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PHARMACOLOGICAL MODULATION OF POSITIVE AMPA RECEPTOR MODULATOR EFFECTS ON NEUROTROPHIN EXPRESSION
Antagonists of group 1 metabotropic glutamate receptors (mGluR) potentiate the effect of positive AMPA receptor modulators on neurotrophin expression, such as brain-derived neurotrophic factor (BDNF). The findings described herein suggest a combinatorial approach for drug therapies, using both positive AMPA receptor modulators and mGluR antagonists, to enhance brain neurotrophism.
http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2007124348&F=0&QPN=WO2007124348
Have a nice day
Erbse
Update Pipeline
Hi DewDiligence,
I come from germany and my english is to bad for a comment. I learned only some years school english. I think, you cannot understand what i mean. Thank you for your comment to MEMY.
Have a nice weekend
Erbse
Hi bladerunner1717,
i hear nothing about Organon and Schering. All about Organon is a secret. I have no sources at Organon.
Excuse me, but i cannot help you.
Have a nice weekend
Erbse
OT Memory Pharmaceuticals Announces Positive Phase 2a Results for MEM 3454 in Alzheimer's Disease
http://biz.yahoo.com/prnews/071102/nyf029.html?.v=101
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Erbse
Memory Pharmaceuticals Announces Positive Phase 2a Results for MEM 3454 in Alzheimer's Disease
Friday November 2, 6:00 am ET
- Statistically Significant Improvement on Primary and Secondary Endpoints -
- Cognitive Benefits Support Further Development -
- Company to Host Conference Call Today at 9:00 a.m. EDT -
MONTVALE, N.J., Nov. 2 /PRNewswire-FirstCall/ -- Memory Pharmaceuticals Corp. (Nasdaq: MEMY - News) today announced positive top-line data from the randomized, placebo-controlled, multi-center Phase 2a proof-of-concept trial of MEM 3454, the Company's lead nicotinic alpha-7 receptor partial agonist, in 80 patients with mild to moderate Alzheimer's disease over an eight week treatment period. The trial was an exploratory efficacy study to learn about MEM 3454 as a potential treatment for Alzheimer's disease. The primary endpoint of the trial was the change from baseline in the Quality of Episodic Secondary Memory (QESM) factor score of the Cognitive Drug Research (CDR) battery. QESM is a composite score derived from memory tests in the CDR battery that measure the ability to store, hold and retrieve information. There were three oral daily doses of MEM 3454 tested in the trial, 5 mg, 15 mg and 50 mg. The CDR battery was administered at baseline and on six days during the treatment period, at four time points (pre-dosing and 2, 4 and 8 hours post-dosing) each day. For the eight hour post-dose time points over the treatment period, subjects receiving 5 mg and 15 mg of MEM 3454 demonstrated a statistically significant effect on the QESM compared to placebo (p=0.023 and p=0.050, respectively).
Secondary endpoints in the trial included other composite scores from the CDR battery that measure working memory, attention and executive function, and the Alzheimer's Disease Assessment Scale -- cognitive subscale (ADAS-Cog). On secondary CDR battery measures, using all time points combined over the treatment period, the trial showed that the 5 mg and 15 mg doses achieved statistically significant positive results on Quality of Working Memory (p=0.031 and p=0.047). The 15 mg group also demonstrated trends to efficacy on Speed of Memory (p=0.080). Quality of Working Memory is a composite score derived from accuracy measures in the CDR battery that reflect how well subjects can hold information in working memory. The Speed of Memory composite score reflects the time it takes to recall an item from memory. For the ADAS-cog, the 15 mg group showed numeric improvements favoring treatment over placebo. There were two additional secondary endpoints in the study from the CDR battery, Power of Attention and Continuity of Attention, and on these measures the study found no statistically significant differences between treatment and placebo. The 50 mg group also showed no statistically significant differences favoring treatment at any endpoint in the study.
In analyses of QESM at certain other time points, and for all time points combined, the placebo group performed statistically significantly better than the treatment groups due to substantially lower QESM scores at baseline for the placebo group, at the 2 and 4-hour time points, as compared to the treatment groups. After adding a covariate for baseline scores to the statistical model, the MEM 3454 5 mg group demonstrated a statistically significant change from baseline on QESM at all time points combined compared to placebo (p=0.032). The MEM 3454 5 mg and 15 mg dose groups demonstrated statistical significance (p=0.003 and p=0.023, respectively), and the 50 mg dose group demonstrated a trend favoring treatment (p=0.083) for the eight hour post-dose time points on QESM. In addition, the 5 mg and 15 mg dose groups demonstrated a statistically significant effect on Quality of Working Memory, over all time points combined (p=0.006 and p=0.004, respectively). The 5 mg dose group also demonstrated a statistically significant effect on Speed of Memory (p<0.001) over all time points combined.
"Overall, the data from this study demonstrate that MEM 3454 is providing cognitive benefit and these results are consistent with our previous work with this compound in volunteers. When an appropriate baseline covariate is included, the results of this trial are even more robust," stated Keith Wesnes, Ph.D., the developer of the CDR battery. "It is exciting to improve the ability of Alzheimer's patients to store and retrieve information from both working and episodic memory, not only in terms of accuracy but also speed. These improvements have clinical relevance."
"We believe these trial results provide evidence of MEM 3454's potential to treat Alzheimer's disease," stated Stephen R. Murray, M.D., Ph.D., Chief Medical Officer of Memory Pharmaceuticals. "This data is consistent with our preclinical and Phase 1 results and reinforces our belief that MEM 3454 warrants continued development. We look forward to commencing our Phase 2a trial of MEM 3454 in cognitive impairment associated with schizophrenia in the near term."
MEM 3454 was well-tolerated in this trial, with the exception that the number of subjects with constipation was higher in the treatment groups (43%) compared to placebo (5%). There was one treatment-emergent serious adverse event in the 15 mg group, which was deemed not to be treatment-related by the investigator.
Study Design
The Phase 2a trial was a randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability and cognitive effects of three doses of MEM 3454. The trial enrolled 80 subjects with mild to moderate Alzheimer's disease at five sites in the United States. Subjects in the study were randomized at enrollment to receive 5 mg, 15 mg or 50 mg of MEM 3454 or placebo once daily for a period of eight weeks. The primary objective of the trial was to assess the effect of MEM 3454 using the QESM factor score from the CDR battery. Secondary objectives included assessing the safety, tolerability, and pharmacokinetics of MEM 3454 and the drug candidate's effect on additional psychometric test items from the CDR battery and the ADAS-cog.
Memory Pharmaceuticals Announces Positive Phase 2a Results for MEM 3454 in Alzheimer's Disease
Friday November 2, 6:00 am ET
- Statistically Significant Improvement on Primary and Secondary Endpoints -
- Cognitive Benefits Support Further Development -
- Company to Host Conference Call Today at 9:00 a.m. EDT -
MONTVALE, N.J., Nov. 2 /PRNewswire-FirstCall/ -- Memory Pharmaceuticals Corp. (Nasdaq: MEMY - News) today announced positive top-line data from the randomized, placebo-controlled, multi-center Phase 2a proof-of-concept trial of MEM 3454, the Company's lead nicotinic alpha-7 receptor partial agonist, in 80 patients with mild to moderate Alzheimer's disease over an eight week treatment period. The trial was an exploratory efficacy study to learn about MEM 3454 as a potential treatment for Alzheimer's disease. The primary endpoint of the trial was the change from baseline in the Quality of Episodic Secondary Memory (QESM) factor score of the Cognitive Drug Research (CDR) battery. QESM is a composite score derived from memory tests in the CDR battery that measure the ability to store, hold and retrieve information. There were three oral daily doses of MEM 3454 tested in the trial, 5 mg, 15 mg and 50 mg. The CDR battery was administered at baseline and on six days during the treatment period, at four time points (pre-dosing and 2, 4 and 8 hours post-dosing) each day. For the eight hour post-dose time points over the treatment period, subjects receiving 5 mg and 15 mg of MEM 3454 demonstrated a statistically significant effect on the QESM compared to placebo (p=0.023 and p=0.050, respectively).
Secondary endpoints in the trial included other composite scores from the CDR battery that measure working memory, attention and executive function, and the Alzheimer's Disease Assessment Scale -- cognitive subscale (ADAS-Cog). On secondary CDR battery measures, using all time points combined over the treatment period, the trial showed that the 5 mg and 15 mg doses achieved statistically significant positive results on Quality of Working Memory (p=0.031 and p=0.047). The 15 mg group also demonstrated trends to efficacy on Speed of Memory (p=0.080). Quality of Working Memory is a composite score derived from accuracy measures in the CDR battery that reflect how well subjects can hold information in working memory. The Speed of Memory composite score reflects the time it takes to recall an item from memory. For the ADAS-cog, the 15 mg group showed numeric improvements favoring treatment over placebo. There were two additional secondary endpoints in the study from the CDR battery, Power of Attention and Continuity of Attention, and on these measures the study found no statistically significant differences between treatment and placebo. The 50 mg group also showed no statistically significant differences favoring treatment at any endpoint in the study.
In analyses of QESM at certain other time points, and for all time points combined, the placebo group performed statistically significantly better than the treatment groups due to substantially lower QESM scores at baseline for the placebo group, at the 2 and 4-hour time points, as compared to the treatment groups. After adding a covariate for baseline scores to the statistical model, the MEM 3454 5 mg group demonstrated a statistically significant change from baseline on QESM at all time points combined compared to placebo (p=0.032). The MEM 3454 5 mg and 15 mg dose groups demonstrated statistical significance (p=0.003 and p=0.023, respectively), and the 50 mg dose group demonstrated a trend favoring treatment (p=0.083) for the eight hour post-dose time points on QESM. In addition, the 5 mg and 15 mg dose groups demonstrated a statistically significant effect on Quality of Working Memory, over all time points combined (p=0.006 and p=0.004, respectively). The 5 mg dose group also demonstrated a statistically significant effect on Speed of Memory (p<0.001) over all time points combined.
"Overall, the data from this study demonstrate that MEM 3454 is providing cognitive benefit and these results are consistent with our previous work with this compound in volunteers. When an appropriate baseline covariate is included, the results of this trial are even more robust," stated Keith Wesnes, Ph.D., the developer of the CDR battery. "It is exciting to improve the ability of Alzheimer's patients to store and retrieve information from both working and episodic memory, not only in terms of accuracy but also speed. These improvements have clinical relevance."
"We believe these trial results provide evidence of MEM 3454's potential to treat Alzheimer's disease," stated Stephen R. Murray, M.D., Ph.D., Chief Medical Officer of Memory Pharmaceuticals. "This data is consistent with our preclinical and Phase 1 results and reinforces our belief that MEM 3454 warrants continued development. We look forward to commencing our Phase 2a trial of MEM 3454 in cognitive impairment associated with schizophrenia in the near term."
MEM 3454 was well-tolerated in this trial, with the exception that the number of subjects with constipation was higher in the treatment groups (43%) compared to placebo (5%). There was one treatment-emergent serious adverse event in the 15 mg group, which was deemed not to be treatment-related by the investigator.
Study Design
The Phase 2a trial was a randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability and cognitive effects of three doses of MEM 3454. The trial enrolled 80 subjects with mild to moderate Alzheimer's disease at five sites in the United States. Subjects in the study were randomized at enrollment to receive 5 mg, 15 mg or 50 mg of MEM 3454 or placebo once daily for a period of eight weeks. The primary objective of the trial was to assess the effect of MEM 3454 using the QESM factor score from the CDR battery. Secondary objectives included assessing the safety, tolerability, and pharmacokinetics of MEM 3454 and the drug candidate's effect on additional psychometric test items from the CDR battery and the ADAS-cog.
OT PRX-07034 Selected for TURNS Clinical Trial
EPIX also announced today that PRX-07034 has been selected by the Treatment Units for Research on Neurocognition and Schizophrenia (TURNS), a project of the U.S. National Institute of Mental Health, for a future clinical trial to be conducted in conjunction with TURNS. EPIX will work with TURNS to develop the trial protocol and timeline. TURNS assesses and selects those compounds it feels are important to the study and treatment of neurocognitive disorders and schizophrenia. A collaborative trial could start as early as 2Q08.
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Erbse
EPIX Pharmaceuticals Reports Preliminary Findings from Phase 1b Clinical Trial of Novel 5-HT6 Drug Candidate
PRX-07034 Results in Significant Weight Loss in Obese Adults;
Conference Call to be Held Today at 4:30 p.m. EDT
LEXINGTON, Mass.--(BUSINESS WIRE)--Oct. 29, 2007--EPIX Pharmaceuticals, Inc. (NASDAQ: EPIX) today announced statistically significant results from its Phase 1b clinical trial of PRX-07034 in obesity, the company's internally-discovered, novel 5-HT6 antagonist being developed for obesity, Alzheimer's disease and cognitive impairment associated with schizophrenia. Findings from the randomized, double-blind, placebo-controlled trial of 21 obese, but otherwise healthy, adults demonstrated that adults taking 600mg PRX-07034 twice-daily (n=11) for 28 days lost an average of 0.45 kg (1 pound), while adults on placebo (n=10) gained 1.37 kg (3 pounds) during the same period; p less than 0.005.
Key Findings:
-- After 28 days of dosing, the average difference in weight in
the intent-to-treat population between subjects receiving
PRX-07034 and those receiving matched placebo was 1.82kg; p
less than 0.005
-- After 42 days - the 28-day dosing period and a 14-day
follow-up period - subjects on PRX-07034 (n =10) lost an
average of 0.26 kg overall compared to an average of 1.25 kg
gained by placebo (n=10) patients; p less than 0.005
-- PRX-07034 was associated with a significant reduction in serum
leptin levels, a marker of fat stores in the body (p less than
0.036)
-- Overall, only one of the 10 subjects on placebo (10%) lost any
weight during the trial, while seven of the 11 subjects on
PRX-07034 (approximately 64%) lost weight
-- PRX-07034 appeared well-tolerated and there were no serious
adverse events reported; an increase in corrected QT interval
(QTc) was apparent at the dose tested, with a mean increase
over the duration of the study of 10.7 msec for the drug group
versus a decrease of 1.7 msec for the placebo group
"We are very excited about the level of weight loss seen for PRX-07034 in an obesity indication," said Michael G. Kauffman, M.D., Ph.D., chief executive officer of EPIX. "In this 28-day study, not only did the adults on PRX-07034 lose weight while those on placebo gained weight, but they were able to do so without any constraints on eating habits. We also note that subjects in this study did not follow any pre-specified dietary or exercise program."
This Phase 1b trial was designed primarily to study the safety, tolerability and pharmacokinetics of a 600mg dose administered orally twice daily for 28 days in a population of obese, but otherwise healthy, adults (average weight 104.7 kg or 230 pounds).
Although there was evidence of QT prolongation in the ECG in subjects who received drug in the study, there were no corresponding clinical adverse events reported. Further development of the drug is expected to be conducted using the R-enantiomeric form of the drug because the Company believes, based on preclinical data, that the S-enantiomer is predominantly responsible for these QT findings.
Throughout the course of the trial, PRX-07034 appeared well-tolerated and there were no serious adverse events reported. Of the full intent-to-treat population of 21 adults, one patient on drug discontinued the trial due to a rash that resolved rapidly. There were no discontinuations on placebo.
The 21-person trial, which was conducted in an outpatient setting (subjects spent three nights of the total 28-day trial as inpatients to accommodate measurements and physician examinations), included secondary endpoint measures to assess potential effects on body weight, hunger and satiety and exploratory endpoint measures of cognitive function.
EPIX is continuing to gather and analyze findings from the Phase 1b trial, including data for additional secondary and exploratory endpoints including cognitive assessments.
Earlier this year, EPIX reported statistically significant improvements in cognitive function and trends in weight loss from a Phase 1b trial of PRX-07034 in doses up to 600mg once daily administered for 28 days. In that trial, PRX-07034 met the primary endpoint of safety and tolerability with no dose-limiting toxicity, no serious adverse events and no patient withdrawals.
PRX-07034 Selected for TURNS Clinical Trial
EPIX also announced today that PRX-07034 has been selected by the Treatment Units for Research on Neurocognition and Schizophrenia (TURNS), a project of the U.S. National Institute of Mental Health, for a future clinical trial to be conducted in conjunction with TURNS. EPIX will work with TURNS to develop the trial protocol and timeline. TURNS assesses and selects those compounds it feels are important to the study and treatment of neurocognitive disorders and schizophrenia. A collaborative trial could start as early as 2Q08.
EPIX Pharmaceuticals Completes Enrollment in Two Key Clinical Trials
Rapid Enrollment of Phase 2b Depression Trial Moves-up Timeline -
Data Now Expected in 1Q08
Data from Phase 2a Alzheimer's Trial 0n Track for 4Q07
LEXINGTON, Mass.--(BUSINESS WIRE)--Oct. 25, 2007--EPIX Pharmaceuticals, Inc. (NASDAQ: EPIX) today announced that it has met its enrollment target of 330 patients in U.S. centers for its Phase 2b trial of PRX-00023 in Major Depressive Disorder (MDD). As a result of this rapid enrollment, EPIX expects to announce results of this trial in the first quarter of 2008. Further, EPIX has completed enrollment of its Phase 2a clinical trial of PRX-03140 in Alzheimer's disease and reaffirmed that it is on track to announce the findings of this study by the end of 2007.
"We are very pleased to achieve these significant milestones for these two important clinical trials," stated Michael G. Kauffman, M.D., Ph.D., chief executive officer of EPIX. "We believe that the rapid pace at which we were able to recruit patients into the Phase 2b MDD trial is indicative of the interest in, and need for, new and improved treatments for depression."
PRX-00023 Phase 2b in Major Depressive Disorder
PRX-00023 is a novel, highly selective 5-HT1A partial agonist discovered using the company's proprietary G-Protein Coupled Receptors (GPCR) modeling, screening and lead optimization technology. PRX-00023 is targeting a significant unmet medical need for a selective 5-HT1A agonist used in the treatment of depression that avoids the sexual dysfunction, withdrawal symptoms and sleep disturbances typically associated with selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs), lacks the addictive and sedative effects of the benzodiazepines, and does not have the slow onset, short half-life, and side effects of a chemical class of 5-HT1A agonists called azapirones. EPIX has secured composition of matter patent protection for PRX-00023 through 2024.
In the first randomized trial of PRX-00023 conducted last year, 80 mg once daily of PRX-00023 showed significant improvement (p=0.009) in the pre-specified endpoint of MADRS in patients with generalized anxiety disorder. The current randomized, double-blind, placebo-controlled Phase 2b trial is designed to evaluate the effect of treatment with up to 120 mg of PRX-00023 twice-daily for eight weeks as determined by change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) compared with placebo. Patients in the current trial randomized to the drug treatment will begin with 40 mg PRX-00023 twice daily, and increase the dose, if tolerated, to a maximum of 120 mg twice daily within the first week. The trial has met its enrollment target of 330 adult patients with MDD. Changes in the Hamilton Anxiety Score (HAM-A), Clinical Global Impressions Improvement Scale (CGI-I) and Clinical Global Severity of Illness Scale (CGI-S) will be measured as secondary endpoints. PRX-00023 has been studied in more than 250 subjects to date and previous clinical trials have shown the drug to be well tolerated up to 320 mg per day with a low incidence of sexual dysfunction and sleep disorders.
PRX-03140 in Alzheimer's Disease
PRX-03140 is EPIX's second of four clinical drug candidates discovered utilizing its proprietary computer-based G-Protein Coupled Receptors (GPCR) models and optimized with integrated computational-medicinal chemistry. PRX-03140 is selective for the 5-HT4 receptor in the brain, and preclinical studies have shown that it may improve cognitive function and increase levels of acetylcholine, soluble amyloid precursor protein (sAPP) and brain-derived neurotrophic factor (BDNF) in regions of the brain known to be important for memory. GlaxoSmithKline has an exclusive option to license PRX-03140 for further development and commercialization on a worldwide basis once EPIX has achieved clinical proof of concept.
This Phase 2a clinical trial is designed to further evaluate PRX-03140 as monotherapy and in combination with donepezil (Aricept(R)) for the treatment of Alzheimer's disease. The current Phase 2a trial is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PRX-03140 administered orally once-daily stable dose of 10mg donepezil.
Vanda Pharmaceuticals to Present New Data on Iloperidone at the 2007 American Society of Human Genetics Annual Meeting
Monday October 22, 5:00 pm ET
ROCKVILLE, Md., Oct. 22 /PRNewswire-FirstCall/ -- Vanda Pharmaceuticals Inc. (Nasdaq: VNDA - News) announced today that it will present five posters on the pharmacogenetics of iloperidone at the 57th American Society of Human Genetics (ASHG) annual meeting to be held in San Diego, CA, from October 23 through October 27, 2007. This announcement follows the submission of the NDA filing for iloperidone on September 27, 2007. Iloperidone is an investigational atypical antipsychotic for the treatment of schizophrenia.
The following posters will be presented on Thursday, October 25, 2007, from 4:30 p.m. to 6:30 p.m. PDT, at the San Diego Convention Center.
POSTER 1035 - Whole Genome Association Study Identifies Polymorphisms in
the NPAS3 Gene Associated with Enhanced Response to
Iloperidone Treatment in Patients with Schizophrenia
POSTER 1036 - Pharmacogenetic Study of Iloperidone Treatment in Patients
with Schizophrenia Identifies Markers Associated with
Efficacy
POSTER 1037 - Pharmacogenetic Analysis Shows Differences in Markers
Associated with Response Between Two Atypical
Antipsychotics, Iloperidone and Ziprasidone, in the
Treatment of Patients with Schizophrenia
POSTER 1039 - Whole Genome Association Study Identifies Polymorphisms in
the CERKL Gene Associated with QT Prolongation during
Iloperidone Treatment of Patients with Schizophrenia
POSTER 1040 - Single-Nucleotide Polymorphisms in the CYP2D6 Gene Are
Correlated with Iloperidone Drug Exposure Levels, Affecting
the Degree of QTc Prolongation Associated with Iloperidone
Treatment
Molecular Coronary MR Imaging of Human Thrombi using EP-2104R, a Fibrin-Targeted Contrast Agent: Experimental Study in a Swine Model.
Spuentrup E, Katoh M, Wiethoff AJ, Buecker A, Botnar RM, Parsons EC, Guenther RW.
Department of Diagnostic Radiology, Aachen Technical University, Aachen, Germany.
PURPOSE: The aim of this study was to investigate the use of a fibrin-specific contrast agent (EP-2104R, EPIX Pharmaceuticals, Lexington, Massachusetts, USA) for targeted molecular magnetic resonance (MR) imaging of human clot material removed from patients in a model of coronary thrombosis in swine. MATERIALS AND METHODS: Freshly ex vivo engineered clots from human blood and human in situ developed clots removed from patients were delivered into the coronary arteries of nine domestic swine. For MR imaging a navigator-gated, free-breathing, cardiac-triggered 3D inversion recovery black-blood gradient echo sequence was performed prior to clot delivery (baseline), after clot delivery but prior to contrast media administration, and two hours after systemic (i. v.) injection of 4 micromol/kg EP-2104R.
MR images were analyzed by two investigators and the contrast-to-noise ratio and Gadolinium (Gd) concentration in the clots were assessed. RESULTS: On baseline images and prior to contrast media application no thrombi were visible. Post contrast administration all 10 coronary emboli (five ex vivo engineered clots and five human clots removed from patients) were selectively visualized as white spots with a mean contrast-to-noise ratio to the blood pool and the surrounding tissue of > 12 and a mean Gd concentration of > 100 microM. CONCLUSION: Molecular MR imaging using the fibrin-targeted contrast agent EP-2104R allows selective visualization of human clot material in a model of coronary thrombosis in swine.
PMID: 17948194 [PubMed - in process]
Gallium Maltolate Abstract
Pharmacokinetics of gallium maltolate after intragastric administration in neonatal foals.
Martens RJ, Mealey K, Cohen ND, Harrington JR, Chaffin MK, Taylor RJ, Bernstein LR.
Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843.
Objective-To determine the pharmacokinetics of gallium maltolate (GaM) after intragastric administration in healthy foals. Animals-6 healthy neonatal foals. Procedures-Each foal received GaM (20 mg/kg) by intragastric administration. Blood samples were obtained before (time 0) and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours after GaM administration for determination of serum gallium concentrations by use of inductively coupled plasma mass spectroscopy. Results-Mean +/- SD pharmacokinetic variables were as follows: peak serum gallium concentration, 1,079 +/- 311 ng/mL; time to peak serum concentration, 4.3 +/- 2.0 hours; area under the serum concentration versus time curve, 40,215 +/- 8,420 ng/mL/h; mean residence time, 39.5 +/- 17.2 hours; area under the moment curve, 1,636,554 +/- 931,458 ng([h](2)/mL); and terminal half-life, 26.6 +/- 11.6 hours. The mean serum concentration of gallium at 12 hours was 756 +/- 195 ng/mL. Conclusions and Clinical Relevance-Gallium maltolate administered via nasogastric tube at a dose of 20 mg/kg to neonatal foals resulted in gallium serum concentrations considered sufficient to suppress growth or kill Rhodococcus equi in macrophages and other infected tissues.
Mehr zu Rhodococcus equi im folgendem Artikel. Dies könnte auch für Bayer interessant sein, da sie eine eigene Veterinär Sparte besitzen.
Therapie von Rhodococcus Equi beim Fohlen
Rhodococcus Equi ist ein grampositives kokkoides Stäbchen. Im Zusammenhang mit Atemwegserkrankungen beim Fohlen ist er einer der wichtigsten Keime. Der Erreger besitzt eine hohe Tenazität in staubigen trockenen Böden und kann in betroffenen Aufzuchtbetrieben eine Krankheitshäufigkeit von bis zu 60 % erreichen.
Vor allem Fohlen im Alter zwischen zwei und sechs Monaten erkranken. Die Tiere zeigen meist respiratorische Symptome wie Husten und Ruhedyspnoe. Bei der Auskultation von Lunge und Trachea fallen eine rasselnde Atmung oder ein giemendes Geräusch auf. Hinzu kommen Symptome wie Fieber (39 bis 41°C), eitriger Nasenausfluss und Leukozytenzahlen von über 13000/µl. In der ultrasonographischen Untersuchung kann man oft einen oder mehrere Lungenabszesse finden.
Da der Erreger innerhalb der Abszesse und auch intrazellulär erreicht werden muss und er darüber hinaus zur Resistenzentwicklung neigt, ist die Therapie schwierig und langwierig. Die Mindestbehandlungsdauer liegt bei vier Wochen. Derzeit besteht die gängige Behandlungsmethode von Infektionen mit Rhodococcus Equi in der Verabreichung von Rifampicin (Dosis: 10 mg/kg 2 x tägl. p.o.) in Kombination mit Erythromycin (Dosis: 25 mg/kg 4 x tägl. p.o.) oder in Kombination mit Azithromycin (Dosis: In der ersten Woche 1 x tägl. 10 mg/kg p.o., danach jeden 2. Tag 10 mg/kg p.o.). Da Rhodococcus Equi ein fakultativ intrazellulär Erreger ist, eignen sich diese Antibiotika besonders gut zur Bekämpfung, denn sie reichern sich in Makrophagen und Leukozyten sowie in peripheren Geweben an. Sie erreichen dort trotz eines niedrigen Plasmaspiegels einen hohen Wirkspiegel. Der Nachteil beim Erythromycin ist das Risiko, bei Fohlen, die älter als fünf Monate sind, eine lebensbedrohliche Colitis zu verursachen, sowie der durch die vier mal tägliche Verabreichung hohe Behandlungsaufwand. Aus diesen Gründen haben sich die Autoren der vorliegenden Studie bei der ersten Fohlengruppe für die Kombination von Rifampicin mit Azithromycin entschieden. Eine zweite Fohlengruppe wurde mit dem Medikament Tulathromycin (Draxxin®) behandelt, welches derzeit bei Rindern und Schweinen zur Behandlung von Atemwegserkrankungen eingesetzt wird. Die Fohlen der zweiten Gruppe erhielten das Tulathromycin in einer Dosierung von 1 ml/40 kg mit etwas Aqua ad inj. verdünnt einmal wöchentlich in die lange Sitzbeinmuskulatur. Die Behandlung wurde beendet, wenn zwei Wochen in Folge sowohl die klinische als auch die sonographische Untersuchung ohne besonderen Befund war und die Zahl der Blutleukozyten unter 13000/µl lag; frühestens jedoch nach vier Wochen.
Die erforderliche Therapiedauer war in der zweiten Gruppe länger als in der ersten und es waren mehr Therapieumstellungen erforderlich. Demgegenüber war die Zahl der Fohlen, die nach abgeschlossener Untersuchung erneut einen Lungenabszess entwickelten, nach der Behandlung mit Tulathromycin geringer. Die Studie hat ergeben, dass Azithromycin in Kombination mit Rifampicin zur Zeit die besseren Behandlungserfolge liefert als die Monotherapie mit Tulathromycin. Es bleibt abzuwarten, ob durch Änderung der Dosierung oder des Verabreichungsintervalls eine Verbesserung der Ergebnisse erreicht werden kann. Um der Entstehung von Resistenzen vorzubeugen, ist auch für Tulathromycin die Kombination mit Rifampicin zu erwägen.
Article in English:
Rhodococcus Equi Pneumonia Of Foals
http://www.omafra.gov.on.ca/english/livestock/horses/facts/90-056.htm
Have a nice day
Erbse
Oh no ampakineman,
these mice buy cheese factories and not Ampakines.
Tschüss
Have a nice weekend
Erbse
Ampakine and Rett syndrome
Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome.
http://www.erbse.vm-elsig.de/form/base/YaBB.pl?num=1191597578/0
Have a nice day
Erbse
Epix Update
Hi gfp927z,
i have no new patents for COR at the European Patent Office.
Not for "ampa" or "Cortex Pharmaceuticals" Perhaps it is only announced and yet not registered.
There is a new patent for Glaxo.
http://v3.espacenet.com/results?AB=ampa&sf=a&DB=EPODOC&PGS=10&CY=ep&LG=en&ST...
Sorry gfp, i cannot help you
Erbse
OT NASDAQ NeuroInsights Neurotech (^NERV)
http://finance.yahoo.com/q?s=%5ENERV
Have a nice day
Erbse
Epix Pipeline Factsheet Sept. 2007
Vanda Pharmaceuticals Submits Iloperidone New Drug Application
Thursday September 27, 9:00 am ET
ROCKVILLE, Md., Sept. 27 /PRNewswire-FirstCall/ -- Vanda Pharmaceuticals Inc. (Nasdaq: VNDA - News) announced today that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for iloperidone, an investigational atypical antipsychotic for the treatment of schizophrenia. The application includes data from 35 clinical trials and more than 3,000 patients treated with iloperidone.
Iloperidone has demonstrated efficacy in treating the symptoms of schizophrenia both in the acute and the chronic setting. Iloperidone's binding to a number of dopamine and serotonin receptors provides a favorable safety profile on adverse symptoms, such as weight gain, extrapyramidal symptoms, akathisia and prolactin elevation. The NDA submission also contains pharmacogenetic data aimed to further improve the benefit/risk profile of iloperidone in the treatment of patients with schizophrenia.
"The submission of the iloperidone NDA marks a significant milestone for Vanda. Iloperidone may become an important instrument in the treatment of patients with schizophrenia and may help to usher the field of psychiatry into an era of personalized medicine," said Mihael H. Polymeropoulos, M.D., President and CEO, Vanda Pharmaceuticals Inc.
"For a serious brain disorder like schizophrenia, which affects about three million Americans in the prime of life, it is vital that new pharmacotherapeutic agents be developed in light of the fact that existing antipsychotic treatments work partially in some patients and not others, leaving many patients continuously disabled. The NIMH-funded CATIE effectiveness study revealed the efficacy or safety limitations of current agents. Iloperidone is a new antipsychotic that could offer an important new option for many patients suffering from schizophrenia," said Dr. Henry Nasrallah, Professor of Psychiatry, Neurology, and Neuroscience, University of Cincinnati College of Medicine.
Titan Adds Dr. Marc Rubin to Executive Management Team as President and Chief Executive Officer
Wednesday September 26, 9:20 am ET
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Titan Pharmaceuticals, Inc. (AMEX: TTP - News) today announced that Dr. Marc Rubin, M.D. will join Titan as President and Chief Executive Officer starting October 1, 2007. Dr. Rubin will also be a member of the Board of Directors.
Dr. Rubin was formerly the Head of Global Research and Development for Bayer Schering Pharma, and a member of the Executive Committee of Bayer Healthcare and the Board of Management of Bayer Schering Pharma.
Dr. Louis R. Bucalo, Titan's founder and current Chairman, President and Chief Executive Officer, who led the recruitment of Dr. Rubin, will continue as Chairman of the Company.
"We are very pleased to have Marc join Titan as President and CEO," stated Dr. Bucalo. "Marc's 18 years of industry experience and record of success in pharmaceutical development make him an exceptional industry leader, and an outstanding person to lead Titan forward to future achievements. Titan's several products in development, including iloperidone which completed Phase III testing for schizophrenia, Probuphine® in Phase III testing for opiate addiction, and Spheramine® in Phase IIb testing for advanced Parkinson's disease, as well as our other products in earlier stage development, provide a strong foundation for future growth. I and our Board of Directors have great confidence that Marc, together with our management team, will continue to drive our company forward to a successful future."
"I am delighted to join Titan and help lead the company forward," stated Dr. Rubin. "Titan is poised to enter an exciting phase and has built an excellent platform for future growth. With innovative programs spanning early and late stage development, we have a tremendous opportunity to provide significant advances in innovative new therapeutics."
Prior to his position at Bayer Schering Pharma, Dr. Rubin was a Member of the Executive Board and President of Development for Schering AG, as well as Chairman of Schering Berlin Inc. and President of Berlex Pharmaceuticals, a division of Schering AG. His position included responsibility for 3 Global Business Units.
Before joining Schering AG, Dr. Rubin held several positions of increasing responsibility at GlaxoSmithKline, with development as well as commercial responsibility. There he had oversight of the development, approval and commercial strategy for numerous pioneering programs.
Dr. Rubin received his MD from Cornell University Medical College in 1980, and completed his Internship and Residency at The Johns Hopkins Hospital, and subspecialty training at the National Institutes of Health.
Epix Neuroscience 2007 Abstracts
Preclinical and clinical antidepressant effects of the 5-ht1a receptor agonist prx-00023
PRX-00023 [N-(3-(4-(4-(cyclohexylmethylsulfonamido)butyl)piperazin-1-yl)phenyl)acetamide] is a potent and highly selective partial agonist for the 5-HT1A receptor. Potential preclinical antidepressant effects of PRX-00023 were evaluated using the modified rat forced swim test (FST). PRX-00023 was active at 10 and 20 mg/kg (sc), causing reduced immobility, increased swimming but no change in climbing behavior. These antidepressant-like effects were not due to changes in locomotor activity. The pattern of response of PRX-00023 in the FST, reducing immobility and increasing swimming, was similar to that produced by fluoxetine. PRX-00023 was further evaluated in an 8-week, double-blind, placebo-controlled human clinical trial in patients with generalized anxiety disorder (GAD).
Male and female patients (aged 18-65 years), with a diagnosis of GAD were randomized to receive PRX-00023 (80 mg/day) or placebo. Since depression is often co-morbid with anxiety, depression, was evaluated with the Montgomery Asberg Depression Rating Scale (MADRS) as a secondary endpoint. For the primary endpoint, the Hamilton Anxiety Scale (HAM-A), the difference from placebo did not reach statistical significance at week 8 (p=0.1135) although a trend was apparent. By contrast, there was a significant drop in the MADRS score at the end of the study (p=0.0094) for patients receiving PRX-00023. Sexual function was assessed with the MGH sexual function scale and showed no impairment with PRX-00023 with a trend towards improvement that did not reach significance. There were no serious adverse events and the drug was well tolerated with headache as the most common adverse event (15.6% of patients vs. 10.9% of placebo). Based on these data, PRX-00023 is currently being evaluated in a trial involving patients with major depressive disorder. Results are anticipated in the second quarter of 2008
PRX-07034, a 5-HT6 antagonist, reduces weight gain and enhances memory in a neurodevelopmental model of schizophrenia
Post-weaning social isolation in the rat induces a range of behavioral and neurochemical alterations similar to those observed in schizophrenia (Lapiz et al. 2003). The aim of this study was to evaluate PRX-07034, a novel and potent 5-HT6 antagonist (Ki 4nM) with demonstrated procognitive effects, in rats raised in social isolation. Thirty-eight male Lister hooded rats were raised in isolation from weaning (day 20-24) and 10 rats from the same litters were raised in social groups of 3-4. From days 33-37 group-housed controls received vehicle intraperitoneal (ip) injections daily, and isolates received vehicle or PRX-07034 (1, 3, or 10mg/kg) ip injections daily. Locomotor activity was monitored on Day 36. On day 37 novel object discrimination (NOD) was assessed using a 2 hr inter-trial-interval with a 40-min pre-treatment (King et al. 2004). Prior to the start of injections (day 33), isolates tended to be heavier than social controls. This effect was normalized by PRX-07034. Cumulative weight gain across the treatment period was significantly lower in the 3 and 10mg/kg PRX-07034-treated groups compared to vehicle-treated social isolates (P<0.05 & P<0.001, respectively).
Isolates exhibited increased levels of rearing and ambulation (P<0.001) which were returned to social control levels by PRX-07034 (3 & 10 mg/kg). Social controls discriminated the novel from the familiar object (P<0.01), but isolates did not. PRX-07034 restored object discrimination in the isolates at all doses tested (1 & 3mg/kg P<0.01, 10mg/kg P<0.05). These results confirm that the procognitive effects of PRX-07034 previously observed in normal animals were maintained in rats exhibiting an isolation rearing-induced cognitive deficit. PRX-07034 also reversed the isolation-induced effects on activity and weight gain. Results support a potential role for PRX-07034 in the treatment of cognitive dysfunction associated with schizophrenia, as well as atypical antipsychotic-induced weight gain.
PRX-03140, a partial 5-HT4 agonist, potentiates the memory enhancing effect of an efficacious dose of donepezil on delayed spontaneous alternation
PRX-03140 is a 5-HT4 receptor partial agonist undergoing a Phase 2 clinical trial in an Alzheimer’s disease population. The clinical study includes a PRX-03140 monotherapy arm as well as PRX-03140 in combination with donepezil, an acetylcholinesterase inhibitor. Donepezil is one of the most commonly prescribed treatments to alleviate cognitive impairments in Alzheimer’s disease albeit with limited efficacy and dose-limiting side effects. Other treatments shown to enhance memory may provide additional benefits when given in combination with donepezil. Previous studies demonstrated that PRX-03140, a partial 5-HT4 receptor agonist, simultaneously enhances memory and potentiates hippocampal acetylcholine release during a spatial working memory test.
The present experiment investigated whether an efficacious, but suboptimal dose of donepezil would be enhanced by a low dose of PRX-03140. In a delayed spontaneous alternation paradigm, rats (n=6-9 per group) were administered either vehicle, PRX-03140 (0.03, 0.1 or 1.0 mg/kg, ip) or donepezil (0.3 mg/kg, ip) alone or a combination of PRX-03140 (0.1 mg/kg, ip) and donepezil (0.3 mg/kg, ip) 30 minutes prior to delayed spontaneous alternation testing. Testing was carried out in a 4-arm cross maze. A test session lasted 15 minutes and a 30 second delay was inserted between each arm choice. Results indicated that PRX-03140 at 0.03 or 0.1 mg/kg did not affect delayed spontaneous alternation performance. PRX-03140 at 1 mg/kg produced significant enhancement (p<0.01 vs vehicle-treated). Donepezil (0.3 mg/kg) had a modest significant effect on delayed spontaneous alternation performance.
In contrast, the combination of PRX-03140 (0.1 mg/kg) and donepezil (0.3 mg/kg) produced a significant enhancement of delayed spontaneous alternation performance that was much greater than donepezil alone (p<0.01). The findings suggest that a low dose of PRX-03140 may further enhance the effects of donepezil resulting in a greater improvement in cognitive function than that produced by donepezil alone.
Update Pipeline in German
Cortex Update in German
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Pipeline Update
Org 24448 to Treat Depression
This study is ongoing, but not recruiting participants.
Source: http://www.clinicaltrials.gov/ct/show/NCT00113022?order=1
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Milestones Epix Pharmaceuticals 2008
Targacept Milestones 2007
Targacept to Present at BioCentury Newsmakers and Bear Stearns Conferences
Friday August 31, 11:30 am ET
WINSTON-SALEM, N.C.--(BUSINESS WIRE)--Targacept, Inc. (NASDAQ:TRGT - News), a clinical-stage biopharmaceutical company developing a new class of drugs known as NNR Therapeutics (TM), today announced that Alan A. Musso, Vice President and Chief Financial Officer, is scheduled to present at the "Newsmakers in the Biotech Industry" conference sponsored by BioCentury. The conference will be held on Thursday, September 6, 2007 at the Millennium Broadway Hotel & Conference Center in New York City. Mr. Musso will speak at 4:00 p.m. Eastern Daylight Time in Presentation Room 402/403.
Mr. Musso is also scheduled to present at the Bear Stearns 20th Annual Healthcare Conference on Monday, September 10, 2007 at The Grand Hyatt in New York City. His presentation will begin at 2:00 p.m. Eastern Daylight Time in the Carnegie/Alvin Room.
Both presentations will be webcast and accessible from the Investor Relations page of the Company's website at www.targacept.com. The webcasts will also be available for replay on the Company's website for two weeks following each conference. To ensure a timely connection, it is recommended that users register at least 15 minutes prior to the scheduled start time.
Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function.
Levin ED, Rezvani AH.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
People with schizophrenia often have substantial cognitive impairments, which may be related to nicotinic receptor deficits, (alpha7 and alpha4beta2), documented in the brains of people with schizophrenia. The large majority of people with schizophrenia smoke cigarettes. Thus, nicotinic interactions with antipsychotic drugs are widespread. Complementary co-therapies of novel nicotinic ligands are being developed to add to antipsychotic therapy to treat the cognitive impairment of schizophrenia. Thus, it is critical to understand the interaction between nicotinic treatments and antipsychotic drugs. Nicotinic interactions with antipsychotic drugs, are complex since both nicotine and antipsychotics have complex actions. Nicotine stimulates and desensitizes nicotinic receptors of various subtypes and potentiates the release of different neurotransmitters. Antipsychotics also act on a verity of receptor systems. For example, clozapine acts as an antagonist at a variety of neurotransmitter receptors such as those for dopamine, serotonin, norepinepherine and histamine. In a series of studies, we have found that in normally functioning rats, moderate doses of clozapine impair working memory and that clozapine blocks nicotine-induced memory and attentional improvement. Clozapine and nicotine can attenuate each other's beneficial effects in reversing the memory impairment caused by the psychototmimetic drug dizocilpine. A key to the clozapine-induced attenuation of nicotine-induced cognitive improvement appears to be its 5HT(2) antagonist properties. The selective 5HT(2) antagonist ketanserin has a similar action of blocking nicotine-induced memory and attentional improvements. It is important to consider the interactions between nicotinic and antipsychotic drugs to develop the most efficacious treatment for cognitive improvement in people with schizophrenia.
PMID: 17714691 [PubMed - as supplied by publisher]
Brain Cells Work Differently Than Previously Thought
Source: University of California - Irvine
Finding that axons process information may shed light on root of cognitive disorders
Scientists know that information travels between brain cells along hairlike extensions called axons. For the first time, researchers have found that axons don’t just transmit information – they can turn the signal up or down with the right stimulation.
This finding may help scientists develop treatments for psychiatric disorders such as depression and schizophrenia in which it is thought that different parts of the brain do not communicate correctly with each other.
“Until now, scientists have thought that in the brain’s cortex -- where most cognitive processes occur -- information was only processed in the cell body,” said Raju Metherate, author of the study, associate professor of neurobiology and behavior, and director of the Center for Hearing Research at UC Irvine. “The result of our study suggests that we must consider the axons as sites of information processing – and of potential problems when things go wrong.”
This study appears online Aug. 19 in Nature Neuroscience.
Increasingly, studies are beginning to show that complex information processing, and perhaps consciousness itself, may result from coordinated activity among many parts of the brain connected by bundles of long axons. Cognitive problems may occur when these areas don’t communicate properly with each other.
Cognitive function occurs when millions of brain cells communicate with each other at the same time. A brain cell has a network of branches called dendrites through which it receives and processes information from other cells. The body of the cell then relays the processed information along an axon to a terminal that links to another cell’s dendrites. At the terminal, chemicals called neurotransmitters are released, allowing the information to enter the receiving cell. Until now, scientists believed axons were just the wires between point A and point B.
“Axons, we thought, were like wires in a radio conveying signals, but we found that if you stimulate the axon, the signal can be altered, like turning the volume knob on the radio,” Metherate said.
Originally, Metherate and his colleagues had hoped to confirm the idea that the drug nicotine alters information that is processed in the cell body or terminal. Puzzled by several negative tests, they developed an experiment in which they could study the intervening axon.
In their experiment, they examined a section of mouse brain associated with hearing that contained a brain cell with an axon connecting to the cortex. Using nicotine, they stimulated the axon to determine how it would affect a signal the brain cell sent to the cortex. Without applying nicotine, about 35 percent of the messages sent by the brain cell reached the cortex. But when nicotine was applied to the axon, the success rate nearly doubled to about 70 percent.
“We looked for more conventional reasons why the response was enhanced, but the evidence just kept pointing to the axon. Nicotine activated the proteins that we think are on the axon,” Metherate said. “This is a completely new idea about how the brain works.”
OT Brain Cells Work Differently Than Previously Thought
http://www.erbse.vm-elsig.de/form/base/YaBB.pl?num=1187623437/0#0
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Gary Lynch's UC Irvine brain research lab struggles to map the elusive molecular underpinning of retention and recall.
By Terry McDermott : times staff writer, Second of four parts
August 20, 2007
http://www.erbse.vm-elsig.de/form/base/YaBB.pl?num=1187535008/0
LA TIMES: http://www.latimes.com/news/nationworld/nation/la-na-memorysecond20aug20,0,3871623.story?page=1&...
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Abstracts TC-5214 and TC-6499
TC-6499: an orally effective and selective alpha4beta2 neuronal nicotinic receptor agonist with anti-allodynic activity
Differential effects of TC-5214 [S-(+)-mecamylamine] and TC-5213 [R-(-)-mecamylamine] at low and high sensitivity human alpha4beta2 nicotinic receptors and in animal models of depression and anxiety
Source: http://www.erbse.vm-elsig.de/form/base/YaBB.pl?num=1187502087
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Comment NeuroInvestment
AstraZeneca has launched two PhIIb trials for TC-1734: a 500pt Alzheimer's study, and a 400pt schizophrenia trial, where TC-1734 is an adjunct to antipsychotic therapy. Data will not come from those trials until late next year. We expect that Targacept and AstraZeneca will expand the deal, to fold in TC-5619 for schizophreniform cognition. The depression possibilities for Targacept are more diffuse: they have mecamylamine, but they are choosing to instead develop its enantiomer TC-5214, which at the very least, offers patent protection. There is also TC-2216, an inhouse designed compound. A dental pain acute pain trial for TC-2696 is now expected to produce data near year-end. GSK. Pain, Parkinson's, obesity, addiction are all covered. The most important attribute, reflected in the $35 million upfront ($20 million via equity buy) and the $1.5 billion in theoretically available biobucks in milestones and royalties, is the distinct sense of collegiality in the deal. Targacept's ongoing contributions to the discovery/development process led GSK to pay Phase II prices for what is primarily a preclinical platform. As it should.
Entry into a Material Definitive Agreement, Unregistered Sale of Equity Securities
Item 1.01. Entry into a Material Definitive Agreement.
On July 27, 2007, Targacept, Inc. (the "Company") entered into a product development and commercialization agreement with SmithKline Beecham Corporation, doing business as GlaxoSmithKline, and Glaxo Group Limited (together, "GSK") that sets forth the terms of an alliance designed to discover, develop and market product candidates that selectively target specified neuronal nicotinic receptor ("NNR") subtypes in five therapeutic focus areas-pain, smoking cessation, obesity, addiction and Parkinson's disease. GSK is participating in the alliance through its Center of Excellence for External Drug Discovery, or CEEDD.
Under the agreement, GSK has agreed to make an initial payment of $35.0 million to the Company, which includes a non-refundable payment of $20.0 million and the purchase of 1,275,502 shares of the Company's common stock, par value $0.001 per share, for an aggregate purchase price of $15.0 million pursuant to a stock purchase agreement between the Company and Glaxo Group Limited entered into in conjunction with the product development and commercialization agreement. In addition, the Company is eligible to receive up to $1.5 billion in future non-refundable payments from GSK, contingent on the achievement of specified discovery, development, regulatory and commercial milestones across the five therapeutic focus areas of the alliance, as well as tiered double-digit royalties dependent on sales achieved for any product licensed by GSK.
Under the agreement, the Company has agreed, for specified periods of time and at its sole expense, to use diligent efforts to conduct research activities designed to discover product candidates that target specified NNR subtypes, to develop the product candidate identified as the lead for each therapeutic focus area through a Phase 2 proof of concept trial and to develop up to two other product candidates for each therapeutic focus area to a specified stage of preclinical development. The Company is eligible to receive success-based milestone payments from GSK as the Company advances product candidates in each therapeutic focus area through preclinical and clinical development. The Company's research and development activities in the alliance are to be overseen by a joint steering committee comprised of representatives of both the Company and GSK.
With respect to each therapeutic focus area in the alliance, if the Company achieves clinical proof of concept with respect to a lead product candidate, GSK would have an exclusive option for an exclusive license to that lead product candidate and up to two other product candidates in development in the alliance for the same therapeutic focus area on a worldwide basis. If GSK exercises its option and pays a non-refundable exercise fee, GSK would become responsible for using diligent efforts to conduct later-stage development and commercialization of the lead product candidate at its sole expense. GSK's exclusive license would include all fields of use other than those indications that are the focus of the Company's collaborative research and license agreement with AstraZeneca AB, which the Company entered into in December 2005. The indications that are the focus of the Company's agreement with AstraZeneca include Alzheimer's disease, cognitive deficits in schizophrenia, attention deficit hyperactivity disorder, other diseases and disorders characterized by cognitive impairment and schizophrenia.
The Company's lead product candidates for pain are subject to the alliance. These product candidates are TC-2696, which is currently in a Phase 2 clinical trial in third molar extraction patients, and TC-6499, a preclinical product candidate that is currently planned for development for neuropathic pain. Under the agreement, if GSK's option were to be triggered with respect to either or both of TC-2696 and TC-6499 and if GSK were to exercise the option, the Company would retain an option to co-promote those licensed products for pain to specialists and hospital-based physicians in the United States.
The Company's ongoing Phase 2 clinical trial of TC-2696 in third molar extraction patients does not constitute a proof of concept trial under the agreement. Accordingly, if TC-2696 continues to be subject to a future option of GSK following completion of the third molar extraction trial, the Company would conduct a separate Phase 2 clinical trial of TC-2696 in another pain population designed to establish clinical proof of concept under the agreement. If GSK's option were to be triggered with respect to TC-2696 and if GSK were to exercise the option, the Company would be required to pay the University of Kentucky Research Foundation a low single digit percentage of payments received from GSK with respect to TC-2696 and could also be required to pay two other university licensors a low single digit percentage of payments received from GSK with respect to TC-2696.
With respect to each licensed product that, at the time of first commercial sale in a particular country, is covered by an issued Targacept patent with adequate scope under the agreement, GSK's royalty obligation with respect to sales of the product in the country generally would terminate upon the later of the expiration of the last Targacept patent with adequate scope or fifteen years after the first commercial sale of the product in the country. The royalty rate payable to the Company would be subject to reduction in specified circumstances under the agreement, including in any country if the product is no longer covered by a patent with adequate scope under the agreement in that country or if GSK licenses patent rights from any third party in circumstances in which such license is reasonably considered necessary to avoid the infringement of the third-party patent rights.
The Company has agreed that, for so long as it is required under the agreement to conduct research activities in a particular therapeutic focus area or for so long thereafter as there are any product candidates in development or being commercialized in the alliance, it will work in the alliance's therapeutic focus areas exclusively with GSK with respect to product candidates with NNR-derived activity. The Company has also agreed to work exclusively with GSK with respect to product candidates that target the NNR subtypes specified for each therapeutic focus area under the agreement and with respect to product candidates with substantially the same mechanism of action, as defined in the agreement, as product candidates being developed or commercialized in the alliance, in each case for a specified period of time. Some or all of the Company's exclusivity obligations would expire if GSK were to in-license from a third party a product candidate with NNR-derived activity for a therapeutic focus area of the alliance. GSK has agreed for a specified period of time not to conduct internal activities for any of the alliance's therapeutic focus areas with respect to product candidates that target the NNR subtypes specified under the agreement for such therapeutic focus area.
If GSK does not exercise any of its options, or if the Company does not achieve clinical proof of concept in any of the therapeutic focus areas of the alliance within a specified period, the agreement would expire. Otherwise, the agreement would expire with respect to each licensed product and country upon the expiration of the payment obligations of GSK for that licensed product in that country and would expire in its entirety upon the expiration of the last payment obligation of GSK for the last licensed product in the last country.
Either the Company or GSK has the right to terminate the agreement if the other party becomes insolvent or commits an uncured material breach of the agreement, except that, if the uncured material breach is of a party's diligence obligations with respect to a product candidate for a particular therapeutic focus area under the agreement, the other party's right is only to terminate the agreement as applied to that therapeutic focus area. GSK also has the right to terminate the agreement without cause upon 90 days written notice, either in its entirety or as to any particular therapeutic focus area. The Company also has the right to terminate the agreement as to any particular therapeutic focus area, if GSK challenges the scope, validity or enforceability of certain patents that cover compounds in development in the alliance for that therapeutic focus area. In addition, the agreement can be terminated by the Company or any successor following a change of control of the Company that meets specified conditions, upon payment of a specified sum to GSK and the grant to GSK of a license to a specified number of product candidates then in development in each of the therapeutic focus areas of the alliance. The rights and obligations of the parties that survive termination of the agreement, including license grants, product candidates to which the license grants would apply and payment obligations, vary depending on the basis of the termination.
Item 3.02 Unregistered Sales of Equity Securities.
As described above, the Company entered into a stock purchase agreement on July 27, 2007 pursuant to which the Company issued and sold to Glaxo Group Limited on that date 1,275,502 shares of its common stock for an aggregate purchase price of $15.0 million. Under the terms of the agreement, the shares of common stock purchased by Glaxo Group Limited are restricted and may not be sold, transferred, pledged, hypothecated or otherwise disposed of to an unaffiliated third party prior to July 27, 2008.
The shares of common stock were offered and sold to Glaxo Group Limited in reliance on Section 4(2) of the Securities Act of 1933, as amended, based on representations made by the purchaser as to its sophistication in financial matters, access to material information, investment intent and status as an "accredited investor," as that term is defined by the rules and regulations of the Securities and Exchange Commission.
Look and Learn: Watching Neurons Make Memories
http://www.schizophreniaforum.org/new/detail.asp?id=1382
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Hallo gfp927z, from my german research board
http://www.wallstreet-online.de/dyn/community/thread.html?thread_id=940011&mode=pages
Hope this helps.
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Targets for the development of memory-enhancing drugs.
The production of memory-related synaptic changes occurs in three stages. Step 1: induction. Released transmitter binds to AMPA-type glutamate receptors, which then depolarize the postsynaptic region and unblock NMDA-type receptors. Step 2: expression. NMDA receptors admit calcium and thereby modify AMPA receptors so as to increase the size of subsequent excitatory currents. Step 3: consolidation. NMDA receptors also trigger changes that stabilize the modifications to the AMPA receptors. A rapidly developing aspect of this (3A) involves adhesion receptors, whereas a more delayed component requires genomic events (3B). Current strategies for drug development (red asterisks) target the AMPA receptor component of induction or the gene-signaling component of consolidation.
The production of memory-related synaptic changes occurs in three stages. Step 1: induction. Released transmitter binds to AMPA-type glutamate receptors, which then depolarize the postsynaptic region and unblock NMDA-type receptors. Step 2: expression. NMDA receptors admit calcium and thereby modify AMPA receptors so as to increase the size of subsequent excitatory currents. Step 3: consolidation. NMDA receptors also trigger changes that stabilize the modifications to the AMPA receptors. A rapidly developing aspect of this (3A) involves adhesion receptors, whereas a more delayed component requires genomic events (3B). Current strategies for drug development (red asterisks) target the AMPA receptor component of induction or the gene-signaling component of consolidation.
Pipeline and article from TRGT
Targacept NNR Platform Lands In Billion-Dollar GSK Alliance
By Jennifer Boggs
Targacept Inc. got an impressive stock boost Friday, jumping 20 percent on an early stage deal with GlaxoSmithKline plc to develop drugs targeting neuronal nicotinic receptors for pain and other disorders.
The alliance is accompanied by a $35 million up-front payment, comprised $20 million in cash and $15 million in an equity investment. London-based GSK agreed to purchase 1.3 million shares of Targacept's common stock priced at $11.76 per share, a nice premium to Thursday's closing price of $9. Beyond that, Targacept is eligible to receive up to $1.5 billion in potential milestones - with $1 billion of that to come from pre-commercial achievements - upon the successful development of product candidates across five therapeutic areas: pain, smoking cessation, obesity, addiction and Parkinson's disease. Targacept also would receive tiered double-digit royalties, depending on product sales.
"These are the kinds of deals that come along once in a lifetime," said Donald deBethizy, president and CEO of Targacept. "We've been celebrating."
The excitement was echoed on Wall Street, which sent shares of Targacept (NASDAQ:TRGT) up $1.79, or 20 percent, to close at $10.79.
Analyst Terence Flynn, of Lazard Capital Markets, maintained a "buy" rating on the company's stock and wrote in a research note that the GSK alliance further validates "the concept of targeting nicotinic receptors for therapeutic purposes and . . . the strength of Targacept's pipeline and Pentad discovery platform."
It's a platform that the Winston-Salem, N.C.-based firm has been perfecting since its days as a subsidiary of the R. J. Reynolds Tobacco Co. aimed at studying the chemistry and biology of nicotine. The company focuses on a class of drugs targeting neuronal nicotinic receptors (NNRs), which are found on nerve cells and work to regulate the central nervous system.
Targacept's Pentad technology is designed to discover small-molecule drugs targeting NNRs, and the company has identified a range of potential indications, such as Alzheimer's disease, schizophrenia, anxiety and pain, to name a few.
"We knew we had a great" platform, deBethizy told BioWorld Today, and "we've been chomping at the bit to get enough resources to get some of the discovery deals going."
Enter GSK, which signed Targacept under its Centers of Excellence for External Drug Discovery (CEEDD) program, which aims at building the pharma company's pipeline by investing in early biotech efforts.
Mark Strobeck, vice president of drug discovery transactions for GSK, said during a conference call that the goal of CEEDD is to allow a biotech firm "to partner with a large pharmaceutical company earlier in the development process and maintain its independence through clinical proof of concept," all the while receiving a stream of success-based funding.
Those kinds of early stage deals are becoming an industry trend. "There's a lot of new science emerging, so people are starting to take a little more risk," deBethizy said. As a result, biotech firms are able to sign preclinical deals "with Phase IIb economics."
As part of its role in the collaboration, Targacept will be responsible for research and discovery of small-molecule therapies that target predefined NNR subtypes and then will develop the most promising candidate in each of those five therapeutic areas through proof-of-concept studies. After that, GSK would have the option to take the programs into late-stage development and commercialization. And one of the best parts of the deal, deBethizy said, is that the financial structure ensures Targacept adequate funding for its work. Up to $16 million in milestones could be doled out for each of the five therapeutic programs prior to starting proof of concept.
Though alliance negotiations initially included only preclinical programs, Targacept's two lead pain products soon were added to the mix. TC-2696, which is designed to modulate the activity of the alpha4beta2 NNR, is in a Phase II trial for acute postoperative pain in patients undergoing third molar extraction, and pending successful results, expected by the end of this year, will enter a proof-of-concept trial. Following behind is TC-6499, which also targets the alpha4beta2 NNR. That compound is slated to start clinical testing before the end of 2007.
For both pain products, Targacept has retained a co-promotion option in the U.S. "We want to make sure we hold on to specialty opportunities," deBethizy said, adding that the company has a similar arrangement in its potential $300 million 2005 deal with London-based AstraZeneca plc. That collaboration includes TC-1734, now AZD3489, which started a 500-patient Phase IIb trial earlier this month in Alzheimer's disease. AstraZeneca is expected to start a separate Phase IIb study next month to test the compound in cognitive deficits in schizophrenia. (See BioWorld Today, Dec. 29, 2005.)
Targacept also is progressing clinical candidates on its own. Earlier this month, the company started a Phase I trial of TC-5619, a small molecule aimed at modulating the alpha7 NNR, believed to regulate inflammation arising from injury or infection, with possible implications on cognitive function. It also is in Phase I with TC-2216, which modulates alpha4beta2 to treat depression and anxiety.
Targacept, which has not yet reported its second-quarter earnings, posted a net loss of $4.8 million for the three months ending March 31. Alan Musso, the company's vice president and chief financial officer, reported during the conference call that the firm's current cash position, including the $35 million up-front payment from GSK, exceeds $90 million. He added that Targacept should end the year with about $75 million in the bank.
Source: http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forc...
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