| Lilly Tests New Schizophrenia Drug .sidesteps the weight gain linked to current treatmentsApril 27 2011 at 8:51 AM | so that's an admission Zyprexa kills |
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Lilly Tests New Schizophrenia Drug
http://online.wsj.com/article/SB10001424052748703778104576287070215410378.html?mod=googlenews_wsj
Eli Lilly & Co. hopes to introduce the first of a new class of schizophrenia drugs that sidesteps the weight gain linked to current treatmentsand which might work best in people with a certain genetic makeup.
After seeing signs of promise in earlier tests, Indianapolis-based Lilly recently started large-scale, late-stage clinical trials of the drug, code-named LY2140023, some of which are expected to be completed by early 2013.
If the trials are successful and regulators approve it, the drug could hit the market in 2014 and eventually generate $1 billion in peak annual sales, estimated BMO Capital Markets analyst Robert Hazlett. "It's a novel approach that appears to be effective, at least modestly," Mr. Hazlett said.
Lilly is betting on the schizophrenia drug and other potential new products to help replace revenue due to be lost in coming years to patent expirations that trigger generic competition for top-selling drugs, including its antipsychotic Zyprexa.
There is no guarantee the Lilly drug's safety, efficacy or genetic link will be born out by the larger clinical trials. While weight gain may not be an issue, there have been other safety and efficacy issues in trials to date. Even if the drug makes it to market, it will face competition from cheaper generics and possibly newer schizophrenia drugs under development at such companies as Roche Holding AG.
Lilly says there is an unmet medical need in schizophrenia, a mental illness in which patients experience hallucinations, delusions and other symptoms. Widely used drugs known as atypical antipsychoticswhich include Zyprexa and AstraZeneca PLC's Seroquelcarry safety risks including weight gain and elevated blood sugar (the companies have paid hundreds of millions of dollars to settle lawsuits alleging the drugs caused diabetes and other injuries).
LY2140023 is designed to stimulate substances in the brain known as metabotropic glutamate receptors, or mGlu for short. This approach differs from atypicals, which generally block the effects of the chemical dopamine in the brain.
One midstage study published in Nature Medicine in 2007 showed Lilly's drug improved symptoms versus a placebo and didn't increase the risk of weight gain. "It's actually a side-effect profile that's much more attractive from a long-term view," said Jan Lundberg, head of Lilly's research and development arm.
In another study released in 2009, however, the drug performed no better than placebo. But Lilly deemed the outcome inconclusive because the study's design may have contributed to higher-than-normal improvements in placebo recipients.
In a six-month safety study presented at a medical conference this month, the drug was comparable to standard treatments including Zyprexa in the time to treatment discontinuation due to lack of tolerability. However, discontinuation due to lack of efficacy was significantly greater for LY2140023 compared with standard treatment. Mr. Hazlett, the BMO analyst, said the drug's efficacy is acceptable but not its strong suit.
Lilly's LY2140023 was associated with higher rates of insomnia, vomiting, agitation and indigestion, while patients on standard treatment had higher rates of weight gain and a movement disorder.
One patient in the trial had two seizures a day after discontinuing three weeks of treatment of the Lilly drug and initiating treatment with a conventional antipsychotic. The patient recovered with no residual side effects, researchers reported.
Joseph T. Coyle, a professor of psychiatry and neuroscience at Harvard Medical School who has studied the role of glutamate receptors in schizophrenia, said the Lilly drug has potential to improve treatment of so-called negative symptoms of the disease, which include social withdrawal, and cognitive symptoms, while avoiding weight gain. But he said that needs to be proved in late-stage trials. He has consulted for Lilly previously but isn't directly involved in developing Lilly's mGlu drug.
The potential genetic angle is part of a broader shift toward "personalized medicine," or the use of genetic information to determine whether individual patients are likely to respond to certain drugs.
A study published last year in the Pharmacogenomics Journal found patients with certain DNA sequences treated with the Lilly drug showed the largest reduction in schizophrenia symptoms.
"Intriguing preliminary data suggest it could be possible to identify a subpopulation of patients which responds better," Mr. Lundberg said. Lilly will track how LY2140023 performs in a predefined genetic subpopulation of patients in its late-stage trials, he said.
Dr. Coyle called the potential genetic link "preliminary," and said more comprehensive genetic analysis would be needed before concluding that it will be possible to identify in advance which patients are likely to benefit from the Lilly drug.
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| | Author | Reply | Anonymous
| amazing .......clinical trial lasts a whole 17 weeks | April 27 2011, 8:53 AM |
Verified on April 2011 by Eli Lilly and Company
| Sponsor: |
Eli Lilly and Company |
|---|
| Information provided by: |
Eli Lilly and Company |
|---|
| ClinicalTrials.gov Identifier: |
NCT01052103 |
|---|
The purpose of this study is to determine whether LY2140023, when added to standard-of-care antipsychotic treatment, will improve negative symptoms. | Study Type: |
Interventional | | Study Design: |
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment | | Official Title: |
A 17-Week, Phase 2, Multicenter, Randomized, Double-Blind Study of Treatment With LY2140023 Combined With Standard of Care Compared to Placebo Combined With Standard of Care in the Treatment of Patients With Prominent Negative Symptoms of Schizophrenia |
Primary Outcome Measures:
- Change from baseline in the 16-item Negative Symptoms Assessment (NSA-16) [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Change from baseline in Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: No ]
- Change from baseline in Clinical Global Impression Severity Scale (CGI-S) [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: No ]
- Change from baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) [ Time Frame: Baseline, 17 weeks ] [ Designated as safety issue: No ]
- Change from baseline in University of California at San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) [ Time Frame: Baseline, 17 weeks ] [ Designated as safety issue: No ]
- Change from baseline in Barnes-Akathisia Scale [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: Yes ]
- Incidence of epileptiform activity in Electroencephalograms (EEGs) [ Time Frame: Up to 19 weeks ] [ Designated as safety issue: Yes ]
- Incidence of potentially clinically significant changes in QT intervals Electrocardiograms (ECGs) [ Time Frame: Up to 17 weeks ] [ Designated as safety issue: Yes ]
- Incidence of change in Neurological Examination [ Time Frame: Up to 17 weeks ] [ Designated as safety issue: Yes ]
- Change from baseline in blood pressure [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: Yes ]
- Change from baseline in weight [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: Yes ]
- Incidence of potentially clinical significant change in laboratory values [ Time Frame: Up to 17 weeks ] [ Designated as safety issue: Yes ]
- Incidence of potentially clinical significant change of Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Up to 17 weeks ] [ Designated as safety issue: Yes ]
- Change from baseline to 17 weeks endpoint in Personal and Social Performance (PSP) Scale [ Time Frame: Baseline, 17 weeks ] [ Designated as safety issue: No ]
- Time to discontinuation [ Time Frame: Up to 17 weeks ] [ Designated as safety issue: No ]
- Change from baseline in Simpson Angus Scale [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: Yes ]
- Change from baseline in Abnormal Involuntary Movement Scale (AIMS) [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: Yes ]
- Change from baseline in pulse rate [ Time Frame: Baseline, 16 or 17 weeks ] [ Designated as safety issue: Yes ]
- Change from 1 week to 18 weeks endpoint in the Schizophrenia Resource Use Module (S-RUM) [ Time Frame: 1 week, 18 weeks ] [ Designated as safety issue: No ]
- Change from baseline to 17 weeks endpoint in the EuroQol Questionnaire-5 Dimension (EQ-5D) [ Time Frame: baseline, 17 weeks ] [ Designated as safety issue: No ]
- Change from baseline to 17 weeks endpoint in the Subjective Well-Being Under Neuroleptic Treatment-Short Form (SWN-S) [ Time Frame: baseline, 17 weeks ] [ Designated as safety issue: No ]
| Estimated Enrollment: |
280 | | Study Start Date: |
January 2010 | | Estimated Study Completion Date: |
March 2012 | | Estimated Primary Completion Date: |
March 2012 (Final data collection date for primary outcome measure) |
| Arms |
Assigned Interventions |
|---|
LY2140023: Experimental
Interventions:
- Drug: LY2140023
- Drug: Standard of Care
|
Drug: LY2140023
40mg, oral tablets, twice daily: 20 mg in the morning, 20 mg in the evening, for 16 or 17 weeks. The dose may be adjusted to a minimum of 20mg or a maximum of 80mg. Drug: Standard of Care
U.S. label prescribed dose of one of the following Standard of Care Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine)
| Placebo: Placebo Comparator
Interventions:
- Drug: Placebo
- Drug: Standard of Care
|
Drug: Placebo
Placebo oral tablets, twice daily: in the morning and in the evening, for 16 or 17 weeks. Drug: Standard of Care
U.S. label prescribed dose of one of the following Standard of Care Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine)
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| Ages Eligible for Study: |
18 Years to 65 Years | | Genders Eligible for Study: |
Both | | Accepts Healthy Volunteers: |
No |
Inclusion Criteria:
- Clinical diagnosis of schizophrenia
- Patients must have been receiving monotherapy treatment for at least 3 months prior to study entry with one of 4 atypical antipsychotic medications (aripiprazole, olanzapine, risperidone, quetiapine)
- Disease symptoms must meet a certain range as assessed by the clinician
- Patients must have evidence of prominent negative symptoms of schizophrenia (i.e. blunted affect, emotional withdrawal, or motor retardation)
- Patients must be considered reliable, have a level of understanding sufficient to perform all tests and examinations required by the protocol, and be willing to perform all study procedures
- Patients must be able to understand the nature of the study and have given their informed consent
Exclusion Criteria:
- Patients who are actively suicidal
- Patients who are pregnant or nursing
- Patients who have had electroconvulsive therapy (ECT) within 3 months of screening or who will have ECT at any time during the study
- Patients with uncorrected narrow-angle glaucoma, history of or current seizure disorder, uncontrolled diabetes, certain diseases of the liver, renal insufficiency, uncontrolled thyroid condition or other serious or unstable illnesses
- Patients with Parkinson's disease, psychosis related to dementia or related disorders
- Patients with known Human Immunodeficiency Virus positive (HIV+) status
Please refer to this study by its ClinicalTrials.gov identifier: NCT01052103
| Contact: There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or |
1-317-615-4559 |
|
 Show 23 Study Locations
Eli Lilly and Company
| Study Director: |
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) |
Eli Lilly and Company |
No publications provided | Responsible Party: |
Eli Lilly ( Chief Medical Officer ) | | ClinicalTrials.gov Identifier: |
NCT01052103 History of Changes | | Other Study ID Numbers: |
13261, H8Y-MC-HBCO | | Study First Received: |
January 13, 2010 | | Last Updated: |
April 9, 2011 | | Health Authority: |
United States: Food and Drug Administration; Israel: Ministry of Health; Italy: Ministry of Health; Spain: Ministry of Health |
Additional relevant MeSH terms:
Schizophrenia
Schizophrenia and Disorders with Psychotic Features
Mental Disorders
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ClinicalTrials.gov processed this record on April 25, 2011
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| Anonymous
| it failed in 2009 because "placebo response exceptionally high" | April 27 2011, 8:57 AM |
LY-404,039
From Wikipedia, the free encyclopedia
LY-404,039 is a drug used in scientific research that acts as a selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3.[1] It has anxiolytic and antipsychotic effects in animal studies, but without causing sedation.[2]
Early human trials using a prodrug form of LY-404,039 called LY-214,0023 have also given encouraging results.[3][4][5] A trial in 2009 failed to prove superiority over placebo or Olanzapine, but Lilly explained this as being due to an exceptionally high placebo response.[6]
[edit] See also
[edit] References
- ^ Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD (April 2007). "Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039)". The Journal of Pharmacology and Experimental Therapeutics 321 (1): 30817. doi:10.1124/jpet.106.110809. PMID 17204749.
- ^ Rorick-Kehn LM, Johnson BG, Knitowski KM, Salhoff CR, Witkin JM, Perry KW, Griffey KI, Tizzano JP, Monn JA, McKinzie DL, Schoepp DD (July 2007). "In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders". Psychopharmacology 193 (1): 12136. doi:10.1007/s00213-007-0758-3. PMID 17384937.
- ^ Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (September 2007). "Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial". Nature Medicine 13 (9): 11027. doi:10.1038/nm1632. PMID 17767166.
- ^ Lebois EP (2008). "Neither typical nor atypical: LY404039 provides proof of concept that selective targeting of mGluR2/3 receptors is a valid mechanism for obtaining antipsychotic efficacy". Current Topics in Medicinal Chemistry 8 (16): 14801. PMID 19006848.
- ^ Fraley ME (June 2009). "Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia". Expert Opinion on Therapeutic Patents 19 (9): 125975. doi:10.1517/13543770903045009. PMID 19552508.
- ^ Eli Lilly and Company - Lilly Announces Inconclusive Phase II Study Results for mGlu2/3 at the International Congress on Schizophrenia Research, Eli Lilly, 29 March 2009
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Agonists: Glutamate/acite site competitive agonists: Aspartate Glutamate Homoquinolinic acid Ibotenic acid NMDA Quinolinic acid Tetrazolylglycine; Glycine site agonists: ACBD ACPC ACPD Alanine CCG Cycloserine DHPG Fluoroalanine Glycine HA-966 L-687,414 Milacemide Sarcosine Serine Tetrazolylglycine; Polyamine site agonists: Acamprosate Spermidine SpermineAntagonists: Competitive antagonists: AP5 (APV) AP7 CGP-37849 CGP-39551 CGP-39653 CGP-40116 CGS-19755 CPP LY-233,053 LY-235,959 LY-274,614 MDL-100,453 Midafotel (d-CPPene) NPC-12,626 NPC-17,742 PBPD PEAQX Perzinfotel PPDA SDZ-220581 Selfotel; Noncompetitive antagonists: ARR-15,896 Caroverine Dexanabinol FPL-12495 FR-115,427 Hodgkinsine Magnesium MDL-27,266 NPS-1506 Psychotridine Zinc; Uncompetitive pore blockers: 2-MDP 3-MeO-PCP 8A-PDHQ Alaproclate Amantadine Aptiganel ARL-12,495 ARL-15,896-AR ARL-16,247 Budipine Delucemine Dexoxadrol Dextrallorphan Dieticyclidine Dizocilpine Endopsychosin Esketamine Etoxadrol Eticyclidine Gacyclidine Ibogaine Indantadol Ketamine Ketobemidone Loperamide Memantine Meperidine (Pethidine) Methadone Methorphan ( Dextromethorphan, Levomethorphan) Methoxetamine Milnacipran Morphanol ( Dextrorphan, Levorphanol) NEFA Neramexane Nitrous oxide Noribogaine Orphenadrine PCPr Phencyclamine Phencyclidine Propoxyphene Remacemide Rhynchophylline Riluzole Rimantadine Rolicyclidine Sabeluzole Tenocyclidine Tiletamine Tramadol Xenon; Glycine site antagonists: ACEA-1021 ACEA-1328 ACPC Carisoprodol CGP-39653 CKA DCKA Felbamate Gavestinel GV-196,771 Kynurenic acid L-689,560 L-701,324 Lacosamide Licostinel LU-73,068 MDL-105,519 Meprobamate MRZ 2/576 PNQX ZD-9379; NR2B subunit antagonists: Besonprodil CO-101,244 (PD-174,494) CP-101,606 Eliprodil Haloperidol Ifenprodil Isoxsuprine Nylidrin Ro8-4304 Ro25-6981 Traxoprodil; Polyamine site antagonists: Arcaine Co 101676 Diaminopropane Acamprosate Diethylenetriamine Huperzine A Putrescine Ro 25-6981; Unclassified/unsorted antagonists: Chloroform Diethyl ether Enflurane Ethanol (Alcohol) Halothane Isoflurane Methoxyflurane Toluene Trichloroethane Trichloroethanol Trichloroethylene Xylene | | |
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