Treatments for Depression and Anxiety ........in the pipe line

December 23, 2005

Treatments for Depression and Anxiety

Drug Name Pharmacologic Action Company Indication Developmental

Phase Links

EMSAM ® (selegiline) MAO-B inhibitor, weak MAO-A inhibitor [at

higher doses]; administered transdermally Bristol-Myers Squibb,

Somerset (Mylan/)

Depression Approvable - the PDUFA date is Feb. 26 [6/16/05 press

release] [2002 Clinical Trial]

Valdoxan (agomelatine, S-20098) 5-HT2C antagonist, 5-HT2B

antagonist, melatonin M1/M2 receptor agonist Servier Depression,

anxiety, sleep disorders Submitted in the European Union - Decision

expected early to mid-2006 [Receptor activity] [Oct 2005 press

release]

Gepirone ER 5-HT1A partial agonist Fabre-Kramer Depression,

anxiety Amended NDA scheduled to be submitted 12/05 [June Press

Release]

DVS-233 SR

(desvenlafaxine) Metabolite of Effexor ® (venlafaxine) Wyeth

Depression, anxiety Pre-registration. NDA to be submitted in early

2006 [June Press Release]

SR 58611 beta-3-adrenoceptor agonist Sanofi-Aventis Depression,

anxiety Phase III [sR 58611 is a selective beta-3-adrenoceptor

agonist]

Saredutant (SR 48968) NK2 antagonist Sanofi-Aventis Depression,

anxiety Phase III [Effects of SR 48968 on rodents]

PRX-00023 5-HT1A agonist, sigma receptor antagonist Predix Anxiety,

ADHD, depression Phase III (still in phase II for depression)

Radafaxine, GW353162 Norepinephrine reuptake inhibitor and weak

dopamine reuptake inhibitor (metabolite of bupropion) GSK

Depression, obesity Phase III - to begin in 2006

GW372475, NS2359 Dopamine, serotonin, and norepinephrine, reuptake

inhibitor GSK, NeuroSearch Depression Phase II

Ocinaplon GABA-A modulator DOV Anxiety Phase III - Discontinued

[DOV's info]

DOV 216,303 DA/NE/5-HT reuptake inhibitor DOV/Merck Depression,

anxiety Phase II - complete [DOV's info]

Nemifitide

(INN 00835) Pentapeptide analog of melanocyte-inhibiting factor (MIF-

1) administered intravenously (mechanism unknown) Innapharma

Depression Phase II [innapharma's info] [Antidepressant-like

effects of a novel pentapeptide, nemifitide, in an animal model of

depression] [MIF-1 may regulate ACTH secretion]

Miraxion, LAX-101 " Purified " Omega-3 [EPA] Amarin Huntington's

Disease, Depression Phase II

ORG 34517/34850 GR antagonist Organon Depression Phase II

CP-122,721 NK1 antagonist Pfizer Depression, anxiety Phase II

[Effects of CP-122,721 on gerbils]

VPI-013, OPC-14523 5-HT1A agonist, sigma receptor agonist [also a

serotonin reuptake inhibitor at higher doses] Vela

Depression Phase II [OPC-14523 responses in rats]

Vestipitant, GW597599 NK1 antagonist GSK Depression, anxiety Phase

II

YKP-10A, R228060 Phenylalanine derivative Janssen ( &

)/SK Pharmaceuticals Depression Phase II [First Phase II

Study]

ORG 4420 NaSSA (noradrenergic/specific serotonergic antidepressant)

Organon Sleep disorders, depression, anxiety Phase II

Elzasonan, CP-448,187 5-HT1B and 5-HT1D receptor antagonist Pfizer

Depression, anxiety Phase II

MN-305 5-HT1A partial agonist MediciNova Anxiety Phase II

Vilazodone 5-HT1A partial agonist, serotonin reuptake inhibitor

Genaissance Pharmaceuticals Depression, anxiety Phase II [9/04

press release]

GW679769 NK1 antagonist GSK Depression, anxiety Phase II

LY354740 mGluR2, mGluR3 agonist Eli Lilly Anxiety Phase II [LY354740

is a nonsedative anxiolytic]

XBD173 Peripheral mitochondrial benzodiazepine receptor agonist

Novartis Anxiety Phase II

R-tofisopam R-isomer of racemic tofisopam (a 2,3-benzodiazepine)

Vela Anxiety, IBS Phase I

DOV 21, 947 Dopamine, serotonin, and norepinephrine, reuptake

inhibitor DOV/Merck Depression, ADHD, RLS Phase I [Antidepressant-

like actions of DOV 21,947]

GW823296 NK1 antagonist GSK Depression, anxiety Phase I

PRE703 MgluR agonist Prescient Anxiety Phase I

SSR149415 V1B antagonist Sanofi-Aventis Depression, anxiety,

hyperphagia Phase I [sSR149415 review]

Delucemine, NPS 1506 NMDA antagonist NPS Depression, stroke Phase

I [NPS-1506 provides neuroprotection]

Lu AA21004 5-HT reputake inhibitor Lundbeck Depression, anxiety

Phase I

SEP-225289 DA/NE/5-HT reuptake inhibitor Sepracor Depression,

anxiety Phase I

DMP904 CRF1 antagonist Bristol-Myers Squibb Depression, anxiety

Phase I [DMP904 has an anxiolytic effect in rats]

DMP696 CRF1 antagonist Bristol-Myers Squibb Depression, anxiety

Phase I [DMP696 is highly selective and potent]

CP-316,311 CRF1 antagonist Pfizer Depression, anxiety Phase I

GW876008 CRF1 antagonist Neurocrine/GSK Depression, anxiety Phase

I

ONO-2333Ms CRF1 antagonist Ono Pharmaceuticals Depression, anxiety

Phase I

JNJ-19567470 or TS-041 CRF1 antagonist Janssen ( & ),

Taisho Depression, anxiety Phase I [Taisho's press release]

SSR 125543 CRF1 antagonist Sanofi-Aventis Depression, anxiety,

hyperphagia Phase I

ND7001 PDE2 inhibitor Neuro3d Depression, anxiety Phase I

YKP3089 Undisclosed mechanism of action SK Pharmaceuticals Anxiety

Phase I

R1576 GPCR modulator Roche Depression, anxiety Phase I

-- CRF1 antagonist Neurogen Depression, anxiety Pre-clinical

SSR 126374 CRF1 antagonist Sanofi-Aventis Depression, anxiety,

hyperphagia Pre-clinical

SSR 411298 FAAH (fatty acid amide hydrolase) inhibitor Sanofi-

Aventis Depression, anxiety, hyperphagia Pre-clinical

SSR 101010 FAAH (fatty acid amide hydrolase) inhibitor Sanofi-

Aventis Depression, anxiety, hyperphagia Pre-clinical

SSR 241586 NK2 and NK3 receptor antagonist Sanofi-Aventis

Depression, anxiety, IBS, COPD Pre-clinical

CRF1 antagonist (backup) CRF1 antagonist GSK/Neurocrine

Depression, anxiety Pre-clinical

AZD2327 AstraZeneca Anxiety Pre-clinical

R1661 Roche Anxiety Pre-clinical

SAR 102279 NK2 receptor antagonist Sanofi-Aventis Depression,

anxiety Pre-clinical

YKP581 Undisclosed mechanism of action SK Pharmaceuticals (J & J)

Depression Pre-clinical

Treatments for Sleep Disorders

Drug Name Pharmacologic Action Company Indication Developmental

Phase Links

Rozerem ® (ramelteon, TAK-375) Melatonin MT1, MT2 receptor agonist

Takeda Insomnia characterized by difficulty with sleep onset

Approved, product currently available in most pharmacies [Product

website]

Ambien CR ® (Zolpidem MR) sustained-release version GABA-A modulator

Sanofi-Aventis Sleep disorders Approved, product currently available

in most pharmacies [Product website]

Xyrem ® (sodium oxybate) Oral form of gamma-hydroxybutyrate (GHB)

Orphan Medical Excessive daytime sleepiness in narcolepsy

Approved, product currently available in most pharmacies [submission

press release for narcolepsy]

Indiplon IR; Indiplon MR GABA-A modulator (at BZ1 sites)

Neurocrine/DOV Sleep disorders NDAs submitted. Feb. 15, 2006 PDUFA

date for IR capsules and March 27, 2006 PDUFA date for MR tablets

[Neurocrine's info]

Gaboxadol (aka THIP) GABA-A agonist (gaboxadol acts as a full or

partial agonist depending on the subunit composition of the GABA-A

receptors that it binds to) Lundbeck, Merck Sleep disorders Phase

III [Full/Partial agonism] [Gaboxadol does not produce tolerance to

its sleep inducing effects]

Eplivanserin, SR 46349 5-HT2A receptor antagonist Sanofi-Aventis

Sleep disorders Phase II - complete [phase III to begin in 2006]

VEC-162 Melatonin receptor agonist Vanda Pharmaceuticals Sleep

disorders, depression Phase II - complete [Vanda's info]

Zaleplon (Sonata ®) extended-release GABA-A modulator King

Pharmaceuticals (Mylan) Sleep disorders Phase II

PD-6735 Melatonin receptor agonist Phase 2 Discovery Sleep

Disorders Phase II

ORG 50081 NaSSA (noradrenergic/specific serotonergic

antidepressant) Organon Sleep disorders, hot flashes Phase II

M-100907 5-HT2A antagonist Sanofi-Aventis Sleep disorders Phase II

[M-100907 review]

PD-200,390 Voltage-gated calcium channel alpha(2)delta subunit

modulator Pfizer Sleep disorders Phase II

NG2-73 GABA-A modulator Neurogen Sleep disorders Phase I

Pruvanserin, EMD 281014 5-HT2A antagonist Eli Lilly Sleep

disorders Phase I

APD125 5-HT2A inverse agonist Arena Sleep disorders Phase I

GW649868 Orexin antagonist GSK Sleep disorders Late-stage Pre-

clinical [GSK presentation (PDF)]

AVE 8488 5-HT2A antagonist Sanofi-Aventis Sleep disorders Late-

stage Pre-clinical

Treatments for Psychosis/Bipolar Disorder

Drug Name Pharmacologic Action Company Indication Developmental

Phase Links

Paliperidone IM, ER Full 5-HT2/partial D2 antagonist with high

affinity for 5-HT7 receptors. Active metabolite of Risperdal®

& Psychosis NDA Submitted [Nov. 30 press release]

Corlux ® (AKA mifepristone or RU-486) Glucocorticoid receptor type

II (GRII) antagonist, progesterone receptor antagonist Corcept

Psychosis, depression Phase III, granted fast track status by FDA

[Corcept's info]

Bifeprunox (DU-127090) Partial agonist at dopamine D2 and serotonin

5-HT1A receptors Solvay, Wyeth Psychosis Phase III (additional

trials were recently announced) [Oct 2005 presentation]

Asenapine (ORG 5222) 5-HT2 antagonist, D2 partial agonist Organon,

Pfizer Psychosis Phase III [Organon 2003 press release]

Zomaril (Iloperidone) Selective DA/NE/5-HT antagonist Vanda

Pharmaceuticals Psychosis Phase III

Ocaperidone D2/5-HT2 antagonist Neuro3d, Janssen Psychosis Phase III

Drug profile

SLV 308 D2 partial agonist, 5-HT1A agonist Solvay Psychosis,

Parkinson's disease Phase III

LIC477D (licarbazepine) Voltage-gated sodium channel inhibitor

Novartis Psychosis Phase III

ORG 34517/34850 Glucocorticoid receptor type II (GRII) antagonist

Organon Depression, psychosis Phase II

ORG 24448 AMPA modulator Organon/Cortex Psychosis Phase II

ACP-103 Serotonin 5-HT2A receptor inverse agonist, dopamine D2/D3

receptor partial agonist, acetylcholine M1 receptor agonist Acadia

Antipsychotic-induced side effects, Parkinson's disease Phase II

[9/2004 press release]

ACP-104 Metabolite of clozapine Acadia Psychosis Phase II

RG2133 (triacetyluridine) Prodrug of uridine Repligen Bipolar

disorder Phase II [Repligen's info] [10/21/05 press release]

Lonasen (blonanserin) D2, 5-HT2A antagonist Dainippon

Pharmaceuticals Psychosis Phase II

Mirapex ® (pramipexole) Dopamine D2, D3 receptor agonist

Boehringer-Ingelheim Bipolar Disorder Phase II

Lu-35-138 D4/5-HT antagonist Lundbeck Psychosis Phase II

Lurasidone (SM 13496) D2, 5-HT2A antagonist Merck, Sumitomo

Psychosis Phase II

Talnetant (SB-223412) NK-3 antagonist GSK Psychosis, IBS, overactive

bladder Phase II

RG1068, secretin Endogenous pancreatic hormone Repligen Psychosis,

autism, anxiety Phase II

SLV 310,313 5-HT2A antagonist Solvay Psychosis Phase II

SSR 181507 D2/5-HT2 antagonist Sanofi-Aventis Psychosis Phase I

ABT-089 Nicotinic acetylcholine receptor agonist Abbott

Laboratories Psychosis Phase I

GW742457 5-HT6 antagonist GSK Psychosis, Alzheimer's disease Phase

I

GW773812 D2, 5-HT antagonist GSK Psychosis Phase I

TC-1827 Selective alpha4beta2 nicotinic acetylcholine receptor

agonist Targacept Cognitive impairment associated with schizophrenia

Phase I

SSR 146977 NK3 antagonist Sanofi-Aventis Psychosis Phase I

SSR 125047 Sigma receptor antagonist Sanofi-Aventis Psychosis Phase

I

AVE 1625 CB1 antagonist Sanofi-Aventis Psychosis Phase I

JNJ-17305600 GLYT1 inhibitor & Psychosis Phase I

PNU 170413 Pfizer Psychosis Phase I

MEM 3454 alpha7 nicotinic acetylcholine receptor partial agonist

Memory Pharm./ Roche Psychosis Late-stage Preclinical [Memory's

drug profile]

PDE10A PDE10A inhibitor Memory Pharm./ Roche Psychosis Late-stage

Preclinical

SSR 504734 GLYT1 (Type 1 glycine transporter) inhibitor Sanofi-

Aventis Psychosis Late-stage Preclinical

SSR 125047 GLYT1 (Type 1 glycine transporter) inhibitor Sanofi-

Aventis Psychosis Late-stage Preclinical

Treatments for Attention Deficit Hyperactivity Disorder (ADHD)

Drug Name Pharmacologic Action Company Indication Developmental

Phase Links

Sparlon ® (modafinil) aka Provigil ® Alpha-1-adrenoceptor agonist,

dopamine reuptake inhibitor Cephalon, & ADHD

Approvable

Daytrana ®

(methylphenidate transdermal system) Dopamine reuptake inhibitor,

weak norepinephrine reuptake inhibitor Shire Pharmaceuticals/Noven

Pharmaceuticals

ADHD The FDA advisory panel has backed approval. PDUFA date is

12/28/05 [shire 7/26/05 press release]

NRP104

NRP104 is lysine linked to d-amphetamine single salt. Until it is

metabolized in the gastrointestinal tract, NRP104 is inactive. At

plasmalemmal catecholamine transporters, amphetamine indirectly

increases the efflux of cytosolic catecholamines so that they are

released into the synaptic cleft (1). The drug causes the release of

norepinephrine more potently than it causes the release of dopamine;

it is much less effective as a serotonin releasing agent (1) The

drug also directly inhibits norepinephrine and dopamine reuptake at

higher concentrations (1). Amphetamine- induced activation of

protein kinase C (PKC) beta(II) is responsible for the drug's effect

on dopamine efflux (2). Na+ is cotransported with amphetamine as it

enters neurons via catecholamine transporters; amphetamine-induced

increases in intracellular Na+ may stimulate Na+/Ca2+ antiporters,

resulting in an influx of Ca2+ into the cytosol (3). The activity of

a Ca2+ dependent enzyme, phospholipase C (PLC), is increased by

amphetamine, and PLC may be responsible for the increase in PKC beta

(II) activity associated with amphetamine (3). Intracellular

dopamine is also required for amphetamine- induced increases in PKC

activity (3). Amphetamine increases the activity of phospholipase A2

(PLA2), perhaps by increasing intracellular pH (3). Low PLA2

activity may increase the activation of PKC, while high PLA2

activity may decrease the activation of PKC by amphetamine (3).

Amphetamine, a weak base, increases cytosolic dopamine and

norepinephrine through two mechanisms. First, amphetamine inhibits

vesicular sequestration of dopamine and norepinephrine into vesicles

by directly interacting with vesicular monoamine transporter-2 (VMAT-

2) (4). Second, amphetamine decreases VMAT-2 activity by reducing

the pH gradients that drive monoamine uptake into vesicles (5).

At higher concentrations, amphetamine may act as a competitive

antagonist at NMDA receptors (6). In addition, the drug is an

agonist at TA1, a trace amine receptor (7).

Shire Pharmaceuticals/ New River Pharmaceuticals ADHD Pre-

registration. Filing expected in the fourth quarter of 2005. [New

River compound info]

SPD-503 (guanfacine) Alpha-2-adrenoceptor agonist Shire

Pharmaceuticals ADHD Pre-registration. Filing expected in the first

quarter of 2006.

SPD-465 (longer acting Adderall XR ®) Long-acting amphetamine

product (see above for amphetamine's mechanism of action) Shire

Pharmaceuticals ADHD Phase III

NS-2359 DA/NE/5-HT reuptake inhibitor NeuroSearch ADHD Phase

II

SGS-742 GABA-B receptor antagonist Saegis/ Novartis Adult ADHD

Phase II

ABT-089 Nicotinic acetylycholine receptor modulator (agonist,

partial agonist, or antagonist depending on the subtype) Abbott

ADHD Phase II

CX-717 AMPA receptor modulator Cortex Pharmaceuticals ADHD Phase

II [Cortex 7/28/05 press release]

Altropane Highly selective dopamine transporter radioligand Boston

Life Sciences ADHD (diagnosis) Phase II

DOV-102,677 DA/NE/5-HT reuptake inhibitor (with preferential action

on the dopamine transporter) DOV Pharmaceuticals ADHD Phase I

SON-216 (bifemelane) Sosei ADHD

DAR-0300 ADHD

PGI-256 ADHD

PGI-415 ADHD

SPD-483 Shire Pharmaceuticals ADHD Preclinical

Recently Discontinued Drugs

Drug Name Pharmacologic Action Company Indication

ND1251 PDE4 inhibitor Neuro3d Depression

NGD 96-3 GABA-A modulator Neurogen Sleep disorders

AAG561 CRF1 antagonist Novartis Depression

APPENDIX 1

Terms glossary

Phase I:

Phase I includes the initial introduction of an investigational new

drug into humans. Phase I studies are typically closely monitored

and may be conducted in patients or normal volunteer subjects. These

studies are designed to determine the metabolism and pharmacologic

actions of the drug in humans, the side effects associated with

increasing doses, and, if possible, to gain early evidence on

effectiveness. During Phase I, sufficient information about the

drug's pharmacokinetics and pharmacological effects should be

obtained to permit the design of well-controlled, scientifically

valid, Phase II studies. The total number of subjects and patients

included in Phase I studies varies with the drug, but is generally

in the range of 20 to 80.

Phase II:

Phase II includes the controlled clinical studies conducted to

evaluate the effectiveness of the drug for a particular indication

or indications in patients with the disease or condition under study

and to determine the common short-term side effects and risks

associated with the drug. Phase II studies are typically well

controlled, closely monitored, and conducted in a relatively small

number of patients, usually involving no more than several hundred

subjects.

Phase III:

A phase III trial frequently compares a new treatment to a standard

treatment or to no treatment, and treatment allocation may be

randomly assigned and the data masked. These studies usually

involve a large number of participants followed for longer periods

of treatment exposure. Phase III studies are expanded controlled and

uncontrolled trials. Phase III studies usually include from several

hundred to several thousand subjects.

NDA: New Drug Application. NDA refers to the data that the drug

company submits to the FDA at the time of the drug's application

filing.

Approvable: Term giving to a drug's approval status by the FDA.

Before the drug can be launched, the company has to fulfill ongoing

clinical and manufacturing concerns brought up by the FDA.

REFERENCES

1. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll

FI, Partilla JS.

Amphetamine-type central nervous system stimulants release

norepinephrine more potently than they release dopamine and

serotonin.

Synapse 2001 Jan;39(1):32-41 [Abstract]

2. LA, Guptaroy B, Lund D, Shamban S, Gnegy ME.

Regulation of amphetamine-stimulated dopamine efflux by protein

kinase C beta.

J Biol Chem. 2005 Mar 25;280(12):10914-9. [Abstract]

3. Giambalvo CT.

Mechanisms underlying the effects of amphetamine on particulate PKC

activity.

Synapse. 2004 Feb;51(2):128-39. [Abstract]

4. kson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E.

Distinct pharmacological properties and distribution in neurons and

endocrine cells of two isoforms of the human vesicular monoamine

transporter.

Proc Natl Acad Sci U S A. 1996 May 14;93(10):5166-71. [Full Text]

5. Sulzer D, Rayport S.

Amphetamine and other psychostimulants reduce pH gradients in

midbrain dopaminergic neurons and chromaffin granules: a mechanism

of action.

Neuron. 1990 Dec;5(6):797-808. [Abstract]

6. Yeh GC, Chen JC, Tsai HC, Wu HH, Lin CY, Hsu PC, Peng YC.

Amphetamine inhibits the N-methyl-D-aspartate receptor-mediated

responses by directly interacting with the receptor/channel complex.

J Pharmacol Exp Ther. 2002 Mar;300(3):1008-16. [Full Text]

7. GM, Verrico CD, Jassen A, Konar M, Yang H, Panas H, Bahn

M, R, Madras BK.

Primate trace amine receptor 1 modulation by the dopamine

transporter.

J Pharmacol Exp Ther. 2005 Jun;313(3):983-94. [Abstract]

December 23, 2005