Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Neuro, Just wondering if you're ready to go on the record about the odds of a PIPE in the near future (Q4-06/Q1-07)? Thanks.
Aiming, The thing with AD is that a high impact is the way to go. Low impacts like CX-717 will probably only provide symptomatic relief, although based on the lack of current treatments that could still be something big (just look at junk like Aricept, and only slightly better Namenda).
Ideally it would be best to save the neurodegenerative rights for when Cortex has a proven high impact in the clinic, but Cortex needs the money now and is thus forced to lose the rights. On the bright side, we can still do some type of high impact deal later with the BP (for the compound), even though the neurodegenerative rights are gone.
Aiming, Dr. Stoll does seem to be going in that direction (non-Ampakine in-license), and Cortex may have identified the program they want. However, Cortex doesn't have sufficient cash reserves at the moment, and with CX-717 still in partial limbo due to the dose restrictions (the severity of which we'll hopefully find out in the conf call), the BP deal proceeds may not be available until Q1/Q2. Other sources of money include the warrant proceeds and a PIPE.
Cortex may be worried that another company will grab the coveted in-license program first. If Stoll wants the in-license deal immediately, he might have to do a PIPE. I'm not a big fan of the in-license idea, and therefore wouldn't favor a less than favorable PIPE just to accomplish it. We'll see what happens.
Thanks Neuro. If the upper end 800 mg BID dose is not currently allowed by the dosing restriction (perhaps Dr. Stoll may clarify this in the conf call), wouldn't it seem logical for BPs to want to see that restiction lifted prior to consummating a deal? BPs have to figure that the FDA could still shoot down CX-717 based on a problem in the 3 month primate tox study.
Also, with Shire becoming the one-stop shop for ADHD, doesn't a deal with them seem increasingly possible? They probably aren't interested in AD/neurodegenerative, and could out-license those themselves to a BP. Or do you think Cortex will prefer a bonafide BP partner like Lilly, Glaxo, etc? Thanks.
Daviddal, With the FDA, some of what we perceive as bias/malice might only be the lack of resources/funding and general incompetence. Government agencies are screwed up on many levels. CYA/butt covering is also a big factor at the FDA, more than usual.
At least the partial lift of the hold indicates that the data we did send the FDA was clean. I'm still curious as to what the nature of the acute histo "finding" was, tissue type, etc. Perhaps Dr. Stoll can now discuss it in more detail. It'll also be interesting to get the particulars on the dose limitations. At the least, it's probably safe to assume that a relatively high dose/longer duration ADHD Phase 2b won't be allowed until after the dosing limitations are removed.
Daviddal, Yes, that was an anticipatory/preemptive move which turned out to be wise. BTW, do you remember if the original 3 month tox study in two species was in dogs and rats? I seem to remember that, but no longer have my original transcribed notes to verify it (only the audio tapes of the various conf calls/presentations). Thanks.
It figures that the FDA would be pricks about lifting the hold completely. On the other hand, wanting to see a second set of 3 month tox data is understandable, particularly if the original data was in dogs, and the histo "finding" was in primates.
Until we get clarification from the conf call, here's how I'm tentatively looking at the situation -
1) The clinical hold on CX-717 is partially lifted, but only for a specified/limited dose range. Presumably this means the lower doses. It might also mean shorter duration of dosing. Once the new 3 month tox data is completed and the results analyzed, then the dosing restrictions could be removed by the FDA.
2) The AD PET scan trial can resume (the only clinical trial that was still underway at the time the clinical hold was put into effect). The press release doesn't say anything about the initiation of new trials (presumably this would be OK, but subject to the dosing restrictions).
3) An ADHD Phase 2b of the type Cortex or a BP would want to run (high dosing levels, longer duration) probably can't be initiated until the new 3 month tox study is completed and the dosing restrictions are removed.
4) BP negotiations will resume but will probably not be consumated until after the FDA analyzes the new 3 month tox data and lifts the dosing restrictions.
A few other thoughts -
a) Based on yesterday's volume, we might (hopefully) be seeing some significant warrant share activity. Proceeds from those warrants would help replenish Cortex's cash, which is otherwise estimated at only $8-10 mil by year end. Warrant proceeds would reduce the need for a Q4 financing, though we might get one anyway.
b) The partial lifting of the hold (with dosing restrictions) should delay consumating the BP deal, and this delay could subsequently delay completion of the non-Ampakine in-licensing. This could be a problem if other companies are also interested in acquiring that program and have ready cash.
c) I don't remember Dr. Stoll publicly saying that they were repeating the 3 month tox study in 2 species (unless I missed it). All along we had been under the impression that the problem/deficiency was only in the short term acute studies. The FDA apparently didn't request the new 3 month tox studies, but these were probably recommended by the consultants Cortex hired, just in case. Hiring those guys was a smart move.
Neuro, Without my detailed notes I'm having to rely on memory, but wasn't the histo "finding" seen in primates (acute short term primate tox data)? Also relying on memory, the original 3 month tox study was done on dogs and rats (not primates). So the FDA now logically wants to see longer term 3 month PRIMATE tox data.
The original 3 month tox study (the results of which were supposedly not a factor in the clinical hold), were needed in order to do longer term Phase 2b type studies. So it seems unlikely that the FDA will approve a Phase 2b IND before seeing the results of this new 3 month tox trial.
Dr. Stoll never told us that they were doing additional 3 month tox studies. As you said, these were probably (wisely) recommended by the consultants hired by Cortex to help deal with the FDA.
The conf call should be very interesting.
Cortex did run 3 month tox studies on CX-717 already, though I think they were in dogs and rats (I'll check my notes). From today's press release, the new 3 month studies the FDA wants to see (and that will be finished by year end) are in primates and rats.
It's possible that the 800 mg BID dose used in the ADHD trial is beyond the dose that the FDA is currently allowing for CX-717. That would be a problem if 800 mg BID is the upper dose being planned for a Phase 2b. We'll find out more specifics on the FDA's dosing limitations in the upcoming conf call.
A big question is how far BP negotiations can proceed if the 800 mg BID dosing level is beyond what is currently allowed for CX-717. Even without this factor however, I figure we're probably looking at a financing before year end, unless we get some significant warrant excercising.
Daviddal, Nice summary. I'm figuring the odds at approx 80% or better for the clinical hold to be lifted on the first try (by mid October), with the stock moving quickly to $5-6. Sometime before year end I figure a $20-25 mil financing should happen, perhaps in the $4-5 range. After a temporary dip, the stock then quickly moves back up to the $5-6 range, and then gradually trends higher in anticipation of the BP deal. I figure the stock could see $7-8 or more after the BP deal is announced (possibly Q1-07). If some institutions start to pile in, these estimates could be conservative.
Of course if the lift of the clinical hold is delayed (I figure under 20% chance), then we're in for some serious trouble for a while, with an unfavorable financing being needed by early '07. But overall, the current "binary event" odds seem very favorable (80% good vrs 20% bad). I don't have any funds available for bio betting right now, but if I did I'd probably place a decent sized wager on Cortex.
Davey, Recent company guidance is for $8-10 mil in cash remaining at year end, so there is obviously a need for additional money soon. Possible sources -
1) BP deal for CX-717/neurodegenerative rights.
2) Proceeds from excercising of warrants.
3) PIPE, or some type of secondary offering.
Hopefully there will be a significant amount of #2 right after the clinical hold is lifted (there is over $20 mil in potential warrant proceeds out there). The other possibility is that #1 might happen quickly right after the clinical hold, though more likely it may take into Q1-07 to finalize the deal. Alternatively #3, a 5 mil share PIPE at say $4-5 would yield a fast $20-25 mil, allowing Cortex to bargain with BPs from a position of strength (Cortex then having the cash available to do an in-house ADHD Phase 2b if necessary, rather than having our backs to the wall). Also, don't forget that Cortex will need even more money to acquire the in-licensed non-Ampakine program and move it through the clinic. All things considered, a PIPE in the $4-5 range or better would be a wise move all around. In the bio world, smart CEO's grab the cash when the grabbing is good.
Dr. Stoll said that the new info had been sent to the FDA on Sept 8th, and that the FDA had received it on Sept 11th. So as I understand it, the FDA should give their decision within 30 days of Sept 11th. At the Roth Conf, Dr. Stoll said they should have a response by "mid-October, roughly speaking".
Concerning the "toast" scenario, if something really dire was readily apparent in the new results, Cortex would have almost certainly said something since it would have been material. A second possibility is that there may have been something abiguous seen in the results, not clearly dire but possibly not right, and Cortex submitted that ambiguous data to the FDA, not saying anything about the data publicly one way or the other. A third possibility is that the data looked totally clean to Cortex, but the FDA might want additional data/studies for some other reason. And a forth possibility is that the data looked totally clean, and the hold is lifted immediately.
Clinical holds are apparently not all that uncommon. When it happens to a big company, it's not necessarily considered "material" and the public never even hears about it. Microcaps often have everything riding on their lead compound, so the existence of the hold has to be made public.
Looks like the market is in party mode today - Nasdaq up 2%. Well, my 5.76% CDs were up .0158% today, yippee.
Aiming, One would think that Dr. Stoll would want to allow the share price to rise as far as it could get before doing the PIPE. What might potentially be a drag on the up move could be - a) significant block sales of shares following warrant excercising, b) the overall perception that a PIPE is coming, and c) the usual shenanigans that go on during the PIPE pricing period. The existence of $5 options on Cortex might also be a factor. Still, I'd be surprised if we don't spike to at least $5, even if the PIPE is priced lower than that.
Looking farther out, what bothers me is the non-Ampakine in-licensing strategy. I still can't warm up to that idea, though I can see the rationale for it.
I was talking to someone recently who has early stage Parkinson's, and we discussed high impact Ampakines. I'm wondering when Lilly is going to get a trial started. And there's nothing stopping Servier from starting a Parkinson's trial with S-18986 either, to go along with their MCI trial. A Parkinson's trial could really be a high profile event for the entire Ampakine concept/platform.
Thanks, Erbse. So we can add Sanofi-Aventis to the growing list of companies with AMPA upregulating programs. It looks like dipyrazoles affect NMDA activity also.
A few other AMPA programs are Boehringer Ingelheim's which has been around for a while (now with something called BIIR-777). There's also "Stargazin", which is a TARP (Transmembrane AMPA Receptor Regulatory Protein), which is apparently involved in the surface delivery and anchoring of AMPA receptors, and may also be an allosteric modulator.
I'm going to go out on a limb and predict that the clinical hold will be lifted on CX-717 on the first try (I figure a 80% chance or better). The next big question then will be whether or not a financing will occur between now and the completion of the BP deal. I'm figuring it's fairly likely, for several reasons -
1) A $8-10 mil cash level at year isn't near enough to allow Cortex to bargain with BPs from strength.
2) Dr. Stoll appears to be going the non-Ampakine in-licensing route, which will cost some money.
Of course if there's a considerable amount of warrant excercising after the clinical hold is lifted (or if the BP deal happens very quickly after the clinical hold is lifted), then a financing might be avoided. On the other hand, it might be foolish to not take advantage of the opportunity to grab some favorable cash with the stock at the $5 or better level - the standard "get the money when you can" biotech approach.
Looking at the potential downside scenarios -
1) FDA wants additional studies done for some less than dire reason, causing another 6 month delay. This isn't that likely, but you never know. This puts Cortex in an early '07 cash bind, with an unfavorable financing likely.
2) A seriously bad finding in the new studies, and CX-717 is toast. This is very unlikely, and we would have probably already heard something from Cortex.
I'm figuring the most likely scenario is - a) clinical hold is lifted by mid-October, b) a financing occurs not too long afterwards, c) the BP deal occurs by early '07, followed shortly by d) the announcement of a non-Ampakine in-licensing.
BTW, I wonder if Jim Haynes is still out there holding his gigantic position? Jimbo, what's up? :o)
If nothing else, that Lifelike Biomatic patent provides a good overview of the various families of compounds out there that have AMPA upmodulating activity -
1) Benzoylpiperidines - CX-516, CX-546 (Cortex)
2) Benzoxazines - CX-614 (Cortex)
3) Benzothiadiazides - Cyclothiadiazide
4) Benzothiadiazines - S-18986 (Servier)
5) Benzoylpyrrolidines - CX-554 (Cortex)
6) Biarylpropylsulfonamides - LY-392098, LY-404187, LY-503430 (Lilly)
7) Pyrrolidinones - Aniracetam, Piracetam
8) Azepines - Benzoxazepines (Organon has some patents on these).
I didn't see Benzofurazans listed (Org-24448), though perhaps these might overlap into one of the above families.
The idea of using an NMDA upmodulator in combination with an AMPA upmodulator could have some merit, though it adds another layer of potential side effects. The NMDA receptor is downstream of the AMPA receptor, so upregulating AMPA already indirectly upregulates NMDA activity. The NMDA receptor can also be stimulated directly via its glycine binding site. A potential advantage of stimulating NMDA activity indirectly via an Ampakine is that by being allosteric at the AMPA receptor, the Ampakine merely magnifies the normal existing neural activity, as opposed to a direct NMDA agonist which initiates new neural activity all by itself.
The idea of actually fusing the functional moiety of an AMPA upmodulator with the functional portion of a NMDA modulator (into a single molecule) is an interesting idea worth getting a broad patent on, but we'll see if anything ever comes of it.
While we wait, here's one of the more interesting Ampakine related patents to come along in a while. We discussed this several months ago, but since it's a slow day --
Some backround - Dr. Baudry (prominent USC researcher) co-founded the company - Lifelike Biomatic. He previously co-authored numerous papers with Cortex related authors (Lynch, Gall, Lauterhorn, etc), and was one of the authors of the calpain/spectrin papers. A while back we heard rumors that he had a falling out with Dr. Lynch.
This Baudry/Lifelike Biomatic's patent attempts to cover the use of AMPA modulators (Ampakines) when used in combination with NMDA modulators ("Nemdakines"), at doses lower than which are effective when each is given alone (the theory being that given together there is an additive/synergistic effect). The patent also covers use of Ampakine and Nemdakine compounds when their functional moieties are fused together into one molecule (pretty wild concept). The patent attempts to cover just about every family of AMPA modulators out there (see my next post) -
>>> United States Patent Application 20060063707
Kind Code A1
Baudry; Michel ; et al. March 23, 2006
--------------------------------------------------------------------------------
Compositions for enhancing memory and methods therefor
Abstract
Compositions for enhancing memory of a subject comprising a combination of a positive modulator of an AMPA receptor and a positive modulator of an NMDA receptor are provided, wherein each modulator of the combination is present at a subtherapeutic dose for effecting memory enhancement. Methods for using such compositions in the treatment of cognitive impairment associated with aging, age-related diseases, and CNS disorders, for example, are provided. New fusion molecules are also provided that combine the positive modulator functionalities into one molecule.
--------------------------------------------------------------------------------
Inventors: Baudry; Michel; (Irvine, CA) ; Bischoff; Serge; (Robion, FR)
Correspondence Name and Address: HAYNES AND BOONE, LLP
901 MAIN STREET, SUITE 3100
DALLAS
TX
75202
US
Assignee Name and Adress: Lifelike Biomatic, Inc.
Roanoke
TX
Serial No.: 229423
Series Code: 11
Filed: September 16, 2005
Claims
1. A method for enhancing memory of a subject, the method comprising: administering to the subject a therapeutically effective amount of a combination of a positive modulator of AMPA receptors and a positive modulator of NMDA receptors, wherein each modulator of the combination is present at a subtherapeutic dose for effecting memory enhancement.
2. The method of claim 1 wherein the subject has symptoms of a neurodegenerative disease.
3. The method of claim 1 wherein the subject has symptoms of cognitive impairment due to aging, Alzheimer's disease, dementia, schizophrenia, attention deficit hyperactivity disorder, or Parkinson's disease.
4. The method of claim 1 wherein the subject is in need of improvement in performance of a cognitive task.
5. The method of claim 1 wherein the method of administering is oral, nasal, topical, via injection, or via a catheter.
6. The method of claim 1 wherein the positive modulator of an AMPA receptor comprises an azepine, a benzamide, benzoylpiperidine, benzoylpyrrolidine, benzoxazine, benzothiadiazide, benzothiadiazine, biarylpropylsulfonamide, pyrrolidinone, pyrroline, tetrahydropyridine, phenoxyacetamide, sulfur-containing organic nitrate ester, lectin, a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
7. The method of claim 1 wherein the positive modulator of an NMDA receptor is an L-alanine, D-alanine, D-cycloserine, N-methylglycine, L-serine, D-serine, N, N, N-trimethylglycine, 3-amino-1-hydroxypyrrolid-2-one (HA966), (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (ALX5407), N-methyl-N-[3-[(4-trifluoromethyl)phenoxy]-3-phenyl-propyl]glycine (ORG 24598), polyamine, neurosteroid, a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
8. A composition comprising: a combination of a positive modulator of AMPA receptors and a positive modulator of NMDA receptors in a therapeutically effective amount for effecting memory enhancement, and a pharmaceutically acceptable carrier, wherein each modulator of the combination is present at a subtherapeutic dose for effecting memory enhancement.
9. The composition of claim 8 wherein the positive modulator of an AMPA receptor comprises an azepine, a benzamide, benzoylpiperidine, benzoylpyrrolidine, benzoxazine, benzothiadiazide, benzothiadiazine, biarylpropylsulfonamide, pyrrolidinone, pyrroline, tetrahydropyridine, phenoxyacetamide, sulfur-containing organic nitrate ester, lectin, a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
10. The composition of claim 9 wherein the positive modulator of an AMPA receptor comprises a benzoylpiperidine and the benzoylpiperidine comprises a 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516), 1-(1, 4-benzodioxan-6-ylcarbonyl)piperidine (CX546), 1-(4'-methoxymethylbenzoyl)piperidine, 1-(3'-methoxymethylbenzoyl)piperidine, 1-(4'-ethoxymethylbenzoyl)piperidine, 1-(4'-hydroxymethylbenzoyl)piperidine, 1-(4'-(3', 4'-methylenedioxyphenoxy)-methylbenzoyl)piperidine, 1-(1, 3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), (R, S)-1-(2-methyl-1, 3-benzodioxol-5-ylcarbonyl)-piperidine, 1-(1, 3-benzoxazol-6-ylcarbonyl)-piperidine, 1-(1, 3-benzimidazol-5-ylcarbonyl)-piperidine, a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
11. The composition of claim 9 wherein the positive modulator of an AMPA receptor comprises a benzoxazine, and the benzoxazine is 2H, 3H, 6aH-pyrrolidino[2', 1'-3'2']1, 3-oxazino[6', 5'-5, 4]benzo[e]1, 4-dioxan-10-one (CX614), (R, S)-6-methoxymethyl-2, 3-dihydro-1H-pyrrolo[2, 1-b][1, 3]benzoxazine-9(3aH)-one, R, S)-7-methoxymethyl-2, 3-dihydro-1H-pyrrolo[2, 1-b][1, 3]benzoxazine-9(3aH)-one, 7, 8-dihydro-5aH, 10H-1, 3-dioxolo[4, 5-g]oxazolo[2, 3-b][1, 3]benzoxazin-10-one (1), 8, 9-dihydro-6aH, 11H-1, 4-dioxan[2, 3-g]oxazolo[2, 3-b][1, 3]benzoxazin-11-one, 7, 8-dihydro-2, 2-dimethyl-5aH, 10H-1, 3-dioxolo[4, 5-g]oxazolo[2, 3-b][1, 3]benzoxazin-10-one, 7, 8-dihydro-5aH, 10H-1, 3-dioxolo[4, 5-g]thiazolo[2, 3-b][1, 3]benzoxazin-10-one, 7, 8-dihydro-7-methyl-5aH, 10H-1, 3-dioxolo[4, 5-g]oxazolo[2, 3-b][1, 3]benzoxazin-10-one, 7, 8-dihydro-8-methyl-5aH, 10H-1, 3-dioxolo[4, 5-g]oxazolo[2, 3-b][1, 3]benzoxazin-10-one, 8, 9-dihydro-5aH, 7H, 10H-1, 3-dioxolo[4, 5-g][1, 3]oxazino[2, 3-b][1, 3]benzoxazin-11-one, 7, 8-dihydro-5a-methyl-10H-1, 3-dioxolo[4, 5-g]oxazolo[2, 3-b][1, 3]benzoxazin-10-one, a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
12. The composition of claim 9 wherein the positive modulator of an AMPA receptor comprises a benzothiadiazide and the benzothiadiazide is cyclothiazide, diazoxide, IDRA21, bendroflumethiazide, benzthiazide, buthiazide, chlorothiazine, epithiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, methalthiazide, polythiazide, trichlormethiazide, 5-ethyl-benzothiadiazide (compound D1), a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
13. The composition of claim 9 wherein the positive modulator of an AMPA receptor comprises a benzothiadiazine and the benzothiadiazine is 7-chloro-3-methyl-3-4-dihydro-2H-1, 2, 4 benzothiadiazine S, S, dioxide, (S)-2, 3-dihydro-[3, 4]cyclopentano-1, 2, 4-benzothiadiazine-1, 1-dioxide (S18986-1), a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
14. The composition of claim 9 wherein the positive modulator of an AMPA receptor comprises a benzoylpyrrolidine and the benzoylpyrrolidine comprises 2H, 5aH-pyrrolidino[2', 1'-3', 2']1, 3-oxazino[6', 5'-5, 4]benzo[d]1, 3-dioxolan-9-one (BDP-20, CX554), 1(1, 3-benzodioxol-5-ylcarbonyl)-pyrrolidine), a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
15. The composition of claim 9 wherein the positive modulator of an AMPA receptor comprises a biarylpropylsulfonamide and the biarylpropylsulfonamide comprises N-2-(4-(3-thienyl)phenyl)propyl-2-propanesulfonamide (LY392098), N-2-(4-(cyanophenyl)phenyl)propyl-2-propanesulfonamide (LY404187), (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-c- arboxylic acid methylamide (LY503430), a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
16. The composition of claim 9 wherein the positive modulator of an AMPA receptor comprises a pyrrolidinone, and the pyrrolidinone comprises aniracetam, piracetam, oxiracetam, (R)-1-p-anisoyl-3-hydroxy-2-pyrrolidinone (AHP), a salt thereof, an ester thereof, a precursor thereof, a metabolite thereof, a derivative thereof, a racemic mixture thereof, or a combination thereof.
etc <<<
Dew, Here's a DPD related abstract. They note that a "decrease in DPD activity results in toxicity to 5-FU in cancer patients", and recommend that cancer patients be screened for low DPD activity prior to 5-FU treatment. Eniluracil irreversibly inhibits DPD (the enzyme that breaks down 5-FU), so it has the potential to greatly increase 5-FU's toxicity -
>>> Dihydropyrimidine Dehydrogenase (DPD)
(Toxicity to 5-FU Anti-Cancer Drugs)
DPD is the rate limiting enzyme involved in the catabolism of pyrimidines
like thymidine and uracil.
DPD is also the main enzyme involved in the degradation of structurally
related compounds like 5-Fluorouracil (5-FU), a widely used anticancer
drug.
Decrease in DPD activity results in toxicity to 5-FU in cancer patients.
A guanine to adenine point mutation in the 5'-splice site consensus
sequence was noted in subjects with DPD deficiency.
On the basis of catalytic activity, and on the basis of the mutation
frequency. a 3% frequency for heterozygotes (-/+) to DPD was predicted,
projecting a 1:1000 homozygotes (+/+) for this mutation across racial lines.
Even heterozygosity for this mutation can result in a large decrease in DPD
activity and an increase in toxicity to 5-FU.
It is recommended that screening for this mutation should be accompanied
by direct measurement of DPD activity prior to 5-FU treatment in cancer
patients. Although this particular mutation is much more frequent than
other mutations in the DPD gene, absence of this splice site mutation does
not rule out the possibility of a decrease in DPD activity due to another
mutation. <<<
Dew, Concerning ADH -- by blocking the activity of the enzyme DPD, eniluracil should increase the toxicity of 5-FU. It also looks like eniluracil "temporarily blocks the activation of 5-FU into the metabilites responsible for its anti-cancer activity". That doesn't sound like a particularly promising combination of effects (greater toxicity and possibly less efficacy). ADH says that they're trying to get around these problems by altering the dosing levels/schedules. Have the ADH studies completed to date indicated that they're on the right track? The fact that Glaxo previously abandoned eniluracil is not reassuring. Thanks for your insights.
From the ADH press release - >>> GSK’s clinical development program for the combination of 5-FU and eniluracil met with success in early development. However, three Phase III trials undertaken by GSK failed and development was stopped. Since then, Adherex has generated data which provide a new understanding of the mechanism of action of eniluracil - namely that eniluracil not only inhibits the breakdown of 5-FU, it also temporarily blocks the activation of 5-FU into the metabolites responsible for its anti-cancer activity. As a result, the Company has identified three factors that are necessary to optimize the combination of eniluracil and 5-FU: 1) the dose of eniluracil, 2) the ratio between the eniluracil and 5-FU dosages, and 3) the schedule of administration of the two drugs. <<<
Thanks for the input. I'd love to try CX-717 and Provigil and compare them. After passing 50 recently, I've noticed that my memory and energy level just ain't what they used to be.
Lol. Dew, I remember you mentioned that you had tried some of the current neuro-related pharmaceuticals. I was wondering if you've tried Modafinil/Provigil, and what you thought of it? I've been thinking about trying it to regain some of my diminishing energy /mental focus/ stamina. I didn't want something that causes insomnia however. Thanks.
Dew, From the DARPA website - >>> Among the approaches currently under investigation include novel pharmaceuticals that enhance neural transmission, nutraceuticals that promote neurogenesis, cognitive training, and devices such as transcranial magnetic stimulation. <<<
So it looks like DARPA is trying a shotgun approach. Their stated goal is to produce soldiers who can stay awake for 10 straight days with no sleep - a ridiculous goal, but that's the direction. If Cortex or a BP partner runs a wildly successful Sleep Related trial some day, DARPA will likely become very interested again.
The good thing about DARPA's poor Shift Work results is that it's made it a lot easier for Cortex to carve out the Sleep Related indications from the upcoming BP deal.
I still think DARPA made a bad decision in turning their backs on Ampakines. A better designed Sleep Deprivation trial, along the lines of Cortex's successful UK study but with even longer sleep deprivation, would very likely show outstanding results.
Dr. Stoll hasn't said much on the situation with DARPA publicly, or the potential shortcomings of their Shift Work trial design. He did make it sound like DARPA has no further interest in CX-717. I always wondered if DARPA's previous strong interest in CX-717 might have been considered an overall negative by potential BP partners, since it might have meant some loss of control over the compound's development. If that's the case, perhaps Dr. Stoll wasn't all that upset by the poor Shift Work results and subsequent withdrawal of DARPA from the picture.
The Sleep Related indications still appear very viable though - just look at the UK Sleep Dep results from last year, and also Dr. Deadwyler's phenomenal primate studies. Instead of the non-Ampakine in-licensing strategy, another approach for Cortex to consider is a pure Ampakine pipeline consisting of some combination of the following programs -
1) ADHD Phase 2b with CX-717 (followed by a bigger BP deal).
2) Narcolepsy/Sleep Related Phase 2 with CX-701, once the Phase 1 is completed next year.
3) Huntington's, Frag-X, or Parkinson's trials with CX-929, once the compound is through tox and Phase 1.
In-licensing a non-Ampakine compound from another company carries with it a whole new set of risks. I'd rather see Cortex stick to its area of expertise, if at all possible.
Thanks Daviddal. So the TURNS/NIMH combo study will be happening, that's good news. The other Org-24448 combo trial I've seen that was supposed to start soon was with the CRO "ATP Group" which I assume is going ahead with Organon's blessing. Perhaps Organon also has another combo study they'll run on their own. Thanks for the info.
Alertmeipp, I probably would get back in with something if I had some high risk cash available, but I don't have much to play with at the moment (had to buy a new car several months ago, and just got back from a trip to Europe). My finances have been greatly depleted over the last 5 years, so I'm probably stuck in watching mode when it comes to bio stocks for the forseeable future.
Daviddal, I'm not sure I follow you on the the CX-717 ADHD Phase 2b strategy - are you saying that Cortex would start the Phase 2b and then do the BP deal mid-trial? Wouldn't it be more likely to either 1) outlicense it now and let the BP run the Phase 2b, or 2) have Cortex run the entire Phase 2b in-house until completion and then do the BP deal?
Also, Concerning the Org-24448 Schizo combo Phase 2b, I assume you're referring to the "ATP Group" trial, since TURNS/NIMH isn't happening? Or is Organon doing another combo Schizo trial in addition to the one by the CRO "ATP Group"? Thanks.
Personally I'd like to see Cortex pursue a strategy that dispenses with the need for the non-Ampakine in-licensing altogether.
AlohaDan, If the expected sequence of events is - 1) the clinical hold is lifted, followed by - 2) a good BP deal, then a warrant holder would probably just wait until after the BP deal to excercise their warrants. However, like us they may figure that a financing is likely in the period between event 1 and 2, since Dr. Stoll won't want to go into final BP negotiations runing on fumes. Avoiding the fumes scenario requires either a) considerable pre-BP deal warrant excercising proceeds, b) a PIPE financing, or c) a very quick BP deal in Q4.
Another timing wildcard is the non-Ampakine in-licensing event. One would logically expect this to occur with the money from a BP deal, but it might instead occur with the proceeds of a PIPE. There is also the issue of the market response to the in-licensing event itself.
Another variable is an alternate strategy that Stoll may be considering -- to forgo the BP deal for now and do a CX-717 Phase 2b ADHD trial in-house. Such an approach would require a post clinical hold lift financing. This approach has some merits, including a) the prospects for a bigger BP deal later, and b) no/less need for the non-Ampakine in-license. While conducting the CX-717 ADHD Phase 2b, Cortex could concurrently be getting CX-701 through Phase 1 and ready/into Phase 2. At the same time, CX-929 would also been moving toward the clinic. This would keep Cortex as an Ampakine company. Part of the rationale for the non-Ampakine in-license idea is that once CX-717 is outlicensed to BP, there's a big time gap before another Cortex compound can get up to speed. The above approach addresses that problem. The downside is that a PIPE would be needed, though after the clinical hold is lifted that could presumably be done in the $4-5 area, lessening the dilutive impact.
FWIW, I think the other scenario is more likely (BP deal in early '07, followed by in-licensing of another company's non-Ampakine program). However, if Stoll is going that way, a Q4 PIPE is still very possible, and if he can do it in the $4-5 range or better it would probably be wise either way (say 5 mil shares yielding $20-25 mil).
Neuro, Any thoughts on the liklihood of a PIPE prior to the BP deal? Dr. Stoll obviously doesn't want to go into final BP negotiations with only the $9-10 mil in cash that he projected for year end. I figure one way to avoid a PIPE would be if there's a lot of warrant excercising right after the clinical hold is lifted (last I checked there was approx $25 mil in potential proceeds out there, with an average excercise price just over $3). I'd hate to see a PIPE rain on the post-clinical hold lift parade, so perhaps the warrant holders will come through and help refill Cortex's coffers.
Neuro, With different head honchos running the two new CNS divisions of the FDA, with each having somewhat different approaches/agendas/egos, I wonder if there could be some regulatory confusion during the transition period? With Ampakines spanning the full spectrum of both Neurological and Psychiatric indications, won't there have to be some coordination between these two new CNS branches of the FDA when it comes to Ampakines?
Dew, Yes, those two companies (along with PARS) would make good case studies on the perils of bio investing, shady management, corporate desperation, etc.
OT - BTW, I ran across this hedge fund article today. There might be a lesson here for all us current/former bio-gunslingers --
>>> How do you lose $5 billion in one week?
Risky bets on natural gas prices threaten to swamp one of the nation's biggest hedge funds.
Amaranth Advisors has violated a cardinal rule of investing: Never make a trade that could put you out of business.
The Greenwich, Conn.-based hedge fund was scrambling today to sell holdings after a wrong-way wager on natural gas cost it roughly half of its $9.5 billion portfolio.
Amaranth's brokers -- including Goldman Sachs and other big financial firms -– stepped in to help the hedge fund raise cash by liquidating some of its assets.
Amaranth made about $1 billion last year, when energy prices were going up. But its energy desk failed to predict the extent of the recent downturn in natural gas prices, the fund told investors in a letter that went out on Monday.
The trade that led to the huge loss was attributed to 32-year-old Brian Hunter, an experienced energy trader who headed Amaranth's energy desk for the past five months. His trades brought in $800 million for the firm last year, and Hunter pocketed at least $75 million in compensation, according to Trader Monthly magazine.
Hunter's downturn was as sudden as it was shocking. He was up about $2 billion as recently as the end of August, The Wall Street Journal reports. Then Hunter's trades lost $5 billion in about a week.
Hunter thrived on volatility, reaping profits on price declines and surges alike, the Journal reports. But late last week, Hunter watched with growing alarm as gas prices took a steep dive, particularly in futures contracts for delivery of gas for this coming winter.
"(Hunter) thought he knew what the market was doing," says Journal editor Phil Kuntz, who worked on the newspaper's coverage of the Amaranth debacle. "The commodities market is very, very volatile. You make a lot of money very, very quickly but you can lose a lot of money very quickly," Kuntz adds. "(Hunter) made about $1 billion in April. He lost a bunch of money in May, then he made a bunch of money back. He had a great August -– by the end of August (the Amaranth trading desk) was up upwards of 20% (year to date) but then they took a big hit in the course of a week in September."
Fund investors feeling the sting of Amaranth's recent losses include Morgan Stanley, Credit Suisse, pension funds and individual investors. Amaranth is the second hedge fund in the last month to be whipsawed by the volatile energy markets. MotherRock, a $400 million fund run by former New York Mercantile Exchange President Bo Collins, lost all of its investors' capital last month when it mistimed the natural gas markets.
Wall Street was waiting to see where the next shoe would drop.
"You're going to see (a ripple effect) in September results, when the funds of (hedge) funds start reporting results," says the Wall Street Journal's Kuntz. "You're going to see it in other institutional investors, like pension funds. They're going to be taking huge hits from this."
"There are also winners on the other side of it," Kuntz says. "Some of the big Wall Street firms were taking essentially the opposite side -– not of specific bets that Brian Hunter and Amaranth were taking but taking basically the opposite view of the market. They made a lot of money in the last month."
Hedge-fund insiders say the sheer number of competitors chasing returns can lead some traders to assume outsized risks. "It's hard to find ideas that aren't picked over, and harder to get real returns and differentiate yourself," says hedge-fund manager Steve Cohen. "We're entering into a new environment. The days of big returns are gone."
Other insiders point to what they see as a lack of talent running some of the 7,000 hedge funds in the United States. "There's $1 trillion, and possibly $1.5 trillion, in capital in hedge funds, and there's certainly not enough talent to shepherd that capital adequately, and certainly not talent to justify the fees," says Antoine Bernheim, president of Dome Capital Management, which advises European institutional and private investors on their hedge fund portfolios. Bernheim also publishes Hedge Fund News, a quarterly newsletter that tracks the industry.
This week's implosion was not the first for Hunter, says Kuntz. "He had a previous blowup at Deutsche Bank that the CEO of Amaranth told us they were quite aware of when they hired him. They said they ran the checks and he completely checked out," Kuntz says. "They prided themselves on their risk management." <<<
Dimension, The AMEX site that I have access to only shows the date of the last transaction for each of the various options, but we had been following that big 5000+ put position closely since it was first taken back in May.
The large put position was taken not long after the clinical hold was announced. As you said, it was probably either 1) a hedge by someone sitting with a big long position, 2) a naked put position taken by a speculator, or 3) perhaps part of a more elaborate strategy.
Dimension, The AMEX options site I'm looking at shows the last trade of the Nov $5 puts on Thursday Sept 14th (assuming that AMEX site is kept up to date). Back in May, someone took a big 5000+ position in those $5 Nov puts, and this position was still there as of several weeks ago. Now it's down to 600, so whoever the holder was, it looks like they recently unloaded most/all of their puts (several days after Stoll's Bear Stearns presentation).
Other than that, it looks like the only other recent activity (in September) has been with the Nov and Feb 2.50 and $5.00 calls, all having some modest trades in the past several weeks. Someone also traded some Nov $2.50 puts at the end of August, but the open interest there is only 79.
Concerning the Nov $5 put option, this was the one with the recent very large 5000 position, but it's now down to only 600. So that would "appear" to be a bullish sign.
Thanks Neuro. I guess now having two separate CNS regulatory mini "fiefdoms" (Neurological and Psychiatric), with different directors/philosophies might complicate the regulatory path to some extent, since Ampakines cross over into both neuro areas.
Dew, Bianco probably figures this deal can get him back into that corporate jet for a few more years.
Hi Erik, Good point. BTW, how about CTIC today - looks like xyotax may not be dead after all, and I see Novartis also has an option for pixantrone.
Sexual Dysfunction abstract, from the YH board. Wow, is there anything Ampakines CAN'T do? --
Posts: 299
AMPA-Type Glutamate Receptor Modulators and Sexual
« on: Yesterday at 20:18:18 » Quote
The Effects of AMPA-Type Glutamate Receptor Modulators on Sexual Behavior of Aged Male Rats
Cheng-Ling (Greg) Chen & Vincent Van
Mentor: Danielle Simmons
Sexual behavior decreases as a mammal ages, due to decreases in testosterone (T). T acts in the brain, including the medial preoptic area (MPOA), to control male sexual behavior. In the MPOA, T can affect male sexual behavior by regulating the signaling of the neurotransmitter glutamate. Both types of glutamate receptor, AMPA and NMDA, are present in MPOA cells that also contain T receptors. This study’s purpose is to investigate the effects of positive AMPA modulators (called AMPAkines) on the sexual behavior of aged male rats. Sexually experienced aged male rats were either given AMPAkines (CX614 or CX689) or vehicle for one test and then given the opposite treatment for another test. The treated rats were given a sex behavior test with a receptive female, and measures of sexual motivation (e.g. mounting) and performance (e.g. ejaculation) were recorded. We found that when aged rats were given AMPAkines, the time to their first mount and ejaculation was decreased, as was the time they waited after ejaculation to start copulating again compared to when they received vehicle. Also, the number of times they ejaculated was increased with AMPAkine. The AMPAkine increased both sexual motivation and performance. Thus, our results further support the importance of glutamate in sexual behavior. In addition, our results suggest that AMPAkines can increase sexual behavior. This is important because its shows that AMPAkine may provide a treatment for sexual dysfunctions caused by age.
Stargazin - This is the first paper I've seen by Cortex researchers on "Stargazin", which is a member of a recently identified protein family called "transmembrane AMPA receptor regulatory proteins" or TARPS. These are trafficking proteins that participate in the surface delivery and anchoring of AMPA receptors, and may also act as positive allosteric upmodulators of AMPA receptor ion channels. There have been numerous papers published on Stargazin already, but this is the first one I've seen coming from Cortex researchers -
Program#/Poster#: 424.5/C22
Title: Effects of stargazin on allosteric, positive modulators of AMPA receptors (Ampakines)
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Monday, Oct 16, 2006, 1:00 PM - 2:00 PM
Authors: *Y. LI, L. NILSSON, M. A. VARNEY, G. ROGERS;
R & D, Cortex Pharmaceuticals, Inc, Irvine, CA.
Stargazin (STG) was characterized initially by homology as the second member (γ2) of the voltage-gated calcium channel γ subunit family. Recently, it has been reported that STG enhances the surface expression of AMPA receptors, controls receptor gating and slows channel desensitization as an auxiliary subunit of the receptors. Ampakines are a family of small molecules that increase the currents through AMPA receptors by binding to an allosteric site. The ligands do not have direct agonistic properties, but instead modulate the receptor rate constants for transmitter binding, channel opening, or desensitization. The effects of the Ampakine, CX614 and cyclothiazide (CTZ) were compared on homomeric GluR1-flip receptors expressed on HEK293 cells by transient transfection with or without STG gene. STG dramatically enhanced the surface expression of AMPA receptors. 500 μM Glutamate-induced steady-state currents were increased from 5.4 ± 1.2 pA/pF (n=4) to 125 ± 55 pA/pF (n=4) when STG was co-expressed, and the ratios of 500 μM kainate and 500 μM glutamate activated steady-state currents were increased from 0.58 ± 0.03 to 16.4 ± 6.5. STG speeded the association rates and slowed the dissociation rates for both CX614 and CTZ on desensitized receptors. The estimated Kd value for CX614 was lowered from 340 μM to 70 μM, whereas that for CTZ was lowered from 170 μM to 6 μM by STG. The data suggest that Stargazin can dramatically alter the conformation of the receptor dimer interface where CX614 and CTZ are known to bind.
Disclosures: Y. Li , None; L. Nilsson, None; M.A. Varney, None; G. Rogers, None.
One from Lilly - LY-450108 and Parkinson's -
Program#/Poster#: 76.18/HH25
Title: The ampa receptor potentiator LY450108 helps regenerate the damaged nigrostriatal pathway: mechanistic studies in the 6-OHDA model of Parkinson’s disease
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Saturday, Oct 14, 2006, 2:00 PM - 3:00 PM
Authors: *M. J. MESSENGER1, T. K. MURRAY2, W. A. MARK2, M. J. O'NEILL2;
1Eli Lilly & Co. Ltd, London, UNITED KINGDOM, 2Neurodegeneration, Eli Lilly & Co. Ltd, London, UNITED KINGDOM.
Current treatments for Parkinson’s disease (PD) relieve the symptoms of the disorder but have no effect on disease progression. Neurotrophic factors have been used as a neurorestorative treatment in PD to induce neurite outgrowth and synaptogenesis to repair the nigrostriatal tract. We have discovered a series of AMPA receptor potentiators (LY404187, LY450108, LY503430), that increase BDNF in vitro. Since BDNF can protect against neurotoxin-induced lesions of the nigrostriatal system we hypothesized that these compounds could act as a neurotrophic treatment for PD.
In the present studies we investigated the neurotrophic potential of the AMPA receptor potentiator, LY450108, after a severe 6-OHDA lesion of the nigrostriatal pathway in rats. Chronic treatment with LY450108 (0.1 and 0.5 mg/kg p.o.) produced a robust improvement in apomorphine-induced rotational behaviour and tyrosine hydroxylase immunoreactivity in the striatum, but had no effect on the number of cells in the substantia nigra. To gain insight into the mechanism of action, we carried out time-course studies (1, 3, 8 and 15 days) to evaluate the effect of LY450108 on [3H]-Mazindol ligand-binding and mRNA expression for a range of trophic factors (BDNF, NGF, NT-3), RGS2 and GAP-43 by in situ hybridization. A large increase in [3H]-Mazindol ligand-binding in the striatum and an increase in GAP43 expression in the substantia nigra occurred between eight and fifteen days following 6-OHDA in LY450108-treated rats. We also observed a transient increase in RGS2 mRNA in the striatum from two to fifteen days post-lesion. In contrast, no increase in BDNF, NGF or NT-3 gene expression was detected in the nigrostriatal pathway.
LY450108 appears to have neurotrophic properties, increasing dopaminergic innervation of striatal terminals and improving functional outcome. Modulation of AMPA receptors may provide a means of both halting the progression and perhaps reversing the degeneration in PD.
Disclosures: M.J. Messenger, Eli Lilly & Co. Ltd, A. Employment (full or part-time) ; T.K. Murray, Eli Lilly & Co. Ltd, A. Employment (full or part-time) ; W.A. Mark, Eli Lilly & Co. Ltd, A. Employment (full or part-time) ; M.J. O'Neill, Eli Lilly & Co. Ltd, A. Employment (full or part-time) .