neuropathic pain: a new...

Neuropathic Pain: A New Frontier

Ginger S. Johnson, PhDDefined Health

March 1, 2006


• Beyond Debate: Pharma’s Innovation Bar and the Need for Uniquely Advantageous Therapeutics

• Will Can Pharma / Biotech Clear the Innovation Bar?• Complex Therapies Redux: Therapeutic Vaccines, Cell and Gene Therapy

– A New Game for New Players?• Staring up the Face of the Mountain -- Strategies for Launching into

Uncharted Therapeutic Areas• The Future of Cardiovascular Therapeutics: Is there Life Beyond Statins,

and other Existential Issues• Good, Better, Best: The Ethics of Improvement and Enhancement That

Face the Pharma and Biotech Industries (Arthur L. Caplan, PhD, Keynote)• Pharmacogenetics is Not Just for Targeted Therapies -- Making Intelligent

Space for Chemotherapy in the 21st Century• Not Your Father’s Drug Delivery: Novel Approaches to Novel Therapies• Style or Substance: The Lifestyle Drug Continuum

Plenary Sessions


Karen Bernstein, PhD, Chairman & Editor-In-Chief, BioCenturyAlexis Borisy, AM, President & Chief Executive Officer, CombinatoRxArthur L. Caplan, PhD, Chair, Department of Medical Ethics, Director, Center for Bioethics, University of Pennsylvania School of Medicine (Keynote) Michael D. Clayman, MD, VP, Lilly Research Laboratories, Eli Lilly Bruce Cohen, President & CEO, Cellerant TherapeuticsDavid DeMarco, PhD, Formerly Vice President, Strategy & Corporate Development, CambrexFrederick Frank, Vice Chairman & Director, Lehman BrothersRobert H. Glassman, MD, Managing Director, Healthcare Investment Banking, Merrill LynchMitchell H. Gold, MD, President & Chief Executive Officer, DendreonJames W. Harris, PhD, Founder and Chief Scientific Officer, Bioavailability SystemsJuergen Lasowski, Former VP, Head of Business Development & Strategy, US, sanofi-aventis Brian Leyland-Jones, MD, Professor & Founding Chairman, Dept. of Oncology, McGill University Clive A. Meanwell, MD, Chairman & CEO, The Medicines Company Paul C. Nakagaki, PhD, Head, Pharma Research Strategy, Pharmaceuticals Div., RocheRoger S. Newton, PhD, SVP, PGRD, Director, Esperion TherapeuticsDouglas E. Onsi, VP Business Development, Genzyme Genetics Richard Pasternak, MD, VP, Clinical Research Cardiovascular/Atherosclerosis, Merck Research Laboratories Jorge Plutzky, MD, Director, The Vascular Disease Prevention Prgm., Brigham and Women's Hospital Paul M. Ridker, MD, MPH, Cardiovascular Medicine, Department of Medicine, Brigham and Women's HospitalMary C. Tanner, Partner, Life Sciences Partners, LLCThomas Tillett, President and CEO, RheoGeneRobert E. Ward, VP Commercial Dev., NPS Pharmaceuticals

Speakers to Date


Female Sexual Dysfunction

Premature Ejaculation

Obesity

Erectile DysfunctionUrin

ary Incontinence

Narcolepsy

Neuropathic Pain & FibromyalgiaNew Therapeutic Frontiers


Neuropathic Pain Insight Series –Tonight’s Discussion Topics

1. Neuropathic Pain (and Fibromyalgia): Study the Terrain

2. Can You Learn From Those Who Have Gone Before You?

3. Can You Compete with the Next Generation?


Before You Embark on Your Journey, Study the Terrain


Neuropathic Pain

It’s BIG, it’s Growing and it’s Underdeveloped

Neuropathic pain is one of the most common types of pain, but it is often under-recognized and under-treated.


0

100,000

200,000

300,000

400,000

500,000

600,000

Painful DiabeticNeuropathy

PostherpeticNeuralgia

Cancer-Associated

Spinal CordInjury

CRPS HIV -Associated

MultipleSclerosis

Phantom Pain Post-Stroke TrigeminalNeuralgia

It’s BigThere Are an Estimated 15 M People in the US who Suffer From Neuropathic Pain (examples and prevalence are shown below)

Note: Numbers are approximate


0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

Painful DiabeticNeuropathy

PostherpeticNeuralgia

Cancer-Associated

Spinal Cord Injury CRPS HIV - Associated M ultipleSclerosis

Phantom Pain Poststroke TrigeminalNeuralgia

Low Back Pain-Associated

It’s BigAmong the most common of pain states is low back pain, and we are now

beginning to understand that persistent a percentage of low back pain (~10%), particularly after one or two surgeries, is probably a neuropathic phenomenon.

Note: Numbers are approximates


Published: January 9, 2006

Diabetes and Its Awful Toll Quietly Emerge as a Crisis By N. R. KLEINFIELD

Begin on the sixth floor, third room from the end, swathed in fluorescence: a 60-year-old woman was having two toes sawed off. One floor up, corner room: a middle-aged man sprawled, recuperating from a kidney transplant. Next door: nerve damage. Eighth floor, first room to the left: stroke. Two doors down: more toes being removed. Next room: a flawed heart. As always, the beds at Montefiore Medical Center in the Bronx were filled with a universe of afflictions. In truth, these assorted burdens were all the work of a single illness: diabetes. Room after room, floor after floor, diabetes. On any given day, hospital officials say, nearly half the patients are there for some trouble precipitated by the disease. An estimated 800,000 adult New Yorkers -- more than one in every eight -- now have diabetes, and city health officials describe the problem as a bona fide epidemic. Diabetes is the only major disease in the city that is growing, both in the number of new cases and the number of people it kills. Already, diabetes has swept through families, entire neighborhoods in the Bronx and broad slices of Brooklyn, where it is such a fact of life that people describe it casually, almost comfortably, as ''getting the sugar'' or having ''the sweet blood.'' But as alarmed as health officials are about the present, they worry more about what is to come.

Neuropathic Pain: It’s Growing

And it is growing quickly, even as other scourges like heart disease and cancers are stable or in decline.

Just considering the diabetes population in the US & the associated manifestations of the disease, including diabetic neuropathy, neuropathic pain will continue to be

among the most rapidly growing patient populations.


• FMS is a widespread musculoskeletal pain and fatigue disorder and is associated with fatigue, sleep disturbance, depression, cognitive dysfunction and generally diminished quality of life.

• FMS is much more common in women (3.5% prevalence) than in men (0.5% prevalence).

Neuropathic Pain’s Close Cousin, Fibromyalgia, Could Nearly Double the Size of the Market

Dysfunction

CognitiveDifficulties

Diminished QOL

Fatigue

Depression

SleepDisturbance

Fibromyalgia

Dysfunction

CognitiveDifficulties

Diminished QOL

Fatigue

Depression

SleepDisturbance

Fibromyalgia Syndrome (FMS), which technically may or may not be a neuropathic pain, affects an estimated 6-12 M people in the US


Great Divide Basin, WY

Neuropathic Pain Market = Potential

15 M patients in the US+ Fibromyalgia6-12 M more patients

50 M patients in the US

Chronic Nociceptive Pain

The Neuropathic Pain Great Divide:Size / Value Disconnect

$2.5 billion market

$20 billion market

Current Market Size Does Not Reflect the Potential

$?? market


Neuropathic Pain is Difficult to Recognize, Diagnose and Treat

Why the Size / Value Disconnect?

Nociceptive Pain Mixed Type Neuropathic PainCaused by activity in neural pathways in

response to potentially tissue-damaging stimuli

Caused by a combination of both primary injury and

secondary effects

Initiated or caused by primary lesion or

dysfunction in the nervous system

Postoperative pain

Mechanical low back pain

Sports/exerciseinjuries

Sickle cell crisis

ArthritisPostherpetic

neuralgia

Neuropathic low back pain

Distal polyneuropathy

(e.g., diabetic, HIV)

Central post-stroke pain

Trigeminal neuralgia

CRPS*

*Complex Regional Pain Syndrome


WHO 3-STEP ANALGESIC LADDER FOR THE TREATMENT OF CHRONIC PAIN

Unlike nociceptive pain, no treatment algorithm for neuropathic pain exists. A mixed bag of pharmaceuticals are used for the treatment of neuropathic pain, 90% of which are

generic and do not carry a neuropathic pain-specific indication.

A Mixed Bag of Pharmaceuticals



Unlike nociceptive pain, no treatment algorithm for neuropathic pain exists. A mixed bag of pharmaceuticals are used for the treatment of neuropathic pain, 90% of which are

generic and do not carry a neuropathic pain-specific indication.

A Mixed Bag of Pharmaceuticals

Antiepileptics / Anticonvulsants

(gabapentin, carbamazepine,

pregabalin)

Tricyclic Antidepressants (amitriptyline, desipramine,

nortriptyline)

SNRIs (venlafaxine, duloxetine)

SSRIs (paroxetine, citalopram, duloxetine)

GABA Agonists (baclofen)

Oral Sodium Channel

Blockers (mexiletin

e)

Alpha-2-Adrenergic

Agonists (clonidine,

tizanidine)NMDA Receptor A

ntagonists

(ketamine, dextromethorphan)

Topical Analgesics (capsaicin, lidocaine patch)

Opioids



• gabapentin, carbamazepine• amitriptyline, desipramine, • venlafaxine, duloxetine• baclofen• mexiletine• clonidine• ketamine• topical capsaicin, lidocaine

patch• Tramadol, morphine

Treating Neuropathic Pain is Like Playing a Game of Darts



Sedation, nausea, itching, constipation(Tolerance, abuse, addiction)

Every 4 -12h

Tramadol, Oxycodone, Morphine, etc.

Opioids

Local skin irritationVaries; PRN

Lidocaine, various anesthetics

Topical local anesthetics

Sedation, ataxia, peripheral edema, nausea; carbamazepineassociated with rare cases of bone marrow, liver, cutaneousreactions

Every 6 -8 hours

Gabapentin, Carbamazepine (ER)

Antiepileptics

Dry eyes, mouth; constipation, cognitive changes; sedation; orthostatic hypotension; tachycardia; urinary retention; blurred vision

QDNortriptyline,Desipramine, Amitriptyline

Tricyclics

Side EffectsDosingSpecific AgentsClass

At best, 50% reduction in

pain in 50% of patients

Efficacy

Treatment Is Empirical…And Not Satisfactory


Product Labels


• At this point, it is unclear whether or not there is an underlying pathogenesis. • Several theories exist, however, translation of these mechanisms to therapeutic options

and therapeutic decision making has not yet been realized.


There Is No Proven Hypothesis For a Central Mechanism of Neuropathic Pain

Fields, H.L. Medscape 2005, Multiple Mechanisms of Neuropathic Pain: Evolving Concepts & Treatments

Neuropathic Pain: Possible Mechanisms

• Nervi nervorum (PNS)

• Cytokines (PNS)• Intrinsic hyperexcitability of nociceptive neurons (CNS or PNS)• Catecholamine hypersensitivity (PNS)• Loss of inhibition (CNS)


Why the Size / Value Disconnect?As compared to nociceptive pain … where the mechanism of pain is fairly well understood and there are multiple drugs (both branded and generic) labeled

specifically for nociceptive pain indications.

Adapted from Beydoun A. Univ Michigan Med Center “Pain Pathways and Physiology” presentation and Hyman SE, Cassem NH. Pain. In: Scientific American Medicine, III. 1996;XIX:11.

AscendiPERIPHERAL NERVES

Dorsalhorn

A-delta fiber

A-delta fiberC fiber

Dorsalhorn

A-delta fiber

A-delta fiberC fiber

BRAIN

SPINAL CORD

GlutamaIon chan

Agents tpathway

•Glutamat•Ion chan


Primary Care

FMS

Psychiatrist

Rheumatologist

Neurologist

Pain SpecialistDermatologist

PHN

PDN

TGN

Endocrinologist


Neuropathic Pain Encompasses Different Disease Types, Different Patient Groups & Different Physicians who Treat


Primary Care

FMS

PHN

PDN


Peripheral Diabetic Neuropathy (PDN), Post-Herpetic Neuralgia (PHN) & Fibromyalgia Syndrome (FMS) are Largely Treated by PCPs

DH primary research


Neurologist

Pain Specialist

TGN


While Other Types of Neuropathic Pain, Such as Trigeminal Neuralgia (TGN), are Almost Exclusively Treated in the Specialty Setting

DH primary research


Neuropathic Pain Market Categories

Other, 38%

PHN, 9%

Diabetic Neuropathy,

17.7%

Peripheral Neuropathy,

18.6%TrigeminalNeuralgia,

16.3%

15,000 affected

600,000 affected


The PCP-Heavy Neuropathic Pain Markets are Relatively Untapped

Company Reports, WR Hambrecht + Co

500,000 affected



Other, 38%

PHN, 9%


17.7%

Peripheral Neuropathy,

18.6%TrigeminalNeuralgia,

16.3%

15,000 affected

600,000 affected

The New Entrants are Attempting to Repair the Size / Value Disconnect


500,000 affected

As Pfizer and Lilly Aggressively Market New Neuropathic Pain Drugs, Sales in the More “PCP-Heavy” Segments Are Likely to Bulge



PHN, 9%


17.7%

The New Entrants are Attempting to Repair the Size / Value Disconnect


As Pfizer and Lilly Aggressively Market New Neuropathic Pain Drugs, Sales in the More “PCP-Heavy” Segments Are Likely to Bulge


Neuropathic Pain Patients are Still in Pain

Several Features of Neuropathy Distinguish it From Other Types of Pain

Pain descriptors vary between patients and don’t reliably reveal the etiology.

NP Pain Descriptors:• Numbness• Electric• Tingling• Pins and Needles• Lancinating• Burning• Icy Cold• Frostbite• Deep, Dull, Bonelike Ache• Aching


Allodynia: Pain from a stimulus that does not normally evoke pain-Thermal -Mechanical

Hyperalgesia: Exaggerated response to a normally painful stimulus

Patients Still Hurt

Signs and Symptoms of Neuropathic Pain:


Medscape 2005, Neuropathic Pain: New Strategies to Improve Clinical Outcome, Bruce D. Nicholson

Treatment Is Empirical…And Not Satisfactory

Neuropathic Pain Patients are Still in Pain



Neuropathic Pain (and Fibromyalgia): Study the Terrain

1.

Can You Learn From Those Who Have Gone Before You?

2.

Can You Compete with the Next Generation?3.


Epilepsy

Depression

Nociceptive Pain


Neuropathic Pain

The Accidental Pioneers: Most Neuropathic Pain Agents Were Developed for Some Other Indication


0

500

1,000

1,500

2,000

2,500

$US

(mill

ions

)

1 3 5 7 9 11 13 15 17

Year

Neurontin US Sales (historical and projected)

‘94 ’95 ‘96 ‘97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’09 ‘10

2003: Neurontin loses patent exclusivity

1994: Launched by Warner-Lambert in the US as adjunctive therapy for the treatment of partial seizures

2002: US FDA approves for post-herpetic neuralgia (563 patients in pivotal studies)

2005: Ivax launches generic Neurontin

Can You Learn From Those Who Have Gone Before You?Neurontin Clears a Path for Others to Follow

EvaluatePharma, Company Press Releases


0

500

1,000

1,500

2,000

2,500

$US

(mill

ions

)

1 3 5 7 9 11 13 15 17

Year

Neurontin US Sales (historical and projected)

‘94 ’95 ‘96 ‘97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’09 ‘10

2004: Pfizer pays big fines

1996: David Franklin files lawsuit citing illegal marketing strategy

“I was trained to deceive, to lie to

doctors.”

Can You Learn From Those Who Have Gone Before You?Neurontin Clears a Path for Others to Follow?

EvaluatePharma

MSNBC


In a landmark healthcare fraud prosecution in the US last week, Pfizer Inc., world's largest pharmaceutical company, agreed to plead guilty and pay 430 million US dollars in fines and settle charges in a case involving its Warner-Lambert unit flouting the US federal law by promoting non approved uses of one of its drugs. The settlement with Pfizer includes a 24.6 million dollar payment for whistleblower, David Franklin, a scientist who reported the marketing abuses of the company to the US authorities first. The company agreed to plead guilty of violating the Food, Drug and Cosmetics Act and pay 240 million dollars criminal fine, the second largest ever in a healthcare fraud prosecution in the US. Pfizer also will have to pay 152 million US dollars in civil fines to be shared among the state and federal Medicaid agencies. Another 38 million dollars will go to state consumer protection agencies.


PharmaBiz.com

Pfizer Inc GuiltyWednesday, May 19, 2004 8:00 IST P A Francis


PDNPHN, PDNEstablished clinical path

SSRI / SNRI (Effexor)GABA analogue, Ca++ channel modulator (Neurontin)

Based on established MOA:

“Pfizer indicated that Lyrica is the most frequently detailed product among high-writing

PCPs in the US.”

“Lilly has indicated that its sales force reorganization efforts will

result in a double-digit percentage increase in Cymbalta

details in 2006.”

Can You Learn From Those Just Entering the Territory?

Bear Stearns, Jan 9, 2006, The Bottle Report

Taking the Safer Route?


“This represents a fraction of sales that Neurontin would likely have posted in 2004 (estimated at $3 billion assuming 10% YOY growth) had generics not been launched in 3Q04.” Bear Stearns, Jan 9, 2006

Lyrica Vs. Neurontin

> 9 days (titrate to effective dose of 1800 mg/d)

1 day (effective starting dose of 150 mg/d)

Time to effective dose (PHN)

TIDBID or TIDDosing (PHN)

60% 900mg 34% 2400mg47% 1200mg 33% 3600mg

>90% all dosesOral bioavailability

Nonlinear (plasma concentration increases disproportionately to dose)

Linear (plasma concentration is dose proportionate)

Pharmacokinetic profile

Selectively binds to the a2ō site in CNS tissues

Selectively binds to the a2ō site in CNS tissues

Mechanism of action

Postherpetic neuralgiaDPN & postherpetic neuralgiaIndication

GabapentinPregabalin

Comparing Pregabalin Against Gabapentin

Analysts Project Global Lyrica Sales of $925 M in 2006, Increasing to $2.4 B by 2010

Fishman, S.M., Medscape 2005


$0.28 - $2.11 $3.25 - $4.88 9 Cost per Day of Therapy (WAC)

Titration not requiredSlow, careful titrationTitration Requirements

4+ weeks~ 1 weekTime to Relief of Symptoms

Non-scheduledSchedule VSchedule Status

Somnolence, DizzinessSomnolence, Dizziness, Weight Gain, Peripheral Edema

Side Effects / Safety Issues

3-4 x daily2-3 x dailyDosing

~30 - 50% (depending on dose)


Efficacy (% Showing 50%+ Reduction in Mean Pain Score)

PHN, epilepsyPHN, DPN, epilepsyLabel Indication

Lyrica Vs. Neurontin

Lyrica’s primary differentiation is based on less frequent dosing, no need to titrate and faster time to relief of symptoms…not efficacy or side effects (at highest doses).

Fishman, S. M., Medscape 2005; Bear Stearns, Jan 9, 2006, The Bottle Report


• Tough call.

• Is more convenient dosing, no need for titration and a faster onset a real advance for the treatment of neuropathic pain?

• What is the Managed Care perspective?

– Managed Care considers Lyrica to be a modestly differentiated drug in a crowded, chronic care therapeutic class that is dominated by a mighty generic competitor.

Can the Success of LyricaSurpass That of Neurontin?

Strategyx


Sept. 2004: Approved in the US for PHN, DPN and epilepsy (adjunct for partial onset seizures).

Non-Approvable letter for generalized anxiety disorder (GAD). Pfizer conducting additional studies to secure US regulatory approval.

Jan. 2006: Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a positive opinion recommending marketing authorization of Lyrica for the treatment of GAD in adults.

Currently: Phase III in the US for Fibromyalgia, Panic Disorder and Social Phobia.

Can the Success of LyricaSurpass That of Neurontin?Additional Indications Could Drive Lyrica’s Success Beyond That of Neurontin

Press Releases


DepressionAnxiety, FatigueEffective for treatment of co-morbid symptoms

Non-scheduledSchedule VSchedule Status

Nausea, Somnolence, Dizziness, Sexual Side Effects, Potential Liver Problems

Somnolence, Weight Gain, Peripheral Edema

Side Effects / Safety Issues

QD2-3 x dailyDosing



Efficacy (% Showing 50%+ Reduction in Mean Pain Score)

DPNPHN, DPNLabel Indication

How Does Lyrica Compare to Cymbalta?

Differentiation is Based on Dosing, Side Effects & Treatment of Co-Morbid Disease, But Efficacy for Neuropathic Pain is Similar

Fishman, S. M., Medscape 2005; Bear Stearns, Jan 9, 2006, The Bottle Report


50 % revenue on-label (PHN)

50 % revenue off-label …and growing

Analysts forecast Lidoderm US sales of $420 million in2006, and peak sales of over $600 million in 2009.


EvaluatePharma; WR Hambrecht Dec. 2005 Report

2005 US revenue = $ 309 M

Lidoderm (Endo) Shows That Success Doesn’t Require “High Science”


NEW YORK and SAN DIEGO, Jan. 5 /PRNewswire-FirstCall/ --

Forest Laboratories, Inc. (NYSE: FRX) and Cypress Bioscience, Inc. (Nasdaq: CYPB) today announced that they will initiate a third randomized, double-blind, placebo-controlled pivotal Phase III study evaluating milnacipran as a treatment for fibromyalgia (FMS) in the first quarter of 2006.

In addition, the Companies announced that based on an analysis of the results from the first Phase III study, which was supportive of milnacipran's effect in fibromyalgia patients, certain modifications have been made to the ongoing second Phase III study.

These modifications include increasing the size of the second study from approximately 800 patients to 1,200 patients.

Based on the anticipated time necessary to recruit the additional patients the Companies expect to announce initial results from the second Phase III study no earlier than mid-calendar 2007.

Can You Learn From Those Who Are Almost There…

PRNewswire


NEW YORK and SAN DIEGO, Jan. 5 /PRNewswire-FirstCall/ --

Key Points

Forest Laboratories, Inc. (NYSE: FRX) and Cypress Bioscience, Inc. (Nasdaq: CYPB) today announced that they will initiate a third randomized, double-blind, placebo-controlled pivotal Phase III study evaluating milnacipran as a treatment for fibromyalgia (FMS) in the first quarter of 2006.

…increasing the size of the second study from approximately 800 patients to 1,200 patients.

…initial results from the second Phase III study no earlier than mid-calendar 2007.


neramexane for moderate to

severe Alzheimer’s

disease

nebivolol forcongestive

heart failure

RGH-896 for chronic pain and

other CNS conditions

Namenda (memantine) for mild AD

milnacipran for FMS

neramexane for chronic pain

RGH-188 for schizophrenia and

bipolar mania

nebivolol for hypertension

desmoteplasefor

acute stroke (2b/3)

memantine for neuropathic pain

GRC-3886 (oglemilast) for chronic

obstructive pulmonary

disorder (COPD) and asthma

mGLUR1/5 for various CNS conditions

NDA/sNDAPhase IIIPhase IIPhase IPreclinical

The ForestPipeline

Can You Learn From Those Who Are Almost There…

Forest Website


Sativex® (GW Pharmaceuticals, Bayer AG), received an approval with conditions from Health Canada in April 2005 for use as an adjunctive treatment for the symptom relief of neuropathic pain in Multiple Sclerosis.

Sativex® was launched in Canada in June 2005.

Currently in Phase III trials for allodynia associated with peripheral neuropathic pain.

Ubiquitous Cannabinoids

GW Pharmaceuticals Press Release



Neuropathic Pain (and Fibromyalgia): Study the Terrain

1.


2.

Can You Compete with the Next Generation?3.


The Next Generation


ApprovedPhase I Phase II Phase III

Neuropathic Pain: The Next Generation

Adis R&D Insight

Neurontin (gabapentin)• Ca blocker, Pfizer• PHN

Lyrica (pregabalin)• Ca blocker, Pfizer• PHN, PDN • Ph III - FMS

Cymbalta (duloxetine)• SNRI, Lilly• PDN• Ph III – FMS

Tegretol (Carbamazepine)• Antiepileptic, Novartis• TGN

Lidoderm• Lidocaine transdermal, Endo• PHN

XP 13512• Gabapentin XP (BID), XenoPort• PHN

Gabapentin XR (BID)•Depomed

Keppra (levetiracetam)• Antiepileptic, UCB• Various NPP types

Gabitril (tiagabine)• Antiepileptic, Abbott/Cephalon• Various NPP types

Namenda (memantine)• NMDA antagonist, Forest• PDN

Perzinfotel• NMDA antagonist, Wyeth

Civamide• Topical capsaicin, Winston Labs• TGN

Amitriptyline/Ketamine• Topical; Epicept• PDN

KDS 2000 (anandamide)• Topical, Kadmus• PHN

Lamictal (lamotrigine)• Antiepileptic, GSK• PDN

Harkoseride (lacosamide)• Antiepileptic, Schwarz• PDN

Mexitil (mexiletine)• Oral anesthetic, antiarrhythmic, BI• PDN

Clonidine gel• Topical clonidine, Curatek• PDN

NGX 4010• Transdermal capsaicin, NeurogesX• PHN, HIVNP

Ziconotide• Intrathecal conotoxin, Elan• PHN, Phantom limb pain, RSD, HIVNP

Neurodex(dextromethorphan/quinidine)

• Combination NMDA antagonist and enzyme inhib, Avanir• PDN

ABT 894• Ion channel modulator, Abbott/Neurosearch• NPP unspecified

T 62 • Adenosine agonist, King• NPP unspecified

Looks a Lot Like Last Generation US Clinical Development Pipeline for Neuropathic Pain



The Big Guys Will Continue to Dominate

• Big pharma is focusing on established mechanisms / classes.

• There are seven anti-epileptics either on the market or in late-stage development.

• Lilly, Forest and Wyeth are betting on the SSRIs / SNRIs.Adis R&D Insight


• XenoPort is developing XP13512 for the treatment of PHN and restless leg syndrome (both Phase II US) using a proprietary drug delivery technology to potentially allow less frequent dosing (BID) and improved bioavailability.

– Unclear at this point which of these two indications will be pursued initially.

• Depomed is developing Gabapentin XR, an extended release version of gabapentin, for the treatment of PHN.

– Anticipated once-daily dosing, which would represent an improvement over both gabapentin (3-4x) and pregabalin (2-3x).

– Could potentially have more linear kinetics (compared to gabapentin), given the controlled release technology, which may result in an improved side effect profile and less onerous titration requirements.


Drug Delivery Promises to Improve on Gabapentin in Terms of Convenience and Perhaps Allow it To Compete Even More Effectively With Pregabalin

Adis R&D Insight


ApprovedPhase II Phase III


Adis R&D Insight

US Clinical Development Pipeline for Neuropathic Pain

Lidoderm• Lidocaine transdermal, Endo• PHN

Clonidine gel• Topical clonidine, Curatek• PDN

NGX 4010• Transdermal capsaicin, NeurogesX• PHN, HIVNP

Civamide• Topical capsaicin, Winston Labs• TGN

Amitriptyline/Ketamine• Topical; Epicept• PDN

KDS 2000 (anandamide)• Topical, Kadmus• PHN

Local Pain Relief For Local Pain


Fibromyalgia: Entering an Asteroid Field?

The US Fibromyalgia Pipeline:• To date, no drugs have been approved for the treatment of FMS, but big pharma is moving in.

Cypress/Forest’s milnacipran may be the first, but it will follow Lilly’s (Cymbalta) and Pfizer’s (Lyrica) multi-year lead with other label indications.

• Orphan Medical’s marketed agent (for the treatment of cataplexy associated with narcolepsy), Xyrem, is in Phase III for FMS. Orphan Medical was recently (6/05) acquired by Jazz Pharmaceuticals.

• Provigil (Cephalon) is used off-label to fight fatigue associated with FMS. Cephalon also has Gabatrilin Phase II for a NPP indication.

• Wyeth recently (12/05) filed an NDA for its next generation SSRI/SNRI, desvenlafaxine, FVS-233, for depression. The predecessor to this agent, Effexor, is often used off-label for the treatment of fibromyalgia.

Company Press Releases, DH knowledgebase


Points For Discussion

In the Near-Term, There is Room in the Neuropathic Pain Market for Both “High Science” & Minimally Differentiated Products

• Unmet needs run the gamut.

• Incremental improvements in dosing, time to onset, side effects, drug-drug interactions, etc. (through tweaks on existing compounds / mechanisms or new delivery technologies) can take a piece of a very big pie.

• The real opportunity for transdermal products (e.g., Lidoderm, Endo) may be in indications outside of the traditional neuropathic pain types (e.g., low back pain, osteoarthritis pain).


• If you are in for the long haul, you will need to figure this disease out.

– The current pipeline does not address the real unmet need – efficacy.

– The lack of novelty reflects the complexity of the disease and a lack of understanding of the various pain mechanisms.


Eventually, Physicians, Patients & Managed Care Will Demand Meaningfully Differentiated Products


Meaning drugs that treat the mechanism of the neuropathic pain (e.g., irritable nociceptor), regardless of the classification of disease (e.g., post-herpetic neuralgia

versus diabetic neuropathy).

Glutamate receptor antagonists, calcium channel modulators (NK1,COX2, NOS)Central sensitization

Opioid agonists, antidepressants, a2-adrenoreceptor agonists, GABA-or glycine-receptor agonists

Loss of inhibitionDescending facilitation

Anticonvulsants, sodium/calcium channel blockers, potassium channel openersEctopic activity

Trophic factors, stem cell (potential)Neural damage

Treatment OptionsProposed Mechanism

Rational Treatment

Can Neuropathic Pain (and/or Fibromyalgia) be Treated With “Targeted” Therapy?

Fields, H.L., Medscape 2005, Multiple Mechanisms of Neuropathic Pain: Evolving Concepts & Treatments



• How can the appropriate treatment be determined? (e.g., establishment of treatment algorithms and physician education programs).

• What physician type(s) will treat?

• Does a rational approach require NCEs, or is neuropathic pain ripe for another round of repurposing?

Can Neuropathic Pain (and/or Fibromyalgia) be Treated With “Rational” Therapy?

If so…


neuropathic pain: a new...

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