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Dew, If I become an I-Hub board moderator, will I get a check from Yahoo after the buyout? :o)
More evidence that upregulating glutamate pathways has a synergistic effect with antipsychotic meds -
>>> 1: Pharmacol Biochem Behav. 2006 Jun 16; [Epub ahead of print] Links
Positive modulation of glutamatergic receptors potentiates the suppressive effects of antipsychotics on conditioned avoidance responding in rats.Olsen CK, Kreilgaard M, Didriksen M.
Department of Psychopharmacology, Pharmacological Research, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby-Copenhagen, Denmark.
Non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist administration induces a syndrome indistinguishable from schizophrenia including positive and negative symptoms and cognitive deficits. Concordantly, augmentation of the NMDA receptor function by glycine-site agonists such as d-serine and d-cycloserine has been reported to improve negative symptoms and some cognitive deficits in schizophrenia patients when added to conventional antipsychotic treatment, although they appear less effective when combined with clozapine specifically. In contrast, administration of the AMPAkine CX-516 (which positively modulate the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor) as an adjuvant to clozapine, has been shown to exert some beneficial action on the negative symptoms and cognitive deficits in schizophrenia. In the rat, selective suppression of conditioned avoidance response (CAR) behaviour has been widely reported to be a test with high predictive validity for antipsychotic efficacy. We found that d-serine and CX-516, at doses ineffective by themselves, significantly potentiated the suppression of CAR induced by threshold doses of risperidone (0.16 mg/kg, s.c.), olanzapine (0.63 mg/kg, s.c.) and clozapine (1.3 mg/kg, s.c.) without causing additional motor disturbances. Thus, the adjunct enhancement of NMDA or AMPA receptor function observed clinically, appears reflected in the present rat CAR study. Consequently, our data lend further support to the potential use of the CAR test in the investigation of augmentation strategies involving the addition of non-dopaminergic target compounds to existing atypical antipsychotics.
PMID: 16782180 [PubMed - as supplied by publisher] <<<
Neuro, I don't think Dr. Stoll was committed to keeping CX-717 for the orphan indication, but instead, as you previously postulated, committed to carving out the orphans and a backup compound like CX-701. Hasn't Stoll's assumption all along (or our interpretation of it) been that the BP partner would not allow co-use of CX-717? Do you think co-use of CX-717 is now a feasible scenario? Thanks.
Neuro, Something I've been wondering about concerns the range of tissue types that are generally tested for in CNS animal tox trials. In addition to microscopic examination of liver, kidney, cardiac, muscle, etc tissues, I assume they also examine tissue samples from the various areas of the brain/CNS. I wonder what the chances are that the histo "finding" might possibly have been found in CNS tissue?
The only effect I can think of relating to Ampakines that might conceivably be detectable would be from the calpain mediated spectrin protein breakdown phenomenon, though this apparently only occurs with high impacts, and then only over long periods of dosing. I wonder what the odds might be that the histo "finding" might have been seen in CNS tissues (as opposed to liver, cardiac, etc)? As we know, Ampakines have shown a remarkable lack of systemic side effects. In the past, when other CNS drugs have been red-flagged for adverse effects, is it usually due to systemic effects (QT interval changes for example), or are CNS tissue findings sometimes seen?
Another question I had concerned the relationship with Servier. We know Cortex is seeking to end the ongoing R+D collaboration early, but that Servier will still own the Euro neurodegenerative and anxiety rights. As we know, their S-18986 compound doesn't fall within the existing agreement, so I was wondering if you thought Servier might seek an updated agreement for S-18986 sooner rather than later, or instead wait until they see the results of their ongoing MCI Phase 2? Thanks Neuro.
An earlier version of the Schizophrenia use patent -
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsear...
The comp of matter patent covering CX-717 and Org-24448/CX-691 (both are benzofurazans) -
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsear...
The Sexual Dysfunction use patent -
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsear...
The BDNF/Neurotrophin upregulation use patent -
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsear...
Another Lynch endocrine upmodulation use patent -
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsear...
The schizophrenia use patent -
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsear...
While I'm at it, here's the use patent covering Ampakines when used in combination with ACHase inhibitors (Aricept, Reminyl, etc) -
http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsea...
Someone asked about Ampakines and insulin, here's the endocrine upmodulation use patent -
http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsea...
BDNF related paper -
: J Neurophysiol. 2006 Aug;96(2):677-85. Epub 2006 May 17. Related Articles, Links
Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor.
Rex CS, Lauterborn JC, Lin CY, Kramar EA, Rogers GA, Gall CM, Lynch G.
Gillespie Neuroscience Research Facility, University of California, Irvine, CA 92697-4292. jclauter@uci.edu).
Restoration of neuronal viability and synaptic plasticity through increased trophic support is widely regarded as a potential therapy for the cognitive declines that characterize aging. Previous studies have shown that in the hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested whether increasing endogenous brain-derived neurotrophic factor (BDNF) could reverse this age-related change. We report here that in middle-aged (8- to 10-mo-old) rats, in vivo treatments with a positive AMPA-type glutamate receptor modulator both increase BDNF protein levels in the cortical telencephalon and restore stabilization of basal dendritic LTP as assessed in acute hippocampal slices 18 h after the last drug treatment. These effects were not attributed to enhanced synaptic transmission or to facilitation of burst responses used to induce LTP. Increasing extracellular levels of BDNF by exogenous application to slices of middle-aged rats was also sufficient to rescue the stabilization of basal dendritic LTP. Finally, otherwise stable LTP in ampakine-treated middle-aged rats can be eliminated by infusion of the extracellular BDNF scavenger TrkB-Fc. Together these results indicate that increases in endogenous BDNF signaling can offset deficits in the postinduction processes that stabilize LTP.
PMID: 16707719 [PubMed - in process]
OT - One of the nice things about I-Hub are the dating service ad photos of amazingly beautiful babes. A pleasant relief after staring at stock charts and Form 10-Ks all day :o)
Dew, Neuro, As two of the brainiest people I know of, I'm sure you guys can coexist well on this re-energized Cortex board. Dew can be extremely critical, but is one of the brightest bio guys out there, and of course we're all well aware of Dr. Tracy's vast experience and knowledge of the neuro sector. Between you guys, and everyone else on the thread, we should be in really good shape going forward. We're all here for a common purpose - to assemble and disseminate useful/interesting information, and (hopefully) make some money. Good luck to us :o)
Dew, Novartis getting into the act would be great, though we haven't seen any evidence of that, yet. They have a ton of money available for acquisitions/partnering though. So far BP interest speculation has centered on - 1) Lilly, who have had an AMPA upregulating program for some time (biarylpropylsulfonamides), and have challenged Cortex's use patent in Europe (twice), and 2) Glaxo, who got into the act several years ago using compounds from NeuroSearch, and who have joined Lilly in the patent challenge in Europe. Other potential players might conceivably be - 3) Amgen (former Neuro head at Lilly jumped over to Amgen several years ago), 4) Pfizer, who previously partnered an unrelated CNS drug with Cortex's partner Servier, and possibly 5) Merck (in an interview several years ago, their neuro head called AMPA upmodulation one of the most promising new neuro platforms). Also, Boehringer Ingelheim has done work with AMPA upmodulators. Then of course there are other players, big and small, who may have a particular interest in ADHD.
Gersh, In the last conf call, Dr. Stoll said that Cortex wouldn't be commenting on the actual results of the new animal studies one way or the other until after the FDA has made its decision on lifting the hold.
Even if the histopath finding is found again in the new study, Cortex should still submit all the data to the FDA and await their input. As previously discussed, the animal data in question was the basis for the FDA allowing the Phase 2a trials to proceed in the first place, and the histopath "finding" was present in that data. Either the FDA didn't originally notice the "finding", or they did notice it but didn't deem it serious enough to red flag the Phase 2a trials. Cortex almost certainly noticed it, but apparently were unconcerned, and so proceeded with the Phase 2a trials.
So my conclusion is that the histopath "finding" must be fairly subtle, and Cortex would do some additional testing if it appears again in the new study, rather than immediately abandoning CX-717. FWIW, I'm guesstimating roughly 50/50 odds for the clinical hold to be lifted immediately vrs additional studies to be required, with the "CX-717 is toast" scenario being extremely unlikely without at least one more additional study beyond the current ones.
Today's press release is good news, since Cortex appears to be right on schedule in getting the necessary work done. Dr. Stoll isn't going to talk about whether the new data is favorable or unfavorable, but at least he's keeping everybody updated on their progress.
This paper suggests that while benzamide type AMPA upmodulators (Cortex's CX-546, CX-516) have considerable activity in the hippocampus, they don't produce much effect in the thalamus. The authors point out that this could possibly have clinical implications, since the thalamus is involved in wakefulness and vigilance, while the hippocampus is involved in memory encoding. That might indicate, in theory at least, that Sleep Deprivation/Shift Work may not be the ideal indications for benzamide type compounds. Cyclothiazide, on the other hand, appeared to have significant activity in both the hippocampus and the thalamus (benzothiadiazides like Servier's S-18986, and biarylpropylsulfonamides (Lilly's compounds), are related to the cyclothiazide structure). Of course upregulating thalamic activity might perhaps have other (undesirable) consequences -
>>> J Pharmacol Exp Ther. 2005 Apr;313(1):277-85. Epub 2004 Dec 30. Related Articles, Links
Positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators have different impact on synaptic transmission in the thalamus and hippocampus.
Xia YF, Kessler M, Arai AC.
Department of Pharmacology, Southern Illinois University, School of Medicine, Springfield, IL 62794-9629, USA.
Earlier studies showed that positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors enhance synaptic responses and facilitate synaptic plasticity. Those studies focused mainly on hippocampal functions. However, AMPA receptors have regionally distinct subunit compositions and thus potencies and efficacies of modulators may vary across the brain. The present study compared the effects of CX546 [1-(1,4-benzodioxan-6-ylcarbonyl) piperidine], a benzamide-type modulator, on synaptic transmission in neurons of the reticular thalamic nucleus (RTN), which regulates the firing mode of relay cells in other thalamic nuclei, and on hippocampal CA1 pyramidal cells. CX546 greatly prolonged synaptic responses in CA1 pyramidal cells, but at the same concentration it had only weak modulatory effects in RTN neurons. Effects on miniature excitatory postsynaptic currents (EPSCs) were similar to those on EPSCs in both regions, suggesting that variations in neuronal morphology and transmitter release kinetics do not account for the differences. Relay cells in the ventrobasal thalamus also exhibited weak modulatory effects that were comparable with those in RTN neurons. Regionally different effects on response duration were also observed with CX516 [BDP-12, 1-(quinoxalin-6-ylcarbonyl)piperidine], a second benzamide drug. In contrast, 100 microM cyclothiazide produced comparable synaptic enhancements in hippocampus and RTN. The regional selectivity of benzamide drugs (ampakines) may be explained, at least in part, by a lower potency at thalamic AMPA receptors, perhaps due to the prevalence of the subunits GluR3 and 4. Although regional preferences of the ampakines were modest in their extent, they may be sufficient to be of relevance when considering future therapeutic applications of such compounds.
PMID: 15626725 [PubMed - indexed for MEDLINE] <<<
The genius who dreamt up that new Yahoo format should be shot. I-Hub is better anyway - for one thing there's no length limitations on posts, so one can cut/paste an entire article in a single post. And the board moderator can delete garbage posts (goodbye "Lapdogski"). I'm for dumping Yahoo and moving our discussions over here.
Dew, Just wondering if you see some turnaround potential in Neurocrine from these post-implosion levels? Thanks.
Is Novartis the Future of Generics?
By Stephen D. Simpson, CFA (TMFWildWeasel)
06/26/2006
Monday mornings lend themselves to idle speculation. Keep that in mind as you read what follows, as I'm not necessarily predicting that any of this is going to happen, but rather speculating on what could happen.
But ever since Merck(NYSE: MRK) announced that it was going to take aggressive pricing action on its Zocor cholesterol drug, and thereby imperil the profits of Teva Pharmaceutical's(Nasdaq: TEVA) 180-day exclusivity period, I've began to wonder about the space. I should also point out that some of these thoughts were developed in an email exchange with a reader who'd prefer to be nameless (or at least not mentioned here).
The problem
Big Pharma (that is, companies like Pfizer(NYSE: PFE), Merck, EliLilly(NYSE: LLY), and so forth) have all been beset to varying degrees by competition from generic drugmakers like Teva, Mylan, and others. That's not particularly new in and of itself -- generics have been around for a long time.
What has changed over the years, though, is the extent to which generics firms will aggressively pursue potential opportunities. U.S. law gives them an incentive to challenge Big Pharma patents that they believe are incorrect, invalid, or otherwise unenforceable -- the incentive being that the first to challenge is awarded an 180-day period of marketing exclusivity. Since competition in the generics space ultimately devolves into who can produce and distribute their drugs most cheaply, that window of exclusivity (in which the price of the drug is usually cheaper than the branded version, but not so cheap as when the 180-day window expires) is a key component of profitability.
As you might imagine, this provides a tremendous incentive for generics firms to muster their legal teams and go after high-profile drugs. What's more, many generics advocates will tell you that Big Pharma goes to sometimes ridiculous extremes in an attempt to extend patent protection and squeeze every drop of profits from a drug. On the flip side, Big Pharma will tell you that that's the only way they can continue to sink billions of dollars of R&D into fields like cancer, Alzheimer's, and autoimmune disease, where the likelihood of success is very small.
Big Pharma attacks
One way in which Big Pharma has sought to fight back is through so-called authorized generic agreements. These basically give the generics company the right to sell a given drug under a license agreement. Big Pharma doesn't make as much money as they would if they won the patent challenge outright, but they certainly get more money than if they had to face the sudden revocation of a patent and the loss of high-value sales on major drugs. In other words, it lets Big Pharma manage their portfolio and their profits a little more effectively.
Trouble is, though, that there are some anti-trust concerns about this practice. What's more, it's clearly aimed at devaluing that 180-day exclusivity window and thus discouraging generic companies from challenging patents. It also leaves some generics in a tough spot -- do you invest millions of dollars in a legal battle that you might lose, or do you accept a more certain (but less lucrative) alternative in the form of an authorized generic agreement?
Big Pharma attacks again
Authorized generics are controversial, but perhaps not nearly as controversial as what Merck is doing with its Zocor drug. As I wrote last week, Merck has reached special agreements with health benefits companies like UnitedHealth(NYSE: UNH) and WellPoint(NYSE: WLP) to offer sweetheart discounts on Zocor. The details differ from deal to deal, but the gist is that Merck will be selling Zocor at a price below what Teva was intending for its 180-day window.
That's a major shot across the bow. What if all Big Pharma decides to do likewise?
Let's say that a drug company can sell Supercalifragilisticor for $5 a pill while it's under patent, but it only costs about $1 to make and distribute. A generics company that challenges the patent might be able to charge $3 or $4 a pill in that 180-day window (the discounts vary with the popularity of the drug in question) before seeing other generics jump in and charge something like $1.10. Obviously a half-year of the higher price makes a big difference if it's a massively popular drug like Lilly's Prozac.
If you don't get that 180-day window of profits, you can't afford the multi-million dollar legal bills that it takes to overturn a patent, and you're instead forced to accept that $1.10 price that everyone else gets and you have to wait longer for it. That's a tough spot for a generics company that wants to grow its business and its earnings, and reward shareholders.
The future ... maybe
Novartis(NYSE: NVS) might just be the face and future of the generics industry to come. As you may recall, they made some major purchases last year to become a big player in the generics space. And if Big Pharma succeeds in pressuring generic companies, that just might be more common.
See, it takes money to develop generics. Sure, not nearly as much money as to develop (and test) a new branded drug, but money all the same. What's more, investors are attracted to growth, and it might be tough for a lot of generics companies to post real growth if Big Pharma decides to aggressively price their drugs during those 180-day windows.
Using that prior example, it's probably not worth spending the money to challenge a patent on a $5/pill drug if you know that the owner of that drug is going to slash its prices in the aftermath. And it may be hard to justify investing in new capacity and R&D if you're only going to get the run-of-the-mill generics price. But if you're another Big Pharma company, you probably already have the spare manufacturing capacity and know-how, so you might be willing to offer a generic and reap a little extra money (think of it as almost being like earning rent from spare machinery).
What may end up happening is a wave of consolidation where leveraging a huge production base can pay off (economies of scale, that is). It could also mean that large generics firms that have the wherewithal might also begin focusing more on branded drugs -- using the higher profits of a branded drug franchise to subsidize a profitable (but not as profitable) generics business. In other words, it might become like the steel or chemical industries, where it's very hard for small players to compete in the most commodity-like niches.
Can this happen?
In short, I have no idea. The fact of the matter is that our Congress has a powerful incentive to prop up the generics industry (given the huge expenditures on healthcare). On the other hand, so long as Big Pharma doesn't collude or price drugs below their cost of production, I'm not sure what lawmakers can do about it. I mean, if Merck wants to drop its price for Zocor, that's pretty much their right in a free market.
One way or another, this whole story is likely to get more and more interesting. Perhaps the solution lies in a modified version of authorized generics, where Big Pharma allows generics companies a window of higher profits in exchange for less aggression on the patent front.
Or maybe the solution simply lies in scale -- getting big enough that you can compete profitably no matter what the price. In the meantime, investors should keep an eye on stocks like Teva, Barr Labs, and Mylan; I can't imagine that Congress will let the generics industry fail, and big players like these should be the ones to ultimately come out on top.
For more non-generic Foolishness:
Reddy More Steady?
Time to Make Room for Teva?
Novartis: A Good Story Repeated
Dew, I would tend to agree about Cortex - it may just drift lower/sideways until we get to the FDA decision period this Fall. One of the big negatives from the poor DARPA results is that without the expected pop in the stock price, there can't be much additional warrant excercising, and Cortex will really need those added funds (projected cash level for year end '06 is only around $10 mil). So not only does Cortex desperately need to get the clinical hold lifted, they need it lifted on the first try (late September/early October) to avoid having to do another unfavorable PIPE in late'06/early'07.
I was also curious if you see the Zocor phenomenon (off-patent branded drugs being priced at/below the price of generics) becoming a future trend? If so, that could really put the generic companies at a disadvantage relative to where they were previously.
Blade, Do you know if there was a specific problem encountered with Avastin use in macular degeneration which prompted DNA's warning to the retinal docs, or was the warning merely because it's an off-label use and DNA is worried about their own liability? Thanks.
Thanks Dew / board. Looking at the Lucentis Phase 3 data, it looks like vision was maintained or improved in 95% of patients after 1 year, vrs 62% for patients not receiving the drug (using a once/month injection regimen). They have another trial using less frequent injections (monthly for the first 3 months, then one injection every 3 months), but it looks like the results aren't nearly as good.
While the prospect of getting stuck in the eye every month isn't too appealing, it certainly beats the alternative. Thanks for the input.
Dew, Just wondering if you have some insights into the merits of the injectible monoclonal antibody approach (anti-angiogenesis) now being used to treat wet macular degeneration? My mom has this condition in one eye (rupturing of the retinal blood vessels) and her ophthalmologist is planning to inject one of the anti-angiogenesis Mabs that is nearing FDA approval but is not yet approved. There apparently are several similar treatments, approved and in development (Avastin for example). I'm trying to get some info on how successful this anti-angiogenesis approach has been, and if there is any other/better alternative. Thanks for any info you could provide.
Dew, Is there still a chance that the EMEA could decide against Atryn in spite of the CHMP recommendation (as occasionally occurs in the US)? That possibility (or the perception) might explain some of the weakness in the stock.
Other possible factors -
1) The very weak stock market overall / sudden aversion to higher risk sectors,
2) The perception that another financing could be coming soon for GTCB,
3) The market for Atryn as currently approved might be viewed as small. Any estimates on the market size of Atryn for the currently approved indication, and time to revenue ramp up? Any idea of the approx time to achieving expanded approvals?
Did GTCB have a large overhang of shares/warrants from previous PIPES to work through? Thanks for your insights Dew.
With this first transgenics approval seemingly "in the bag", the floodgates should be wide open, at least in Europe. GTCB should be extremely well positioned going forward, and one would think the stock would be a screaming buy at these levels. Even considering the major global stock market correction, the muted response to the GTCB news is puzzling.
Novartis/Hep C -
>>> Motley Fool
Novartis Can't Say No
Wednesday June 7, 12:14 pm ET
By Stephen D. Simpson, CFA
I'm beginning to wonder whether there are any deals that Novartis (NYSE: NVS - News) hasn't accepted in the past few quarters. In the last few days, the company has sealed three separate deals to add compounds to its pipeline -- at the cost of hard cash.
Today, news broke that Novartis will be buying British biotech company NeuTech Pharma for about $569 million in cash. For that price, Novartis is getting a company focused on treatment-resistant infections, with two late-stage drugs in the pipeline. Mycograb, targeted at dangerous fungal infections, could be submitted for U.S. approval in 2009, while Aurograb (for staph infections) looks like it's about a year later in the queue.
But wait, there's more!
Yesterday, the company announced a deal with Human Genome Sciences (Nasdaq: HGSI - News) for the rights to Albuferon, a hepatitis C treatment. Assuming this drug reaches approval (a phase 3 trial should begin later this year), the companies would cooperate in the U.S. market, while Novartis would handle foreign sales and distribution. Under this deal, Novartis pays $45 million up front and potentially more than $500 million in future milestones.
But wait, there's even more!
Novartis also announced a licensing deal with Genelabs Technologies (Nasdaq: GNLB - News). The deal will cost Novartis about $20 million over two years, and as much as $175 million in potential milestones, if a successful drug comes out of this agreement. The disease in question? Yep, you guessed it -- hepatitis C.
Obviously, Novartis wants to establish a major franchise in hepatitis C, given both of these deals and past agreements with Idenix (Nasdaq: IDIX - News) and Anadys (Nasdaq: ANDS - News). There's certainly a ripe and underserved market here, and I also think that Novartis has a logical underlying philosophy. It's looking at several different and possibly complementary approaches to the disease, with the hope of combining them in different ways to treat various subtypes of the disease and patients who don't adequately respond to existing therapies.
If you're a company with a hep-C drug or a development program in that area, stay by the phone -- Novartis will probably be calling you, too. As for Novartis shareholders, I'm not quite sure what to think. I know it takes money to build a pipeline, but these guys have been doing deals left and right. Then again, we're talking about a strong pharmaceutical company in a weak sector that's still somewhat undervalued -- not exactly the worst story I've seen this week. <<<
OT - In Pharmacology, all drugs have two names, a trade name and generic name. For example, the trade name of Tylenol also has a generic name of Acetaminophen. Aleve is also called Naproxen. Amoxil is also call Amoxicillin and Advil is also called Ibuprofen.
The FDA has been looking for a generic name for Viagra. After careful consideration by a team of government experts, it recently announced that it has settled on the generic name of Mycoxafloppin. Also considered were Mycoxafailin, Mydixadrupin, Mydixarizin, Dixafix, and of course, Ibepokin.
Pfizer Corp. announced today that Viagra will soon be available in liquid form, and will be marketed by Pepsi Cola as a power beverage suitable for use as a mixer. It will now be possible for a man to literally pour himself a stiff one. Obviously we can no longer call this a soft drink, and it gives new meaning to the names of "cocktails", "highballs" and just a good old-fashioned "stiff drink". Pepsi will market the new concoction by the name of: MOUNT & DO.
Thought for the day: There is more money being spent on breast implants and Viagra today than on Alzheimer's research. This means that by 2040, there should be a large elderly population with perky boobs and huge erections and absolutely no recollection of what to do with them
Cubicin gets approval for bacteremia and endocarditis -
>>> FDA Approves Expanded Label for IV Antibiotic CUBICIN(R) to Add Bloodstream Infections Including Right-Sided Infective Endocarditis Caused by MSSA and MRSA
Thursday May 25, 7:20 pm ET
Cubist Confirms 2006 Guidance for U.S. Net Product Revenues of $190-$205 Million
LEXINGTON, Mass.--(BUSINESS WIRE)--May 25, 2006--Cubist Pharmaceuticals, Inc. (Nasdaq: CBST - News) today announced that the U.S. Food & Drug Administration (FDA) has approved the supplemental new drug application (sNDA) for CUBICIN® (daptomycin for injection) as once-a-day therapy at 6 mg/kg for the treatment of Staphylococcus aureus (S. aureus) bloodstream infections (bacteremia) including right-sided endocarditis caused by MSSA (methicillin-susceptible S. aureus) and MRSA (methicillin-resistant S. aureus). Cubist estimates that these infections account for 30,000 deaths in the U.S. alone each year. CUBICIN will be the only IV antibiotic approved for this indication based on the results of a prospective, randomized, controlled registration trial. Cubist will commence marketing of CUBICIN for the new indication immediately to acute care infectious disease doctors and specialists who treat S. aureus bloodstream infections. The full text of the expanded label will be available within a few days on the company's corporate web site, www.cubist.com as well as on the CUBICIN web site, www.cubicin.com.
The FDA decision today follows the positive recommendations of the Anti-infective Drugs Advisory Committee, which at its March 6th meeting reviewed data from a landmark Phase 3 trial conducted by Cubist, a study of the efficacy and safety of CUBICIN at 6 mg /kg once-a-day as monotherapy vs. dual therapy standard of care therapy (semi synthetic penicillin plus initial gentamicin for infections caused by MSSA or vancomycin plus initial gentamicin for infections caused by MRSA) for the treatment of S. aureus bacteremia and endocarditis.
Mike Bonney, President and CEO of Cubist said, "I'm very proud of the team that conceived, conducted, and presented this historic study to the FDA. I am also thankful to the infectious disease experts and FDA scientists who worked with us, the investigators at 76 sites in the U.S. and Europe, and the patients who were treated as part of the clinical trial. The approval received today provides the clinicians who treat these complicated infections with an alternative therapy backed by prospectively collected, controlled, and comparative clinical data. Based on the expanded label approved today, we are very comfortable confirming our previously issued U.S. net product revenue guidance for 2006 of between $190 and $205 Million."
Dr. Ralph Corey said, "Doctors who treat patients with bloodstream infections caused by S. aureus, particularly for infections caused by MRSA, need alternative therapies. The "Bad Bugs/No Drugs" initiative of the Infectious Disease Society of America has identified MRSA as one of six top priority, dangerous, drug resistant microbes. The FDA approval of CUBICIN today for the treatment of these complicated, and life threatening infections is good news." Dr. Corey is professor of Medicine and Infectious Disease at Duke University Medical Center and director of Infectious Disease at Duke Clinical Research Institute. Dr. Corey chaired the Independent External Adjudication Committee (IEAC) which, blinded to therapy, assessed outcomes for all patients in the Phase 3 trial.
CUBICIN was originally approved on September 12, 2003, at 4 mg/kg intravenously once daily for the treatment of complicated skin and skin structure infections (cSSSI) caused by Gram-positive organisms, including both susceptible and resistant strains of S. aureus (MSSA and MRSA respectively). In September of 2005, Cubist submitted to the FDA a sNDA for an expanded label. The file was accepted and given Priority Review designation by the FDA on November 25th, followed by an FDA Approvable Letter on March 24th. The results of the Phase 3 trial on which the sNDA is based were presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy in December, 2005. The trial results showed that, for the treatment of S. aureus bacteremia and endocarditis, CUBICIN at 6 mg/kg intravenously once daily met both primary end points for non-inferiority vs. comparator consisting of dual therapy (semi synthetic penicillin plus initial gentamicin for infections caused by MSSA or vancomycin plus initial gentamicin for infections caused by MRSA.) For full prescribing information, visit www.cubicin.com. <<<
Israeli Index funds coming in June. Note that in addition to the 16 stock options based index, the Nasdaq is launching a 75 stock Israeli index fund (see end of article) -
>>> Options
Israeli Options Index Nears
By Elinor Arbel
TheStreet.com Contributor
5/23/2006 4:29 PM EDT
URL: http://www.thestreet.com/options/options/10287608.html
TEL AVIV, Israel -- Investors seeking exposure to Israel's market in the wake of Berkshire Hathaway's (BRK.A:NYSE) $5 billion purchase of Iscar will soon be offered an all-Israeli options index, the first of its kind.
According to sources close to the matter, the index is being planned for a mid-June launch, pending final legal approval of the agreement between the exchange and the broker-dealer firm. The index, which will be administered by Hapoalim Securities USA and traded on the Philadelphia Stock Exchange, will consist of 16 Israeli companies that trade dually on the Tel Aviv market and on the New York Stock Exchange or Nasdaq as American depositary receipts.
Among the companies included in the index would be generic drugmaker Teva Pharmaceutical (TEVA:Nasdaq ADR) ; Nice Systems (NICE:Nasdaq ADR) , which makes systems that monitor businesses' customer interactions; Partner Communications (PTNR:Nasdaq ADR) , Israel's second-largest cellular operator by users; drug developer XTL Biopharmaceuticals (XTLB:Nasdaq ADR) ; and Delta Galil Industries (DELT:Nasdaq ADR) , an intimate-apparel and underwear company.
An options index gives investors exposure to an entire segment by following an underlying index, similar to an exchange-traded fund. Unlike a stock-based ETF, the options index provides exposure to its components by creating synthetic contracts -- buying calls and selling puts.
Like other traded indices, the Israeli options index will be evaluated periodically and rebalanced whenever an occasion would arise requiring a component change, a source close to the matter said.
Barbara Sorid, a spokeswoman for the Philadelphia Stock Exchange, said the exchange doesn't comment on prospective business matters.
"An Israeli company index or fund, whether options-based or securities-based, makes complete sense under the current market conditions," says Ronen Zeharia, vice president of investments at Meitav, an Israeli investment house. "There is definitely a growing interest in Israeli companies; it makes you wonder why this hasn't been done yet."
Zeharia says that this type of a financial vehicle probably won't attract herds of investors to Israeli companies, but will draw private investors or smaller money-management firms wishing to include an emerging-market component in their portfolio. "Merrill Lynch or Deutsche Bank won't be needing such an index; they already have enough presence here and can do the stock picking themselves. It is the smaller ones who are likely to want a 1% or so exposure to Israel who could benefit from this," Zeharia said.
The trading job in the options index has already been assigned to a Philadelphia-based options-trading firm, which requested anonymity pending legal approval of the index. The firm declined to provide any details on the deal with Hapoalim Securities.
Bank Hapoalim, Israel's largest bank and the options-index sponsor, didn't have a broker-dealer operation until March, when it acquired the New York-based broker-dealer firm Investec US for roughly $40 million. Hapoalim Securities emerged as the new entity formed under the deal.
Bank Hapoalim itself registered its own shares on the U.S. over-the-counter market in late March, right after the Investec deal was completed, meaning that it could, theoretically, make it into the index. Bank Hapoalim declined to comment.
The new options fund comes against the backdrop of a bullish time in Israel. The Berkshire-Iscar deal once again highlighted the country as a fertile ground for growing investment-grade companies. Also in the background are a successful election that brought a moderate, peace-seeking government and a whopping 6.6% gross domestic product growth in the first quarter of this year, which followed a 7% growth rate in the previous quarter.
"The transfer of power from [Ariel] Sharon to [Ehud] Olmert without a hitch shows that Israel is truly the only democracy in the Middle East, " says Laura Goldman, who runs LSG Capital and is based in Tel Aviv. "After the disengagement, Israel seems to be on the road to peace. With less money spent on defense, Israel will have more money to develop the nation."
Goldman is bullish on Teva, Partner, M-Systems (FLSH:Nasdaq) , Given Imaging (GIVN:Nasdaq) and DSP Group (DSPG:Nasdaq) , adding that "investors can also benefit from Israeli companies as a diversification from the dollar."
Meanwhile, Charlotte Crosswell, Nasdaq's vice president for Europe, Middle East and Africa, announced at a conference in Tel Aviv Sunday that Nasdaq plans to launch an Israeli index, consisting of the 75 Israeli companies listed on the market.
Asaf Homossani, Nasdaq's managing director of Israel and Central Eastern Europe, said in an interview that there is strong demand for Israeli securities at the Nasdaq. "That's why we decided to launch this index," he said. "We hope it will help increase the visibility for these companies." The index is projected to launch by the end of June <<<
Aiming, I probably should revise my pps guesstimate for excellent DARPA results to $4+ rather than the $5-6 range, just to be on the conservative side. That level should hopefully still trigger a good deal of warrant excercising though. The warrant proceeds could turn out to be extremely critical down the road if the clinical hold isn't lifted on schedule for some reason. Without that extra warrant related cash, Cortex is probably looking at another less than favorable PIPE in early 2007.
A big potential risk to watch out for now, is if the pps erodes way down in the next few weeks, say into the low/mid $2s, and then only manages to bounce back up to the low $3s upon release of excellent DARPA news. Then we have a problem, since low $3s is under the price needed to trigger significant excercising of the PIPE #2,3 warrants (which were priced at $3.25,$3.00 respectively). There could be some excercising of remaining PIPE #1 warrants (excercise price $2.55), but this could only yield a maximum of an additional $4.8 mil in cash to Cortex. There is over $18 mil in cash to be had from the PIPE #2,3 warrants, but the pps has to get significantly above the $3-3.25 range to trigger the excercising of those.
So summarizing, the way I see it, Cortex needs to see excellent DARPA results, propelling the stock to a minimum of $3.75-4.00 or so to ensure a good amount of warrant proceeds flowing to the company ($10 mil or greater). We'll see what happens. There's a decent chance of seeing blowout great DARPA results. Let's just hope that the clinical hold doesn't mute the market response (and also that the response, even if strong, doesn't begin at too low a pps base).
Aiming, Actually Dr. Stoll said that the DARPA results should be released to the public sometime between the middle and end of June (rather than in 2 weeks). He also estimated that they would submit the new animal data to the FDA in August, with the FDA decision coming in September (not November, though it may end up actually being in November since Stoll's timelines have always been on the optimistic side).
I may be in the minority here, but having watched the FDA for a while, I think there's perhaps a 50/50 chance that they'll want even more data in the Fall. One reason would be the fact that, as Dr. Stoll said, it's going to be very difficult to get the dose much higher than they already have due to the emesis/vomiting problem (I hadn't previously realized the extent of that problem). So the FDA may not be satisfied with the "only a little higher" dosing level in the new MTD trials that Stoll indicated they could get. The FDA wants a much higher dose that will produce, as Dr. Stoll put it, "a lot more side effects". Cortex simply isn't going to be able to get the dose that high.
The other reason is that once a company has hit a roadblock with the FDA, there are often continued problems with the FDA after that. For whatever reason, it often turns out that way. To determine the odds of that happening here, one needs figure out the true reason for the negative FDA stance. There can be any number of reasons, from an ultra-cautious FDA generally, to the recent heat on the FDA over CNS/ADHD drugs, to AMPA modulation being a brand new platform that has always been viewed with great skepticism by the scientific world, to the excitotoxicity problems the FDA saw previously with Lilly's AMPA upmodulators, to someone at the FDA not liking someone at Cortex, to the FDA not liking the emerging concept of "lifestyle" drugs, etc. All we can say for sure is that the FDA has erected a barrier for reasons only they know, and now CX-717 is in limbo.
It sounds like Cortex has hired some very experienced consultants with former ties to the FDA, which could help a lot (assuming these people are not on bad terms with the current folks running the FDA for some reason). Bottom line though is that now there's not only the usual clinical/science risk, but a large added layer of regulatory risk to put into our investment equation. It's too early to conclude that Cortex/CX-717 are in the FDA's "doghouse" for good (ala Epix, or DSCO, or GTCB with the EMEA). But if after seeing the widespread abuse of modafinil that's starting to happen, and the abuse of ADHD drugs by teenagers generally, etc, the FDA may have decided to nip the emerging "lifestyle" drug phenomenon in the bud -- that's my biggest worry, since the FDA can easily erect barriers to stonewall any drug indefinitely.
The good thing investment-wise is that there's probably a good trading window right now ahead of the DARPA news, assuming the results turn out to be good (which is very likely IMO). Cortex could run back up into the $5-6 area on excellent DARPA results, after which I would then unload and reevaluate the situation as we get toward the Fall. If I were still in the bio "game" I'd be tempted to take a trading position ahead of these DARPA results (while still maintaining a diversified approach to the sector). And the put options now available also make it possible to get some insurance during these binary type events, albeit at the risk of reducing one's profit to some extent.
Mjx, Just in case you're thinking of basing your buy/hold/sell decision on anything I've said, I should let you know that I no longer own Cortex or any other bio stocks, and just follow them as a hobby. Don't let my ultra-cautious stance discourage you from having a position. If today's SHM info is good, there could/should be a nice recovery in the stock. However, due to the unpredictable nature of this sector, my advice as always is to diversify.
PS - An additional consideration now is that there are options available on Cortex for hedging, so if one wants to maintain a core position through the SHM, you could counterbalance the current risk by buying some put options as insurance. Anyway, good luck with your decision :o)
Mjx, I wouldn't put too much faith in what R+R says since they've had a funding relationship with Cortex in the past (numerous PIPES). Piros emphasized the "acute" phrase in the Cortex press release as a reason to expect a fast/easy resolution to the clinical hold, but the jury is still out on that until we hear from Dr Stoll tomorrow.
The "problem" could turn out to be relatively trivial, and the FDA could merely be looking for any excuse so they can "look tough" on ADHD drugs for a while. On the other hand, the FDA could instead be looking for an excuse to derail CX-717 because they consider it an emerging "lifstyle" drug (as modafinil is rapidly becoming), and CX-717's clinical hold could be part of an emerging FDA attack on lifestyle drugs generally. Then we have a bigger problem - an FDA determined to thwart the progress of CX-717 for years. Government regulators can stonewall any technology indefinitely if they decide that they don't like it for whatever reason. Of course this may not be the reason for the clinical hold, but for now it would have to be considered a possibility. It wouldn't be the first time for regulators to do such a thing (Epix and GTCB come to mind).
Mjx, I've followed Cortex since around 2002 and they've always done an audio webcast of the SHM over those years.
FWIW, I'm expected a fairly detailed explanation from Stoll of the nature of the "problem" (ie - was it 1) toxicity/side effect related, or 2) was there a lack of sufficiently high dosing multiples in animals, or perhaps 3) the FDA now wants some animal data on some new clinical parameter, etc). Stoll should then discuss the remedy proposed by the FDA if one has been established (however they may still be in the discussion stage on that with the FDA so details may be lacking), and an approx timeline to complete what is required. At the very least, we should come away knowing the nature of the "problem" that prompted the clinical hold.
ATP Clinical Research, Inc.
3151 Airway Ave
Bldg T, Ste 3
Costa Mesa, CA
Tel: 714-277-4472
Fax: 714-545-5748
>>>(My note - FARAMPATOR is Org-24448)<<<
Upcoming Studies
A multi-center, randomized, double-blind, fixed-dose, efficacy and safety trial of farampator (250 and 500 mg b.i.d) vs. placebo as augmentation therapy in schizophrenia subjects currently receiving risperidoe (2 or 3 mg b.i.d.)
Gus Alva, MD, is medical director of ATP Clinical Research. He has served as a principal investigator for the past 10 years conducting investigation in a myriad of neuropsychiatric conditions; Alzheimers and other dementias, depression, anxiety disorders, bipolar disorder and psychotic conditions. As a clinician and investigator, Dr Alva’s focus is on the genetics, neuroimaging, and latest treatments available for each afore mentioned condition, as well as aspects of ethnicity and their correlation within clinical situations. He has published numerous articles, and presents at both national and international meetings and conferences. galva@theatpgroup.net
Bobby Shih is a Clinical Research Coordinator at ATP Clinical Research, Inc. Bobby assists in the conducting of the clinical research studies for a myriad of neuropsychiatric aliments, which include Alzheimer’s disease, schizophrenia, and bipolar disorder. While he performs many physical assessments, such as electrocardiograms, vital signs and blood work, Bobby also performs cognitive assessments that assist in gauging the degree of impairment of our patients’ memory and executive functioning. He graduated the University of California , Irvine with a degree in Biological Sciences and Philosophy. bshih@theatpgroup.net
Efficacy and Safety of S18986 in the Treatment of Mild Cognitive Impairment Patients
This study is currently recruiting patients.
Verified by Servier September 2005
Sponsored by: Institut de Recherches Internationales Servier
Information provided by: Servier
ClinicalTrials.gov Identifier: NCT00202540
Purpose
The purpose of this study is to demonstrate a long term efficacy of S18986 versus placebo on episodic memory performance in patients with MCI
Condition Intervention Phase
Mild Cognitive Impairment
Drug: S18986
Phase II
MedlinePlus related topics: Mental Health; Neurologic Diseases
Genetics Home Reference related topics: Neurologic Diseases
Study Type: Interventional
Study Design: Randomized, Double-Blind, Placebo Control, Parallel Assignment
Official Title: Efficacy of 15 Mg and 50 Mg of S18986 on Cognitive Symptoms in Mild Cognitive Impairment Patients Treated Over a 12-Month Oral Administration Period
Further study details as provided by Servier:
Primary Outcomes: Episodic memory
Secondary Outcomes: Other cognitive domains, activities of daily living, global impression of change, MRI, safety.
Expected Total Enrollment: 450
Study start: June 2005
Eligibility
Ages Eligible for Study: 55 Years and above, Genders Eligible for Study: Both
Criteria
Inclusion Criteria:
Memory complaint
Acetylcholinesterase inhibitors stopped at least 3 months before selection
Exclusion Criteria:
Dementia
Parkinson's disease
Vascular disorder
Depression
Epilepsy
Location and Contact Information
Please refer to this study by ClinicalTrials.gov identifier NCT00202540
Bruno Vellas, MD + 33 5 61 77 76 49
France
Hôpital la Grave-Casselardit, Toulouse, 31000, France; Recruiting
Bruno Vellas, MD + 33 5 61 77 76 49
Study chairs or principal investigators
Bruno Vellas, MD, Study Chair, Hôpital la Grave-Casselardit, Toulouse
More Information
Study ID Numbers: CL2-18986-009
Last Updated: December 8, 2005
Record first received: September 12, 2005
ClinicalTrials.gov Identifier: NCT00202540
Health Authority: France: Afssaps - French Health Products Safety Agency
ClinicalTrials.gov processed this record on 2006-05-04
U.S. National Library of Medicine, Contact NLM Customer Service
National Institutes of Health, Department of Health & Human Services
Copyright, Privacy, Accessibility, Freedom of Information Act
Randomized, Placebo-Controlled Trial of an AMPAkine in Major Depressive Disorder
This study is not yet open for patient recruitment.
Verified by Mount Sinai School of Medicine December 2005
Sponsors and Collaborators: Mount Sinai School of Medicine
National Institutes of Health (NIH)
Information provided by: Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT00262665
Purpose
The purpose of this study is to test a candidate drug, Org 24448,in a phase II clinical trial in adult patients with moderately treatment-resistant unipolar major depressive disorder.
Condition Intervention Phase
Major Depressive Disorder
Drug: ORG 24448
Phase II
MedlinePlus related topics: Mental Health
Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Single Group Assignment, Efficacy Study
Official Title: Randomized, Placebo-Controlled Trial of an AMPAkine in Major Depressive Disorder
Further study details as provided by Mount Sinai School of Medicine:
Primary Outcomes: Reduction of depressive symptoms as measured by the several depression rating scales at 8 weeks
Secondary Outcomes: Effect on neuropsychological functioning measured at 7 weeks
Study start: January 2006; Expected completion: January 2009
Major depressive disorder (MDD) is a common, severe, chronic and often life-threatening illness. Major depression contributes to significant morbidity and mortality. Available pharmacotherapies for major depression are suboptimal in terms of speed of onset, efficacy, and tolerability. Current medications for severe, chronic mood disorders are not based on pathophysiological models of illness, but rather are variation of monoaminergic-based therapies. Org 24448 represents a new treatment approach for depression, by potentiating the AMPA receptor subfamily of ionotropic glutamate receptors. This drug has been shown to have antidepressant features in preclinical models, as well as cognitive-enhancing qualities.
Eligibility
Ages Eligible for Study: 18 Years and above, Genders Eligible for Study: Both
Criteria
Inclusion Criteria:
Clinical Diagnosis of MDD
Have not responded to an adequate trial of one antidepressant in the current episode or have not completed antidepressant trials due to intolerance to 3 antidepressant medications in the current or a previous episode
Exclusion Criteria:
1. Presence of psychotic features, OCD, drug or alcohol dependency with the preceding 3 months
Location and Contact Information
Please refer to this study by ClinicalTrials.gov identifier NCT00262665
Sanjay Mathew, MD 212-241-4480 sanjay.mathew@mssm.edu
New York
Mount Sinai School of Medicine, New York, New York, 10029-6574, United States
Study chairs or principal investigators
Dennis S Charney, MD, Principal Investigator, Mount Sinai School of Medicine
More Information
Study ID Numbers: GCO # 05-0384
Last Updated: December 8, 2005
Record first received: December 6, 2005
ClinicalTrials.gov Identifier: NCT00262665
Health Authority: United States: Institutional Review Board
ClinicalTrials.gov processed this record on 2006-05-04
U.S. National Library of Medicine, Contact NLM Customer Service
National Institutes of Health, Department of Health & Human Services
Copyright, Privacy, Accessibility, Freedom of Information Act
Org 24448 to Treat Depression
This study is currently recruiting patients.
Verified by National Institutes of Health Clinical Center (CC) January 17, 2006
Sponsored by: National Institute of Mental Health (NIMH)
Information provided by: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00113022
Purpose
This study will evaluate the effectiveness of the experimental drug, Org 24448, for short-term treatment of depression. It will examine the effects of the drug on symptoms, such as low mood and persistent sadness, poor sleep and appetite, poor motivation and lack of enjoyment of things people normally enjoy, negative thinking, and feeling slowed down or having trouble concentrating. It will also assess whether the drug improves cognitive function, especially memory.
Patient with major depression who do not have a serious, unstable medical illness and who are 21 to 55 years of age may be eligible for this study. Candidates are screened with a psychiatric and medical history, diagnostic interview, physical examination, electrocardiogram, blood tests and, for women, a pregnancy test.
Participants are tapered off anti-depression drugs (and any other medications not allowed on the study) over a 3-week period and then begin a 2-week drug-free period. During these 2 weeks they have an electroencephalogram (EEG) with light stimulation, and those whose EEG indicates a seizure disorder are excluded from the study. Also at the beginning of the drug-free period they begin taking a placebo ("sugar pill") twice a day. After 2 weeks on placebo, some patients begin treatment with Org 24448, while others remain on placebo. They continue the medication for 8 weeks, during which time they have a weekly check of vital signs, blood and urine tests, and rating scales for depression and anxiety. Level of functioning is evaluated twice during the study. After 8 weeks of treatment, patients have a physical exam, electrocardiogram (ECG), EEG, blood tests, and begin to come off the study drug, tapering the medication over a week.
In addition to the above procedures, some patients undergo the following tests during the 2-week drug-free period and again toward the end of the 8-week medication phase:
-Neuropsychological testing, including measurements of cognitive abilities such as memory, attention, problem-solving, and language skills.
-Positron emission tomography (PET): This nuclear medicine test provides information about different brain regions. The patient lies on a table in the PET scanner (similar to a CT scanner), with a mask placed over his or her face that helps keep the head still. A sugar fluid with a radioactive material attached to it is injected into a catheter (plastic tube) that has been inserted into a vein in the patient's arm. The scanner detects the radiotracer in brain areas, showing patterns of sugar metabolism. Saliva specimens are collected during a 24-hour period before the PET scan to examine different chemicals in the body.
-Magnetic resonance imaging (MRI): MRI uses a magnetic field and radio waves to produce images of the brain. The patient lies on a table that is moved into the scanner (a narrow cylinder), wearing earplugs to muffle loud knocking and thumping sounds that occur during the scanning process. The procedure lasts about 45 minutes, during which the patient will be asked to lie still for minutes at a time.
-Lumbar puncture (spinal tap): For this procedure, a local anesthetic is given and a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle.
When the study ends, patients receive standard clinical treatment for up to 3 months and are then transferred to the care of an outside clinician.
Atendemos pacientes de habla hispana.
Condition Intervention Phase
Depression
Drug: Org 24448
Phase II
MedlinePlus related topics: Depression
Study Type: Interventional
Study Design: Treatment, Safety/Efficacy
Official Title: An Investigation of the Antidepressant Efficacy and Safety of an AMPAkine (Org 24448) in Major Depressive Disorder, A Double-Blind, Placebo-Controlled, Randomized Study
Further study details as provided by National Institutes of Health Clinical Center (CC):
Expected Total Enrollment: 90
Study start: May 31, 2005
Depression is a devastating illness that is estimated to affect 12% to 17% of the population at some point during the lifetime of an individual. Despite the availability of a wide range of antidepressant drugs, 30% to 40% of patients with major depression fail to respond to first-line antidepressant (e.g., selective serotonin reuptake inhibitors (SSRIs)) treatment, despite adequate dosage, duration, and compliance. Thus there is a clear need to develop novel and improved therapeutics for major depression. Current pathophysiological theories regarding the neurobiology of depression include alterations in intracellular signaling cascades, and impairments of cellular plasticity and resilience. There is recent evidence suggesting that promoting growth factors such as brain derived neurotrophic factor (BDNF) may provide a mechanism for the treatment of depression. New information indicating modulation of glutamate receptors in the actions of antidepressant treatments suggests a novel approach to develop a new class of antidepressants. Studies have shown that the biarylpropylsulfonamide AMPA receptor potentiators (LY392098 and LY451616) have antidepressant effects in animal models of depression. Several studies have demonstrated that AMPA receptor activation can increase expression of BDNF both in vitro and in vivo. Thus, one possible new approach for the treatment of depression is to use an AMPA receptor potentiator.
In this study we propose to compare the ampakine receptor potentiator Org 24448 to placebo for the treatment of Major Depression. Inpatients and outpatients (primarily outpatients), ages 21 to 55, with a diagnosis of Major Depression (without psychotic features), will be randomized to double-blind treatment to either Org 24448 or placebo for a period of 8 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Approximately 90 patients with acute major depression will be enrolled in the study in order to reach the goal of randomizing 70 patients in the controlled trial.
Eligibility
Genders Eligible for Study: Both
Criteria
INCLUSION CRITERIA:
1. Male or female subjects, 21 to 55 years of age.
2. Female subjects who are not of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year) or must be using a medically accepted means of contraception. Women using oral contraceptive medication for birth control must also be using a barrier contraceptive. Women of childbearing potential must also have a negative serum Beta-HCG at pre-study.
3. Subjects must fulfill DSM-IV criteria for Major Depression (296.3) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, the Structured Clinical Interview for DSM-IV TR Axis I Disorders, (SCID-P).
4. Subjects have a history of at least one previous episode of depression prior to the current episode.
5. Subjects must have an initial score of greater than or equal to 32 on the IDS-C at Visit 1 and Visit 2.
6. Subjects must not have greater than a 25% decrease in the IDS-C total scores during washout (between Visits 1 and 2).
7. Each subject must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document.
8. Current major depressive episode of at least 4 weeks duration.
9. Subjects who have not responded to adequate previous trials of at least one antidepressant as determined by the Antidepressant Treatment History Form (ATHF) criteria (score greater than or equal to 3). Additionally, patients who have not completed antidepressants trials of adequate dose and duration due to intolerance to therapy may be induced if they have demonstrated intolerance to greater than or equal to 3 antidepressant medications in the current or a previous episode, and did not meet ATHF criteria for a single adequate treatment trial in the current episode. 3 intolerant trials would count as an adequate failed trial. If this criteria has not been met, the Principal Investigator may allow for a four-week prospective trial of a standard antidepressant (at the patients' and clinicians' discretion) for potential participants who have not responded to at least one adequate trial for the current episode per inclusion criteria.
EXCLUSION CRITERIA:
10. Presence of psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder or bipolar disorder as defined in the DSM-IV.
11. Subjects with a diagnosis of Obsessive Compulsive Disorder as defined in the DSM-IV.
12. Subjects reporting Borderline or Antisocial Personality disorders. Other Axis II disorders do not qualify one for exclusion from the study.
13. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months.
14. Female subjects who are either pregnant or nursing.
15. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
16. Clinically significant abnormal findings of laboratory parameters, physical examination, EEG, or ECG.
17. Subjects with a lifetime history of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome.
18. Subjects with uncorrected hypothyroidism or hyperthyroidism.
19. Subjects with one or more seizures without a clear and resolved etiology.
20. Treatment with a reversible MAOI within 2 weeks prior to Visit 2.
21. Treatment with fluoxetine within 4 weeks prior to Visit 2.
22. Treatment with clozapine or ECT within 3 months prior to study Visit 2.
23. Judged clinically to be at serious suicidal or homicidal risk.
24. Participation in a clinical trial of another investigational drug within 1 month prior to study entry (visit 1).
25. Patients starting hormonal treatment (e.g., estrogen) in the last 3 months prior to visit 1.
26.Patients undergoing current nonpharmacologic antidepressant treatments, such as light therapy and psychotherapy.
27. Patients will be excluded who have previously failed greater than or equal to 3 lifetime adequate antidepressant trials by ATHF criteria (Sackeim 2001).
28. Patients with any evidence of a seizure disorder as assessed by an EEG with photic stimulation.
ADDITIONAL INCLUSION AND EXCLUSION CRITERIA FOR PET SCANS ONLY: THIRTY SUBJECTS WITH MAJOR DEPRESSIVE DISORDER WILL PARTICIPATE IN THE IMAGING COMPONENT OF THIS STUDY.
INCLUSION:
1. Subjects who are ages 21-55.
2. Subjects with an early age of onset (before age 40).
3. Subjects who either meet melancholic subtype criteria and/or have a first degree relative with bipolar disorder.
4. Negative pregnancy test within 24hrs. of PET, in women of childbearing potential.
EXCLUSION:
1. Subjects will have been off psychotropic drugs (including zolpidem) for at least 3 weeks (8 weeks for fluoxetine) prior to PET.
2. Subjects with a history of lifetime DSM-IV substance dependence (except for nicotine or caffeine).
3. Subjects with substance abuse within 12 months (except for nicotine or caffeine).
4. Subjects with a current or lifetime history of hypertension or diabetes.
5. Subjects who have reached the annual research radiation exposure limit.
Location and Contact Information
Please refer to this study by ClinicalTrials.gov identifier NCT00113022
Maryland
National Institute of Mental Health (NIMH), 9000 Rockville Pike, Bethesda, Maryland, 20892, United States; Recruiting
Patient Recruitment and Public Liaison Office 1-800-411-1222 prpl@mail.cc.nih.gov
TTY 1-866-411-1010
More Information
Detailed Web Page
Publications
Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry. 2000 Mar;57(3):270-6.
Austin MP, Mitchell P, Goodwin GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry. 2001 Mar;178:200-6. Review.
Austin MP, Mitchell P, Wilhelm K, Parker G, Hickie I, Brodaty H, Chan J, Eyers K, Milic M, Hadzi-Pavlovic D. Cognitive function in depression: a distinct pattern of frontal impairment in melancholia? Psychol Med. 1999 Jan;29(1):73-85.
Study ID Numbers: 050161; 05-M-0161
Last Updated: April 1, 2006
Record first received: June 2, 2005
ClinicalTrials.gov Identifier: NCT00113022
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2006-05-04
U.S. National Library of Medicine, Contact NLM Customer Service
National Institutes of Health, Department of Health & Human Services
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