 was orally available, penetrated the blood-brain barrier well, and had a plasma halflife of 8.5 h after oral administration. Thus, this compound was suitable for further in vivo models of learning and memory. In the passive avoidance test in rats, 30 mg/kg p.o. significantly reduced the proamnesic effect of alprazolam (0.45 mg/kg i.p.). In the rat object recognition test, BIIR 777 significantly augmented memory at 3, 10, and 30 mg/kg p.o.
These data show that BIIR 777 is a potent positive allosteric modulator of AMPA receptor function with promising properties in models of learning and memory in vivo. <<<
Speaking of Lilly, here's an SFN paper of theirs on Parkinson's, this time using a different compound, LY-450108 -
>>> 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. <<<
Here's one of two Baudry papers showing CX-614's potential for Parkinson's disease. This builds on the stellar Lilly research done several years ago using their biarylpropylsulfonamides in animal models of Parkinson's -
Program#/Poster#: 76.8/HH15
Title: Protection against neurotoxicity after treatment with positive modulators of AMPA receptors in a model for Parkinson’s disease
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Saturday, Oct 14, 2006, 4:00 PM - 5:00 PM
Authors: *L. HAMO1, T. OKA1,2, H. JOURDI1, M. BAUDRY1;
1Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, 2Biomedical Reserch Laboratories, Daiichi Asubio Pharma Co., Ltd., Osaka, JAPAN.
Parkinson’s disease (PD) is a neurodegenerative disease affecting dopaminergic neurons of the substantia nigra (SN). The etiology of PD is still unknown, but the discovery of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces symptoms similar to those found in PD patients, has provided significant advances in our understanding of the disease as well as a model to test possible therapeutic treatments. We used an in vitro model wherein a metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+), elicits a specific pattern of neurodegeneration in cultured mesencephalic slices. As brain-derived neurotrophic factor (BDNF) has previously been shown to protect against MPTP neurotoxicity, and since positive AMPA receptor modulators (ampakines) increase BDNF expression in vivo and in cultured slices, we treated cultured mesencephalic slices with the ampakine CX614 prior to MPP+ treatment. We found that treatment with CX614 48 h before MPP+ treatment resulted in a significant reduction in MPP+-induced neurotoxicity as well as in an increased expression of BDNF. This effect was blocked by K252a, a high-affinity Trk-family receptor inhibitor, as well as by TrkB Fc, a widely used high-affinity ligand for endogenously released BDNF. Immunohistochemical studies were also conducted to quantify the extent of protection of the tyrosine hydroxylase-positive dopaminergic neurons of the substantia nigra. These results as well as those of the accompanying poster (Oka et al., this meeting) strongly suggest that ampakines might represent a useful therapy for PD treatment. <<<
One more - Short acting Ampakine given BID for 4 days boosts BDNF and restores LTP in rats. This gives support to Dr. Lynch's "burst" dosing strategy using ultra short acting high impacts -
>>> Program#/Poster#: 423.22/C14
Title: In vivo administration of ampakine to middle-aged rats elevates BDNF and rescues LTP stabilization
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Monday, Oct 16, 2006, 2:00 PM - 3:00 PM
Authors: *C. S. REX1, J. C. LAUTERBORN2, E. A. KRAMAR3, G. A. ROGERS4, C. M. GALL5, G. LYNCH6;
1Dept Neurobiology & Behavior, Univ California Irvin, Irvine, CA, 2Dept Anatomy & Neurobiology, Univ California Irvin, Irvine, CA, 3Dept Psychiatry & Human Behavior, Univ California Irvin, Irvine, CA, 4'', Cortex Pharmaceuticals, Inc, Irvine, CA, 5Dept Anatomy & Neuorbiology, Univ California Irvine, Irvine, CA, 6Dept Psych & Hum Behav, Univ California Irvine, Irvine, CA.
Reductions in trophic support may contribute to deficits in synaptic plasticity and cognitive function that arise with age. Previous studies have shown that in the rat hippocampal CA1 basal dendritic field, deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested if increasing endogenous Brain Derived Neurotrophic Factor (BDNF) levels could reverse this age-related change. Middle-aged (8-10 mo) Sprague Dawley rats were administered a short-lived, positive AMPA-type glutamate receptor modulator (ampakine) systemically twice-daily for 4 days and were sacrificed for electrophysiological (hippocampal slice) and neurochemical (ELISA, Western blot) analyses 18 hrs after the last injection. Ampakine treatment significantly increased mature BDNF protein levels in hippocampus. This effect was accompanied by a restoration of LTP stabilization in the CA1 basal dendritic field. The rescue of enduring LTP was not due to acute effects of the drug (half-life <30 min) or to enhanced synaptic transmission (input-output curves and baseline fEPSPs did not differ between ampakine- and vehicle-treated rats). Bath administration of the extracellular BDNF scavenger TrkB-Fc to hippocampal slices completely eliminated the restoration of basal dendritic LTP in experimental rats but had no effect on LTP in this field in middle aged, vehicle-control animals. These results indicate that ampakine-induced increases in BDNF signaling offset age-related deficits in processes that stabilize LTP and suggest the possibility that intermittent, in vivo ampakine treatments might ameliorate deficits in synaptic plasticity and cognitive function with aging. <<<
Also from SFN, this study shows that when given several days prior to an ischemic insult, CX-614 ELIMINATED cell death from the ischemia. BDNF given directly also eliminated cell death -
>>> Program#/Poster#: 759.17/FF13
Title: Intermittent ampakine treatment sustains increased BDNF levels and provides neuroprotection from ischemia in vitro
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Wednesday, Oct 18, 2006, 8:00 AM - 9:00 AM
Authors: *E. A. PINEDA, J. C. LAUTERBORN, C. M. GALL;
Anat & Neurobiol, Univ California-Irvine, Irvine, CA.
Previous studies have shown that positive modulators of AMPA-class glutamate receptors (ampakines) increase neuronal Brain Derived Neurotrophic factor (BDNF) gene expression and protein content. BDNF is known to reduce neuronal vulnerability to ischemic insult. The aim of the present study was to test if ampakine-induced increases in endogenous BDNF expression reduce neuronal cell death with ischemic insult of cultured hippocampal slices. We have shown that spaced ampakine treatments (50 µM CX614, 3hr/day) can sustain increased BDNF protein levels in hippocampal slices as assessed with ELISA and western blots. Using the in vitro hippocampal slice model of ischemic insult described by Frantseva et al. (1999) we find that 45 min submersion in deoxygenated, glucose free aCSF results in significant CA1 cell death as assessed by FluoroJade labeling and Lactate Dehydrogenase activity assays 24 hrs after ischemia. This cell death is eliminated by pretreatment with ampakine CX614 (3 hrs/day for 2 days; last treatment 21 hrs before insult) or exogenous BDNF application. The neuroprotective effect of ampakine pretreatment was blocked by the tyrosine kinase inhibitor k252a or the BDNF scavenger TrkB-Fc applied during ampakine pretreatment and post-ischemic intervals. These results indicate that ampakine-induced increases in endogenous BDNF mediate protection from ischemic insult, and support the possibility of using ampakines as therapeutics to enhance endogenous neurotrophin expression and promote neuronal survival after ischemia. <<<
Speaking of modafinil, here's an SFN paper from Dr. Deadwyler showing the different areas of the brain affected by CX-717 vrs modafinil -
>>> Program#/Poster#: 573.5/LL83
Title: Evidence for the differential effects of modafinil and the ampakine CX717 on task-related brain glucose metabolism in sleep-deprived monkeys
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Tuesday, Oct 17, 2006, 8:00 AM - 9:00 AM
Authors: *S. A. DEADWYLER, L. J. PORRINO, J. B. DAUNAIS, M. MILLER, C. A. HANLON, A. R. MORGAN, K. E. GILL, J. LONG, S. RAMIREZ, M. TODD, R. E. HAMPSON;
Dept Physiol & Pharmacol, Wake Forest Univ Sch Med, Winston-Salem, NC.
The effects of modafinil were compared with the prior published results (Porrino et al. PLoS:Biology 3:e299 2005) showing that the ampakine CX717 (Cortex Pharmaceuticals, Inc.) reversed the detrimental influence of 30-36 hrs of sleep deprivation in monkeys performing a delayed-match-to-sample (DMS) task. Modafinil was tested at three different dose levels (5, 10 and 15 mg/kg) in alert monkeys (n =5), and then at 15 mg/kg in sleep deprived animals while performing the DMS task. PET scans of cerebral glucose metabolism were obtained with 18[F]-fluorodeoxyglucose injections during test sessions with the same monkeys. Sleep deprivation decreased DMS performance in monkeys by 17-24%; modafinil alleviated the deficit in these same conditions by 10-15% (F(1,64)=16.4, p<0.001) whereas CX717 reversed the deficit by improving DMS performance by 20-29%. As reported previously, PET scans in sleep-deprived animals performing the task showed a decrease in brain glucose utilization in dorsolateral prefrontal cortex (PFC), dorsal striatum (STR) and thalamus (THAL), and increased utilization in the medial temporal lobe (MTL; including hippocampus). Modafinil significantly reversed glucose utilization changes in PFC and THAL produced by sleep deprivation, but not in STR or MTL. These effects were different from CX717, which reversed sleep deprived changes in PFC and MTL but not THAL. This reversal of sleep deprivation changes in cerebral metabolism in PFC and THAL but not MTL by modafinil may account for the incomplete reversal of the behavioral deficits in comparison to CX717. However, reversal of decreased metabolism in THAL was specific to modafinil and did not occur with CX717 or other stimulants tested (amphetamine and caffeine). The findings indicate that there are different brain processes targeted by drugs that can reverse the effects of sleep deprivation. <<<
Here's some good backround info on modafinil/provigil. Its mode of action looks considerably more complex than that of low impact Ampakines like CX-717.
BTW, the online encyclopedia "Wikipedia" is pretty amazing, with tons of detailed info on everything from rock bands, to history, politics, pharmaceuticals, you name it -
http://en.wikipedia.org/wiki/Modafinil
Here's an SFN calpain related paper from Dr. Baudry. In this study, the high impact CX-614 was found to upregulate AMPA receptors in the first 4 hours, but then decrease the number of AMPA receptors at 8 hours. The downregulation process was mediated by calpain, and involved the degradation of AMPA receptor interacting proteins -
>>> Program#/Poster#: 232.12/D19
Title: Internalization of AMPA receptors (AMPArs) induced by positive modulators of AMPArs: Roles of calpain and calpastatin
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Sunday, Oct 15, 2006, 4:00 PM - 5:00 PM
Authors: *H. M. JOURDI1, N. IWATA2, T. C. SAIDO2, M. BAUDRY1;
1Neurosci Prog, Univ South California, Los Angeles, CA, 2Proteolytic Neurobiology, RIKEN-Brain Science Institute, Wako City, Saitama, JAPAN.
Prolonged exposure of cultured hippocampal slices to positive modulators of AMPArs (a.k.a. ampakines) causes a down-regulation of AMPArs, an effect mediated by calpain activation and the resulting degradation of SAP97 and GRIP1, two AMPAr-interacting PDZ proteins (Jourdi et al., 2005). In the present study, we used primary neuronal cultures to analyze the mechanisms involved in ampakine-mediated down-regulation of AMPArs. Brief treatment of dissociated neurons with the ampakine CX614 resulted in a biphasic effect on the levels of AMPArs; 4 hr after addition of CX614, levels of AMPA receptors subunits were increased, while after 8 hr, levels were decreased. This decrease was associated with calpain-mediated degradation of GRIP1 and SAP97, an effect similar to that previously observed in cultured hippocampal slices. As CX614-induced down-regulation of AMPAr protein levels might be preceded by internalization of surface-bound receptors, we analyzed the interaction of ampakines with signaling pathways known to be involved in AMPAr internalization, such as the NMDA receptor - protein kinase C pathway. To further assess the role of calpain in ampakine-mediated down-regulation of AMPA receptors and BDNF regulation, we performed similar experiments in cultured slices prepared from mice lacking or over-expressing the endogenous inhibitor of calpain, calpastatin. Our results indicate that prolonged activation of AMPA receptors results in calpain-mediated degradation of AMPA receptor-interacting proteins and internalization and down-regulation of AMPA receptors. These results provide important information regarding mechanisms of synaptic plasticity and of the roles of calpains in these processes. <<<
An SFN paper from Organon studying the high impact site. This site was identified several years ago, and is where high impacts AMPA upmodulators bind (CX-546, CX-614, cyclothiazide, Lilly's compounds, etc, and aniracetam also binds here). Dr. Rogers discussed related research at the annual SHM several years ago -
>>> Program#/Poster#: 231.5/D2
Title: Biostructural studies of the AMPA GluR1flip and GluR2flip receptor complexes
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Sunday, Oct 15, 2006, 1:00 PM - 2:00 PM
Authors: *J. A. MORROW1, B. KAZEMIER2, S. M. BASTEN2, J. K. MACLEAN3;
1Molecular Pharmacology, Organon Laboratories Limited, Newhouse, UNITED KINGDOM, 2Molecular Pharmacology, NV Organon, Oss, THE NETHERLANDS, 3Medicinal Chemistry, Organon Laboratories Limited, Newhouse, UNITED KINGDOM.
AMPA receptors are ligand-gated ion channels that mediate fast excitatory amino acid transmission in the CNS and participate in forms of synaptic plasticity underlying learning and memory. Drugs that positively modulate the AMPA receptor hold promise for the treatment of cognition related disorders such as Alzheimer’s disease and schizophrenia. The receptor is a heterotetrameric complex formed from subunits encoded by four genes GluR1-4 each of which exists in alternative splice variants termed flip and flop. The receptor subunit and splice variant composition confer unique functional and pharmacological properties on the receptor. Structural studies performed using the GluR2 flop subunit has identified a binding pocket for AMPA receptor positive modulators, thereby advancing our understanding of the biophysical effects elicited by different classes of modulators. We have performed biostructrural studies on the GluR2flip and GluR1flip subunits and compared this with the published GluR2flop structure. The GluR2flip and GluR2flop S1S2 ligand binding domain (LBD) constructs differ by only four amino acids. High resolution crystal structures demonstrate the GluR2 flip LBD structure is essentially identical to that of the published for GluR2flop. Furthermore, cyclothiazide binds GluR2 flip in a manner identical to that predicted by the GluR2flip N754S mutant. Co-crystallisation studies with the ampakine CX546 in the GluR2 flip construct reveal that a single molecule of CX546 occupies a binding site a the hinge region of the LBD ‘clamshell’ similar to that observed with aniracetam and CX614. The interactions between CX546 and the binding pocket are predominantly hydrophobic in nature. High resolution crystal structure studies with the GluR1flip reveal subtle differences in comparison to GluR2flip. While the allosteric modulator binding pockets are quite similar, any differences are propagated at changes in the agonist binding site with the ‘clamshell’ being slightly more closed in the GluR1-glutamate bound complex in comparison with the GluR2-glutamate complex. A greater understanding of the structural differences between AMPA receptor subunits should lead to rational structure base drug design of subtype selective AMPA receptor modulators with enormous clinical potential. <<<
Here's a SFN paper on "Stargazin" by Drs. Rogers and Varney. Others have published quite a bit on Stargazin over the past several years. Stargazin is a "TARP" or Transmembrane AMPA Receptor Regulatory Protein. These participate in the surface delivery and anchoring of AMPA receptors, and may also act as positive modulators of AMPA receptor ion channel function. It figures that Cortex would get interested in these -
>>> Program#/Poster#: 424.5/C22
Title: Effects of stargazin on allosteric, positive modulators of AMPA receptors (Ampakines)
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Monday, Oct 16, 2006, 1:00 PM - 2:00 PM
Authors: *Y. LI, L. NILSSON, M. A. VARNEY, G. ROGERS;
R & D, Cortex Pharmaceuticals, Inc, Irvine, CA.
Stargazin (STG) was characterized initially by homology as the second member (γ2) of the voltage-gated calcium channel γ subunit family. Recently, it has been reported that STG enhances the surface expression of AMPA receptors, controls receptor gating and slows channel desensitization as an auxiliary subunit of the receptors. Ampakines are a family of small molecules that increase the currents through AMPA receptors by binding to an allosteric site. The ligands do not have direct agonistic properties, but instead modulate the receptor rate constants for transmitter binding, channel opening, or desensitization. The effects of the Ampakine, CX614 and cyclothiazide (CTZ) were compared on homomeric GluR1-flip receptors expressed on HEK293 cells by transient transfection with or without STG gene. STG dramatically enhanced the surface expression of AMPA receptors. 500 μM Glutamate-induced steady-state currents were increased from 5.4 ± 1.2 pA/pF (n=4) to 125 ± 55 pA/pF (n=4) when STG was co-expressed, and the ratios of 500 μM kainate and 500 μM glutamate activated steady-state currents were increased from 0.58 ± 0.03 to 16.4 ± 6.5. STG speeded the association rates and slowed the dissociation rates for both CX614 and CTZ on desensitized receptors. The estimated Kd value for CX614 was lowered from 340 μM to 70 μM, whereas that for CTZ was lowered from 170 μM to 6 μM by STG. The data suggest that Stargazin can dramatically alter the conformation of the receptor dimer interface where CX614 and CTZ are known to bind.
Disclosures: Y. Li , None; L. Nilsson, None; M.A. Varney, None; G. Rogers, None. <<<
They don't have to cover in 10 days, that's just how long it would theoretically take for all the short positions to be covered based on the current average daily trading volume.
The top-line DARPA findings were presented at the 2006 Sleep meeting several months ago (press release below). There were some positive effects seen on sleep architecture (see below). As of June however, Cortex hadn't received the full data set from DARPA, only a study report -
>>> News
Top-line findings on CX717 from the DARPA-sponsored shift work simulation study will be presented at sleep 2006 meeting
— additional CX717 data from the UK sleep deprivation study to be presented at the same meeting —
IRVINE, Calif., June 21, 2006 - Cortex Pharmaceuticals, Inc. (AMEX: COR), announced that results from two studies with its lead Ampakine® drug, CX717, will be presented at the Sleep 2006 meeting in Salt Lake City, UT. Dr. Thomas Balkin, Chief, Department of Behavioral Biology, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, will briefly present the top-line findings from the simulated night shift work study conducted at WRAIR and funded by the Defense Advanced Research Projects Agency (DARPA). That study assessed the effect of CX717 on cognitive performance and alertness across 4 nights of simulated night shift work and restricted daytime sleep. The primary finding from the study was that CX717 did not enhance cognitive performance relative to treatment with placebo. However, similar to the observations in the previously reported UK sleep deprivation study, CX717 did alter the recovery sleep architecture as measured by EEG polysomnography in a dose-related manner. The 1000 mg dose of CX717 statistically (p < 0.05) reduced the amount of slow wave sleep during each of the 4 recovery sleep periods and increased (p < 0.05) the minutes of wake time after sleep onset during 2 of the 4 recovery sleep periods. CX717 was well tolerated, and no serious adverse events or other significant safety concerns were observed.
Additionally, two presentations will be made detailing the positive findings from the UK sleep deprivation study performed at the University of Surrey in the United Kingdom. Dr. Julia Boyle, Acting Head, Human Psychopharmacology Research Unit, University of Surrey, Guildford, UK will present the primary results from the study. Dr. Nicola Wright, Centre for Human Sciences, QinetiQ, Farnborough, UK will present new data using spectral EEG polysomnography to evaluate the effect of CX717 on the recovery sleep period during the study. In support of the key study findings, the spectral EEG analysis indicated that CX717 increased the level of arousal during recovery sleep.
Differences in study design and the implementation of certain study procedures may have contributed to some of the divergent results between the shift work simulation study and the UK study. While Cortex has received a study report from WRAIR, we look forward to receiving the full data set in order to compare the exact differences in drug performance between the two sleep studies.
From a business perspective, the Company’s licensing discussions have focused on ADHD, Alzheimer’s disease, and other neurodegenerative disorders. The top-line findings from the DARPA-sponsored study do not have a direct impact on the potential of CX717 in those disorders. Cortex’s strategy has always been to retain the sleep deprivation uses as well as Orphan Drug uses of the low impact AMPAKINE® drugs for its internal development program. Cortex does not anticipate that future partnering discussions would include sleep disorder indications such discussions are unlikely to be affected by the shift work study findings.
“Our Phase II pilot program which included studies in sleep deprivation, ADHD, and Alzheimer’s disease was designed to help us determine the most promising development pathway for CX717,” said Dr. Roger Stoll, Chairman & CEO of Cortex. “While we are pleased to see some of the findings from the UK study confirmed in the DARPA-sponsored study, given the strong signal from our study in adults with ADHD our current plan is to prioritize ADHD in our future studies with CX717. We also remain committed to the program in Alzheimer’s disease as we await the results from our Phase II study in that disorder. Moreover, we anticipate having the opportunity to conduct additional studies on sleep disorders with either CX717 or with CX701, a back-up compound that should enter clinical trials early next year.”
Cortex will host a conference call and webcast later today, at 2:00 p.m. ET, to further elaborate on this information. Following the conference call, the company will open the phone lines to answer questions from investors and members of the media. Those who wish to participate may do so using the following dial-in information: In the United States, call (877) 407-0782. Internationally, call (201) 689-8567. An audio replay of the conference call will be available through Wednesday, June 28, 2006 by dialing (877) 660-6853 for U.S. participants and (201) 612-7415 for international participants. When prompted, participants should enter account number 286 and conference ID number 206297. For the webcast please use the following link: http://www.vcall.com/IC/CEPage.asp?ID=106039. A replay of the webcast will be available through June 28, 2006.
About the shift work simulation study
The shift work study was a randomized, double-blind, placebo-controlled, parallel group study in healthy young adult male volunteers. Fifty (50) subjects were assigned to one of three CX717 dose groups or placebo. Study medication was taken once per evening for four days. Each night subjects were assessed on a variety of cognitive parameters and tests of alertness in a protocol designed to simulate night shift work. The subjects’ daytime sleep was restricted to 4 hours per day to mimic operational conditions involving chronic, restricted sleep.
About Cortex Pharmaceuticals
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. (http://www.cortexpharm.com/)
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 additional tests and activities may further delay clinical studies. As discussed in the Company’s Securities and Exchange Commission filings, the Company’s proposed products will require additional research, lengthy and costly clinical testing and regulatory approval. Ampakine compounds are investigational drugs and have not been approved for the treatment of any disease.
Contacts:
Roger G. Stoll, Ph.D.
Chairman, President and CEO
Cortex Pharmaceuticals, Inc.
(949) 727-3157
Damian McIntosh/Dian Griesel, Ph.D.
Media Contact: Janet Vasquez
The Investor Relations Group
(212) 825-3210 <<<
Looking at the last 2 PIPES, they were priced at $2.66 and $2.75, with 5 year warrants at $3.00 and $3.25. So with the stock currently at $2.85, if a PIPE were to occur right now it would probably also be priced around that level. Not exactly what I was hoping to see, but we'll see what happens. I've been figuring a PIPE would happen closer to year end or early '07. It's a shame that we don't have a shelf registration set up, where one can quickly issue shares at the optimum moments.
Aiming, Well, it looks like you'll be getting that buying opportunity in the 2s. The question now is how much info will Dr. Stoll be able to give us in the conf call. This excuse of not wanting to give the competition useful info seems lame to me, though the probable real reason (not wanting to irritate the FDA) has merit. Still, I don't see what harm a brief overview of the dosing restrictions would do. Not giving any details at all will only encourage more selling, and at a time when we need to raise money. It's frustrating to have such a promising technology, but a chronic lack of funds to develop it.
Moosedogger, While low BDNF doesn't cause AD, it's associated with it and many other neurodegenerative conditions. Elevating neurotrophin levels would almost certainly help AD patients, even if it doesn't actually halt or reverse its progression. Compared to what's available now (essentially zilch) that would be a huge step forward.
Here's a related article on BDNF/AD. Also, look on PubMed for tons of info on BDNF and its actions -
http://www.alzforum.org/res/for/journal/cotman/default.asp
When you think about it, Lilly is still the most obvious choice as a BP partner. Not only have they done a lot of work with AMPA upmodulation for many years, their biarylpropylsulfonamide family of compounds is likely still experiencing excitotoxicity related troubles. In Dr. Rogers' SHM presentation several years ago, he made it sound like Lilly's compound family was doomed to having very high seizure risk, due to its extremely strong action at the receptor binding site. So Lilly could probably use an alternate approach chemistry-wise.
Lilly also has a strong interest in ADHD with Strattera. And of course Lilly (along with Glaxo) has been trying to overturn Cortex/UCI's broad use patent in Europe for years, so far unsuccessfully. When the final BP bids are tallied, it would be hard to imagine Lilly not being involved, although to date they have apparently remained stubbornly aloof.
Daviddal, I like it. And retaining the N.Amer neurodegenerative rights would give Cortex another big payday down the road. Keeping co-use of CX-701 for Sleep Related would also be great. And perhaps Shire and another company interested in ADHD could get into a bidding war for CX-717, leading to better than expected upfronts.
Neuro is probably busy at the SFN, but concerning the non-Ampakine in-licensing strategy, I wonder if there might conceivably be a situation out there where a company has a drug that's already approved and marketed for a larger indication, but which might also have potential activity for an orphan indication. The orphan indication is too small for the pharma company to bother with, but perfect for a small outfit like Cortex. Cortex then in-licenses the drug, and runs the small orphan trials. If the drug is already approved for a larger indication, that would eliminate much of the risk from Cortex's perspective. Just wondering if this might be a possibility, as opposed to a brand new drug entity, with all the risk that entails.