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BTW, I see that Questcor is one of the participating companies at that Montreal conference. Several of the top management at Cortex have been associated with Questcor, including Dr. Stoll, though I'm not sure what his relationship is with them now (was on their Board of Directors as I recall).
Here's a link to the Montreal Conference where Cortex will be presenting next week (4:30 Tuesday). The press release mentioned some animal data on the high impacts for Huntington's and Frag-X, and an update on the non-Ampakine in-license strategy. It would only seem prudent for Cortex to wait until the fate of CX-717 is known (Spring) before committing to an in-licensing deal. Cortex is going to have to be very tight with their money for a while, unless they want a repeat of a $1.50 type financing -
http://www.bmocm.com/conferences/healthcare2006/participating/default.aspx
OT - Pfizer's woes continue - their cholesterol drug has been halted. I must admit I've always considered the cholesterol drug area as a $25 bil/yr sham. But from a business standpoint, Pfizer has lost a lot of their pipeline recently - Indiplon (NBIX), Asenapine (Organon), and now Torcetrapib -
>>> Pfizer under pressure after halting drug
By THERESA AGOVINO
Pfizer Inc. will likely slash staff and accelerate merger and licensing deals as the pressure on it to improve its financial performance intensified after the weekend's announcement that the company ended development of a key drug, analysts said.
Analysts differed on how much they believed Pfizer stock would fall when it opened on Monday. Barbara Ryan, an analyst at Deutsche Bank, said she believed the dividend yield of roughly 4 percent would keep shares from a free fall, but another analyst estimated the stock could plunge to $20 a share. Pfizer shares closed Friday at $27.86 on the New York Stock Exchange.
The world's largest drugmaker said Saturday that an independent board monitoring a study for cholesterol treatment torcetrapib recommended that the work end because of an unexpected number of deaths.
The news is devastating to Pfizer, which had been counting on the drug to revitalize stagnant sales that have been hurt by numerous patent expirations on key products. It has said it was spending around $800 million to develop torcetrapib, which was supposed to fill the void when its best-selling drug, cholesterol treatment Lipitor, loses patent protection in either 2010 or 2011. Lipitor sales totaled $12.2 billion last year.
"This is obviously unfortunate because this was the biggest opportunity in their pipeline," said Ryan. "Clearly there is more pressure on them to do cost cutting."
Two months ago, Pfizer said it would detail plans in January to turn the company into a more nimble organization that would go beyond the program announced last year to cut $4 billion in expenses by 2008. Patent expirations will cost the company $14 billion annually between 2005 and 2007.
In the statement Pfizer issued Saturday, CEO Jeff Kindler said the company's pace of transformation will be expedited because of the loss of torcetrapib although he didn't give any specifics. Last week, Pfizer announced it was cutting 20 percent, or 2,200 jobs, of its U.S. sales force.
Ryan said Pfizer may lay off as many 10,000 people in near future. Pfizer employs roughly 100,000 people. Ryan added that she expects Pfizer to hike its annual dividend from 96 cents to $1.10 per share in the next few weeks in the hopes of putting a floor on the stock.
But Jason Napodano, an analyst at Zacks Independent Research, doesn't think the yield will be enough to prop up the shares. He points out that at the end of last month, Pfizer pulled out of its deal with drugmaker Organon to develop schizophrenia treatment asenapine. Napodano said he expected that drug to add $500 million in sales by 2010 while by that time torcetrapib's sales would total $3 billion.
"Losing asenapine was a hole in the boat. Now they have hit an iceberg," said Napodano.
Pfizer reiterated it hopes to introduce six new products to the market by 2010, but Napodano said its pipeline just doesn't have another drug which offers the sales potential of torcetrapib.
Ryan and Napodano both expect Pfizer to act swiftly to bring new products into the fold, either through acquisition or licensing. But Napodano said that until investors see what those products are, he sees little reason to buy the stock. He said he intends to review his "hold" rating on the stock.
Torcetrapib was designed to raise levels of HDL, or what's commonly known as good cholesterol. Pfizer has two other products in early development to raise HDL, using the same method as torcetrapib. It is too soon say where they will be affected by the compound's demise because it still unclear what caused the patient deaths in the trial.
Torcetrapib had been shown to raise blood pressure in some patients but the other two compounds haven't displayed such a side effect, according to Pfizer.
Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, said it is too soon to say whether the entire class of drugs known as CETP inhibitors is dangerous or if there was something specific to torcetrapib that caused the deaths. He said that Roche Holding AG is developing drugs of the same type, and there's speculation that Merck & Co. is too. Merck declined to say if it had such a drug in its pipeline.
Roche spokesman Darien Wilson said that in clinical trials its compound has not shown a risk of elevated blood pressure and that it was slated for introduction in 2009.
CETP inhibitors work by blocking an enzyme that transforms good cholesterol into bad cholesterol, according to Nissen. Lipitor lowers bad cholesterol and initially Pfizer was planning to sell torcetrapib in combination with Lipitor.
Nissen was conducting a trial for Pfizer which was going to use images of patients' arteries to see if torcetrapib helped reduce plaque, fatty deposits that can build up and reduce blood flow. Just three days ago, Pfizer said it was hoping to use the results of that trial to seek approval for torcetrapib in the second half of next year.
Nissen said he will still examine the results of the study, and that if the trial showed that the drug actually increased plaque, it would indicate that there is something wrong with the way the class of drugs works.
Nissen, who has been an outspoken critic of the pharmaceutical industry, said he doesn't believe Pfizer will face any liability issues over the trial because it acted swiftly to tell the public and researchers about the problem. The results were unexpected because the review board examined the trial data in October and didn't see an increase risk of death, Pfizer said.
"I have to give Pfizer credit. They did everything the right way," Nissen said.
Analysts said that patients sign waivers, acknowledging that they are willingly participating in an experiment, which protect companies from most lawsuits. However, Fordham University School of Law professor Benjamin Zipursky said that warning patients of risks doesn't necessarily mean they can't sue later, especially if information about the trial wasn't adequately detailed or the company downplayed or hid any potential negative data about the drug.
In a statement issued Sunday, the U.S. Food and Drug Administration said it supported Pfizer's decision to suspend the trial and that it will work with the company and other drugmakers developing similar products to ensure there are procedures in place to identify any safety problems quickly.
According to Pfizer spokesman Paul Fitzhenry, 82 patients taking the combination of torcetrapib died, compared to 51 deaths in the arm of the study where patients were taking Lipitor alone. Each arm of the study had 7,500 patients. Pfizer said that the study didn't raise any questions about Lipitor's safety. <<<
I'll paste it -
>>> United States Patent Application 20040171605
Kind Code A1
Grove, Simon James Anthony ; et al. September 2, 2004
Benzoxazepines derivatives and their use as ampa receptor stimulators
Abstract
The present invention relates to benzoxazepine derivative having the general formula I, wherein X represents CO or SO.sub.2; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from H, (C.sub.1-4)alkyl, (C.sub.1-4)alkyloxy, (C.sub.1-4)alkyloxy(C.sub.1-4)alkyl, halogen, nitro, cyano, NR.sup.8R.sup.9, NR.sup.8COR.sup.10, and CONR.sup.8R.sup.9, R.sup.5, R.sup.6 and R.sup.7 are independently H or (C.sub.1-4)alkyl; R.sup.8 and R.sup.9 are independently H or (C.sub.1-4)alkyl; or R.sup.8 and R.sup.9 form together with the nitrogen atom to which they are bound a 5- or 6-membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O, S or NR.sup.11; R.sup.10 is (C.sub.1-4)alkyl; R.sup.11 is (C.sub.1-4)alkyl; A represents the residue of a 4-7 membered saturated heterocyclic ring, optionally containing an oxygen atom, the ring being optionally substituted with 1-3 substituents selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkyloxy, hydroxy, halogen and oxo; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said derivatives, and to the use of these benzoxazepine derivatives in the treatment of neurological diseases and psychiatric disorders which are responsive to enhancement of synaptic responses mediated by AMPA receptors in the central nervous system. 1
--------------------------------------------------------------------------------
Inventors: Grove, Simon James Anthony; (Newhouse Lanarkshire, GB) ; Zhang, Mingqiang; (Montreal, CA)
Correspondence Name and Address: AKZO NOBEL PHARMA PATENT DEPARTMENT
29160 INTERVET LANE
MILLSBORO
DE
19966
US
Serial No.: 480623
Series Code: 10
Filed: December 11, 2003
PCT Filed: June 5, 2002
PCT NO: PCT/EP02/06185
U.S. Current Class: 514/211.04; 514/211.12; 540/488; 540/548
U.S. Class at Publication: 514/211.04; 514/211.12; 540/488; 540/548
Intern'l Class: A61K 031/554; A61K 031/553; C07D 498/04
--------------------------------------------------------------------------------
Foreign Application Data
--------------------------------------------------------------------------------
Date Code Application Number
Jun 11, 2001 EP 01202215.8
--------------------------------------------------------------------------------
Claims
--------------------------------------------------------------------------------
1. A benzoxazepine derivative having the general formula I 19wherein X represents CO or SO.sub.2; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from H, (C.sub.1-4)alkyl, (C.sub.1-4)alkyloxy, (C.sub.1-4)alkyloxy(C.sub.1-4)alkyl, CF.sub.3, halogen, nitro, cyano, NR.sup.8R.sup.9, NR.sup.8COR.sup.10, and CONR.sup.8R.sup.9; R.sup.5, R.sup.6 and R.sup.7 are independently H or (C.sub.1-4)alkyl; R.sup.8 and R.sup.9 are independently H or (C.sub.1-4)alkyl; or R.sup.8 and R.sup.9 form together with the nitrogen atom to which they are bound a 5- or 6-membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O, S or NR.sup.11; R.sup.10 is (C.sub.1-4)alkyl; R.sup.11 is (C.sub.1-4)alkyl A represents the residue of a 4-7 membered saturated heterocyclic ring, optionally containing an oxygen atom, the ring being optionally substituted with 1-3 substituents selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkyloxy, hydroxy, halogen and oxo; or a pharmaceutically acceptable salt thereof; with the proviso that the compounds of formula I wherein X is CO; each of R.sup.1-R.sup.7 is H, and A represents (CH.sub.2).sub.3 or (CH.sub.2).sub.4; the compound of formula I wherein X is CO; R.sup.1 is H; R.sup.2is methyl; each of R.sup.3-R.sup.7 is H; and A represents (CH.sub.2).sub.3; the compound of formula I wherein X is CO; R.sup.1 and R.sup.2 are H; R.sup.3 is methyl; each of R.sup.4-R.sup.7 is H; and A represents (CH.sub.2).sub.3; the compound of formula I wherein X is CO; each of R.sup.1-R.sup.3 is H; R.sup.4 is methyl; each of R.sup.5-R.sup.7 is H; and A represents (CH.sub.2).sub.3; and the compound of formula I wherein X is CO; each of R.sup.1-R.sup.4 is H; R.sup.5 is methyl; R.sup.6 and R.sup.7 are H; and A represents (CH.sub.2).sub.3; are excluded. <<<
Here's an Akzo/Organon composition of matter patent from several years ago for Benzoxazepines as AMPA upmodulators (not to be confused with Benzoxazines like CX-614). This was around the time we first heard about Org-26576, so it's not inconceivable that this new compound could be of their own design -
http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsea....
Daviddal, I had 2 double cheeseburgers from McDonalds today, back to back, so I'll be right behind you in line for that bypass :o) Actually, the post-Chemo and post-CABG indications could be big potential areas for Ampakines some day.
The way things are going however, I wonder if there will be any Ampakine on the market before the use patents expire. Things are really going in slow motion lately (or in reverse motion). My investing style has become a lot more conservative, but even if I had a large enough portfolio to allow for some individual bio stocks, I would now consider Cortex far too risky for anything other than a token position. That's a far cry from several years ago when I used to periodically load up on tens of thousands of shares.
OT - Aiming, Here's a little more on Durect. In addition to their partnership with PTIE/King for Remoxy and other abuse resistant opioids (Remoxy in Phase 3, and 2nd one in Phase 1), their lead in-house program is for a longer lasting version of Bupivacaine, the commonly used surgical anesthetic. Durect's technology allows the anesthetic effect at the surgical site to last for 2-3 days, which greatly reduces the need for post-surgical opioid pain meds and their associated side effects, as well as greatly reducing the need for post operative attention from the surgeon and hospital staff. Surgeons on call are going to love this product since they'll get a lot fewer late night calls due to post-op pain. Not having to use post-op opioid pain meds is another big plus, since these have side effects of their own like respiratory depression (which increases the risks of the patient contracting pneumonia), plus the opioid's actions also make it considerably more difficult to detect various surgical complications early, before they become serious. There's a good chance that Durect's long acting Bupivicaine ("Posidur") could become the standard anesthetic for many surgical procedures (company market analysis estimates 30 mil procedures/year). Durect also has several other proprietary drug delivery systems. Either Remoxy or Posidur alone could make the company a great investment, and both programs look like big winners (IMO) -
>>> Durect's Pain-Free Deal
http://www.fool.com/news/mft/2006/mft06113022.htm
By Brian Lawler
11/30/2006
Sometimes it takes a big partnership deal for investors to get excited over a pharmaceutical company. A deal signed yesterday by drug developer Durect(Nasdaq: DRRX) appears to have done the trick for the small specialty pharma, since shares rose more than 25% today.
The deal Durect inked yesterday with European pharma Nycomed involves its Posidur local anesthesia injection. The drug is in multiple phase 2 trials as a treatment for post-operative pain and is slated to enter phase 3 trials in 2007. If it can achieve regulatory approval, Posidur's biggest potential benefit over other local anesthetics already on the market is its longer-lasting effect.
This deal with Nycomed provides for up to $188 million in payments to Durect if Posidur can hit certain development, regulatory, and sales milestones. Durect will also receive $14 million up front, which should equate to about another half-year's worth of cash (at its current burn rate) to supplement the $74 million already sitting on its balance sheet.
By keeping the upfront payment low and back-loading most of the cash payments, Nycomed hedges its losses in case Posidur doesn't pan out. Regardless, Durect will receive quite a high royalty rate, in the 15%-40% range, depending on the sales level Posidur achieves. Also, Durect gets to keep U.S. and Asian marketing rights for the drug.
The potential for Durect's science and technology has been validated before, when King Pharmaceuticals(NYSE: KG) signed a $400 million collaboration and marketing agreement with Pain Therapeutics(Nasdaq: PTIE), which had licensed Durect's technology for abuse-resistant pain drugs and from which Durect will receive royalties if approved.
With no possible additional drug candidate approvals and subsequent royalties or revenues anywhere close to occurring, farming out Posidur makes great business sense for Durect and will limit any share dilution from financings that may need to be done in the future. It's trading at a market capitalization of more than $330 million as of this writing, though, meaning that shares are a little richly valued for my blood, considering the length of time it will take for meaningful royalties and subsequent earnings to start coming to Durect. <<<
Dew, Thanks for the article. I had heard of the "chemobrain" phenomenon, but was not aware that chemo agents could be so extremely toxic to brain cells. An Ampakine might reduce the cognitive impairments associated with the chemo, representing a gigantic new indication for Ampakines (if we can manage to get a compound past Phase 2..)
So far -
Biarylpropylsulfonamides - bombed out in Phase 2 (LY-451395)
Benzothiadiazines - bombed out in Phase 2 (S-18986)
Benzamides - 1) CX-516 - too weak
2) Org-24448 - still going in multi Phase 2,
3) CX-717 - ?
Neuro, So Servier halted the MCI Phase 2? Did you hear what the toxicity issues were, seizure related or nausea/headache type? I guess I'm not that surprised, but it's still sad to see another AMPA upmodulator bomb out in Phase 2 (to go along with Lilly's LY-451395). Thanks for the info.
BTW, my idea that Organon might not be happy with Org-24448 and thus be bringing up Org-26576 as a replacement was meant to be just one of numerous possible reasons. My point was that since we don't know what the true reason is, we shouldn't assume that the reason is necessarily benign.
Concerning the FDA extending their investigation to Org-24448, if that happens it shouldn't be a surprise to anyone. It's an obvious risk we have going forward, and I'm figuring it as a likely event. If Org-24448 is clean and everyone knows it, that would help remove a lot of the uncertainty we're currently under.
Bladerunner, One could just as easily ask why Organon would put a different AMPA upmodulator into the clinic if they're so happy with Org-24448? So the logic can go both ways. BTW, I don't think it's been firmly established yet that Org-26576 is definitely a Cortex developed compound. It probably is, but Organon does have some AMPA upmodulators of their own. As we saw, Servier decided to go ahead with their own non-Cortex compound, so it's possible that Organon might have also. Also, it's not impossible that the cellular problem is only a class wide phenomenon within Cortex's benzamide family.
All I'm saying is that based on the numerous landmines we've hit over the past year, we should be careful with our assumptions, particularly the rosy type. The only thing we know for sure is that Murphy's Law is still alive and well.
One thing that worries me is that if they're doing their job right, the FDA SHOULD want to see additional tox data on Org-24448. That would only be logical and prudent, since Org-24448 is the sister compound of CX-717. In a presentation a while back, Dr. Stoll explained how Org-24448 was tweaked structurally to create CX-717, to improve upon some of the less favorable metabolic issues seen with Org-24448. If the FDA is being as cautious as they appear to be, there's a reasonable chance that they'll want to see additional data on Org-24448. That possibility is something we need to consider in our risk analysis of this stock.
Neuro, You said "Organon believes", but have you spoken to Organon personally?
OT - Aiming, Here's the latest news on that company who supply the abuse-resistant technology for PTIE's Remoxy. Durect has an interesting pipeline -
>>> Durect shares rocket on pain pact
By Carolyn Pritchard, MarketWatch
Last Update: 6:26 PM ET Nov 29, 2006
SAN FRANCISCO (MarketWatch) -- Durect Corp. shares rocketed 50% higher in late trade Wednesday after the specialty pharmaceutical company signed an agreement to develop a post-operative pain treatment that could be worth as much as $202 million. Shares of the Cupertino, Calif.-based Durect (DRRX ) added $1.90 in after-hours dealings to change hands for $5.70. Durect and privately held Nycomed of Demark have agreed to jointly develop Posidur, a long-acting local anesthetic being developed to treat post-surgical pain that uses Durect's Saber delivery system, an injectable, biodegradable drug delivery technology. Under terms of the agreement, Nycomed will pay Durect an upfront license fee of $14 million, with additional milestone payments of up to $188 million upon achievement of certain development, regulatory and sales milestones. The two will jointly and equally fund Posidur's development; Durect will have commercialization rights in the U.S., Canada, Asia and other countries while Nycomed's rights will cover the European Union and a selection of other countries. Durect will manufacture and supply Posidur to Nycomed for sales outside the U.S. and Nycomed will pay Durect blended royalties ranging on such sales ranging from 15% to 40%. Posidur is currently in Phase II clinical development; it's expected to enter Phase III in 2007. <<<
Neuro, Before we assume that Org-24448 is definitely in the clear, I'd like to hear Dr. Stoll discuss more specifically what new tests Organon has done on Org-24448 and what the results were. One of the biggest risks for Cortex at the moment is the possibility that this could be a class-wide problem. The way things have been going lately, making premature rosy assumptions may not be such a great idea.
Neuro, Aren't you assuming that Organon knows specifically what to look for histologically, and in what organ/location? But has Cortex told Organon exactly where to look to find the histo changes, I wonder? And if Organon did find something suspicious in new tox studies, why would they reveal it, since doing so would bring FDA scrutiny?
Dew, Four if you count Teva, which I assume you'll own again at some point (Elbit, GTCB, Idenix, Teva).
In the infectious disease area, I figure Vertex is expensive but a potential homerun stock worthy of a buy and hold position (I owned it back in the teens/20s). GTCB I picked for the long run once they got the European approval, but their over-reliance on the risky sepsis program would seem to make the near/mid term particularly dicey. Abgenix was a previous favorite on my list, but when their P-mab results came out they got bought out by Amgen.
In the non-bio areas, Elbit looks like a very intriguing company. Garmin I added since my dad is a pilot, and he likes their avionics equipment.
Collegeguy, I'm guessing in the $8-12 mil range will be raised in the first shelf offering. Combined with the approx $8-10 mil Cortex will already have at year end, that gives a total of $16-22 mil in cash, which should be enough to get Cortex to some type of pharma deal for CX-717/N.Amer. Neurodegenerative, hopefully by mid-'07.
The non-Ampakine in-license idea is another variable, but one would think that that won't happen until the fate of CX-717 is known.
OT - Since it's a slow day, here's the diversified portfolio I've come up with for a middle aged investor like myself who is disillusioned with stock picking. Yes it's boring, but here goes -
50% - Fixed Income (CDs, bonds)
30% - Total US Stock Market Index
10% - Total Intl Stock Index (Europe/Asia/Emerging)
5.0 % - Real Estate Investment Trust Fund/Index
2.5% - Natural Resources / Commodities
2.5% - Gold Related
To have something to follow, I've added a virtual/imaginary portfolio of bio stocks, including - Biomarin, Celgene, Cortex, Cubist, Durect, Exelixis, Genzyme, Gilead, GTCB, Idenix, Medarex, MGI Pharma, PDLI, Pain Therapeutics, Senomyx, Teva, and Vertex. In Pharma, the generic sector in general looks interesting. To add some non-bio names to follow, I have Aqua America, Elbit, Garmin, Stericycle, and PHO (water ETF).
FWIW, while the above boring portfolio won't double by next week, I figure I'll do better than going down the same old road to bankruptcy known as bio stock investing..
MarketFest, Yes, this action can really wear down an investor. I remember the post-Shire sub dollar days though, and that was worse. Cortex was still slogging along with CX-516, and the company's continued existence was in doubt - cash levels had dropped to around half a million. So I guess it's all relative.
There's still a decent chance that CX-717 can ultimately be partnered for AD/Neurodegenerative, so the stock's decline at this point looks overdone. There may still be some tax selling to go in December, but if we get closer to a buck, it'll be very tough not to pick up at least a few shares.
The previous financings went through at $1.50 (2003), $2.75 (2004), and $2.66 (2004), so unfortunately this upcoming one could set a new low. I must admit I never expected to see the stock this low again, but such is life in bioland I guess. If there's one thing I've learned in bio investing over the years (the hard way) it's that diversification is not only desirable, it's essential. Dollar cost averaging isn't a bad idea either.
Daviddal, Organon should ideally want to now focus more on the rest of their pipeline. But when something like this happens, companies often do the exact opposite - they put all their available resources into saving their one big program (Asenapine), since they have so much riding on it. Then the rest of their pipeline suffers from lack of funds. CTIC comes to mind - they would have been better off just dumping Xyotax altogether when it ran into trouble, and concentrating on Pixantrone. Instead they continue to whip a dead horse at the expense of the rest of the pipeline.
Having to count on Organon to bail Cortex out of its current mess is not good, but then again we may not have that many other options.
Jerrydylan, Neuro could best address the SSRI patent question, but as for how the AMPA upmodulation IP came to rest in Cortex's hands, I think it was largely because no one else believed AMPA upmodulation could work without creating horrendous excitotoxicity/seizures. By the time other companies finally got interested, Cortex had already locked up all the key use patents. It's unusual for one company to have such a strong IP hold on a new pharma platform.
Ironically, the last time Cortex got into a real funk (the post-Shire debacle / sub-dollar period), it was positive news on the patent challenge front that helped save the day (along with hiring Dr. Stoll and getting some financing).
Since it's a slow day, here's a link to the Lifelike Biomatic website (Dr. Baudry's company). They're attempting to patent the combo use of subtherapeutic doses of AMPA upmodulators (Ampakines) when combined with NMDA upmodulators (Nemdakines). When used in combination, there is apparently a synergistic effect, so the doses can presumably be below the usual therapeutic dose required (I assume they think this is a way around the Cortex/UCI patent). They're also seeking to patent single molecules which combine these two types of compounds, or their active segments. In the past, Dr. Baudry and Dr. Lynch have been listed as co-authors of various papers, but we heard a while back some rumors that they had a falling out -
http://www.lifelikebiomatic.com/careers.htm
Ampakine effects on respiration - this was posted before, but it's one of the more unusual Ampakine related studies I've seen. I had no idea that Ampakines might have an effect on respiration -
>>> Ampakines Alleviate Respiratory Depression in Rats.Ren J, Poon BY, Tang Y, Funk GD, Greer JJ.
Department of Physiology, Division of Neuroscience, University of Alberta, Edmonton, Alberta, Canada.
Rationale: There is a need for improved therapeutic interventions to treat both drug- and sleep-induced respiratory depression. Increased understanding of the neurochemical control of respiration will help identify a basis for advances. Activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors positively modulates respiratory drive and rhythmogenesis in several brain regions including the preBotzinger complex. Ampakines are a diverse group of small molecules that activate subsets of these receptors. Objective: We determined whether the ampakine CX546 would enhance respiratory drive and rhythmogenesis across various stages of development and whether this ampakine could counter opioid- and barbiturate-induced respiratory depression. Methods: Respiratory frequency and amplitude were measured using the following rat models; i) perinatal in vitro brainstem-spinal cord, ii) neonatal in vitro medullary slice, iii) juvenile in situ perfused, working heart-brainstem preparation and, iv) newborn and adult in vivo. Results: The administration of CX546 stimulated baseline respiratory frequency in perinatal in vitro preparations but not older animals (>postnatal day 0). Further, pharmacological depression of respiratory frequency and amplitude was countered at all ages studied by the administration of CX546 in vitro, in situ and in vivo. Significantly, CX546 countered opioid-induced breathing depression in all preparations, without altering suppressing analgesia as assessed by measuring the time to foot withdrawal in response to a thermal stimulus. Conclusions: CX546 effectively reverses opioid- and barbituate-induced respiratory depression without reversing analgesic response. These studies suggest that ampakines may be useful in preventing or reversing opioid-induced respiratory depression and identify a potential for ampakines for alleviating other forms of respiratory depression including sedative use and sleep apnea. <<<
From Erbse's German Cortex board, here's a link to the various Ampakine related presentations that were given at the October 2006 Neuroscience convention. There are 2 additional abstracts on pg 2 -
http://www.erbse.vm-elsig.de/form/base/YaBB.pl?num=1157260563/0
Included in these is a Stargazin related paper co-written with Drs. Rogers and Varney, and several papers by Dr. Baudry, two of which note Ampakine's strong potential for Parkinson's.
Striaterminalis, I wish I had been clever enough to base my online name on green fluorescent protein, but unfortunately I just chose the letters at random :o) My only myelin related experience was back in college when nitrous oxide was all the rage, and over a period of months I managed to get peripheral neuropathy, especially in the feet. Luckily the neurons recovered, but it took a couple years. I think the nitrous permanently wiped out a few million of my brain cells though :o)
Daviddal, I think the R+D collaboration with Servier ends next month (as opposed to Dec '07). As you said, the existing license agreement for ex-US Neurodegenerative and Anxiety continues on, but since S-18986 isn't covered under that agreement, it will have to be updated for Servier to eventually commercialize S-18986.
BTW, I think the enrollment for the S-18986 MCI study was boosted up from 450 to a whopping 500 patients. All I could think of was that they're probably expecting a ton of dropouts, since they dose for a full 12 months (!) I sense another potential disaster in the making, but hopefully they'll still get some useful data. As a benzothiadiazine, S-18986 is probably fairly neurotrophic, but it may have its share of side effects, so one might have expected AD to be a more appropriate target indication. As we saw with the CX-516 MCI study, MCI patients don't tolerate side effects very well at all (and with 12 months of daily dosing, good luck..)
I assume that the compounds that have been jointly developed by Servier and Cortex under the R+D collaboration still fall under the existing/ongoing licensing agreement. I remember several years ago there was an announcement about one jointly developed compound in particular which was 2000 times more potent than CX-516, and neurotrophic. I always assumed it was from Cortex's benzamide family of compounds, since Cortex was involved with its development. Wonder what ever happened to that one? Of course Cortex's new approach is for ultra short acting high impacts, so perhaps that "monster" compound was just too powerful.
Daviddal, It would be great to get some human data on an Aricept/Ampakine combo treatment. With the synergism seen preclinically, a lower dose of the Ampakine could presumably still work well. It seems like most patients are on the Aricept/Namenda combo now, so a 3 drug combo study would also be interesting. If we had data like that now, partnering CX-717 for AD might be easy, even with the dosing limitations.
One thing about Org-24448 - would it hold up to the same level of FDA scrutiny that CX-717 is currently under? I wonder if years ago the same type of 13 week primate study was done on it, or perhaps the two species they selected were rats and dogs instead of primates (?) As we know, the finding didn't show up in dogs for CX-717. And in rats we didn't see the histo finding until Cortex found a way to up the dose dramatically (they previously were limited due to emesis). So the rat doses originally used for Org-24448 likely wouldn't have been high enough to show anything.
Presumably Organon has done further studies on Org-24448 on their own since the clinical hold was announced on CX-717. But with all the secrecy surrounding the nature of the histo finding, did Cortex tell them exactly what to look for and where (or is Cortex keeping that a trade secret)? And if Organon did see something suspicious, why would they say something that might bring down FDA scrutiny?
Logically, one would think that the FDA would require similar scrutiny of Org-24448, since it is the sister compound of CX-717. So far we haven't heard of anything like that happening, though for the FDA it would only seem prudent. So I still wonder if there is another shoe to drop here.
Of course if the FDA's chief motivation in all this is to look tougher on ADHD drugs, then they might not have any interest in examining Org-24448. On the other hand, if they truly want to determine what is happening on a cellular level with AMPA upmodulation, and whether there might be some potential for a class wide effect, then the FDA should examine Org-24448 as well as CX-717. It would probably be better to get it over with now than during/after Phase 3.
Hope everyone has a great Thanksgiving :o)
New Organon paper on Org-24448 (Farampator) just published yesterday. A very small single dose memory study (16 healthy elderly subjects). Results mixed, with improvement in short term memory, but drug seemed to impair episodic memory. Subjects were given a single 500 mg dose, but interestingly, some subjects got higher blood levels of the drug than did others. Those with the higher blood levels had the poorer memory results, but this might have been because they also had more side effects (headache, somnolence, nausea). Each subject also recieved placebo in the other arm of the crossover. Hopefully we'll see Organon's monotherapy Schizo results for Org-24448 published soon -
Acute Effects of the Ampakine Farampator on Memory and Information Processing in Healthy Elderly Volunteers.Wezenberg E, Jan Verkes R, Ruigt GS, Hulstijn W, Sabbe BG.
1Department of Psychiatry (966), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Ampakines act as positive allosteric modulators of AMPA-type glutamate receptors and facilitate hippocampal long-term potentiation (LTP), a mechanism associated with memory storage and consolidation. The present study investigated the acute effects of farampator, 1-(benzofurazan-5-ylcarbonyl) piperidine, on memory and information processes in healthy elderly volunteers. A double-blind, placebo-controlled, randomized, cross-over study was performed in 16 healthy, elderly volunteers (eight male, eight female; mean age 66.1, SD 4.5 years). All subjects received farampator (500 mg) and placebo. Testing took place 1 h after drug intake, which was around T(max) for farampator. Subjects performed tasks assessing episodic memory (wordlist learning and picture memory), working and short-term memory (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Information processing was assessed with a tangled lines task, the symbol digit substitution test (SDST) and the continuous trail making test (CTMT). Farampator (500 mg) unequivocally improved short-term memory but appeared to impair episodic memory. Furthermore, it tended to decrease the number of switching errors in the CTMT. Drug-induced side effects (SEs) included headache, somnolence and nausea. Subjects with SEs had significantly higher plasma levels of farampator than subjects without SEs. Additional analyses revealed that in the farampator condition the group without SEs showed a significantly superior memory performance relative to the group with SEs. The positive results on short-term memory and the favorable trends in the trail making test (CTMT) are interesting in view of the development of ampakines in the treatment of Alzheimer's disease and schizophrenia.Neuropsychopharmacology advance online publication, 22 November 2006; doi:10.1038/sj.npp.1301257.
PMID: 17119538 [PubMed - as supplied by publisher]
Blade, You had me going there for a minute :o) At least I'm not mentioned in the investigation, phew. I could go for a few of those lollipops..
MarketFest, In the conf call, Dr. Stoll said he expected the full package of new tox data to be submitted to the FDA by the end of Q1-07. I figure the FDA might take around 6 weeks or so to decide (I don't think there's a 30 day turnaround guarantee this time), which would put the FDA dosing liberalization decision around the middle of May.
Cortex will have the raw data long before that however, though I guess it takes quite a while to do all the analysis and get it packaged together. One might expect interested BPs to possibly see the data prior to submission to the FDA, though I doubt a licensing deal will be done before getting the official dosing verdict from the FDA, though you never know. It's probably in Cortex's best interests to wait for the FDA's official decision, to avoid getting lowballed by BPs.
If the FDA doesn't allow much/any liberalization of the dose, Cortex could still do a pharma deal for the N.Amer Neurodegenerative rights without CX-717, particularly with Organon who already have several other compounds they could use. Or Cortex could choose to keep the N.Amer Neuro rights, but then we're faced with raising more money again (another shelf offering).
Ticonderoga, No, there have been no outward clinical manifestations associated with the histo finding at all. And in all the human clinical trials to date CX-717 (phase 1, the UK Sleep study, the three Phase 2a studies), they haven't even seen a single SAE/serious adverse event. The sister compound Org-24448 has reportedly also had excellent safety in its Schizo and Depression trials.
It's a real puzzler. I have a few theories on what might be going on, relating to excitotoxicity induced calpain mediated protein breakdown, but that's just a guess. The long term toxicological ramifications (if any) is the big question.
MarketFest, The rational approach, as always, is to include a modest Cortex position as part of a well diversified bio portfolio, within a well diversified overall stock portfolio. We hear this advice over and over from seasoned investment experts, but never follow it (I'm as guilty as anyone, and have the losses to show for it over the years). What stock implosions should teach us is to DIVERSIFY, especially in this the riskiest of all sectors.
Looking at Cortex specifically, if I was still investing in individual stocks (which I'm not), I would be tempted to have a modest position in Cortex, along with the other 20 or so bio stocks I follow. There might be some tax loss selling in December, plus there's a financing coming, so the stock may remain weak for a while. I figure by May or so we'll get the FDA decision on dose liberalization, which will be a key event. Whether or not Stoll will actually disclose what the new liberalized dosing levels are is anyone's guess. You would think he was guarding the secrets of the Manhattan Project or something..
Neuro, Trying to extrapolate human dosing from animal models can be way off. I remember Dr. Stoll once estimating that based on animal models, for cognition/memory we would likely never need to go over the 100 mg level in humans. Then in a subsequent presentation it went up to 200 mg. Next thing you know we were dosing at 1000 mg (and still not getting a good response, at least in the DARPA study).
Piros asked Dr. Stoll to give a rough idea of the human dose currently allowed under the FDA's restictions, but Stoll wouldn't do it. That non-response leaves us and Wall St totally in the dark, and gives the impression, rightly or wrongly, that the level is probably very low. I wouldn't be surprised if for a one time single dose type study (the PET study), they can still dose at 1000 mg, but for any study of duration (1 month or more), the allowed dose is probably 200 mg or less. 200 mg is not going to get us a good BP deal for any indication (IMO), which may explain why Dr. Stoll didn't want to reveal the actual dosing limitations. His refusal at least gives that impression.
MarketFest, Part of the FDA's concern is due to the fact that the cellular effect being seen is as yet unexplained. In the conf call Dr. Stoll said that the FDA's general view is that "until we can get better explanations, we're going to have to stay conservative". One gets the impression that neither Cortex's histopathologists nor the FDA have seen cellular changes quite like this before (which is one reason why one might suspect the changes to be in the brain itself and not in say the liver, kidney, etc). So with the uncertainty over the causes of the cellular changes, the FDA is setting the safety bar for CX-717 higher than usual. Plus AMPA upmodulation is a brand new neurological approach, and the FDA probably remembers Lilly's difficulties with LY-451395 also.
Part of our problem in figuring the odds for CX-717 is that we have very little solid info to go on. Not only don't we know what the histo finding is, or in what organ it's seen, we have no idea what human dosing level is currently allowed by the FDA over various durations (1 month, 3 months). Is it 100 mg for 1 month, or 200 mg, or 500 mg or what? How about BID doses? Without this info we can't get a handle on how much dose liberalization we'll need to get from the FDA for CX-717 to be viable for further studies and for partnering/outlicensing.
Concerning 800 mg BID specifically, this was the highest BID dose given in the Phase 1, in effect the "MTD", though they never did get any serious adverse events, only an increased frequency of headaches (1600 mg was called the single dose MTD). With the dosing of CX-717 being restricted by the FDA (how restricted we don't know), it seems very unlikely that the FDA would allow BID dosing for any length of time at the MTD.
Thinking further about that ADHD trial protocol, if we currently had some data on say 400-500 mg BID, that would reduce some of the uncertainty we're experiencing now over the amount of dosing liberalization we need to get from the FDA. It's doubtful that we'll ever get to dose at 800 mg BID again with CX-717 (though you never know), but we may not have to, since 400-500 mg BID *might* produce decent efficacy. Unfortunately we didn't dose at that level in the Phase 2, so Cortex and potential BP partners remain in the dark on CX-717's effective dosing for ADHD. "For want of a horse, the kingdom was lost.." Well, hopefully not lost, but sometimes destiny can turn on such seemingly small factors.
Daviddal, One area where I thought Cortex had potentially dropped the ball bigtime was in the design of the ADHD trial (only two doses, each at the most extreme ends of the dosing range with nothing in the middle). Luckily everything worked out in the end, but if that super high 800 mg BID dose had caused a lot of dropouts, which was a distinct possibility, then the trial results would have been pretty worthless in assessing CX-717's potential for ADHD. Luckily things worked out, but to me it still seemed like a needlessly risky protocol.
The poor DARPA protocol was something Cortex really had no control over. The poor AD PET scan trial protocol was caused by the sudden emergence of the Aricept/Namenda combo approach, and the lack of previous data on CX-717 for that combo regimen. Cortex can probably be excused for that misstep, though perhaps starting a 2nd different type AD trial earlier could have been done (as they're doing now).
Of course it all gets back to a lack of resources/cash, which is the underlying basis for most of Cortex's troubles (the thin pipeline / over-reliance on CX-717 / lack of progress on the high impacts, etc). They say that the love of money is the root of all evil, but in biotech, it's the lack of money.
OT - Nice article on MABS -
http://www.pharmadd.com/StrategicBriefings/MAbs.asp
Any thoughts on who might be trying to pump the stock over on the Yahoo board? Some of the lead lines are amazingly ridiculous ("FDA Approval Soon", etc). This has been going on for quite a while. I assume it has to do with the financing.
The fat lady (FDA) hasn't sung yet folks, so it's too early to start writing off CX-717 or Cortex. While CX-717 is most likely dead for ADHD, there's a decent chance that it can still be partnered for AD. Here's a likely scenario/timeline -
By early 2007 - Cortex raises approx $10-12 mil from the shelf.
End of Q1-07 - Cortex submits complete package of the new tox data to the FDA.
Mid Q2-07 - Cortex gets FDA's reply on dosing liberalization.
Summer-07 - Possibility #1 - Assuming AD is viable based on CX-717's allowed dosing, a N.Amer Neurodegenerative deal is done with a BP interested in AD.
Summer-07 - Possibility #2 - If AD doesn't look viable based on CX-717's allowed dosing, a smaller N.Amer Neurodegenerative deal could still be done, with Organon likely being the most interested partner (since they already have Org-24448 and Org-26576).
Wildcards - There is an outside chance, unlikely but not impossible, that the FDA could liberalize CX-717's dosing enough to make it viable again for ADHD. In that case Cortex is a homerun stock.
Other considerations - Assuming that one way or another the N.Amer Neurodegenerative rights get partnered next year (#1 or #2 above), the question then becomes whether to try to carve out ADHD from the deal. Some orphans will likely be carved out and available, but getting ADHD carved out would allow Cortex to put all its energies into a low impact backup (like CX-701) for ADHD, with the goal of partnering it a couple years later. The other key priority is to get the lead high impact (CX-929) into the clinic, after which that could also be partnered to the BP who has the N.Amer Neurodegenerative rights. Those two activities (CX-701 for ADHD, and CX-929 for Neurodegenerative, both to be outlicensed after/around Phase 2) would be Cortex's central focus for several years, and the non-Ampakine in-license idea could be shelved.
Summarizing, the above is the best fallback scenario I can come up with. Of course if ADHD becomes viable again for CX-717, then we're golden, but the odds are pretty heavily stacked against that scenario. Biotech is full of surprises though, so you never know.