Neuropathic Pain: A New Frontier

Neuropathic Pain: A New Frontier Ginger S. Johnson, PhD Defined Health March 1, 2006

March, 2006 - Pg. 2

Plenary Sessions 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 March, 2006 - Pg. 3

Speakers to Date Karen Bernstein, PhD, Chairman & Editor-In-Chief, BioCentury Alexis Borisy, AM, President & Chief Executive Officer, CombinatoRx Arthur 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 Therapeutics David DeMarco, PhD, Formerly Vice President, Strategy & Corporate Development, Cambrex Frederick Frank, Vice Chairman & Director, Lehman Brothers Robert H. Glassman, MD, Managing Director, Healthcare Investment Banking, Merrill Lynch Mitchell H. Gold, MD, President & Chief Executive Officer, Dendreon James W. Harris, PhD, Founder and Chief Scientific Officer, Bioavailability Systems Juergen 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., Roche Roger S. Newton, PhD, SVP, PGRD, Director, Esperion Therapeutics Douglas 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 Hospital Mary C. Tanner, Partner, Life Sciences Partners, LLC Thomas Tillett, President and CEO, RheoGene Robert E. Ward, VP Commercial Dev., NPS Pharmaceuticals March, 2006 - Pg. 4

Neuropathic Pain & Fibromyalgia New Therapeutic Frontiers Female Sexual Dysfunction Obesity Premature Ejaculation Urinary Incontinence Narcolepsy Erectile Dysfunction March, 2006 - Pg. 5

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? March, 2006 - Pg. 6

Before You Embark on Your Journey, Study the Terrain March, 2006 - Pg. 7

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. March, 2006 - Pg. 8

It s Big There Are an Estimated 15 M People in the US who Suffer From Neuropathic Pain (examples and prevalence are shown below) 600,000 500,000 400,000 300,000 200,000 100,000 0 Painful Diabetic Neuropathy Postherpetic Neuralgia Cancer- Associated Note: Numbers are approximate March, 2006 - Pg. 9 Spinal Cord Injury CRPS HIV - Associated Multiple Sclerosis Phantom Pain Post-Stroke Trigeminal Neuralgia

It s Big Among 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. 2,500,000 2,000,000 1,500,000 1,000,000 500,000 0 Painful Diabetic Neuropathy Postherpetic Neuralgia Cancer- Associated Note: Numbers are approximates March, 2006 - Pg. 10 Spinal Cord Injury CRPS HIV - Associated M ultiple Sclerosis Phantom Pain Poststroke Trigeminal Neuralgia Low Back Pain- Associated

Neuropathic Pain: It s Growing 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. 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. And it is growing quickly, even as other scourges like heart disease and cancers are stable or in decline. 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. March, 2006 - Pg. 11

Neuropathic Pain s Close Cousin, Fibromyalgia, Could Nearly Double the Size of the Market Fibromyalgia Syndrome (FMS), which technically may or may not be a neuropathic pain, affects an estimated 6-12 M people in the US 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). Dysfunction Fatigue Cognitive Difficulties Fibromyalgia Sleep Disturbance Diminished QOL March, 2006 - Pg. 12 Depression

The Neuropathic Pain Great Divide: Size / Value Disconnect Current Market Size Does Not Reflect the Potential Neuropathic Pain Market = Potential Great Divide Basin, WY 15 M patients in the US + Fibromyalgia 6-12 M more patients 50 M patients in the US Chronic Nociceptive Pain $2.5 billion market $?? market $20 billion market March, 2006 - Pg. 13

Why the Size / Value Disconnect? Neuropathic Pain is Difficult to Recognize, Diagnose and Treat Nociceptive Pain Mixed Type Neuropathic Pain Caused 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 CRPS* Postoperative pain Arthritis Postherpetic neuralgia Trigeminal neuralgia Mechanical low back pain Sickle cell crisis Neuropathic low back pain Central poststroke pain Sports/exercise injuries March, 2006 - Pg. 14 *Complex Regional Pain Syndrome Distal polyneuropathy (e.g., diabetic, HIV)

Why the Size / Value Disconnect? 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. NMDA Receptor Antagonists (ketamine, dextromethorphan) Antiepileptics / Anticonvulsants (gabapentin, carbamazepine, pregabalin) Opioids A Mixed Bag of Pharmaceuticals Alpha-2-Adrenergic Agonists (clonidine, tizanidine) SNRIs (venlafaxine, duloxetine) SSRIs (paroxetine, citalopram, duloxetine) Oral Sodium Channel Blockers (mexiletine) GABA Agonists (baclofen) Tricyclic Antidepressants (amitriptyline, desipramine, nortriptyline) Topical Analgesics (capsaicin, lidocaine patch) March, 2006 - Pg. 16

Why the Size / Value Disconnect? Treating Neuropathic Pain is Like Playing a Game of Darts gabapentin, carbamazepine amitriptyline, desipramine, venlafaxine, duloxetine baclofen mexiletine clonidine ketamine topical capsaicin, lidocaine patch Tramadol, morphine March, 2006 - Pg. 17

Why the Size / Value Disconnect? Treatment Is Empirical And Not Satisfactory Class Specific Agents Dosing Side Effects Efficacy Tricyclics Nortriptyline, Desipramine, Amitriptyline QD Dry eyes, mouth; constipation, cognitive changes; sedation; orthostatic hypotension; tachycardia; urinary retention; blurred vision Antiepileptics Topical local anesthetics Gabapentin, Carbamazepine (ER) Lidocaine, various anesthetics Every 6-8 hours Varies; PRN Sedation, ataxia, peripheral edema, nausea; carbamazepine associated with rare cases of bone marrow, liver, cutaneous reactions Local skin irritation At best, 50% reduction in pain in 50% of patients Opioids Tramadol, Oxycodone, Morphine, etc. Every 4-12h Sedation, nausea, itching, constipation (Tolerance, abuse, addiction) Product Labels March, 2006 - Pg. 18

Why the Size / Value Disconnect? There Is No Proven Hypothesis For a Central Mechanism of Neuropathic Pain 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. Neuropathic Pain: Possible Mechanisms Nervi nervorum (PNS) Cytokines (PNS) Intrinsic hyperexcitability of nociceptive neurons (CNS or PNS) Catecholamine hypersensitivity (PNS) Loss of inhibition (CNS) Fields, H.L. Medscape 2005, Multiple Mechanisms of Neuropathic Pain: Evolving Concepts & Treatments March, 2006 - Pg. 19

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. BRAIN A-delta fiber C fiber A-delta fiber Dorsal horn SPINAL CORD PERIPHERAL NERVES 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. Ascendi Agents t pathway Glutama Ion chan Glutamat Ion chan March, 2006 - Pg. 20

Why the Size / Value Disconnect? Neuropathic Pain Encompasses Different Disease Types, Different Patient Groups & Different Physicians who Treat Psychiatrist Primary Care Rheumatologist FMS Endocrinologist PDN TGN Neurologist PHN March, 2006 - Pg. 21 Pain Specialist Dermatologist

Why the Size / Value Disconnect? Peripheral Diabetic Neuropathy (PDN), Post-Herpetic Neuralgia (PHN) & Fibromyalgia Syndrome (FMS) are Largely Treated by PCPs Primary Care FMS PDN PHN DH primary research March, 2006 - Pg. 22

Why the Size / Value Disconnect? While Other Types of Neuropathic Pain, Such as Trigeminal Neuralgia (TGN), are Almost Exclusively Treated in the Specialty Setting Neurologist TGN DH primary research March, 2006 - Pg. 23 Pain Specialist

Why the Size / Value Disconnect? The PCP-Heavy Neuropathic Pain Markets are Relatively Untapped 500,000 affected Neuropathic Pain Market Categories Other, 38% PHN, 9% 600,000 affected Diabetic Neuropathy, 17.7% 15,000 affected Trigeminal Neuralgia, 16.3% Peripheral Neuropathy, 18.6% Company Reports, WR Hambrecht + Co March, 2006 - Pg. 24

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 500,000 affected Neuropathic Pain Market Categories Other, 38% PHN, 9% 600,000 affected Diabetic Neuropathy, 17.7% 15,000 affected Trigeminal Neuralgia, 16.3% Company Reports, WR Hambrecht + Co Peripheral Neuropathy, 18.6% March, 2006 - Pg. 25

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 Market Categories PHN, 9% Company Reports, WR Hambrecht + Co Diabetic Neuropathy, 17.7% March, 2006 - Pg. 26

Neuropathic Pain Patients are Still in Pain Several Features of Neuropathy Distinguish it From Other Types of Pain NP Pain Descriptors: Numbness Electric Tingling Pins and Needles Lancinating Burning Icy Cold Frostbite Deep, Dull, Bonelike Ache Aching Pain descriptors vary between patients and don t reliably reveal the etiology. March, 2006 - Pg. 27

Patients Still Hurt Signs and Symptoms of Neuropathic Pain: Allodynia: Pain from a stimulus that does not normally evoke pain -Thermal -Mechanical Hyperalgesia: Exaggerated response to a normally painful stimulus March, 2006 - Pg. 28

Neuropathic Pain Patients are Still in Pain Treatment Is Empirical And Not Satisfactory Medscape 2005, Neuropathic Pain: New Strategies to Improve Clinical Outcome, Bruce D. Nicholson March, 2006 - Pg. 29

Neuropathic Pain Insight Series Tonight s Discussion Topics 1. Neuropathic Pain (and Fibromyalgia): Study the Terrain 2. 3. Can You Learn From Those Who Have Gone Before You? Can You Compete with the Next Generation? March, 2006 - Pg. 30

Can You Learn From Those Who Have Gone Before You? The Accidental Pioneers: Most Neuropathic Pain Agents Were Developed for Some Other Indication Nociceptive Pain Depression Neuropathic Pain March, 2006 - Pg. 31 Epilepsy

Can You Learn From Those Who Have Gone Before You? Neurontin Clears a Path for Others to Follow 1994: Launched by Warner- Lambert in the US as adjunctive therapy for the treatment of partial seizures Neurontin US Sales (historical and projected) $US (millions) 2,500 2,000 1,500 1,000 500 2002: US FDA approves for postherpetic neuralgia (563 patients in pivotal studies) EvaluatePharma, Company Press Releases March, 2006 - Pg. 32 0 1 3 5 7 9 11 13 15 17 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 Year 2003: Neurontin loses patent exclusivity 2005: Ivax launches generic Neurontin

Can You Learn From Those Who Have Gone Before You? Neurontin Clears a Path for Others to Follow? Neurontin US Sales (historical and projected) I was trained to deceive, to lie to doctors. MSNBC $US (millions) 2,500 2,000 1,500 1,000 500 1996: David Franklin files lawsuit citing illegal marketing strategy 0 1 3 5 7 9 11 13 15 17 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 EvaluatePharma Year 2004: Pfizer pays big fines March, 2006 - Pg. 33

Can You Learn From Those Who Have Gone Before You? Pfizer Inc Guilty Wednesday, May 19, 2004 8:00 IST P A Francis 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 March, 2006 - Pg. 34

Can You Learn From Those Just Entering the Territory? Taking the Safer Route? Based on established MOA: GABA analogue, Ca++ channel modulator (Neurontin) SSRI / SNRI (Effexor) Established clinical path PHN, PDN PDN 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. Bear Stearns, Jan 9, 2006, The Bottle Report March, 2006 - Pg. 35

Lyrica Vs. Neurontin Analysts Project Global Lyrica Sales of $925 M in 2006, Increasing to $2.4 B by 2010 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 Comparing Pregabalin Against Gabapentin Indication Pregabalin DPN & postherpetic neuralgia Gabapentin Postherpetic neuralgia Mechanism of action Pharmacokinetic profile Oral bioavailability Dosing (PHN) Time to effective dose (PHN) Fishman, S.M., Medscape 2005 Selectively binds to the a 2 ō site in CNS tissues Linear (plasma concentration is dose proportionate) >90% all doses BID or TID 1 day (effective starting dose of 150 mg/d) Selectively binds to the a 2 ō site in CNS tissues Nonlinear (plasma concentration increases disproportionately to dose) 60% 900mg 34% 2400mg 47% 1200mg 33% 3600mg TID > 9 days (titrate to effective dose of 1800 mg/d) March, 2006 - Pg. 36

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). Label Indication Efficacy (% Showing 50%+ Reduction in Mean Pain Score) Dosing Titration Requirements Side Effects / Safety Issues Time to Relief of Symptoms Schedule Status Cost per Day of Therapy (WAC) PHN, DPN, epilepsy ~30-50% (depending on dose) 2-3 x daily Slow, careful titration Somnolence, Dizziness, Weight Gain, Peripheral Edema ~ 1 week Schedule V $3.25 - $4.88 9 PHN, epilepsy ~30-50% (depending on dose) 3-4 x daily Titration not required Somnolence, Dizziness 4+ weeks Non-scheduled $0.28 - $2.11 Fishman, S. M., Medscape 2005; Bear Stearns, Jan 9, 2006, The Bottle Report March, 2006 - Pg. 37

Can the Success of Lyrica Surpass That of Neurontin? 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. Strategyx March, 2006 - Pg. 38

Can the Success of Lyrica Surpass That of Neurontin? Additional Indications Could Drive Lyrica s Success Beyond That of Neurontin 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: Currently: 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. Phase III in the US for Fibromyalgia, Panic Disorder and Social Phobia. Press Releases March, 2006 - Pg. 39

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 Label Indication Efficacy (% Showing 50%+ Reduction in Mean Pain Score) Dosing Side Effects / Safety Issues Schedule Status Effective for treatment of comorbid symptoms PHN, DPN ~30-50% (depending on dose) 2-3 x daily Somnolence, Weight Gain, Peripheral Edema Schedule V Anxiety, Fatigue DPN ~30-50% (depending on dose) QD Nausea, Somnolence, Dizziness, Sexual Side Effects, Potential Liver Problems Non-scheduled Depression Fishman, S. M., Medscape 2005; Bear Stearns, Jan 9, 2006, The Bottle Report March, 2006 - Pg. 40

Can You Learn From Those Who Have Gone Before You? Lidoderm (Endo) Shows That Success Doesn t Require High Science 2005 US revenue = $ 309 M 50 % revenue off-label and growing 50 % revenue on-label (PHN) Analysts forecast Lidoderm US sales of $420 million in 2006, and peak sales of over $600 million in 2009. EvaluatePharma; WR Hambrecht Dec. 2005 Report March, 2006 - Pg. 41

Can You Learn From Those Who Are Almost There 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. PRNewswire March, 2006 - Pg. 42

Key Points 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. 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 midcalendar 2007. March, 2006 - Pg. 43

Can You Learn From Those Who Are Almost There The Forest Pipeline Preclinical Phase I Phase II Phase III NDA/sNDA mglur1/5 for various CNS conditions GRC-3886 (oglemilast) for chronic obstructive pulmonary disorder (COPD) and asthma memantine for neuropathic pain desmoteplase for acute stroke (2b/3) nebivolol for hypertension RGH-188 for schizophrenia and bipolar mania neramexane for chronic pain milnacipran for FMS Namenda (memantine) for mild AD RGH-896 for chronic pain and other CNS conditions nebivolol for congestive heart failure neramexane for moderate to severe Alzheimer s disease Forest Website March, 2006 - Pg. 44

Ubiquitous Cannabinoids 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. GW Pharmaceuticals Press Release March, 2006 - Pg. 45

Neuropathic Pain Insight Series Tonight s Discussion Topics 1. 2. Neuropathic Pain (and Fibromyalgia): Study the Terrain Can You Learn From Those Who Have Gone Before You? 3. Can You Compete with the Next Generation? March, 2006 - Pg. 46

The Next Generation March, 2006 - Pg. 47

Neuropathic Pain: The Next Generation Looks a Lot Like Last Generation US Clinical Development Pipeline for Neuropathic Pain Phase I Phase II Phase III Approved ABT 894 Ion channel modulator, Abbott/Neurosearch NPP unspecified T 62 Adenosine agonist, King NPP unspecified Adis R&D Insight March, 2006 - Pg. 48 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 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

Neuropathic Pain: The Next Generation 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 March, 2006 - Pg. 49

Neuropathic Pain: The Next Generation Drug Delivery Promises to Improve on Gabapentin in Terms of Convenience and Perhaps Allow it To Compete Even More Effectively With Pregabalin 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. Adis R&D Insight March, 2006 - Pg. 50

Neuropathic Pain: The Next Generation Local Pain Relief For Local Pain US Clinical Development Pipeline for Neuropathic Pain Phase II Phase III Approved Civamide Topical capsaicin, Winston Labs TGN Amitriptyline/Ketamine Topical; Epicept PDN KDS 2000 (anandamide) Topical, Kadmus PHN Clonidine gel Topical clonidine, Curatek PDN NGX 4010 Transdermal capsaicin, NeurogesX PHN, HIVNP Lidoderm Lidocaine transdermal, Endo PHN Adis R&D Insight March, 2006 - Pg. 51

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 Gabatril in 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 March, 2006 - Pg. 52

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). March, 2006 - Pg. 53

Points For Discussion Eventually, Physicians, Patients & Managed Care Will Demand Meaningfully Differentiated Products 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. March, 2006 - Pg. 54

Points For Discussion Can Neuropathic Pain (and/or Fibromyalgia) be Treated With Targeted Therapy? 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). Rational Treatment Proposed Mechanism Neural damage Ectopic activity Loss of inhibition Descending facilitation Treatment Options Trophic factors, stem cell (potential) Anticonvulsants, sodium/calcium channel blockers, potassium channel openers Opioid agonists, antidepressants, a 2 -adrenoreceptor agonists, GABAor glycine-receptor agonists Central sensitization Glutamate receptor antagonists, calcium channel modulators (NK1, COX2, NOS) Fields, H.L., Medscape 2005, Multiple Mechanisms of Neuropathic Pain: Evolving Concepts & Treatments March, 2006 - Pg. 55

Points For Discussion Can Neuropathic Pain (and/or Fibromyalgia) be Treated With Rational Therapy? If so 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? March, 2006 - Pg. 56

March, 2006 - Pg. 57