Alzheimer's Disease

Q2 2012 Update Table of Contents

Slide Number I. Introduction • Who is Lumleian and what is a disease state primer? • 3 – 6 • What is our perspective on Neuropathic Pain? • 7 – 9 II. Disease Overview and Care Paradigm 11 • What is Neuropathic Pain? • 12 • Presentation, diagnosis, classification • 13 • Epidemiology by geography and patient segment • 15 • Current care paradigm and clinical evidence • 17 – 23 • Emerging care paradigm • 24 III. Clinical Development Pipeline 26 – 27 • Disease mechanism overview • 28 - 30 • Clinical development pipeline mapping • 31 – 37 • Sodium Channels • 38 – 41 • Trp Channels • 42 - 44 • Cannabinoid • 45 - 47 • Vesicular release • 48 – 50 • NGF Antagonist • 51 – 53 • Other mechanisms (opioid receptors, P2X3, NE reuptake • 54 - 68 inhibition , Anti-TNFα, calcium channel blockade, combinations) IV. Commercial Landscape 70 • Global, US, EU, Japan market size and growth by brand • 71 – 74 • Wall Street consensus forecasts for pipeline assets • 75 • US growth decomposition: Rx volume, pricing, product mix • 76 – 78 • US promotional spending, marketing mix and brand messaging • 79 – 85 V. Appendix • Table of Acronyms • 87 – 88 • More about Lumleian • 89 – 91 2 Lumleian offers the requisite scale and depth of life science expertise required for our client’s most critical investment decisions; We offer universal information and real time knowledge.

Expertise Based Universal Real-Time Decision Life Science Teams Information Knowledge Support Client Base • Experience • Data Mining • Disease State Primers • Academic and - Academic faculty - Regulatory filings - Disease overview Research Institutions - Bio-pharmaceutical - Scientific literature and care paradigm - Portfolio optimization • Early stage - Equity research - Patent filings - Clinical development pipeline - Commercial landscape - Out licensing strategy - Strategy consulting - Company filings • Asset valuation and press releases • Functional Drill Downs

• Expertise • Transaction support • Secondary Data - In licensing assessments - 30+ clinicians • Royalty monetization and Ph.D. scientists - Industry pipelines - Early and late stage • Bio-pharmaceutical Companies • Analytics - Wall Street analysis - Preliminary due dilligence - Asset valuation - 5 Ph.D. economists - US TRx, pricing, - Real-time clinical data

and statisticians promotional spend - Clinical strategy • Proprietary Analytics - In licensing strategy • Primary Research - Asset valuation • Early and late stage - Key opinion leaders - Epidemiologic forecasts - Portfolio optimization - Practicing physicians - Industry benchmarks • Early and late stage - Reimbursement • Drug Development - Preliminary due dilligence and commercial - Patient segment valuations • Life Science Investors - Promotional response models - Asset valuation • Healthcare professional - Clinical strategy and direct to consumer - In licensing strategy

3 To ensure real-time knowledge, across disease states, our team of 30+ clinicians and Ph.D. scientists maintain a comprehensive knowledge management platform, leveraging novel data mining technology and proprietary analytics.

Universe of Public Data Mining Expert Validation Information1 and Analytics and Decision Support

Scientific • Clinical trials • Conference presentations & Clinical: • Gene ontology • Industry pipeline databases • NIH grants • Scientific literature & citations

Academic • Early stage technologies Tech Transfer: • Intellectual property filings • Leverage data mining technology to access • 30+ clinicians and Business • Business development transactions novel data sources Ph.D. scientists Development: • Venture capital investments - Focused by area • Standardize, collate, of expertise Regulatory: • Advisory committee transcripts and link data sources • FDA and EMA filings • 5 Ph.D. economists • Execute Lumleian’s and statisticians proprietary analytical Financial: • Company presentations models • Earnings announcements • Equity research coverage • Investor relations transcripts

Competitive • Disease profiles Landscape: • Industry publications • Sales and Rx data • Treatment algorithms

Notes: 1These are a representative sub-set of the publicly available data sources 4 Our efficient platform and our expertise based teams enable us to both deliver the highest quality product and tailor our offer, to specific client needs: either custom decision support or more standardized research and analytics, e.g. disease state primers.

Decision Support

Proprietary • Clinical strategy Analytics • Portfolio optimization - Pre-Clinical Functional - Clinical Drill Downs • Asset valuation • Transaction support • Epidemiologic forecasts - In licensing Disease • Real-time clinical data • Industry benchmarks - Out licensing State Primers - Trial strategies - Commercial - Results - Clinical Development

• Disease overview • In licensing • Patient segment and care paradigm assessments valuations • Clinical development - Pre-clinical • Promotional pipeline - Clinical response models - Healthcare professional • Commercial • Preliminary due dilligence - Direct to consumer landscape Customized - Scientific • Royalty monetization - Clinical Standardized - Commercial 5 What is a Lumleian’s disease state primer?

What information is included in a disease state primer?

• Lumleian’s objective and fact based perspective on the relative attractiveness of investing in a given disease state • Disease overview and care paradigm - Etiology, Diagnosis and patient segmentation, Global epidemiology, Treatment algorithm, Clinical evidence, Emerging care paradigm • Clinical Development Pipeline - Validated industry pipeline for all assets in clinical development, Select mechanism of action profiles, trial designs and evidence • Commercial landscape - Global, US, EU, Japan market and brand revenue, Pipeline forecasts, US growth decomposition, Promotional spend and messaging

What disease states are planned for 2012? • Autoimmune: Inflammatory Bowel Disease, Lupus, Multiple Sclerosis, Psoriasis, Rheumatoid Arthritis • Cardiovascular: Hyperlipidemia • Central Nervous System: Alzheimer’s Disease, Depression, Pain, Schizophrenia • Endocrine: Type II Diabetes, Obesity • Infectious Disease: Gram Negative Bacteria, Hepatitis C Virus • Oncology: Breast, Colorectal, Leukemia(s), Lung, Lymphoma(s), Melanoma, Ovarian, Pancreatic, Prostate • Pulmonary: Chronic Obstructive Pulmonary Disease, Idiopathic Pulmonary Fibrosis

Are disease state primers real-time, based on the latest validated scientific, clinical, and commercial data? • Quarterly primers are validated by our team: 30+ clinicians and Ph.D. scientists, 5 Ph.D. economists and statisticians • Primers are available at the end of quarter, incorporating new commercial and clinical data from the previous quarter - Particulary dynaimc disease states are updated around key medical conferences, e.g. HCV post EASL in April and post AASLD in November

Do we create specific disease state primers and provide more in-depth functional information? • Yes, we plan to add disease states throughout ’12, per client interest • Yes, we are developing deep drills by function, e.g. Discovery, Clinical development, Business development, Commercial

Why did we create our disease state primers? • We were frustrated by having to repeatedly validate, standardize, and collate pipeline and commercial data • Portfolio optimization requires a standard framework to compare “apples to apples” investment decisions across disease states • Our primers began as a training tool; We require every decision scientist create one from scratch before supporting clients

6 Executive Summary: Neuropathic Pain

• Neuropathic pain is a debilitating disorder affecting 4-7% of the population worldwide and is often a consequence of common disorders such as diabetes, chemotherapy, shingles and HIV-treatment ‐ Associated with loss of intra-epidermal innervation by sensory fibers and hyperinnervation by sympathetic fibers, lack of control by inhibitory systems and inappropriate interpretation by CNS • Common manifestations include continuous pain, spontaneous breakthrough pain, pain in response to light Disease touch/movement or uncomfortable altered sensations Overview and • Associated with significant loss of quality of life such as major depression, sleep interruption, immobility, social isolation Care Paradigm and loss of employment • Currently treated by PCP following a neurological examination and can involve a referral to a neurologist ‐ Emphasis is placed on medical history, description of the pain, duration of symptoms and pain severity • Treatment paradigm involves first line therapy of anti-depressants or anticonvulsants with the addition of topical agents ‐ Opioids are occasionally used as a monotherapy or as an add on to existing treatment • It is estimated that approximately 30% of all NP patients are undiagnosed or under-treated • Low number of Phase I candidates partially attributed to withdrawal from CNS/Pain by large pharma or approval sought for alternative/multiple indications • Goals are to exploit peripherally restricted targets to reduce incidence of off-target effects and centrally mediated adverse events such as drowsiness and dizziness 2+ + Clinical • Targets with increasing interest include certain ion channel family subtypes (eg. Ca , Na , Trp) due to their restricted • The activity,global favorable tolerability and efficacy Development • NGF antibodies are progressing in Phase II for severe cancer-related pain with favorable results; however long-term safety Pipeline may be a concern • Many approved drugs are expanding their indication in Phase III/IV trials (eg. TCA, SNRI and gabapentinoids) for pain indications • The high prevalence of diabetic neuropathy trials is driven both by the large patient population and by the relative ease of clinical trial design • The NP market is expected to grow from $2.4billion to $3.6billion in 2020. Commercial Landscape

7 What are the key questions for 2012?

• Ongoing trials: Phase III trial demonstrating efficacy of Sativex for FDA approval is eagerly awaited - Currently approved for MS spasticity in Canada and EU, it is seeking US approval for cancer pain • Tanezumab: Demonstrated potential for new class of chronic pain medication, although clinical trials are on hold due to rapidly progressing osteoarthritis, we anticipate FDA ruling on clinical development in the near term - Will anti-NGF therapeutics demonstrate broad efficacy results across chronic/neuropathic pain areas in Key Questions addition to a favorable long-term safety profile? • Nucynta: Is currently on the market and approved for severe chronic pain, will it find use? - Clear dominance over existing MOA, Tramadol (generic), has not been demonstrated - Improvement in side-effects is expected against Tramadol but post-marketing data will be needed - RCT Design: Will improvements in identifying likely responders, attempts at improving end-point measurements and mitigating large placebo-response translate to better trial outcome? • A highly attractive indication given the large market, chronic nature and significant unmet need - Neuropathic pain patients experience a significant quality of life deterioration and current treatments rarely provide more than 50% reduction in pain and are associated with problematic side-effect profiles • A number of new MOAs are underdevelopment, including exploration of more targeted therapies within already approved MOAs Lumleian’s - However, a significant challenge remains with designing novel development strategies that can better identify patients more likely to respond and thus reduce the heterogeneity that defines the disease Perspective - Combinatorial approaches between inhibitory and excitatory enhancement is one potential strategy though clinical trial design still remains a challenge • Important progress in RCT design to enrich study population could increase drug success rate in specific populations • Better understanding of specific NP conditions through improved diagnostics in development may allow for a more personalized approach to treatment paradigms that could increase drug efficacy

8 Greenfield investment in late stage clinical development, for Neuropathic Pain is a high risk vs. high reward proposition; likelihood of technical success is relatively low but the levels of unmet need, the regulatory environment, and the commercial landscape are relatively attractive.

Neuropathic Pain: Relative Attractiveness of Greenfield Investment in Late Stage Clinical Development 5 High 4 3 Neuropathic Average Pain 2 1 Low0 Level of Unmet Need Likelihood of Technical Success Regulatory Impetus Commerical Attractiveness Required Investment Level of Likelihood of Regulatory Commercial Required Unmet Need Technical Success Environment Attractiveness Investment

Clinical Unmet Need Etiology Statement Clinical Unmet Need Market Size Phase III Investment • ~30% of NP are un- or • Identifiable targets • ~50% treated respond • $2.4billion • ~2,100 patients in 13 underdiagnosed • Modest reliability of adequately to available phase II trials • Reasonable expectation animal models therapies Condition Statement • Requires >4-6wks of 30-50% pain reduction • Translatability between • Chronic: >10yrs • 30% placebo responders • Common comorbidity of pre-clinical to man is Historical Precedents Global Epidemiology age-related diseases Commercial Spend poor • Safety has been a • ~4-8% World Wide • Average $14M/month for primary concern and • Expected to incr. with Historic Ph. III /IIIB Global Epidemiology Brand spending hurdle for NP disease prevalence Failures • 57.8million WW ‘10 • Where are dollars focused: treatments • Aprepitant (Merck): • 69.5million WW ‘25 - 42% Healthcare professional • Many late state assets Disease Burden Substance P antagonist - 58% Direct to consumer are approved for other Market Expansion • ~$3.7 billion in lost • Ralfinamide (Newron): indications seeking • Diabetes Phase IV Investment productivity in just DPN Nav 1.7 antagonist market expansion • ~22,000 patients in 34 • 3x increase in annual Generic Penetration health care cost Statistical Challenges Phase IV trials Advocacy • US Rx: 61% Generic • > prevalence over 45 yrs • ~30% placebo response • 57 sites • IASP • Upcoming LOE • Clear outcome • Motivating education Cymbalta (06/13), Mortality Statement measures • Associated with primary and access to Lidoderm (09/13) medication disease, not a mortality Target Patient Competitive Launches cause Populations • 49 • DPN, PHN, CIPN, FM Payor (Rx) • Medicaid/3rd party/cash 9 Table of Contents

Slide Number I. Introduction • Who is Lumleian and what is a disease state primer? • 3 – 6 • What is our perspective on Neuropathic Pain? • 7 – 9 II. Disease Overview and Care Paradigm 11 • What is Neuropathic Pain? • 12 • Presentation, diagnosis, classification • 13 • Epidemiology by geography and patient segment • 15 • Current care paradigm and clinical evidence • 17 – 23 • Emerging care paradigm • 24 III. Clinical Development Pipeline 26 – 27 • Disease mechanism overview • 28 - 30 • Clinical development pipeline mapping • 31 – 37 • Sodium Channels • 38 – 41 • Trp Channels • 42 - 44 • Cannabinoid • 45 - 47 • Vesicular release • 48 – 50 • NGF Antagonist • 51 – 53 • Other mechanisms (opioid receptors, P2X3, NE reuptake • 54 - 68 inhibition , Anti-TNFα, calcium channel blockade, combinations) IV. Commercial Landscape 70 • Global, US, EU, Japan market size and growth by brand • 71 – 74 • Wall Street consensus forecasts for pipeline assets • 75 • US growth decomposition: Rx volume, pricing, product mix • 76 – 78 • US promotional spending, marketing mix and brand messaging • 79 – 85 V. Appendix • Table of Acronyms • 87 – 88 • More about Lumleian • 89 – 91 10 Executive Summary: Disease Overview and Care Paradigm

• Neuropathic pain is ‘pain caused by disease or lesion to the nervous system’ - It is a common co-morbidity of diabetes, stroke, herpes zoster, chemotherapy and HIV-retrovirals What is - Between 50-100% of those affected by NP develop depression as well as interference with mobility, sleep and enjoyment of life Neuropathic • Neuropathic pain can develop without any obvious underlying cause but is most commonly a consequence Pain? of sensory nerve damage and inappropriate interpretation of sensory input by the nervous system - Inadequately managed acute pain, onset of associated disease, psychological and genetic factors are key in predisposition to developing NP • A consensus NP definition is lacking, which negatively impacts accurate prevalence/incidence measures • Global NP prevalence was ~57M in 2010, with an annual incidence of ~1M - Prevalence is expected to increase to ~70M in 2025 driven by increase in low-back pain and diabetes What is the - US prevalence is ~21M and incidence of ~1.0M in 2010 disease burden? • Neuropathic pain is not directly associated with mortality, but rather with lost productivity and societal contribution as well as 3x increase in average annual health care costs • DPN alone is estimated to cost $3.65 billion/year in lost productivity • Neuropathic Pain is age associated; prevalence increasing with people 45 and older • Today patients are diagnosed by a method of exclusion and are typically first seen by a PCP who then may refer them to pain specialist or neurologist • Heterogeneous NP etiology and manifestation results in ineffective first-line therapies for ~50% of patients What is today’s and the other 50% generally only receive a ~30% reduction in pain - The MOA of most SOC is currently unknown and many first line therapies are used off-label care paradigm? - Patient comorbidities and therapeutic side-effect profiles often dictate treatment choice - Although data from RCT are lacking, most physicians prescribe combination therapies as synergistic effects decrease individual drug doses and associated side effects • For chronic NP, the goal of therapy is to reduce pain burden and improve quality of life What is the • Looking forward Lumleian foresees step-wise improvement in the care paradigm, including: emerging care - Greater awareness of the presenting symptoms and treatment paradigm - Personalized treatment paradigm given heterogeneous NP populations and treatment responsiveness paradigm? - Development of peripherally restricted, tolerable therapeutics Estmates based on sum of actual numbers translated from percentage estimates of NP prevalence amongst each disease state Sources: Stewart, W.F. et al Lost productive time and costs due to diabetes and diabetic neuropathic pain in the US workforce. J Occup Environ Med. 49(6):672-9 (2007) ; Dworkin R.H., et al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain. 132:237-51 (2007); Berger, A. et al., Clinical characteristics and economic costs of patients with painful neuropathic disorders. J Pain. 5(3):143-9 (2004) 11 What is Neuropathic Pain?

1. Is Neuropathic Pain’s etiology well • Painful stimuli is transmitted to the brain via the spinal cord by the usually understood? well-controlled, peripheral C- and A-fibers Yes No • Neuropathic pain is the continued perception of pain in spite of the 2. Is Neuropathic Pain a primary cause of resolution of an identifiable cause mortality? Description - C- and A-fibers (slowly and rapidly conducting) develop inappropriate firing Yes No properties 3. Is Neuropathic Pain an acute or chronic - Maladaptive interpretation of normal stimuli at PNS and CNS disease? • Can be idiopathic in origin (i.e. CRPS or trigeminal neuralgia) or co-morbidity Acute Chronic of identifiable disease (i.e. HZ, HIV, cancer, diabetes) 4. Is Neuropathic Pain a communicable • NP is associated with disease, dysfunction or lesion of the PNS or/and CNS disease? - Involve alterations in activity, processing or inhibition of painful signals Yes No Etiology - Associated with hyperactivity of some neurons or lack of activity of others 5. What is Neuropathic Pain’s treatment goal? - Inappropriate maintenance of NP by neuro-immune system Symptom Disease Disease - Genetic alterations may predispose people to developing NP Relief Treatment Cure • Initially presents as normal, protective pain for some (e.g. shingles, surgery, 6. Which specialties treat Neuropathic Pain, trauma), in others (e.g. diabetes, chemotherapy), begins as loss or gain of commonly? positive symptoms such as tingling, burning, extreme sensitivity to touch or Pain Symptom PCP Neurology changes in temperature Specialist Progression • NP persisting longer than 6 months is classified as chronic 7. Where is Neuropathic Pain treated, • Associated with wasting, sleep disturbances, severe depression, anxiety, job commonly? loss, isolation, social and psychological impairments Out Inpatient Long Term Patient Hospital Care • NP affects approximately 10% of US/global population (may be higher 8. Who pays for Neuropathic Pain care (Rx), Disease depending on classification of disorder) • The average health care cost is $17,555/yr vs. $5,715/yr1 commonly? Burden • Complicated due to poor diagnostics, confusion or dismissal of symptomology 3rd party Cash Medicaid • US $40 billion per annum in health care, disability and related costs 9. Does Neuropathic Pain impact a special population? Yes No Notes: 1Most recent information is from 2000 Sources: http://www.who.int/mental_health/neurology/neurodiso/en/index.html; Berger, A. et al. Clinical characteristics and economic costs of patients with painful neuropathic disorders. J Pain. 5(3):143-9 (2004) 12 Neuropathic Pain diagnosis and classification is usually conducted using a process of exclusion in which all other potential underlying causes for pain must be ruled out; the co-existence of two or more of the following four diagnostic cues strongly suggests Neuropathic Pain.

Diagnostic Ranked Unlikely NP Probable NP Definite NP Criteria Chronic, distressing-type Chronic pain, presents with test Scale Acute, inflammatory pain pain associated disease

VAS 0-11 • 0-3/11 • >3/11 • >3/11

Word value(0- • Throbbing, wrenching, dull • Burning, shooting, pricking • Same as probable Pain in an SF-MPQ 45) Intensity • <3 intensity • >3 intensity (0-5) area that makes DN4 (0-10) • <4/10 • >4/10 • Same as probable sense LANSS (0-24) • <12/24 • >12/24 • Same as probable

Patient • Resolved or acute • >4 times/week • Continuous description • <3 months • 3-6 months • >6 months

• Present or former disease • Heavy alcohol use • Positive history with pain in Medical Drug abuse, associated with NP • Use of illegal drugs neuroanatomically probable area psychological • Poor coping skills history state • Present or former disease associated with NP

• Unremarkable • Positive sensation • Probable pain descriptors • No sensory loss • Negative sensation • Decreased sensibility in painful Description of • VAS with exam <3/11 • Spontaneous pain area Neurologi pain or VAS (0-11) • Inappropriate responses to evoked • Present or former disease known to spontaneous cal exam stimuli cause nerve lesion sensations • Decreasing sensibility • Nerve lesion confirmed • VAS with exam >3/11 • VAS with exam >3/11

• No changes associated with NP • Alterations in skin (color, hair, • CT/MRI (tumors or herniated disc) Exam Physiological scarring) • Positive results from all four confirmin changes in skin, • Abnormal EMG (sensitive to large general tests g cause CNS or PNS nerve conductance) • Clinical biochemistry

Notes: Each grading test (eg LANSS, DN4) is more or less sensitive for NP

Sources: Gilron I.C. et al., Neuropathic pain: a practical guide for the clinician. CMAJ. 175(3); 265-75 (2006); Treede, R.D. et al., Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 70; 1630-5 (2008); Rasmussen, P.V. et al., Symptoms and signs in patients with suspected neuropathic pain. Pain. 110:461-9 (2004) 13 Current Neuropathic Pain pharmacological treatment paradigms place emphasis on increasing tolerability of pain allowing for normal psycho-social functioning (i.e. pain reduction to <3/11 on VAS); only ~50% treated felt that their pain management was sufficient.

Drug Class Drug Name Choice Drivers

• Anticonvulsant • Neurontin • For Lyrica/Neurontin: high efficacy • Lyrica • Against Lyrica/Neurontin: sedation at higher doses 1st Initiate • For Cymbalta: low side-effect profile line Monotherapy • Antidepressant • Cymbalta • Against Cymbalta: cost, drug interactions (TCA or SNRI) • Nortriptyline • For nor/amitriptyline: low cost, low NNT • Amitriptyline • Against nor/amitriptyine: safety, drug interactions • Antidepressant • Venlafaxine • Switch: – Between 1st-line classes (e.g., Lyrica to Cymbalta) • Anticonvulsant • Lamotrignine – Within same 1st-line class (e.g. Cymbalta to amitriptyline) or to Switch • Opioid • Tramadol alternative within-class therapeutics (e.g. venlafaxine)

– Tramadol has better side-effect profile than traditional opioids 2nd and can be used as 2nd/3rd line mono-therapy or add-on therapy line • Antidepressant • See above • Add-on different drug class if partial pain relief (~30%) obtained – Physicians aim for combination doses lower than typical • Anticonvulsant • See above monotherapy dose to increase efficacy and lower dose-related

Treatment Add • Opioid • Oxycodone side-effects • Tramadol • Opioids are used as add-on but with caution as side-effects are potentiated

• Antidepressant • Paroxetine • Switch: • Citalopram – Between 1st-line classes (e.g., Cymbalta to citalopram) • Bupropion – Within same 1st-line class (e.g. Cymbalta to topiramate) 3rd Switch

line • Anticonvulsant • Topiramate • Valproate • Miscellaneous • Cannabinoids • Cannabinoids or Qutenza have higher success rate for specific Add • Qutenza conditions such as MS for PHN respectively 1st line for TN • Anticonvulsant • Carbamazapine • High degree of efficacy for TN 1st line for localized NP • Topical • 5% lidocaine • Low side-effect profile, specific site of action, peripheral delivery

Sources: Dworkin R.H. et al. Recommendation for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 85(3)S3-14(2010) 14 Global Neuropathic Pain prevalence was ~57M in ‘10, with an incidence of ~1M; prevalence is forecasted to grow by ~23% to ~70M in ’25; US ’10 prevalence was ~20M in ‘10, with incidence of ~131,000K; age and pre-existing conditions are primary risk factors.

Neuropathic Pain Global Prevalence (M) 2010 Neuropathic Pain Global Incidence (M) US Prevalence of Common NP Conditions (M) CAGR CAGR 60 (‘11-’25) 2.0 90 51.1 (’11-’25) 1.7 50 Other 70.4 8.2 WW: 4-8% 1.6 57.4 40 Low Back Pain w/ 60 21.1 RW: 1% 1.2 18.0 Radiculopathy 16.1 1.4 30 27.6 JP: 2% 0.9 1.3 5.7 Cancer associated 23.0 0.8 Moderate NP 30 19.9 EU: 9% 20 12.8 0.5 0.5 9.6 US/CA: 4-17% PHN 24.8 0.4 10 4.4 5.2 20.1 3.7 4.2 7.0 DPN 0 0 0.0 2010 2025 2010 2025 Epidemiologic Studies: Solid bars US EU JP RW Lumleian Estimate: Hashed bars Risk Factors • Age: Patients at 70yrs are ~1.3x more likely to develop NP • Surgery types: Mastectomy, amputations, rhizotomy than at 50yrs • Drug treatment: Chemotherapeutics, anti-retrovirals • Genetics: Variation in ion channels responsible for threshold • Sex: Women are ~1.6x more likely to develop and increases determination may make certain individuals more or less with specific types (ie. fibromyalgia, vulvodynia) susceptible to developing Neuropathic Pain • Psychological: Severe depression, poor coping skills • Life Style: Heavy smoker, alcoholism, chronic illegal drug use, low physical activity

Notes: Global incidence and prevalence estimates exclude the prodromal Neuropathic Pain segment. Neuropathic pain classification has not been fully agreed upon and epidemiology studies are currently varied. Estimates range from 1.7-20% of the general population based on investigator-determined inclusion criterion ; Incidence data of Rest of World assumed to be ~50% that of US incidence. Sources: Bouhassira, D. et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 136(3):380-7 (2008); Dieleman, J.P. et al. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain. 137(3):681-8 (2008); Yawn, B.R. et al. The prevalence of neuropathic pain: Clinical evaluation compared with screening tools in a community population. Pain Med. 10(3):586-93 (2009) ; 15 Neuropathic pain can occur as a key defining characteristic as in trigeminal neuralgia and fibromyalgia, or as a comorbidity associated with a wide range of diseases as in HIV, stroke, trauma and diabetes.

• Prevalence is challenging to determine: • 2010 Prevalence of NP by Etiology (US) – The very definition of NP lacks true consensus 40 37 – Even if consensus exists, definitive NP diagnosis is Total Developing NP: ~28M not always performed 30 26 • Key events that will decrease NP prevalence: Those not developing – Recently introduced herpes-zoster vaccine 20 33.3 16 NP 16.4 12.5 (Zostavax) expected to reduce risk of developing NP Patients PHN ~40% in adults over 60 years 10 11.8 8.1 9.6 – Improvement in preventative care prior to and 0 3.7 4.2 4.4 acutely following amputation surgeries (such as Herpes NP Low Type II Cancer diet and use of high strength pain medication) Zoster# back pain Diabetes • Key events that will increase NP prevalence: – Increase in diabetes prevalence greatly increases the population at risk for NP 6 5.8 – Improvement in early detection of cancers associated with CIPN extends overall use of 4 3.3 chemotherapeutics 5.5 2.4 – Increase in obesity rates is associated with 1.7 Those not developing 2 2.0 1.2 increased prevalence of low back pain 0.3 NP 2.4 0.4 1.3 1.4 0 0.3 0.1 0.4 NP Patients • Other etiologies associated with NP – Spinal cord injury (259,000 affected in 2010 and 67% develop neuropathic pain) – CRPS (24,000 affected in 2010)

Notes: # Herpes Zoster unique as an acute disorder with resolution of symptoms in <6mths, numbers presented are yearly Discrepancies between NP prevalence by etiology and US prevalence reflects classification and epidemiology inclusion criterion used by references ; data based on Sources:most CDC.Gov recent data – Herpes available Zoster Vaccination for Health Care Professionals, SEER fact sheet – cancer; IASP Pain Clinical Updates – Phantom Limb Pain (2000). 3(3) ; CIPN Factsheet - www.oncologypt.org ; Wolf S. et al., Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. EJC (2008) 44:1507-15 ; Ziegler-Graham K., et al., Ach Phy Med Rehab (2008) 89(3):422-9 ; Lawrence RC., et al., Estimates of the prevalence of arthritis and other rheumatic conditions in the United States, Part II. Arthritis Rheum (2008) 58(1):26-35 ; Mueller, D., et al., Prevalence of trigeminal neuralgia and persistent idiopathic facial pain: a population-based study. Ceph (2011) 31(15):1542-8 ; Jensen, TS., et al., Hew perspectives on the management of diabetic peripheral neuropathic pain. Diabetes Vasc Dis. (2006) 3(2):108-19 ; IASP – Clinical Updates (2010) 18(7) ; WHO.org – Neurological Disorders: a public health approach (Ch. 37) 16 Under the current standard of care, Lyrica/Gabapentin as well as TCAs and SNRIs are used equally across all NP conditions and can be continued along disease progression as other medication is added on.

Neuropathic Pain Treatment Paradigm Diagnosis (Current)

• Diagnosis is based on matching positive or negative symptoms Positive NP diagnosis with underlying diseases and excluding all other possible Diagnosis: causes for pain • Traditional sensory signs: spontaneous pain, If trigeminal neuralgia – thermal/mechanical hyperalgesia or allodynia carbamazepine Treatment (Current) 1st line: Neurontin/Lyrica OR Cymbalta OR • Expectations are to: Amitriptyline - Reduce VAS pain score by 30-50% Lidoderm or Qutenza at - Improve sleep any time - Reduce associated depression - Improve quality of life 2nd line: • If improvements are noted - attempt to decrease dose st Switch to different • Pain treatments must be titrated at start Add alternative 1 line st class of 1 line drugs • 2nd line medication initiated upon 1st line failure or intolerance • Opioid based medications are occasionally added to 1st line therapies - Opioids are less commonly used due to high doses needed rd 3 line: Add Tramadol Switch to opioids which are associated with significant CNS effects - Tramadol or morphine/oxycodone is usually relegated to a third line monotherapy • Further consultations with: Clinical Cannabinoids - Psychologists: behavioral/cognitive therapy and associated Trials/Other: Alternative Therapies depression Clinical Trial Enrollment - Nutritionists/dieticians for alterations in diet - Physiotherapy: improve mobility - Alternative therapies: sought by ~20% of NP patients

Psychology Prognosis (Current) Expert referrals: Nutritionist Physiotherapy • Patients are regularly assessed for drug-associated Pain Clinic adverse events • Patients can experience some recovery at 10 years

Sources: de Leon-Casasola, O. New developments in the treatment algorithm for peripheral neuropathic pain. Pain Medicine. (2011) 12:S100-8 ; Dworkin R.H. et al. Recommendation for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. (2010) 85(3)S3-14 17 Anticonvulsants Lyrica (pregabalin) and Neurontin (gabapentin) or antidepressants (Cymbalta or amytriptyline) are the most commonly prescribed systemic 1st-line therapies; Lidoderm is indicated for relief of pain associated with PHN.

Anticonvulsant TCA SNRI Topical Analgesic (ie. Lyrica, Neurontin) (ie. amytriptyline) (ie. Cymbalta) (ie. Lidoderm)

• Ion channel blockade • Inhibition of noradrenaline • Increase availability of • Non-selective sodium ‐ E.g.a2d-calcium channel and/or serotonin reuptake serotonin and noradrenaline channel blocker Mechanism ligand of descending inhibitory in descending inhibitory • Prevents action ‐ Prevents propagation of pain control pathways potential in all of Action action potential and • Antagonism of NMDA sensory, motor, release of excitatory receptors autonomic fibers neurotransmitters Dosing • Oral • Oral • Oral • Patch • Attenuates hyperactivity of • Perpetuates continued • Perpetuates continued • Prevents action Efficacy nociceptive afferents inhibitory activity inhibitory activity potential in all sensory, motor, autonomic fibers • Glaucoma • Orthostatic symptoms • Fall/balance impairment • Cardiac disease • Depression • Hypertension • Liver insufficiency • Dermatological • Erectile dysfunction Safety • Fall/balance impairment • Erectile dysfunction reactions • Weight gain • Suicidal ideation • Peripheral edema • Erectile dysfunction • Weight gain • Lyrica (pregabalin) • Elavil (amitriptyline) • Cymbalta (duloxetine) Brands • Neurontin (gabapentin) • Pamelor (nortriptyline) • Effexor (venlafaxine) • Lidoderm (5% lidocaine) • Tegretol (carbamazepine) • Norpramin(desipramine) • Savella (milnacipran) • Lamictal (lamotrigine) • Imipramine • No (Lyrica) • No (Cymbalta, Savella) Generics • Yes (Neurontin ,Tegretol, • Yes • No • Yes (Effexor) Lamictal) Notes: Cymbalta patent expiration date: 2019 Savella patent expiration date 2029 Source: Product prescription information; Company press release. Spallone, V. et al., Painful diabetic polyneuropathy: approach to diagnosis and management. Clin J Pain (2011); Bril, V. et al., Evidence-based guideline: treatment of painful diabetic neuropathy. Neurology. 76; 1758 (2011); FDA.gov patent and exclusivity search 18 Lyrica among the SoC for NP patients; patient responsiveness is approximately 50% for each drug class; Lyrica leads market share by $1.2B but goes off patent 2018; Neurontin is attractive for generic availability however dose necessary for efficacy higher than Lyrica.

Lyrica (Pregabalin) Neurontin (gabapentin) MoA • Calcium channel a2-d subunit ligand • Calcium channel a2-d subunit ligand Sponsor • Pfizer • Pfizer Formulation • Oral (25,50,75,100,150,200,225,300 mg) • Oral (100, 300, 400, 600, 800mg) (Generic) - US Patent exp date: Dec 30 2018 - US Patent exp date: Jan 2000 Dosing • Tablet: 75mg BID or 50mg TID; max 300mg BID • Oral: 300mg (Day 1); 600mg/day BID (Day 2); 900mg/day TID (Day 3); titrated to 1800mg/day TID up to 3600mg/day TID Pain Indications • Moderate to Severe Neuropathic Pain(~6.5/10) • Moderate to Severe Neuropathic Pain(~6.5/10) (including off-label - Indicated for: DPN, SCI, fibromyalgia, PHN - Indicated for: PHN uses) - Used for: phantom limb pain, neuropathic cancer - Used for: DPN, painful polyneuropathy, amputation, pain, post-stroke pain, painful polyneuropathy neuropathic cancer pain, SCI - SSI vs. placebo in NP associated with PHN, SCI, - SSI vs. placebo in NP associated with PHN ~30% fibromyalgia, ranging from 26-48% - Efficacious in reducing sleep disturbances - Efficacious in reducing sleep disturbances - NNT: DPN (8.1, PHN (5.5) - NNT: DPN (~3.9), PHN (4.9) Adverse Events • Worsening of preexisting tumors (0.66%), • ~15% of trial participants will withdraw for the (Discontinuations %) ophthalmological effects (0.8%), peripheral following adverse events edema (0.6%), weight gain (1.1%), dizziness - Worsening of preexisting tumors, ophthalmological (6.1%), somnolence (3.3%) effects, dizziness, somnolence, behavioral changes Lumleian • There is still a significant percentage of non- • Efficacy in generally similar to Lyrica though TID dosing Commentary responsive patients and significant CNS and side effects are a disadvantage adverse events • Gabapentin is available as generic • Negative results obtained for HIV-NP • Has approximately equal indication profile to Lyrica • Higher selectivity than Neurontin (lower dose)

Sources: Lyrica and Cymbalta prescribing information; Company press releases; O’Connor A.B., Dworkin, R.H. Treatment of Neuropathic Pain: An Overview of Recent Guidelines. Am J Med (2009) 122:S22-32 ; www.uspto.gov 19 Cymbalta is among the SoC for NP due to its relatively good side-effect profile; cost is a common detractor for patients; whereas, amitriptyline has generic availability and better NNT compared to Cymbalta but worse side-effect profile.

Elavil (amitriptyline) Cymbalta (duloxetine) MoA • Tricyclic antidepressant – norepinephrine • Serotonin/norepinephrine reuptake inhibitor reuptake inhibitor Sponsor • Sandoz, Mylan Pharm., Mutual Pharm. • Eli Lilly Formulation • Tablets (10,25,50,75,100,150mg) • Delayed release capsules (20, 30,60 mg) (Generic) • Injection (10mg/ml) - US Patent expires June 2013 - Generic Dosing • Tablet: 25mg QD at night; titrated 25mg QD as • Capsules: 30-60mg QD tolerated to max 150mg Indications • Moderate to Severe Neuropathic Pain • Moderate Neuropathic Pain (including off-label - Indicated for: DPN, PHN - Indicated for fibromyalgia, DPN, chronic muscoskeletal pain uses) - Used for: post-surgical, post-stroke - Initial 30mg titrated to 60mg for fibromyalgia and 60mg - Usually requires a delay of 3-4wks starting dose for diabetic neuralgia - Avg 90mg maintenance had SSI vs. placebo in NP - DPN: ~60% patients experience 30% pain score reduction associated with PHN (34%) - Fibromyalgia: ~40% patients experienced a 30% pain score - NNT: DPN (1.3-3.4), PHN (~2.5), central pain (1.7) reduction - NNT: DPN (5.2) Adverse Events • Suicidal thoughts, dry mouth, sedation, • Tablet: Suicidal thinking/behavior in adults (1.8%), (Discontinuations %) constipation, weight gain, postural hypotension hepatotoxicity (1.32%), worsening of glycemic control, in elderly, not to be used in conjunction with nausea (3.5%), dizziness (~2%) somnolence (1.1%), SSRI headache (1.2%) dry mouth, constipation, insomnia, Lumleian • Care should be exercised in patients with • Has approximately the same efficacy as Lyrica, used Commentary cardiac problems alternatively or in conjunction with Lyrica • Recent data indicate use for combination • Has a good safely profile and unlike other SNRIs, useful therapy with gabapentin reducing mood in fibromyalgia but less effective than TCA interference Sources: Cymbalta prescribing information; FDA product information, Gilron I., et al., Neuropathic pain: a practical guide for the clinician. CMAJ (2006) 175(3):265-75 ; Dworkin R.H. et al. Recommendation for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. (2010) 85(3):S3-14 20 Carbamazepine is the gold standard for trigeminal neuropathy; Lidoderm is approved for moderate/severe PHN and is also used as an add-on therapy for PDN and low back pain.

Carbatrol, Tegretol (carbamazepine) Lidoderm (5% lidocaine patch) MoA • Blocks voltage-gated sodium channels • Blocks voltage-gated sodium channels Sponsor • Novartis • Endo Pharmaceuticals/Grunenthal/Teikoku) Formulation • Tablets (200mg) and (100, 200, 400mg)-XR • Topical patch (700mg) (Generic) • Chewable (100mg) - Also available as gel • Suspension (100mg/5mg) - Generic Dosing • Tablet: starting 100mg BID incr 100mg BID to • Topical: 1patch BID max 3 patches BID. Usually 1200mg efficacious at 3 patches • Suspension: 50mg QID incr 50mg QID to 1200mg Indications • Moderate Neuropathic Pain • Moderate Neuropathic Pain - Indicated for: Trigeminal Neuralgia - Indicated for: PHN - Efficacious in ~70% patients determined by 50% pain - Use for: PDN, low back pain with NP score reduction for reduction pain severity, painful - Initial 10mg-75mg/day titrated to 150mg spontaneous paroxysms - Efficacious at 2wks in ~50% patients determined by - NNT for: Trigeminal Neuralgia (1.5) 30% pain score reduction - Diabetic neuropathy - 52%, - NNT for: PHN (4.4) Adverse Events • Dizziness, drowsiness, unsteadiness, nausea, • Topical: Skin erythema, rash, allergic reactions (Discontinuations) vomiting, blood problems, skin disorders, suicidal thoughts, not to be used in conjunction with TCAs Lumleian • Primary indication for trigeminal neuralgia • Is useful primarily for PHN; however Qutenza is a Commentary however, side-effects can be dose-limiting significant competitor • Addition to gabapentin significantly increased efficacy where pain is localized

Notes: Adverse events are reported discontinuation rates from phase III trials Sources: FDA label information for Tegretol and Lidoderm ; Gilron I., et al., Neuropathic pain: a practical guide for the clinician. CMAJ (2006) 175(3):265-75 21 Tramadol can be used in combination with others during titration for immediate pain relief and is commonly used as add-on therapy for break-through pain.

Durotram, Ryzolt, Ultram (tramadol) MoA • mu-opioid agonist, weak serotonin/norepinephrine inhibitor Sponsor • Purdue, Gebro Pharma Formulation • Tablet-ER (100, 200, 300mg) (Generic) • Tablet (25, 50, 75, 100mg) - Generic Dosing • Tablet: ER initiated at 100mg QD and titrated weekly by 50-100mg/day to pain relief max 400mg/day • Tablet: 25mg QD Indications • Moderate to Severe Pain (~6.5/10) - Indicated for: moderate to moderately severe pain - Used for: DPN, PHN, phantom limb pain, SCI - 300 mg starting dose had SSI vs. placebo in NP associated with, small fiber neuropathy (46%) spinal cord injury after 4wks, PHN (53%), - NNT: PPN (3.4), PHN (4.8), DPN (3.8)

Adverse Events • Respiratory depression, ataxia, sedation, constipation, seizures, nausea, orthostatic (Discontinuations) hypotension, serotonin syndrome Lumleian Commentary • Significant CNS effects, tolerance and the possibility for abuse are decreased with tramadol vs traditional opioids • Not to be used with other SNRIs or TCAs

Notes: Adverse events are reported discontinuation rates from phase III trials

Sources: Ultram FDA label information 22 New to market medications for Neuropathic Pain include: high-dose extended release formulation of gabapentin, long-lasting high-dose capsaicin patch, cannabinoid-based therapy and mixed, opioid/SNRI therapeutics.

Sativex Nucynta (tapentadol) Gralise (Gabapentin) Qutenza (8% capsaicin) (nabiximols)

Mechanism • Mu-opioid agonist with • a2d-calcium channel ligand • TrpV1 agonist • CB1 agonist (cannabis norepinephrine reuptake • Reduction in available extract) of Action inhibition nociceptive afferents • 50mg TID titrated daily to • 300mg QD to max 1800mg • 1x every 3mths • Once every 4hrs to avg Dosing max 700mg/day • Apply for 60min max maintenance of 5 spray/day 4patches • 1spay = 100ml

Formulation • Tablets (50, 75, 100mg) • Tablets (300, 600mg) • Patch: (179g capsaicin) • Spray: (25mg/ml D9-THC, 25mg/ml cannabidiol)

Relative • Tramadol (Ultram) • Neurontin (gabapentin) • Lidoderm • Cesamet, medical marijuana

• Janssen Pharmaceuticals/ • Depomed • NeurogesX/Astellas Pharma • Bayer/GW Pharma Sponsor Grunenthal GmbH • Launched 2011 (US) • Launched 2009 (US) 2010 • Approved 2005 (CDN, Spain, • Launched 2009 (US) 2010 (EU) UK, New Zealand) (EU) 2011 (CDN)

• Combination opioid/SNRI • New formulation • Long lasting effects • Only analgesic indicated for increases potency thereby • Extended release to • Painful for some MS pain/spasms Description increasing dose with increase compliance • First-in-class decreased side-effect • 10hr release • Is an investigational drug in profile the US as an add-on therapy

Generic • No (exp Aug 2022) • No • No (exp 2016) • No Availability

Source: Product prescription information; Company press release 23 Looking forward Lumleian foresees step-wise improvement in the care paradigm, including: (1) genetic testing and diagnostic monitoring, (2) preventative therapy and use of multi MOA treatment cocktails, (3) use of biomarkers to monitor progression and inform treatment.

• Advances in imaging, education and pathophysiology used for diagnosis will improve treatment outcome: - Imaging techniques (e.g. fMRI) to analyze neuroplastic changes occurring within the brain contributing to maladaptive responses - Education in treatment paradigms and diagnostic procedures will reduce the number of patients poorly treated • Genetic tests will also lead to improved diagnosis: Future - Ion channel genetic alterations lead to loss or amplification of pain sensation Diagnosis - The application of pharmacogenetics to NP can identify those who, in combination with predisposing diseases or injury types, are at a higher risk of developing NP or responding to particular treatment regimens • Verification and validation of a number of biomarkers will aid in the treatment of NP - Plasma levels of cytokines in conjunction with punch biopsy results examining relative expression of pain-detecting receptors could improve diagnostic accuracy

• Combination approach between inflammatory and neurological components of NP as needed - Sodium channels such as peripherally targeted NMDA receptors with enhanced inhibitory control e.g. Amiket (EpiCept) - Anti-NGF therapies to address maladaptive proinflammatory/pronociceptive response in conjunction with targeted Future ion channel antagonists e.g. tanezumab (Pfizer) and XEN-402 (Xenon) Treatment • Novel treatment with an oral small molecule disease modifying agent - TRPV3 warm sensitive ion channel antagonist, e.g. SAR-292833 (Sanofi) • Symptomatic agents will likely be used in combination with disease-modifying agents - Inhibition of vesicular release e.g. Botox (Allergan) for the treatment of painful diabetic neuropathy in combination with CB1 agonists to enhance inhibition e.g. Sativex (GW Pharmaceuticals)

Sources: Stephenson DT and Arneric SP (2008) Neuroimaging of Pain: Advances and Future Prospects J Pain 9(7) 567-579 24 Table of Contents

• Two equally important strategies are used: - Enhancing inhibitory regulation through stimulation of opioid and cannabinoid receptors - Descending inhibitory control by NA/5-HT/dopamine agonism in combination with silencing excitatory transmission through ion channels such as sodium and Trp channels • As of Q2, Lumleian validated 65 assets in active clinical development for those Neuropathic Pain What is in the indications progressed furthest in the pipeline although a development program may be ongoing for other industry’s indications: clinical - 7 in Phase IV, 13 in Phase III, 34 in Phase II, and 11 in Phase I development • Neuropathic Pain presents with varying pathology in individual disease subsets: pipeline? - For example chemotherapy-induced NP (CIPN) is due to mitochondrial toxicity and loss of intra-epidermal innervation, PDN is associated with inflammation and glucose toxicity and chronic low-back (CLB) with radiculopathy central sensitization and peripheral sprouting of nociceptive sensory afferents - Predicting efficacy in Phase II/III trials remains difficult as the exact underlying pathology of the disease subsets vary and can account for late-stage failures - Most notably the recent failure of Lyrica Phase III with HIV-associated NP • Evaluation: Late stage asset evaluation includes both novel MOAs and approved drugs seeking an NP indication or existing NP drugs attempting to broaden indications • Calcium Channels: Lyrica dominates in spite of recent RTC data with mixed results; demonstrates better efficacy compared to predecessor Neurontin - Other assets in Phase III trials include Sensodyne however, detailed results have not been released What is the - Lyrica has had mixed results in the effort to expand NP indications evidence for late • Cannabinoid: Top line safety data for Sativex released from post-marketing results in Canada and EU, stage assets? positive Phase II studies has allowed for FDA-approved Phase III program for launch expected 2015 • Mixed: Amiket (combination TCA with NMDA antagonist) in a small Phase II study, met primary endpoints of and received FDA Fast Track status in April 2012 • Sodium channels: Broad acting sodium channel therapies are already approved e.g., Lamictal, however targeted therapies are under development and expected to offer reduced side-effect profile e.g. Tectin – Other assets in this class in Phase II trials, include CNV-1014802

Significant unmet needs still exist in Neuropathic Pain in improving diagnostic procedures correlated with optimized treatment paradigms, improved tolerability for chronic use, development in underserved indications such as CLBP with radiculopathy.

• There has been significant progress in elucidating molecular targets responsible for the transmission of nociceptive stimuli, however: – Potential associated with recent identification of new molecular targets associated with enhanced selectivity yet to be translated to realize full clinical potential – Mixed responder population points to need in ‘me-too’ drugs in classes with minimal competition • Improvements can be made in the area of targeting the interaction between immuno- surveillance cells and Unmet Need neurons thought to be involved in the long-term maintenance of neuropathic pain • NP patient groups with inadequate treatment options include those living with cancer and low back pain – Development of chemotherapy induced NP is a dose-limiting factor with unique MoA – Cancer associated NP as a direct result of altered micro-environment due to tumor growth – Low back pain with radiculopathy faces challenges associated with clinical trial design, target and patient identification • Daytime dosing remains a challenge with most current therapies due to significant drowsiness

• Combination Studies: Investigating novel drug combination to improve tolerability and efficacy, development of empirically-tested disease-specific combination drug paradigms to address the existing opportunities in drug-development and patient care Large • Synergistic Effects: opportunity exists for drugs that are known to exhibit synergistic effects with current Opportunity therapeutics either approaching or at generic status • Compliance: improvement in drug design to improve delivery, dosing, abuse potential, safety and half-life – Peripherally restricted therapeutics for those NP conditions which have localized profiles represents a largely underexplored area with only two marketed drugs available • Disease specific therapeutics: Addressing disease-specific causes underlying the development of NP could result in higher efficacy in select populations and dominate disease-specific treatment regimens, but may also reduce ability to obtain approval (and off-label use) across the NP spectrum of disorders

27 Anti-NGF targeting compounds has 3 Phase II candidates in Neuropathic Pain trials and represents the largest class of novel Neuropathic Pain MOAs that work as receptor / sequestering agents.

NGF: Receptor/Sequestering NP Pipeline: Current (N = 29) • NGF sequestration has demonstrated reduction in pain scores • Three humanized mAbs in Mechanism of Action for Receptor/Sequestering Phase III/IV Phase II Phase I Phase II Agents (N = 6) (N = 18) (N = 5) • Alternative approaches include TrkA antagonism Anti-NGF (N = 3) 3 Opioids: NGF (N=5) TrkA antagonist (N = 1) 1 • Efficacious in reducing some TrkA agonist (N = 1) 1 elements of NP ORL-1, MOR agonist (N = 1) 1 • Typically used as add-on Opioid (N=3) Pre-proENK gene therapy (N = 1) 1 therapy with current OR ligand (N = 1) 1 development attempting to overcome abuse and Serotonergic (N=1) 5HT-1A agonist (N = 1) 1 addiction issues 5HT reuptake inhibitor & SNRI (N=4) 2 2 NA reuptake inhibitor (N=4) SNRI: Cytokine/ Anti-TNFa (N = 1) 1 • Generally shown solid results chemokine (N=2) CCR2B antagonist (N = 1) 1 in clinic • Ongoing trials are focused on CB1 agonist (N = 3) 2 1 Cannabinoid (N=5) expanding indications FAAH inhibitor (N = 2) 2 Orexin, p38 MAPK, H3, erythropoietin, TNFa: triple reuptake, aldose reductase, • Humira is in late-stage trial Other receptor angiotensin II, clostridial 8 1 for NP indication inhibition (N=9) endopeptidase, HSP90/JNK, a2-AR Cannabinioids: (N = 9) • Currently in use in EU and Canada • In late stage trials for US Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd pipeline presentations, analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; TrialTrove 28

Ion channel inhibition is attractive for peripheral selectivity and inhibition of peripheral excitation; however targeted channel blockers difficult to design; Qutenza (TrpV1 agonist) recently launched capitalizes on TrpV1 selective distribution on nociceptive afferents.

Ion Channel Ligands NP Pipeline: Current (N = 20)

Phase Phase II Phase I Mechanism of Action Ion Channel Ligands III/IV (N = 7) (N = 7) Sodium channel: (N = 6) • Selective Nav 1.7 antagonists have Nav 1.7 antagonist (N=6) 2 4 generated good data in select NP indications Sodium Channel Nav 1.1, 1.2, 1.3 2 Trp channels: (N=9) antagonist (N=2) • Peripheral restriction is associated with Nav 1.3, 1.7 (N=1) 1 reduced side-effect profile TrpV1 agonist (N= 2) 1 1 • Large body of basic research is yielding TRP channels TrpV3 antagonist (N=1) 1 fruitful new targets (N=4) Calcium channels: TrpA1 antagonist (N=1) 1 • Lyrica indication expansion trials are a2d Ca2+ channel ligand 1 1 included (N=2) • However, other selective calcium Calcium channel Ca2+ channel antagonist channel blockers are in Phase I/II trials (N=5) 1 (N=1) P2X3: Cav 2.2/3.2 (N=2) 1 1 • Restricted to subtype of peripheral C- fibers P2X3 antagonist (N=1) 1 Glutamatergic: Glutamatergic (N=1) 1 • Key excitatory neurotransmitter (glutamate) in PNS and CNS

Reflecting the diverse peripheral and central nature of NP, a large body of mixed target therapeutics are generating efficacy in late stage clinical trials; however this is again mostly marketed drugs looking for additional indications.

Other MOA NP Pipeline: Current (N = 16)

Mixed: Phase Phase II Phase I • Newer therapeutic formulations have Mechanism of Action Mixed and Other III/IV (N = 8) (N = 0) taken into account the mixed nature and (N =8) higher efficacy of combination therapy CYP450 inhib, NMDA, • Phase II success is capitalizing on this 1 VGSC, Kv antagonist (N=1) observation NMDA antagonist, Kv • Trends include enhancing inhibition 1 1 agonist (N=2) through either the descending inhibitory system or preventing excitatory signals D1/4/5, 5HT, a1/2AR, H1, 1 simultaneously with blocking excitation mAchR antagonist (N=1) Mixed (N=7) Opioid receptor agonist, Other: 1 SNRI (N=1) • Stem cell and vaccine development • Development of varicella vaccine should TCA+NMDA antagonist 1 reduce post-herpetic neuralgia incidence (N=1) by preventing resurgence of latent virus Dopamine antagonist + 1 Vesicular release: GABA agonist (N=1) • The large body of late-stage success is Mesenchymal precursor cells (N=1) 1 primarily Botox Unknown/unidentified (N=5) 5 • Other approved drugs in this class are Varicella-zoster vaccine (N=1) 1 being investigated Vesicular release (N=2) 2

As of Q2 Lumleian validated 65 individual assets in clinical development for various indications associated with Neuropathic Pain in EU, Japan & NA; leading sponsors are: Pfizer (6), Abbott (4); sponsors may have assets in other developmental phases for alternative indications.

Neuropathic Pain Assets in ‘Active’ Clinical Development

20 19

10 10 19

6 6 1 4 5 10 1 6 1 2 2 2 2 2 2 2 2 2 2 4 3 1 1 1 2 1 1 1 2 1 2 0 1 1 1 1 1 1 1

Phase IV(N = 7) Phase III (N = 13) Phase II (N = 34) Phase I (N = 11)

Notes: Clinical trials used to tabulate data are most advanced single trials. Numbers are increased when considering clinical trials for alternative NP-associated indications

Cannabinoid targeting compounds has 5 Phase II candidates and represents the largest class of novel NP MOAs that work as receptor/sequestering agents, NGF-related targets and opioids are two other heavily investigated areas.

Receptor/Sequestering NP Pipeline: Current (N = 29)

Mechanism of Action Phase III/IV (N = 7) Phase II (N = 18) Phase I (N = 4) • ABT-110 (Abbott) Anti-NGF (N = 3) • Fulranumab (J&JPRDLLC) NGF (N=5) • Tanezumab (Pfizer) TrkA antagonist (N = 1) • CT-327 (Creabilis) TrkA agonist (N = 1) • DA-9801 (Dong-A) ORL-1, MOR agonist (N = 1) • GRT-6005(Forest/Grunenthal) Opioid (N=3) Pre-proENK gene therapy (N = 1) • NP-2(Diamyd) OR ligand (N = 1) • KP-201 (KemPharma) Serotonergic 5HT-1A agonist (N = 1) • Befiradol (Pierre Fabre) (N=1) 5HT reuptake inhibitor & • Cymbalta (Eli) • TD-9855 (Theravance) SNRI (N=4) NA reuptake inhibitor (N=4) • Savella (Forest) • Beloxepine (Cubist Pharm) Cytokine/ Anti-TNFa (N = 1) • Humira (Abbott) chemokine

(N=2) CCR2B antagonist (N = 1) • AZD-2423 (AstraZeneca) • Sativex (GW) • Marinol (Echo) Cannabinoid CB1 agonist (N = 3) • Cesamet (Valeant/other) (N=5) FAAH inhibitor (N = 2) • V-158866 (Vernalis) • ARA-290 (Araim) Orexin, p38 MAPK, H3, • EMA-401 (Spinifex) erythropoietin, triple reuptake, • Ranirestat (Eisai/Dainippon) Other receptor • SXN-100323 (Allergan) aldose reductase, angiotensin II, • SEP-432 (Sunovion) inhibition (N=9) • ABT-652 (Abbott) clostridial endopeptidase, • MK-6096 (Merck) HSP90/JNK, a2-AR (N = 9) • AEG-33773 (Aegera) • ARC-4558 (Arcion)

Ion channel inhibition is attractive for peripheral selectivity and inhibition of peripheral excitation; sodium channel targets represent the largest class of ion channel targets under investigation.

Ion Channel Ligands NP Pipeline: Current (N = 20) Mechanism of Action Phase III/IV (N = 6) Phase II (N = 9) Phase I (N = 5) • CNV-1014802 • PF-05089771 (Pfizer) (Convergence) • PF-05150122 (Pfizer) Nav 1.7 antagonist (N=6) • XEN-402 (Xenon) • PF-05186462 (Pfizer) Sodium Channel • PF-05241328 (Pfizer) (N=9) Nav 1.1, 1.2, 1.3 antagonist • Stedesa (BIAL) (N=2) • Lamictal (GSK) Nav 1.3, 1.7 (N=1) • Tectin (Wex) TrpV1 agonist (N= 2) • Qutenza (Astellas) • Civamide (Winston) TRP channels TrpV3 antagonist (N=1) • GRC-15300 (Sanofi) (N=4) TrpA1 antagonist (N=1) • GRC-17536 (Glenmark) a2d Ca2+ channel ligand (N=2) • Lyrica (Pfizer) • DS-5565 (Daiichi) Calcium channel Ca2+ channel antagonist (N=1) • Sensodyne (SantoSolve) (N=5) Cav 2.2/3.2 (N=2) • ABT-639 (Abbott) • CNV-2197944 (Convergence) P2X3 antagonist (N=1) • AF-219 (Afferent Phar) Glutamatergic (N=1) • AV-101(Vistagen)

Other MOA NP Pipeline: Current (N = 16) Mechanism of Action Phase III/IV (N =7) Phase II (N =9) Phase I (N = 0) CYP450 inhib, NMDA, VGSC, Kv • Neurodex (Avanir) antagonist (N=1) • CNSB-015 (Relevare) • Flupirtine (Meda) NMDA antagonist, Kv agonist (N=2) Mixed (N=7) D1/4/5, 5HT, a1/2AR, H1, mAchR • Seroquel (AZ) antagonist (N=1) Opioid receptor agonist, SNRI (N=1) • Nucynta (Grunenthal) TCA+NMDA antagonist (N=1) • AmiKet (EpiCept) Dopamine antagonist + GABA • Xyrem (Jazz Pharm) agonist (N=1) • Mesenchymal precursor cell Mesenchymal precursor cells (N=1) (Mesoblast) • ASP-3652(Astellas) • AGN/EHT-0001 (BMS) Unknown/unidentified (N=5) • BMS-954561 (BMS) • GRT-6010 (Grunenthal) • Carisbamate (J&J) Varicella-zoster vaccine (N=1) • Varivax (Merck) • Botox (Allergan) Vesicular release (N=2) • Keppra (UCB)

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd pipeline presentations, analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; TrialTrove 34 Drug development with respect to Neuropathic Pain spectrum of disorders; highest investment in Painful Diabetic Neuropathy (N=20), unspecified Neuropathic Pain (N=15), Post-herpetic Neuralgia (N=6); does not fully represent population epidemiology of Neuropathic Pain.

Indication Phase III/IV (N = 10) Phase II (N = 20) Phase I (N = 0) • Nucynta (opioid+SNRI) • NP-2 (opioid) • • Cancer-related Sativex (CB1) Fulranumab (NGF) • Tectin (Nav1.7) • Tanezumab (NGF) (N=5) • CNSB-015 (NMDA+Kv) • CNSB-015 (NMDA+Kv)

Chemotherapy induced (N=1) • Cesamet (CB1) • EMA-401 (angiotensin II)

• Qutenza (TrpV1) • ABT-639 (Cav3.2) • DA-9801 (NGF) • Nuedexta (mixed) • ABT-652 (H3) • GRT-6005 (opioid) • Stedesa (Na channel) • ARA-290 (erythropoeitin) • Carisbamate (unknown) • Ranirestat (aldose) • AZD-2423 (CCR2B) • MK-6096 (orexin) Diabetic Neuropathy • Nucynta (mixed) • BMS-954561 (unknown) • Befiradol (serotonin) (N=20) • Lamictal (Na channel) • DS-5565 (Ca channel) • GRC-15300 (TrpV3) • Sativex (CB1) • GRC-17536 (TrpA1) • Amiket (TCA+NMDA) • Botox (Vesicular release) • ARC-4558 (a2-AR) • AEG-33773 (HSP/JNK) • Cesamet (CB1) • Stedesa (Nav 1.1-3)

• Nucynta(mixed) • ABT-110 (NGF) • CNV-1014802 (Na channel) w/o radiculopathy • Botox (Vesicular release) • Mesenchymal cells (stem (N=2) • Savella (SNRI) cells) • Back Tanezumab (NGF) pain • Lyrica (Ca channel) w/ radiculopathy (N=4) • Enbrel (TNFa) (N=1) • Humira (TNFa)

Cervical (N=0) • Botox (Vesicular release)

Notes: Inclusion criteria is those trials either ongoing, positive data obtained or awaiting results. Assets listed in orange are being developed for more than one indication.

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd pipeline presentations, analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; TrialTrove 35 Drug development with respect to Neuropathic Pain spectrum of disorders; highest investment in Painful Diabetic Neuropathy (N=20), unspecified Neuropathic Pain (N=15), Post-herpetic Neuralgia (N=6); does not fully represent population epidemiology of Neuropathic Pain.

Indication Phase III/IV (N = 8) Phase II (N = 7) Phase I (N =11) • Xyrem (Dopamine) • Botox (Vesicular release) Fibromyalgia (N=4) • Seroquel (mixed) • Stedesa (Na channel) • Keppra (Vesicular release) • Flupirtine (NMDA+Kv) • CNSB015 (NMDA+Kv) HIV-related (N=0)

• Humira (TNFa) • Tanezumab (NGF) Interstitial cystitis (N=3) • AF-219 (P2X3) • ASP-3652 (unknown)

• Cesamet (Cb1) • Neurodex (Cyp450/NMDA) MS (N=3) • Cymbalta (SNRI) • Marinol (CB1)

• Seroquel (mixed) • AGN-0001 (unknown) • CNV-2197944 • PF-05241328 (Nav1.7) • Qutenza (TrpV1) • CT-327 (NGF) (Cav2.2) • PF-05186462 (Nav1.7) • KP-201 (Opioid) • Keppra (Vesicular release) • Beloxepin (SNRI) • TD-9855 (SNRI) Neuropathic Pain • GRT-6010 (unknown) • IPI-940 (FAAH) • V-158866 (FAAH) (N=15) • PF-05089771 (Nav1.7) • SEP-432 (TRI) • PF-05150122 (Nav1.7) • AV-101 (NMDA)

Idiopathic • Savella (SNRI) NP(N=1) Burn • Lyrica (Ca channel)

Notes: Inclusion criteria is those trials either ongoing, positive data obtained or awaiting results. Assets listed in orange are being developed for more than one indication

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd pipeline presentations, analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; CenterWatch 36 Drug development with respect to Neuropathic Pain spectrum of disorders; highest investment in Painful Diabetic Neuropathy (N=20), unspecified Neuropathic Pain (N=15), Post-herpetic Neuralgia (N=6); does not fully represent population epidemiology of Neuropathic Pain.

Indication Phase III/IV (N = 5) Phase II (N = 6) Phase I (N = 0) • Varivax (vaccine) • SXN-100323 (endopep.) • Tanezumab (NGF) • Stedesa (Na channel) • BMS-954561 (unknown) • Sensodyne (Ca channel) Post-herpetic neuralgia • Carisbamate (unknown) • EMA-401 (angiotensin) (N=6) • XEN-402 (Nav1.7) • Civamide (TrpV1 • AmiKet (TCA+NMDA)

Post-stroke • Botox(Vesicular release) (N=1)

Spinal cord injury • Lyrica (Ca channel) • Botox (Vesicular release) • (N=0) Befiradol (Serotonin)

Trigeminal neuralgia • Lamictal (Na channel) • CNV-1014802 (Na channel) (N=1)

General (N=1) • AZD-2423 (CCR2B)

Post- • Sensodyne (Ca channel) Amputation traumatic (N=1) (N=3)

TKA (N=1) • Lyrica (Ca channel)

• Cymbalta (SNRI) Chronic pelvic pain • Botox (Vesicular release) (N=0) • Savella (SNRI)

Notes: Inclusion criteria is those trials either ongoing, positive data obtained or awaiting results. Assets listed in orange are being developed for more than one indication

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd pipeline presentations, analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; CenterWatch 37 Subunits of the voltage-gated sodium channel are peripherally restricted to sensory and sympathetic nerve fibers making these an attractive target; recently it has been shown that Nav 1.7 is selectively expressed on nociceptive afferents while Nav 1.3 is pathologically upregulated.

Physiology • Sodium channels are activated in response to changes in membrane voltage - Responsible for the propagation of action potentials along the axon - Culminates in neurotransmitter release in spinal cord - Nav 1.1,1.2,1.3 found in CNS Pathophysiology • Nav 1.7/1.3 a-subunits are found in sensory and sympathetic fibers - Nav 1.7 gain of function associated with inherited erythromelalgia and paroxismal extreme pain disorder - Nav 1.3 only upregulated following injury Hypothesized • Selective blockade of neuronal Mechanism hyperexcitability - Reduces release of neurotransmitters in spinal cord to halt signal propagation Pipeline Potential • Alteration in expression may be disease Considerations specific • Caution exemplified by recent failure of Ralfinamide (Newron), a mixed ion channel including Nav1.7 antagonist, which failed to Phase III • Stedesa (BIAL Group) show efficacy in low-back pain associated with • Tetrodotoxin (Wex Pharmaceuticals) a neuropathic component • Lamictal (GSK) - However this was in contrast to positive Phase II with mixed NP patients Phase II • CNV-1014802 (Convergence Pharmaceuticals) • XEN-402 (Xenon)

Source: Pain as a channelopathy Ramin Raouf, Kathryn Quick, John N. Wood Published in Volume 120, Issue 11 J Clin Invest. 2010; 120(11):3745– 3752; Newron Press Release May 6, 2010 ; 38 Tectin (Tetrodotoxin) inhibits the activity of TTX-sensitive Nav 1.3 and 1.7 found on peripheral nerves; Phase IIa studies demonstrated mixed efficacy results only after post-hoc analysis; good tolerability in a small group of cancer-pain subjects.

Clinical Results (Phase IIa Canadian Tetrodotoxin Study Group) Efficacy: • In a 82 patient Phase IIa study, non-significant analgesic response was observed for primary endpoint of >30% fall in pain score in 42% (60ug) vs 31% placebo p=0.425 - Post-hoc analysis determined a responder was either a fall in pain by 30% or greater than 50% decrease in opioid consumption and a >30% improvement in QoL and found 45% TTX response vs 21% placebo (p=0.043) - Responders did so for an average of 14 day post-induction Safety: • No significant safety or tolerability issues reported; TEA with discontinuations were transient ataxia, transient moderate dysphagia Lumleian • Top-line results suggests moderate efficacy (NNT=4) and it appears to be well tolerated Commentary: • The lack of significant efficacy of primary endpoints was explained due to the complex nature of NP and underlying pathophysiological changes of Nav-expressing peripheral afferents • A larger study with clearly defined inclusion criteria could enhance responders • Differential upregulation of both Nav 1.3 and 1.7 make this an interesting target which may incur very robust positive data when appropriate disease state is found

Phase IIa Program (Completed) Phase III Program (TEC-006 - Ongoing) Patient Segment: • Moderate to severe NP (>4/10) active cancer • Moderate to severe NP (>4/10) active cancer Target Enrollment: • N = 82 • N=120 Randomization: • Placebo-controlled, parallel design • Double blind, parallel, randomized, placebo-controlled

Dosing: • 4 consecutive days of 7.5 μg BID, 15 μg BID, 22.5 μg • Induction: 30μg BID 4days BID, 30 μg BID, 30 μg TID, and 30 μg QID Duration: • Induction: 4 days • Induction: 4 days • Follow up: 11 days • Follow-up: Days 5, 8 & 15 End-Points: • Primary: Reduction in pain intensity • Primary: Improvement of pain intensity or use of analgesics • Secondary endpoints: estimate duration of response and improvement in QoL and QoL improvement • Secondary: Assess onset and duration of analgesic response

Sources: Hagen, NA et al. Tetrodotoxin for Moderate to Severe Cancer Pain: A Randomized, Double Blind, Parallel Design Multicenter Study. J Pain Sym Man (2008) 34:4 420-9 ; NCT00725114 39 Lamictal is currently indicated for epilepsy and has been shown to have efficacy in select Neuropathic Pain conditions; a Phase III study for HIV sensory neuropathy demonstrated significant efficacy compared to placebo.

Clinical Results (Phase III HIV associated sensory neuropathy and Painful Diabetic Neuropathy) Efficacy: • In a Phase III 227 HIV NP patient study, significant improvement was only observed when pain measured by VAS and only in those HIV-treated groups also receiving neurotoxic AZT treatment (58% vs 23%) • In Phase III DPN trial, described demonstrated significant differences for the primary efficacy result between Lamictal (400mg) vs placebo (-2.7 vs -1.6) Safety: • No significant safety or tolerability issues reported; dose-related treatment adverse events noted (rash and headache) Lumleian • Lamictal has generally not demonstrated significant improvement over existing SoC Commentary: • Trial design of HIV population illustrated important differences between AZT treatment groups in responsiveness sodium channel blockers

Phase III HIV Program (Completed) Phase III PDN Program (Completed) Patient Segment: • Moderate to Severe NP (>4/10) and sensory • Moderate to Severe NP (>4/10) associated with either Type neuropathies associated with HIV infection I or II diabetes for greater than 6mths and less than 5yrs Target Enrollment: • Neurotoxic: N=62 (Lamictal) N=30 (Placebo) • Intent to treat: N=679 • Non-neurotoxic: N=88 (Lamictal) N=47 (Placebo) • Safety: N=706 Randomization: • Randomized by neurotoxic ART stratum, double-blind, • Placebo-controlled, randomized, double blind placebo-controlled, parallel design Dosing: • Induction/dose escalation: 25mg • Induction/dose escalation: 25mg • Maintenance: 400mg/day (non-enzyme modifiers) or • Maintenance: 200mg, 300mg, 400mg daily 600mg/day (drug enzyme modifiers) • Acetaminophen only used as rescue analgesic • Analgesics were maintained throughout Duration: • Induction: 7 weeks • Induction: 7 weeks • Maintenance: 4 weeks • Maintenance: 12 weeks End-Points: • Primary: mean change in avg pain vs baseline (using • Primary: Mean daily pain intensity vs baseline NPS Gracely Pain Score) • Secondary: Other demonstrations of symptom relief • Secondary: Other demonstrations of symptom relief Sources: Simpson, D.M., et al., Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology (2003) 60:1508-14 ; Vinik A.I., et al., Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain. (2007) 128:169-79 Sponsor Study ID: NPP30004 and NPP30005 40

XEN-402, a selective Nav 1.7 inhibitor, is initiating Phase II trials for PHN after demonstrating efficacy in Phase I trial with inheritable erythromyalgia patients with Nav1.7 gain-of-function mutation.

Clinical Results (Phase I Inherited Erythromyalgia) Efficacy: • Small cohort of select patient population demonstrated significant efficacy compared to placebo (42% p=0.014) - Pain reduction after 2 day dosing was apparent

Safety: • No significant safety or tolerability issues reported; dizziness and somnolence Lumleian • Top-line results suggests efficacy at the highest dose and it appears to be well tolerated Commentary: • Well designed study, all participants were included based on mutation in Nav 1.7 though it remains to be determined which NP state has the highest frequency of Nav 1.7 gain of function • Point of concern is Phase IIa studies using different formulation than Phase I/II program

Phase I/II Program (Completed) Phase IIa Program (Ongoing) Patient Segment: • Confirmed inherited Erythromyalgia mutation of • Moderate to Severe pain >4/10 post-herpetic neuralgia Nav1.7 Target Enrollment: • N = 4 • N=70 Randomization: • Randomized, double-blind, placebo-controlled, • Randomized, crossover, double-blind, placebo-controlled crossover, each participant randomized to receive placeboactive or activeplacebo Dosing: • Test: 400mg XEN-402 (XPF-001) BID capsule • 8% XEN-402 (XPF-002) application BID topical • No use of existing medication • Rescue: 3g/day acetaminophen Duration: • Treatment: 2 consecutive days • Baseline (1-4 wks) • Washout: 2 day • Treatment (4-12 wks) • Placebo: 2 consecutive days End-Points: • Change of intensity of inducible pain 2hrs post-pain • Change in mean pain score at 3wks induction

Sources: Goldberg Y.P., et al., Treatment of Nav1.7-mediated pain in inherited erythromyalgia using a novel sodium channel blocker. Pain (2012) 153:80-5 (NCT01090622) ; NCT01195636 41

Selective responsiveness of Trp channels to noxious stimuli has heralded a wave of Trp antagonists/agonists with good efficacy; Qutenza’s PHN approval has led the way for development of more selective Trp modulators.

Physiology • Predominantly expressed on sensory PNS neurons (C- and Ad-afferents) - Sensitive to cooling, touch, heat and cold - Ligand-gated calcium channels generate action potential leading to release of neuropeptides in spinal cord to propagate pain- signal - Ligand of TrpV1 is capsaicin, heat and protons Pathophysiology • Enhanced expression in disease state - Increased NGF can increase TrpV1 expression and decrease activation threshold by phosphorylation

Hypothesized • TrpV1 channel Mechanism - Ligand is capsaicin and over-exposure causes neuronal desensitization through inactivation of Na+ channels and temporary destruction of cytoskeleton and excitotoxicity leading to long- lasting effects • Other Trp antagonists - Selective receptor antagonists block Ca2+ influx to prevent action potential generation Pipeline Potential • Use of agonists can be associated with Considerations unpleasant transient side effects • Genetic variation may manifest in responders Phase III • Qutenza (Astellas/NeurogesX) and non-responders • Peripheral expression may reduce adverse • GRC-15300 (GSK) Phase II events • GRC-6211(GSK) • Civamide (Winston Pharmaceuticals)

Source: Raouf, R. et al., Pain as a channelopathy. J Clin Invest (2010) 120(11):3745-52 ; Marchand F., et al., Role of the immune system in chronic pain. Nat Rev Neurosci (2005) 6(7):521-32 42 Qutenza (NGX-4010), a topical capsaicin patch approved for PHN, is attempting to expand indications with little success to date; poor efficacy data in HIV patients with NP has limited the expansion opportunity.

Clinical Results (Phase III HIV-associated NP) Efficacy: • In a Phase III 494 patient study, 2-12 week change response for 60 min application of Qutenza vs control was (-32.8% vs - 30.% p=0.488) for 30 min application (-26.2% vs 19.1% p=0.103); improvements in QoL were significant - Primary endpoints not significant in contrast to earlier study of 307 patients; with significant changes vs control after 30 min application (27.7% vs 10.7% p=0.0007) Safety: • No significant safety or tolerability issues reported Lumleian • 2012 FDA Advisory Committee meeting voted against the use of Qutenza for HIV-NP Commentary: • Change in placebo use in PDN trial reflects potential efficacy associated with low-dose capsaicin

Phase III HIV-NP (Completed) Phase III (STEP) - DPN (Ongoing) Patient Segment: • Moderate to Severe NP (3-9/10 on NPRS) • Moderate to Severe NP (>4) Target Enrollment: • N = 494 • N=360 Randomization: • Randomized, double-blind, controlled study • Double-blind, randomized, placebo-controlled Dosing: • Induction: 30min or 60min QD application of low-dose • Induction: 30min QD application of placebo or 8% capsaicin control or 8% capsaicin patch patch • Use of existing analgesics permitted Duration: • Induction: 30 min or 60 min • Induction: 30min • Follow-up: to 12 weeks • Follow-up: to 12 weeks End-Points: • Primary: Mean percent change from baseline in weeks • Primary: Percent change of average daily pain score 2-12 through weeks 2-8 • Secondary: Patient global impression of change at week • Secondary: Percent change weeks 2-12, QoL improvement 12

Sources: Phase III HIV: Clifford, D.B., et al., A Randomized, Double-Blind, Controlled Study of NGX-4010, a Capsaicin 8% Dermal Patch, for the Treatment of Painful HIV-Associated Distal Sensory Polyneuropathy . JAIDS (2012) 59(2):126-33 (NCT00321672) ; NCT01533428 ; 43

GRC-15300 (aka SAR-292833), a first-in-class TrpV3 antagonist expressed on keratinocytes is activated at 86-104oF; may mediate initial response to warmth from skin to sensory neurons; antagonism represents alternative approach to Qutenza.

Clinical Results (Phase I) Efficacy: • Phase I results were well tolerated and good pharmacokinetic profile - Detailed information unavailable Safety: • No safety or tolerability report included Lumleian • Interest in this compound is high, TrpV3 is expressed on keratinocytes and preclinical results outperform existing SoC Commentary: drugs (ie. Lyrica,Neurontin) • Potential for equal or greater efficacy and safety than current SoC for peripheral NP conditions • Phase I data not available

Phase I - (Completed) Phase IIa - DPN, PHN (Ongoing) Patient Segment: • Healthy controls • Moderate to Severe NP >4 DN4 Target Enrollment: • N = N/A • N=198 Randomization: • Randomized, double-blind, controlled, safety study • Randomized, double-blind, placebo controlled

Dosing: • Induction: 6 single ascending doses • Arm 1: 20mg capsule after breakfast/dinner • Induction: 3 multiple ascending doses • Arm 2: 40mg capsule after breakfast/dinner • Arm 3: Placebo Duration: • Induction: N/A • Induction: 4 weeks • Follow-up: 3 weeks Primary End-Points: • Primary: Safety • Primary: change in average daily pain intensity, mean of last 7days • Secondary: Percent of patients with 30% or 50% pain reduction

Sources: DPN, PHN (NCT01463397 ) 44 Endogenous and exogenous cannabinoids target the PNS- and CNS-located CB1 receptor responsible for analgesic effects; inhibition of fatty-acid amide hydrolase, which degrades endocannabinoids (e.g. anandamide), is a closely related MOA under investigation.

Physiology • CB1 (Gq coupled receptor) is inhibitory and activation reduces Ca2+ release - FAAH catalyses the inactivation of anti- nociceptive anandamide (endocannabinoid) - Anandamide is endogenous ligand to CB1 receptor Pathophysiology • Elevation of endocannabinoids following inflammation and in some NP conditions • Enhanced expression in disease state: - CB1 receptors are increased - Represent adaptive mechanism Hypothesized • FAAH antagonists Mechanism - Blocking degradation of anandamide prolongs its action in the synapse and its availability to CB1 which reduces nociception • CB1 agonists - Selective receptor agonism prevents Ca2+ influx to prevent release of pro-nociceptive effectors Potential • Investigation in CB1and FAAH ligands for Considerations indications ranging from obesity, cancer, Pipeline gastrointestinal, immunological, and cardiovascular • In spite of this potential for off-target effects, • Cesamet (Valeant) Phase IV CNS available marketed analgesics have little Phase III • Sativex (GW Pharmaceuticals) to no side-effects in contrast to earlier studied Phase II peripherally restricted CB1 agonists1 Phase II • Marinol (Echo Pharmaceuticals) • Targeting endogenous inhibitory pathway advantageous when NP syndromes may not be associated with increased channel expression

Notes: 1AZD1940 (NCT00659490 & NCT00689780) and AZD1704 (NCT00692042 & NCT00736788) led to the discontinuation of the peripherally restricted CB1 agonist program at AstraZeneca (2009) due to lack of efficacy and significant side-effects in spite of peripheral restriction. Results taken from company website. Source: Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Disc.(2008) 7:438-55 ; Velasco G. et al., Towards the use of cannabinoids as antitumor agents. Nat Rev Cancer (2012) epub 45 Cesamet (synthetic, weak CB1 agonist) is currently available in US for chemotherapy-associated nausea and vomiting (as is Marinol); demonstrated comparable efficacy to Neurontin for peripheral Neuropathic Pain; paucity of efficacy information in other indications.

Clinical Results (Phase IV PDN) Efficacy: • A Phase IV study of patients receiving care for peripheral neuropathic pain, those receiving Cesamet for 3 & 6mths demonstrated improvement (19% and 39%) vs baseline comparable to those receiving Neurontin (17% and 33%) • Untreated controls demonstrated a 3% worsening at 3 and 6mth compared to baseline - Gabapentin was found to be equally effective in VAS reduction at both 3 and 6 months Safety: • No serious adverse events were noted, a trend towards greater tolerability was noted at 3 & 6mth with Cesamet users (53 and 67 adverse events respectively) compared with Neurontin users (79 and 90 adverse events respectively). Lumleian • Top-line results suggests efficacy at the highest dose and it appears to be well tolerated for NP patients Commentary: • Cesamet, approved for CINV (2006) demonstrated pain efficacy only in MS patients with spasticity-related pain (2005) • The lack of significant efficacy in historical studies suggests little opportunity in other indications

Phase IV - NP (Completed) Phase IV – MS adjuvant (Ongoing) Patient Segment: • Moderate to Severe NP (>4/10) • Moderate to Severe NP associated with MS >5/10

Target Enrollment: • N = 101 • N = 50 Randomization: • Prospective, non-randomized, non-blinded controlled, • Placebo-controlled, adjunctive agent with Neurontin, comparative examination randomized, double-blinded, parallel • Received monotherapy (Neurontin/Cesamet), nothing Dosing: • Induction: Titrated as needed on individual basis • Induction: Titrating doses • Use of existing analgesics permitted Duration: • Induction: As needed to maximal relief • Induction: As needed to maximal relief • Maintenance: To 6 months • Maintenance: 9 weeks • Follow-up: 1 week, 3 and 6 months End-Points: • Primary: Daily average VAS score 3 and 6 mths • Primary: Change in VAS score at 9 weeks • Secondary: QoL assessments • Secondary: QoL assessments

Sources: Bestard J.A. et al., An open-label comparison of Nabilone and Gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Practice (2011) 11(4):353-68 ; NCT00480181 (MS program) 46 Sativex, an active extract of cannabis, is awaiting FDA approval contingent on efficacy of SPRAY III Phase III study; safety profile is good based on EU data; recruitment completion expected 2013

Clinical Results (Phase IIb SPRAY) Efficacy: • In a Phase IIb study of 360 participants, primary endpoint of number of patients with >30% relief on NRS at 5 weeks compared to baseline for low, med and high dose groups was not significant compared to placebo (30,26,22 vs 24) - Secondary endpoint analysis demonstrated low-dose group demonstrated efficacy with respect to change in mean daily NRS pain score from baseline to 5wks compared to placebo (-1.5 vs -0.8; p=0.006) Safety: • Serious adverse events were noted in 31% (high dose), 21% (med dose), 38% low dose) and 25% placebo treated • Discontinuations were 31, 21, 20 in high, med, low groups respectively and 25 in placebo Lumleian • Top-line results suggests efficacy at lowest dose and is coincident with best side-effect profile Commentary: • This trial demonstrated consistently good safety results as well as positive results as adjuvant therapy to opioids in cancer-pain, could be an important addition to the add-on market due to safety/efficacy profile

Phase IIb (SPRAY) – Cancer pain (Completed) Phase III (SPRAY III) – Cancer pain (Ongoing) Patient Segment: • Moderate to Severe NP (>4/10), non-responsive to opioid • Moderate to Severe NP (>4/10), non-responsive to opioid treatment treatment Target Enrollment: • N = 360 • N = 380 Randomization: • Randomized, double-blind, placebo-controlled, parallel, • Randomized, double-blind, placebo-controlled, parallel graded-dose group • Adjuvant to existing inadequate opioid therapy • Adjunctive study with inadequate opioid therapy Dosing: • Dose 1: 1-4 spray/day (1 spray = 2.7mg THC/2.5mg CBD) • Dose: Max 10 spray/day • Dose 2: 6-10 spray/day • Dose 3: 11-16 spray/day Duration: • Titration: 1 week • Titration: 1 week • Treatment: 4 week • Treatment: 4 week • Follow-up: 2 weeks post-study Primary End-Points: • Primary: Daily average VAS score throughout • Primary: Change in VAS score at 5 weeks • Secondary: QoL assessments • Secondary: QoL assessments

Sources: Phase IIb Cancer Pain NCT00530764 ; Phase III Cancer Pain Ongoing NCT01361607 47 Blockade of SNARE and SV2 proteins has demonstrated some success in neuropathic pain by inhibiting neurotransmitter release; both Botox and Keppra are attempting to expand from current, non-pain indications.

Physioogy • SNARE and SV2 required for process of presynaptic membrane fusion of exocytotic vesicles - Release of excitatory/pronociceptive neurotransmitters: Ach, sP, CGRP, glutamate • CNS and PNS effects Pathophysiology • Alterations in membrane excitability and increase in intracellular Ca2+ enhance neurotransmitter release in part by vesicular exocytosis - Enhanced vesicular trafficking to presynaptic membrane propagates painful signal Hypothesized • Botox and Keppra are inhibitory of Mechanism neurotransmitter release by blockade of vesicular SNARE and SV2 proteins - Inhibits stimulated release of nociceptive peptides (e.g., sP and CGRP) - Inhibits release of excitatory neuropeptides (e.g., glutamate and Ach) • Botox has local action by site of administration by injection whereas Keppra is orally available Pipeline Potential • Botox has demonstrated efficacy for defined Considerations regions of pain (e.g. low-back pain, postherpetic neuralgia, trigeminal neuralgia) Phase IV • Botox (Allergan) • Keppra has demonstrated limited success in • Keppra (UCB) Neuropathic Pain syndromes

Source: Foster K.A. The analgesic potential of clostridial neurotoxin derivatives. Expert Opin. Investig. Drugs. (2004) 13(11):1437-43 ; Keppra FDA product label ; Lynch, B.A., et al., The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracepam. PNAS (2004) 101(26):9861-6 48 Botox (Botulinum toxin) is being evaluated for efficacy in other Neuropathic Pain syndromes; treatment guidelines rank it as having good efficacy in some reports for Trigeminal Neuralgia.

Clinical Results (Phase IV Post-Stroke Shoulder Pain) Efficacy: • In a double blind, placebo-controlled study of 21 patients primary outcome measure of mean change in pain rating from baseline did not differ vs. placebo (-18.64 vs 19.88) at 4wks - Other outcome measures were not measured for statistical significance

Safety: • Serious adverse events were reported in 36% of saline injected participants vs 10% of active treatment Lumleian • Lack of efficacy in this indication is in contrast to other studies conducted by academic institutions demonstrating Commentary: efficacy in trigeminal neuralgia1 • Good safety results could indicate this as a second or third-line treatment for some localized Neuropathic Pain conditions however consensus is mixed2

Phase IV – Post-stroke shoulder pain Phase III – Chronic pelvic pain (Ongoing) (Completed) Patient Segment: • Moderate to Severe pain associated following stroke • Moderate to Severe NP (>2/10) associated with any affecting shoulder (>4/10) neuropathic pain syndrome generating tactile allodynia Target Enrollment: • N = 21 • N = 60 Randomization: • Randomized, double-blind, placebo-controlled • Randomized, double-blind, placebo-controlled, parallel • At 12 weeks, blind broken and placebo-controls receive design active treatment Dosing: • Injection into the pectoralis major: single 100U-200U, • Intrasphinscteric injection: 200U/4ml • Existing medication regimen unchanged Duration: • Treatment: 1 day • Treatment: 1 day • Follow-up: 2, 4 and 12weeks • Follow-up: up to 1 year post-injection End-Points: • Primary: Change in VAS score at 4 weeks • Primary: NIH-CPSI • Secondary: QoL assessments • Secondary: NIH-CPSI subscales

Sources: 1PMID20674409 & PMID1606209 ; 2Dworkin, R.H. et al., Recommendation for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. (2010) 85(3):S3-S14 ; Post-stroke Pain – NCT00661089 ; Chronic pelvic pain - NCT00464373 49 Keppra (levetiracetam) is currently approved by the FDA for seizures associated with epilepsy, however limited evidence supports efficacy in Neuropathic Pain indications; available data are with low numbers and mixed results.

Clinical Results (Phase III and IV) Efficacy: • In a Phase III study in patients with painful polyneuropathies, no significant differences in primary endpoint of pain relief was observed compared to placebo (2.29 vs 2.28; p=0.979) or total pain intensity (5.5 vs 5.3; p=0.293) • The open-label assessment in Trigeminal Neuralgia demonstrated significant reduction in number of painful attacks per day compared to baseline (3.3 vs 9.9; p<0.001) Safety: • Safety was not generated from the polyneuropathy study; TN saw 21.7% experience AE and 8.7% withdrew due to AE Lumleian • Keppra is not commonly recommended off-label for Neuropathic Pain indications as a result of mixed efficacy Commentary: • Evidence from the TN study suggests safety profile may be consistent with Tegretol (i.e. dose limiting side-effects such as dizziness)

Phase IV – Polyneuropathy (Completed) Phase IV –Trigeminal Neuralgia (Completed) Patient Segment: • Moderate to severe pain (>4/10) associated with • Moderate to Severe NP associated with trigeminal polyneuropathy for <6mth neuralgia, refractory to current medication Target Enrollment: • N = 40 • N = 25 Randomization: • Randomized, double-blind, placebo-controlled, cross- • Open-label pilot study over • Continuation of current treatments allowed Dosing: • Starting dose: 500mg • Starting dose: 1000mg/day • Maintenance: 3000mg/day • Titrating: 2000-4000mg/day • Maintenance: up to 4000mg/day Duration: • Maintenance: 6 weeks • Titration: 2 weeks • Maintenance: 12 weeks End-Points: • Primary: Pain relief on NRS median value for last • Primary: Change in mean number of painful attacks per day treatment week in each period • Secondary: QoL assessments, VAS pain rating, days with any • Secondary: Pain relief on NRS, brush, cold, pin-prick, attacks per week QoL

Sources: Polyneuropathy – NCT00286260, Holbech, J.V., et al., The anticonvulsant levetiracetam for the treatment of pain in polyneuropathy: a randomized placebo-controlled, cross-over trial. Eur J Pain. (2011) 15(6):608-14 ; Trigeminal Neuropathy – Mitsikostas D.D., et al., An observational trial to investigate the efficacy and tolerability of levetiracetam in trigeminal neuralgia. Headache (2010) 50(8):1371-7 50 NGF antagonists have been touted as the first new class of pain therapeutics; clinical hold in 2010 for osteonecrosis; March 2012 FDA AdCom recommended trials to resume for OA and other unmet pain indications; FDA decision anticipated 2012; trials ongoing for cancer-related pain.

Physiology • Endogenous receptor is TrkA and p75 - Receptor expressed on immune cells resulting in positive feedback • NGF released by mast cells, keratinocytes, macrophages in response to inflammation and injury - Necessary for proper nerve regeneration following axonal injury Pathophysiology • Enhanced NGF levels increases pro-nociceptive signaling • NGF significantly increased in tissue in some NP and chronic inflammatory pain • Promotes sympathetic and sensory sprouting in some NP indications including cancer-related pain • Induces phenotypic changes in nociceptive fibers - Increases TrpV1 protein and decreases threshold of activation resulting in decreased action potential threshold Pipeline Hypothesized • Sequestering NGF prevents nociceptor Mechanism sensitization • Reduces pathological positive feedback between peripheral immune cells and neurons Phase II • Tanezumab(Pfizer) • Fulranumab(J&JPRDLLC) Potential • Decreased NGF expression associated with • ABT-110(Abbott) Considerations cognitive impairment • CT-327(Creabilis) • NGF levels vary for NP conditions and could significantly affect efficacy across disease state

Source: FDA March 12 2012 AdCom meeting minutes; Scholz J, Woolf, C.J., The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci (2007). 10(11):1361-8 ; Patapoutian, A., et al., Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Disc (2009) 8:55-68 51 Tanezumab on clinical hold in 2010 for osteonecrosis in OA trials; 03/2012 FDA advisory committee recommended to resume due to significant unmet need and potential benefit; risk mitigation to be addressed; NGF clinical program development awaiting FDA recommendation.

Clinical Results (Phase II Chronic low back pain) Efficacy: • In a Phase II study of chronic low back pain without radiculopathy, primary endpoint was statistically significant between treatment and naproxen (-3.37 vs -2.54; p=0.004) and treatment and placebo (-3.37 vs -1.96; p<0.001). - Analgesic effect noted at 1wk and maintained through 12wks compared to placebo only

Safety: • Most common TAE was arthralgia (15%) and headache (10%) Lumleian • Results suggested good efficacy and most common side-effects tolerable, pre-clinical results using Tanezumab in bone- Commentary: cancer models are very positive and positive results are expected from upcoming Phase II trial • Long term safety considerations important, for example potential joint overloading on other disease states such as low- back pain should also be considered in light of theories explaining rapidly progressing OA as well as BBB permeability associated with NP for potential CNS effects

Phase II – Chronic low back pain (Completed) Phase II – Cancer Pain (Ongoing) Patient Segment: • Moderate to Severe pain (>4/10) associated with • Moderate to Severe pain associated with prostate, breast chronic non-radiculopathic low back pain cancer, renal cell carcinoma that has spread to bone Target Enrollment: • N = 220 • N = 58 Randomization: • Randomized, double-blind, placebo and active • Open-label controlled • Extension study from Trial A4091003 • completed results not available Dosing: • Single i.v. 200mg/kg tanezumab with oral placebo • Intravenous: 1x10mg injection every 8wks • Single i.v. placebo with 500mg BID naproxen • Single i.v. placebo with oral placebo Duration: • Treatment: 12 weeks • Treatment: 9 months End-Points: • Primary: Change in aLBPI score from baseline to week 6 • Primary: Clinical lab tests, electrocardiograms, AE • Secondary: QoL , other pain inventory questionaires • Secondary: Brief Pain Inventory

Sources: Chronic low-back pain – NCT00584870 ; Katz, N., et al., Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain (2011) 152(10):2248-58 ; Cancer pain – NCT00830160 (Open label extension from trial NCT00545129) 52 Fulranumab (JNJ-42160443), the humanized anti-NGF from JNJ, demonstrated lack of efficacy in low-back pain in contrast to positive results generated from osteoarthritis trials and positive results from Tanezumab.

Clinical Results (Phase II Low Back Pain) Efficacy: • In a Phase II study of low back pain was terminated early due to lack of efficacy; did not attain significance in primary endpoint measurements from baseline to week 12 in any doses studies (p=0.65) nor were significant results obtained for secondary endpoints • OA study demonstrated significant results (at least p<0.05) for all pain outcome measures compared to placebo Safety: • Generally well tolerated, most common AE were diarrhea (7%) and headache (7%) Lumleian • Results suggested poor efficacy in low-back pain indication, common side-effects tolerable, an alternative patient Commentary: population may demonstrate efficacy • Treatment of LBP without radiculopathy by Tanezumab was efficacious however Fulranumab was not

Phase II – Low back pain (Terminated) Phase II – Cancer Pain (Ongoing) Patient Segment: • Moderate to Severe low back pain inadequately • Moderate to Severe NP (>4/10) in terminally ill patients controlled with current pain therapy with active cancer Target Enrollment: • N = 360 • N = 90 Randomization: • Randomized, parallel design, double-blind, placebo- • Randomized, double-blind, placebo-controlled, controlled, single ascending dose adjunctive therapy Dosing: • Single 1mg, 3mg, 3mg after 6mg loading dose, 10mg • Single 10mg/injection • Subcutaneous injection: Day 1, Day 28, Day 56, Day 84 • Subcutaneous injection: every 4wk to 48wks • Current analgesic regimen maintained Duration: • Treatment: 12 weeks • Treatment: 4wks • Extension: 92 weeks • Open-label extension: 48wks • Follow-up: 26 weeks after last dose • Follow-up: 10wks after last dose Primary End-Points: • Primary: Change in VAS score from baseline at 12wk • Primary: Change in VAS from baseline at 4week • Secondary: QoL assessment • Secondary: Patient global impression of change

Sources: 2011 APS meeting abstracts for OA and cLBP. LBP NCT00973024. Cancer pain NCT00929188 53 Opioid receptors are found to inhibit pre- and post-synaptic propagation of pain-stimuli to the brain; current efforts focus on improving formulation of existing opioid-based therapeutics to increase efficacy while reducing side-effect profile and abuse potential.

Physiology • Three classes of opioid receptors: mu-, delta- and kappa - Inhibitory GPCR such that agonist exerts inhibitory activity on nociceptive afferents - Endogenous ligand dynorphin, enkephalin, endorphin, endomorphin - Found throughout CNS and digestive tract Pathophysiology • MOR constitutively available on membrane surface - Chronic pain associated with increase trafficking of DOR to cell surface - DOR agonism not associated with as many side- effects as MOR Hypothesized • Opioid receptor agonists prevent release of Mechanism intracellular calcium stores and inhibit neurotransmitter release Potential • Opioids have proven largely ineffective in Considerations treating chronic neuropathic pain although Pipeline effective in acute (breakthrough) and some types of chronic pain • Side-effect profile include tolerance, Phase III • KP-201 (KemPharm) drowsiness, respiratory depression, constipation and abuse Phase II • NP-2 (Diamyd Medical) • Recommended only for patients not responding • GRT-6005 (Forest Laboratories) to traditional first-line therapeutics

Source: Lambert, D.G. The nociceptin/orphanin FQ receptor: atarget with broad therapeutic potential. Nat Rev Drug Disc. (2008) 7:694-710 ; www.change-pain.fi ; Dworkin, R.H., et al., Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc (2010) 85(3):S3-S14 54 NP-2 is a novel gene-therapy therapeutic that promotes expression of preproenkephalin, an endogenous opioid; novel approach allows for specific sensory ganglia to be targeted via their patented Nerve Targeting Drug Delivery System theoretically preventing off-target effects.

Clinical Results (Phase I & II Cancer Pain) Efficacy: • In a 10 person Phase I trial, the secondary outcomes of NRS were reported from 8 participants; change in pain scores compared to baseline using SF-MPQ at 28d post-dosing for 107, 108, 109 pfu ( +1, -20, -24) respectively • Initial results from Phase II study have demonstrated no significant results at day 3-14 following single dose of drug compared to placebo Safety: • No treatment-related SAE were reported during the 4 month follow-up period Lumleian • Top-line results suggests efficacy at the highest dose and it appears to be well tolerated Commentary: • FDA has not yet approved any gene therapy product, including those for pain indications however, a large number of research programs are ongoing in the area of gene-therapy • Continuation of open-label extension however, other indications may be pursued

Phase I Program (Completed) Phase II Program (Ongoing) Patient Segment: • Moderate to Severe pain associated with end-stage • Moderate to Severe pain primary or metastatic cancer (>4/10 on VAS) Target Enrollment: • N = 10 • N = 32 Randomization: • Open-label, single ascending dose • Randomized, parallel assignment, double-blind, placebo- controlled Dosing: • Induction: 10 individual intradermal injections 100ml • Induction: single 1ml dose intradermally injected each of either 107 108 or 109 pfu • Opiate analgesic use maintained • Opiate analgesic use maintained Duration: • Induction: 1 day • Induction: 1day • Maintenance: 4 weeks • Maintenance: 1, 2, 4 weeks • Follow-up: 4 months • Follow-up: 4 mths End-Points: • Primary: Safety measurements • Primary: Change from baseline of NRS score • Secondary: Efficacy in reducing cancer related pain • Secondary: Change in opioid pain medication use and QoL (NRS, SF-MPQ, SF12)

Sources: Phase 1 - NCT00804076, Fink D.J., et al., Gene therapy for pain: results of a phase I clinical trial. Ann Neurol (2011) 70:207-12 ; Phase II - NCT01291901 and company press release (3 July, 2012) 55 P2X3 is a ligand-gated ion channel found selectively on nociceptive afferents located in the viscera and skin.

Physiology • P2X3 is ligand gated-ion channel found selectively on nociceptive afferents - P2X3 positive afferents found in high density in epidermis and bladder - Endogenous ligand is ATP - Activation generates action potential Pathophysiology • Certain NP conditions associated with upregulation in DRG - Lowers threshold for activation Hypothesized • Selective blockade of P2X3 channels should Mechanism decrease action potential generation and further release of neurotransmitters in spinal cord - Arrests generation of C-fiber specific nociceptive signaling Potential • Compounds generated in non-human primates Considerations display significantly less efficacy than in rat - Potential consideration for drug-development strategy and efficacy studies • P2X3 expressing afferents not found in rat joint Pipeline - Potential consideration for efficacy in arthritis • Phase I trials were completed under Roche; Afferent Pharmaceuticals later in-licensed the compound and is currently in Phase II trials for osteoarthritis and interstitial cystitis pain Phase II • AF-219 (Afferent Pharmaceuticals) • AZ and ABT have discontinued research programs investigating P2X3

Source: ICC-NCT01569438 ; Afferent Pharma press release ; SFN 2009 abstract, AZ and ABT company information 56 Antidepressants such as TCA and SNRIs were accidentally discovered to have analgesic properties; is thought actions on NE reuptake inhibition is key in Neuropathic Pain treatment; SNRIs are the predominant class of antidepressants in clinical trials for Neuropathic Pain indications.

Physiology • Negatively regulates ascending nociceptive pathway - Noradrenaline and serotonin released by vesicles into the synapse and can be transported back into presynaptic neuron by re-uptake transporters - Serotonin and noradrenalin are endogenous ligands to 5-HT and a-adrenergic receptors Pathophysiology • It has been suggested that in NP syndromes there is a dysregulation or dysfunction in the descending nociceptive modulation • FM patients have lower levels of norepinephrine and dopamine in CSF Hypothesized • Theorized mechanisms involved enhancement Mechanism of descending modulation of ascending spinal input to brain • SNRI: Potentiates serotonin and noradrenaline by blocking presynaptic reuptake transporters should stimulate inhibitory control and Pipeline enhance existing pain-suppressing mechanisms • TCA: demonstrate serotonin and NE reuptake inhibition as well as others (ie. H1, muscarinic, Phase IV • Savella (Forest Laboratories) a1-AR, D2, 5-HT) • Also addresses depression, a common co- Phase III • Cymbalta (Eli Lilly) morbidity of NP Potential • Antidepressants with NE potentiation Considerations properties should be evaluated for efficacy in NP disorders

Source: www.cnsforum.com ; Dworkin, R.H., et al., Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc (2010) 85(3):S3-S14 ; Watson, CPN., et al., Nontricyclic antidepressants and pain: are serotonin norepinephrine reuptake inhibitors (SNRIs) any better? Pain (2011) 152(10):2206-10 57 Savella (milnacipran) is an SNRI recently approved for treatment of fibromyalgia; trials ongoing for other Neuropathic Pain disorders such as Neuropathic Pain of Idiopathic Origin and Vulvodynia; paucity of information on combination therapy between 1st line medications.

Clinical Results (Phase III Adjuvant Trial) Efficacy: • In a Phase III open label program, the primary endpoint of PGIC responder rate following addition of Savella to Lyrica treatment with incomplete responsiveness resulted in statistically significant change compared to those that did not receive Savella add-on therapy (83 vs 36 respectively; p<0.001) - Secondary endpoint analysis of VAS change from baseline scores compared to no treatment added (-20.77 vs -6.43; p<0.05) Safety: • SAE were reported in 3% of Lyrica alone patients vs. 2.72% of those receiving Savella as add-on therapy Lumleian • Top-line results suggests efficacy at the highest dose and it appears to be well tolerated Commentary: • Consistent with current SoC, combination therapy for monotherapy for incomplete responders suggest that the addition of an SNRI to current Lyrica treatment is efficacious • No mention as to whether Lyrica dosing was reduced prior to Savella initiation

Phase III Program Adjuvant (Completed) Phase IV Program Idiopathic NP (Ongoing) Patient Segment: • Fibromyalgia with incomplete response to Lyrica • Peripheral neuropathy, pain >6mths Target Enrollment: • N = 364 • N = 52 Randomization: • Randomized, parallel, open label 1:1 • Randomized, parallel, double blind, placebo-controlled

Dosing: • Induction: Titrated to 100mg QD or no treatment • Titration: Day 1, 12.5mg QD Day 2-3,12.5mg BID Day 4-7, • Maintenance: 100mg QD or no treatment 25mg BID to 50mg BID • Concurrent medication: >300mg QD Lyrica • Maintenance: 100mg QD Duration: • Induction: 1 weeks • Induction: 1 week • Maintenance: 10 weeks • Maintenance: 8 weeks End-Points: • Primary: PGIC responder rate • Primary: Change in Likert scale from baseline to week 9 • Secondary: Change from baseline VAS • Secondary: QoL assessment

Sources: Phasae III Adjuvant therapy: NCT00797797 & 2011 American College of Rheumatology Poster Abstract Phase IV Idiopathic NP: NCT01288937 58 Cymbalta is attempting to broaden its Neuropathic Pain indications from fibromyalgia, chronic musculoskeletal pain, diabetic peripheral neuropathy, generalized anxiety disorder and major depressive disorder to include Multiple Sclerosis.

Clinical Results DPN and MS Efficacy: • Phase IV non-inferiority comparison of Cymbalta to Lyrica in PDN sub-optimally treated with neurontin, the primary endpoint was met - no difference found between the use of Lyrica or Cymbalta as add-on therapy (-2.6 and -2.1; p=0.08) • In a Phase III placebo-controlled program treating MS patients with Cymbalta, the primary endpoint of change in avg pain score at 6wks compared to baseline was significantly different vs placebo (-1.83 vs -1.07; p<0.001) Safety: • SAE were observed in 4.5% of Lyrica, 2.2% Cymbalta and 3.7% Neurontin+Cymbalta treated patients • Weight change for those receiving Lyrica alone +1kg vs -2.4kg taking Cymbalta alone and -1.1kg in the Neurontin+Cymbalta group (p<0.001 for both) Lumleian • Demonstrated non-inferiority of Cymbalta compared with Lyrica combined with Neurontin, however the important safety Commentary: consideration of weight gain in diabetic patients was favorable for Cymbalta treatment • Treatment of MS patients experiencing NP demonstrated efficacy in this patient group

Phase IV Program DPN (Completed) Phase III Program MS Pain (Completed) Patient Segment: • Moderate to Severe NP (>4/10) associated with DPN and • Moderate to Severe central NP due to MS (>4/10) continue inadequate response to Neurontin existing medication regimine Target Enrollment: • N = 407 • N = 239 Randomization: • Randomized, open-label, parallel assignment currently • Prospective, randomized, double-blind, placebo-controlled, treated with >900mg QD NRN parallel Dosing: • Arm 1:LYR – 300mg QD mono • Titration: 30mg QD to 60mg QD • Arm 2: CYM – 60mg QD mono • Maintenance: 60mg QD • Arm 3: NRN + CYM - 900mg QD + 60mg QD combo • Open label: 60mg, 90mg, 120mg QD as needed Duration: • Induction: 2 weeks (LYR) 1 week (CYM, CYM+NRN) • Induction: 1 week • Maintenance: 10 weeks (LYR) 11 weeks (CYM, CYM + • Treatment: 6 weeks NRN) • Open label: 12 weeks Primary End- • Primary: Mean change from baseline VAS to 12wks • Primary: Average pain score at 6weeks vs baseline Points: • Secondary: QoL assessments • Secondary: QoL assessments Sources: DPN – Tanenberg, R.J., et al., Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison. Mayo Clin Proc (2011) 86(7):615-26, NCT00385671 ; MS - NCT00755807 59 Blockade of chemokine activity such as TNFa sequestration has demonstrated efficacy in painful chronic inflammatory conditions; investigations into efficacy of existing therapeutics in Neuropathic Pain disorders are ongoing as well as investigations into new chemokine targets.

Physiology • TNFa is one of the first pro-inflammatory cytokine released upon tissue damage and inflammation from peripheral immune cells - E.g. Schwann cells, keratinocytes, macrophages, neutrophils, mast cells • Induces upregulation of other pro-inflammatory and pro-nociceptive agents (eg. NGF) • Important in initiating responses to tissue injury in acute or physiological pain Pathophysiology • Exemplifies the link between the immune and nervous system in genesis and maintenance of NP • Nerve biopsies from NP patients show increased TNFa levels • Injection of TNFa in rats reproduces pain hypersensitivity and reversed by sequestering antibodies • Enhances current from Nav 1.8 channels • In NP, microglia are activated and secrete Pipeline TNFa contributing to central sensitization Hypothesized • Efficacy across indications are varied, raises • Enbrel (Other medical center) Phase III questions about mechanism of action • Humira (Abbott) Mechanism • Binds soluble and membrane bound RNFa Phase II • AZD-2423 (AstraZeneca) - Competitive inhibitor, halts inappropriate persistent immune response

Potential • There are no open trials for AZD-2423 and one Considerations open trial for Humira for Interstitial Cystitis

Source: Pain as a channelopathy Ramin Raouf, Kathryn Quick, John N. Wood Published in Volume 120, Issue 11 J Clin Invest. 2010; 120(11):3745– 3752 60 Clinical investigations using Enbrel to determine efficacy in Low Back Pain patients with radiculopathy were conducted purely by academic groups; results compared to those obtained by Humira in same indication highlight varying efficacies against same target.

Clinical Results (Phase II Sciatica compared to steroid injection or saline) Efficacy: • In a Phase II 84 person study, those receiving the steroid injections reported greater improvement compared to Enbrel for functional capacity (-16.16 p=0.002) and no difference between steroids and etanercept in terms of pain improvement were noted compared to saline • In the Phase II 24 person study comparing Enbrel to saline, there was no significant improvements at 1mth of leg pain compared to placebo (p=0.15), improvement in pooled Enbrel patients was significant compared to placebo (p=0.01) Safety: • No significant safety or tolerability issues reported Lumleian • Enbrel efficacy in low back pain associated with radiculopathy may or may not demonstrate efficacy, both studies Commentary: were conducted with small numbers which may not yield significance • Compliance may not be best if only route of administration in intrathecal or epidural

Phase II Program LBP (Completed) Phase II Program LBP (Completed) Patient Segment: • Moderate to Severe low back pain associated with • Moderate to Severe low back pain associated with radiculopathy radiculopathy Target Enrollment: • N = 84 • N = 24 Randomization: • Randomized, placebo-controlled, parallel-group • Randomized, double-blind, placebo-controlled, single 1:1:1 drug assignment, double-blind ascending-dose study Dosing: • Induction: Single injections in affected spinal regions • Induction: 2, 4, or 6mg epidural injections 2wks apart of 30mg steroid, 2mg etanercept, saline • Existing medication unchanged • Maintenance: Injections repeated 2wks later • Rescue medication: NSAID or tramadol • Existing medication unchanged Duration: • Follow-up visits: 1day post-injection and 1,3&6 mths • Follow-up visits: 1 month post-injection Primary End-Points: • Primary: Change in VAS at 1mth • Primary: Change in VAS at 1mth • Secondary: Reduction in analgesic medications and • Secondary: Reduction in analgesic medication and QoL QoL assessment assessment

Sources: Sciatica with steroids – NCT0073396 Sciatica without steroids - NCT00364572 61 Humira administration to Sciatica patients in this Phase II study demonstrated efficacy by an academic group; ongoing clinical trials by Abbott include Interstitial Cystitis.

Clinical Results (Phase II Crohn’s Disease) Efficacy: • In a Phase II 61 person study demonstrated statistically significant improvement in Humira injected group than placebo for back pain (p<0.001) • There were fewer surgical discectomies in treatment group compared to saline (6 vs 13; p=0.04) - Less than half of participants in treatment group were considered responders (ie. >30% improvement of VAS score for leg/back pain). Safety: • No significant safety or tolerability issues reported Lumleian • Improvement in pain scales are modest, these results are in line with those obtained from Enbrel injections Commentary: demonstrating that TNFa sequestration may not be most efficacious in low-back pain treatment with radiculopathy • Trials with interstitial cystitis may demonstrate efficacy due to increase mast cell infiltration in bladder

Phase II Program Sciatica (Completed) Phase III Program Interstitial Cystitis (Ongoing) Patient Segment: • Moderate to Severe leg pain • Moderate to Severe IC and pain for >6mths Target Enrollment: • N = 61 • N = 40 Randomization: • Randomized, double-blind, parallel design • Randomized, parallel design, double-blind, placebo- controlled Dosing: • Induction: 2 subcutaneous 40mg injections • Induction: 80mg subcutaneously • Maintenance: 40mg every two weeks Duration: • Induction: Day 0 and Day 7 • Maintenance: 6 x 2 weeks dosing • Follow-up: 6mths • Follow-up: 21 weeks Primary End-Points: • Primary: Evolution of leg pain (VAS) • Primary: Improvement of interstitial cystitis symptom index • Secondary: Percentage of amelioration of VAS score • Secondary: QoL

Sources: Sciatica – NCT00470509 ; ICC – NCT01295814 62 Market of calcium channel blockade is dominated by gabapentinoids (e.g. Lyrica and Neurontin) whose mechanism of action is largely unknown; current development target voltage gated N- and T-type (aka Cav 2.2 and 3.2) respectively.

Physiology • Channel opens in response to change in voltage across the membrane. • Channel opening trigger release of pro- nociceptive neuropeptides and neurotransmitters in the periphery (eg. CGRP and glutamate) or synaptic vesicle release and activation of ascending sensory pathway • Regulate neuronal excitability by contributing to initiation of action potential train Pathophysiology • Can modulate propagation and processing of pain signal by: - Channel density may be increased resulting in increased current density in NP conditions - Splice mutations may predispose certain individuals to developing NP - Can lower threshold for action potential generation Hypothesized • Exact MOA of pregabalin/gabapentin is Mechanism unknown Pipeline - Binding by ligands may stabilize membrane and decrease hyperexcitability • Blockade by traditional antagonists of Cav 2.2/3.2 may reduce sensory afferent Phase IV • Lyrica (Pfizer) hyperactivity Phase III • Sensodyne (SantoSolve Pharma) Potential • Key targets for pharmaceutical development is Considerations N- and T-type calcium channels (aka Cav 2.2 & Phase II • ABT-639 (Abbott) 3.2) due to restricted expression on • DS-5565 (Daiichi Sankyo) nociceptive afferents

Source: Voglis G., Tavernarakis N. The role of synaptic ion channels in synaptic plasticity. EMBO reports (2006) 7:1104-10 ; Pexton T., et al., Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development. Expert Opin Investig Drugs (2011) 20(9):1277-84 63 Lyrica (pregabalin) recently terminated Phase III trials in HIV-associated painful neuropathy announced due to negative interim results.

Clinical Results (Phase III HIV-Associated Painful Neuropathy) Efficacy: • In a Phase III trial, primary endpoint analysis demonstrated placebo and pregabalin showed substantial changes from baseline, however this difference was not significant between groups (-2.88 vs -2.63; p=0.39). However, at 1, 2, 7 and 8 weeks, significant differences were observed between groups.

Safety: • Safety data was not entered for this study Lumleian • Results were insufficient to declare Lyrica more effective than placebo Commentary: • Other NP studies with HIV associated NP demonstrated differential efficacy associated with neurotoxic antiretrovirals, these trials did not segment their patients according to this criteria • In spite of these results, Lyrica status as a front-line therapy for the treatment of Neuropathic Pain will remain unchanged

Phase III HIV-Associated NP (Completed) Phase III HIV-Associated NP (Terminated) Patient Segment: • Moderate to Severe Pain Associated with HIV • Moderate to Severe Pain Associated with HIV starting in feet Target Enrollment: • N = 302 • N =391 Randomization: • Randomized, double-blind, placebo-controlled, • Randomized, parallel-group, double-blind parallel-group Dosing: • Induction: 75-150mg/day BID • Induction: 75-300mg BID • Maintenance: Optimal dose • Maintenance: Optimal dose • Existing medication maintained • Existing medication maintained Duration: • Induction: 2 week dose-adjustment • Induction: N/A • Maintenance: 12 week • Maintenance: ~19 week • Extension: Optional 3 month open-label Primary End-Points: • Primary: Mean NPRS score • Primary: Mean average NPRS score • Secondary: Patient global impression of change • Secondary: Patient global impression of change

Sources: HIV-NP – NCT00232141 open label extension NCT00264875 ; Terminated trial – NCT01049217 64 A mixed antagonist/agonist approach has demonstrated efficacy in treating a multi-faceted disorder such as Neuropathic Pain; development of combination therapies may also permit decreased dosing of individual compounds reducing side-effects.

Physiology • Ion channels opening involved in final release of excitatory neurotransmitters, action potential propagation and activation of ascending pain-pathways • Propagation of pain signal involves multiple pain-sensing receptors, ion channels, cell types and neurological systems Pathophysiology • Lack of inhibitory control, reduced activation threshold of excitatory ion channels or maladaptive response to normally non-painful stimuli by the central nervous system contribute to the onset and maintenance of neuropathic pain Hypothesized • Mixed action of combination therapeutics act Mechanism synergistically at multiple targets - E.g., able to block excitatory ion channels and stimulate or enhance descending inhibitory Pipeline control - Mixed target (or dirty) drugs have beneficial effects of being able to hit multiple targets, all of which may be involved in the multifaceted • Seroquel (AstraZeneca) Phase IV disorder of Neuropathic Pain Phase III • CNSB015(Relevare) Potential • Targets include: • Nucynta (Grunenthal) Considerations - Opioid receptors (inhibitory) • Nuedexta (Avanir) - Glutamate receptors (excitatory) • Xyrem (Jazz Pharmaceuticals) - Dopamine (inhibitory) Phase II • Flupirtine (Meda) • Amiket (EpiCept)

Source: Voglis G, Tavernarakis N., The role of synaptic ion channels in synaptic plasticity, EMBO reports (2006) 7:1104-10 65 AmiKet (amitriptyline 4% + ketamine 2%; NP-1) Phase II NP program positive; ketamine efficacy is due to distribution on peripheral sensory afferents; formulation and combination may be key in efficacy; Phase III trials ongoing for CIPN under fast-track status for significant unmet medical need.

Clinical Results (Phase II Chemotherapy Induced Painful Neuropathy) Efficacy: • In a Phase IIb 461 person study primary endpoint in patients on taxane-based therapeutics was change in average daily pain scores from 6wks post-treatment compared to baseline between AmiKet and placebo (p<0.001) - Average daily pain intensity scores reduced in patients receiving taxane-chemotherapy compared to placebo (p=0.034)

Safety: • Safety data was comparable to that obtained with placebo Lumleian • FDA approval for Fast Track status is significant for this treatment population, this is one of very few therapeutics Commentary: seeking approval for CIPN indication • Historical results have been disappointing for ketamine efficacy as pain therapeutic, however this combination of amitriptyline with ketamine could prove highly efficacious

Phase IIb Program CIPN (Completed) Phase III Program CIPN (Planned) Patient Segment: • Moderate to Severe Pain (>4/10) associated with • Moderate to Severe Pain Associated with Cancer therapy taxane chemotherapy beginning with hands or feet Target Enrollment: • N = 461 • N = 800 Randomization: • Double-blind, placebo-controlled, parallel design, • Double-blind, placebo-controlled, randomized sub-grouped according to chemotherapy type Dosing: • Application: AmiKet BID to areas of pain • AmiKet, amitriptyline, ketamine, placebo • Maintain current medication regimen Duration: • Induction/Maintenance: 6 weeks • Induction/Maintenance: 12weeks Primary End-Points: • Primary: Change in average daily pain score at 6wks • Primary: Change in average daily pain score compared to baseline • Secondary: Number of responders with >30% pain improvement and >50% pain improvement, QoL assessments

Sources: CIPN Phase Iib – NCT00471445 ; EpiCept news release (Feb 7, 2011 & 66 Nucynta approved for moderate to severe acute pain; Phase III data demonstrate efficacy in Diabetic Peripheral Neuropathy; leading competitor, Tramadol, is available as a generic and a head- to-head study demonstrated efficacy and safety has yet to be done.

Clinical Results (Phase II Chemotherapy Induced Painful Neuropathy) Efficacy: • In a Phase III 358 study demonstrated that those responding to Nucynta (reduction to 3.6/10 from baseline 7.3/10) maintained efficacy during double-blind randomization phase compared to placebo 3.9/10 vs 4.9/10; p<0.001) • The earlier Phase III 395 study demonstrated a reduction from ~7/10 to 3.5 and those that responded maintained efficacy through 12wks (-0.1 vs 1.3; p<0.001) Safety: • No significant safety or tolerability issues reported Lumleian • 23 withdrawals due to AE in the treatment group vs 13 in placebo, most significant AE was nausea (24% vs 9%) in both Commentary: trials. • The study design is interesting in that it enriches for responders and reduces placebo effects, however, the percentage of respondents experiencing unpleasant AE is still high

Phase III Program DPN (Completed 2011) Phase III Program DPN (Completed 2012) Patient Segment: • Moderate to Severe Pain Associated with DPN • Moderate to Severe Pain Associated with DPN (>5/11) Target Enrollment: • N =395 (completed open-label screening phase) • N = 358 (completed open-label screening phase) Randomization: • Randomized-withdrawal (only those demonstrating • Randomized-withdrawal (only those demonstrating initial initial response continued), open-label followed by response continued), open-label followed by double-blind, double-blind, placebo-controlled maintenance trial placebo-controlled maintenance trial Dosing: • Titration: 100mg-250mg BID to optimal dose • Titration: 100mg-250mg BID to optimal dose • Discontinuation of existing medication • Discontinuation of existing medication Duration: • Induction: 3 week titration, open-label • Induction: 3 week titration, open-label • Maintenance: 12 weeks, placebo-controlled • Maintenance: 12 weeks • Post-treatment: 14 weeks Primary End-Points: • Primary: Change in average daily pain score from • Primary: Change from baseline over last week at week 12 start of double-blind phase to week 12

Sources: Williamson KD et al J Gastroenterol Hepatol Oct2010 Supplement,Vol.25,A96; clinicaltrials.gov 67 Nuedexta (dextromethorphan + quinidine) a combination NMDA antagonist, CYP450 2D6 inhibitor approved for treatment of pseudobulbar effect; investigated for effect in Diabetic Peripheral Neuropathy and MS-Associated Neuropathic Pain.

Clinical Results (Phase III Diabetic Painful Neuropathy) Efficacy: • In a Phase III efficacy study of Nuedexta, primary endpoint data comparing placebo, 30mg/30mg BID and 45mg/30mg BID combination dextromethorphan/quinidine 90day to baseline demonstrated efficacy compared to placebo (-2.0, - 2.2, -2.6; p<0.0001) - Improvements were also noted in activity related pain and sleep quality (p<0.0001) Safety: • SAEs were reported in 8%, 5% and 4% in 45mg/30mg, 30mg/30mg, and placebo treated groups respectively Lumleian • Current results suggest this to be efficacious in treating DPN and a change of 2 points on a pain rating scale is Commentary: considered to be clinically relevant • Side-effect profile is consistent with traditional pain medications (i.e., dizziness, headache, diarrhea)

Phase III Program DPN (Completed) Phase II MS Program (Recruiting) Patient Segment: • Moderate to Severe Pain Associated with DPN • Moderate to Severe Pain (>4/10) Associated with MS for (>4/10) for >3mths >3mths Target Enrollment: • N = 450 • N = 400 Randomization: • Randomized, double-blind, placebo-controlled, • Randomized, parallel, double-blind, placebo-controlled, parallel design, dose-finding study Dosing: • Induction: 45mg dextromethorphan/30mg quinidine • Arm 1: 45mg dextromethorphan/10mg quinidine BID QD or 30mg dextromethorphan/30mg quinidine QD • Arm 2: 30mg dextromethorphan/10mg quinidine BID • Maintenance: 45mg dextromethorphan/30mg • Arm 3: 20mg dextromethorphan/10mg quinidine BID quinidine BID or 30mg dextromethorphan/30mg • Arm 4: placebo BID quinidine BID Duration: • Induction: 1 week • Treatment: 12 weeks • Maintenance: 12 weeks Primary End-Points: • Primary: Change in pain rating compared to baseline • Primary: Pain rating scale at 12wks

Sources: : MS - NCT01324232 DPN: NCT00113620, Shaibani, AI., et al., Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study. Pain Medicine (2012) 13:243-54 68 Table of Contents

Slide Number I. Introduction • Who is Lumleian and what is a disease state primer? • 3 – 6 • What is our perspective on Neuropathic Pain? • 7 – 9 II. Disease Overview and Care Paradigm 11 • What is Neuropathic Pain? • 12 • Presentation, diagnosis, classification • 13 • Epidemiology by geography and patient segment • 15 • Current care paradigm and clinical evidence • 17 – 23 • Emerging care paradigm • 24 III. Clinical Development Pipeline 26 – 27 • Disease mechanism overview • 28 - 30 • Clinical development pipeline mapping • 31 – 37 • Sodium Channels • 38 – 41 • Trp Channels • 42 - 44 • Cannabinoid • 45 - 47 • Vesicular release • 48 – 50 • NGF Antagonist • 51 – 53 • Other mechanisms (opioid receptors, P2X3, NE reuptake • 54 - 68 inhibition , Anti-TNFα, calcium channel blockade, combinations) IV. Commercial Landscape 70 • Global, US, EU, Japan market size and growth by brand • 71 – 74 • Wall Street consensus forecasts for pipeline assets • 75 • US growth decomposition: Rx volume, pricing, product mix • 76 – 78 • US promotional spending, marketing mix and brand messaging • 79 – 85 V. Appendix • Table of Acronyms • 87 – 88 • More about Lumleian • 89 – 91 69 For the commercial analysis, we combine the percent use of the drug in NP with the brand’s total revenue and prescription numbers to derive the estimates for each therapy within the NP market.

Drug uses for NP in 2011 US

Lyrica 58% Uses for NP Gabapentin 41%

Gralise 100%

Carbamazepine 11%

Cymbalta 19%

Savella 100%

Amitriptyline 13%

Nortriptyline 9%

Lidoderm 22%

Qutenza 100%

Tramadol 2%

0% 20% 40% 60% 80% 100%

Sources: SDI (IMS) PDDA 2011 70 Global ’11 brand revenue for NP increased 21.5% to ~$3.4B, and is expected to increase steadily until ’13 to $4.2B, driving by strong growth of Lyrica, Cymbalta and new launches. The market will shrink to $4.0B in ’14 due to patent expiry of Cymbalta and Lidoderm, but the revenue will be balanced by new drug launch throughout ’16.

NP’s Global Brand Revenue ($B) Updated: 08/01/12 Recent and Anticipated New Product Launches - Global $5.0 $4.2 • Cypress’s Savella (Fibromyalgia, 01/09) $4.0 $3.9 $3.9 $3.9 • Neurogesx’s Qutenza (PHN, 11/09) $3.4 Pipeline • Depomed’s Gralise (PHN, 01/11) $2.8 RW $2.5 JP • JNJ’s Nucynta (’12) • Eisai’s Ranirestat (’14) EU

US Recent and Anticipated Line Extensions $0.0 • GSK’s Horizant (PHN, 06/12) 10A 11A 12A/F 13F 14F 15F 16F • PFE’s Lyrica (NP associated with spinal cord injury, 06/12) Actual: Solid bars Consensus Wall Street Forecast: Hashed bars

’13–’16F ’11 Sales ($B) ’10–’11A ’11-’12F CAGR Recent and Anticipated Loss of Exclusivity Global & $3.4 21.5% 12.9% -2.5% • US: Cymbalta (06/13), Lidoderm (09/13) Pipeline US $1.8 10.6% 11.9% -16.1% EU $0.9 16.0% 11.6% 0.3% JP $0.1 193.1% 21.5% 12.2% RW $0.6 66.6% 3.5% 1.6%

Notes: Branded sales excludes generic revenues and non-biologics sales; Pipeline includes: GSK’s Horizant(’12), JNJ’s Nucynta(’12), Eisai’s Ranirestat(’14). Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight 71 United States brand revenue increased by ~11% to ~$1.8B in ’11, and is forecasted to continue this trend to ~$2.0B in ’12. However, despite potential new drugs in the future, the market is expected to drop to ~$1.7B from ’14 throughout ’16, largely driven by Cymbalta’s LOE.

NP’s United States Yearly Brand Revenue ($B) NP’s United States Quarterly Brand Revenue ($B)

Updated: 08/01/12

$3.0 Updated: 08/01/12 $0.6 $0.5 $0.5 $0.5 $0.4 $0.5 $2.2 $0.4

$2.0 Thousands Thousands $1.8 $1.7 $1.7 $1.6 $1.6 US $0.3 $1.5 Pipeline

$0.0 $0.0 Q1 Q2 Q3 Q4 Q1 Q2 10A 11A 12A/F 13F 14F 15F 16F 2011 2012 Actual: Solid bars Wall Street Consensus Forecast: Hashed bars Actual: Solid bars Wall Street Consensus Forecast: Hashed bars

’11 Revenue ’10–’11A ’11-’12F ’13–’16F ’12Q2 HY12 vs. ’12Q2 vs. ($B) CAGR Sales ($B) HY11 ’12Q1 United States $1.8 10.6% 15.0% -9.1% United States $0.51 14.6% 7.1% Lyrica $0.9 6.3% 10.9% -6.9% Lyrica $0.23 8.4% 2.3% Neurontin $0.0 -19.2% -34.9% -37.0% Neurontin $0.00 -32.4% -7.7% Gralise $0.0 25.3% Gralise $0.01 370.6% Cymbalta $0.6 14.5% 14.2% -77.4% Cymbalta $0.18 25.1% 11.3% Savella $0.1 69.8% 12.2% 12.8% Savella $0.03 7.7% 9.8% Lidoderm $0.2 2.6% 0.5% -25.4% Lidoderm $0.05 10.5% 3.2% Qutenza $0.0 700.0% 37.5% 32.0% Qutenza $0.00 80.6% 7.4%

Notes: Branded sales excludes generic revenues; Pipeline includes: GSK’s Horizant(’12), JNJ’s Nucynta(’12), Eisai’s Ranirestat(’14).

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight 72 European Union ’11 brand revenues were ~$0.9B which is forecasted to grow ~2.7% annually between ’13 and ’16, driven by Lyrica’s strong growth; Japan’s ’11 brand revenue was ~$0.1B, and is expected to grow ~15.6% between ’13 and ’16.

NP’s European Union Brand Revenue ($B)

$2.0 Updated: 08/01/12 ’11 Revenue ’10–’11A ’11-’12F ’13–’16F ($B) CAGR EU $1.3 $1.3 European $1.2 $1.3 Pipeline $0.9 16.0% 13.2% 2.7% $1.1 Union Thousands $0.9 $1.0 $0.8 Lyrica $0.7 13.9% 13.4% 3.7% Neurontin $0.1 -7.4% -20.8% -7.8% Cymbalta $0.1 43.0% 18.9% -25.5% Lidoderm $0.0 -4.5% 56.7% $0.0 10A 11A 12A/F 13F 14F 15F 16F Actual: Solid bars Wall Street Consensus Forecast: Hashed bars

NP’s Japan Brand Revenue ($B)

$0.4 Updated: 08/01/12

’11 Revenue ’10–’11A ’11-’12F ’13–’16F $0.2 JP ($B) CAGR $0.2

Thousands Pipeline $0.2 Japan $0.1 193.1% 25.4% 15.6% $0.2 $0.2 $0.1 Lyrica $0.1 331.0% 30.4% 12.9% $0.1 Neurontin $0.0 -7.4% -20.8% -7.8% $0.0 Cymbalta $0.0 233.3% 11.4% 15.4%

$0.0 10A 11A 12A/F 13F 14F 15F 16F

Actual: Solid bars Wall Street Consensus Forecast: Hashed bars Notes: Branded sales excludes generic revenues; Pipeline includes: GSK’s Horizant(’12), JNJ’s Nucynta(’12), Eisai’s Ranirestat(’14).

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight 73 Rest of world brand revenue was ~$0.6B in ’11, and is expected to grow by ~2.6% annually between ’13 and ’16.

NP’s Rest of World Brand Revenue ($B)

$1.0 Updated: 08/01/12 ’11 Revenue ’10–’11A ’11-’12F ’13–’16F $0.8 $0.7 $0.8 $0.7 RW ($B) CAGR $0.6 $0.6 Pipeline

Rest of World $0.6 66.6% 4.1% 2.6% Thousands $0.5 $0.4 Lyrica $0.5 72.1% 2.6% 3.7% Neurontin $0.0 -7.4% -20.8% -7.8% Cymbalta $0.0 43.0% 18.9% -25.5%

$0.0 10A 11A 12A/F 13F 14F 15F 16F

Actual: Solid bars Wall Street Consensus Forecast: Hashed bars

Notes: Branded sales excludes generic revenues; Pipeline includes: GSK’s Horizant(’12), JNJ’s Nucynta(’12), Eisai’s Ranirestat(’14).

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations, rd analyst day transcripts); 3 party equity research reports; Bio-Pharma Insight 74 Wall Street consensus estimates forecast new product launches will increase the ’16 global market by ~$0.6B, driven largely by anticipated launches for GSK’s Horizant(’12), JNJ’s Nucynta(’12), Eisai’s Ranirestat(’14).

Global Pipeline Assets Wall Street Consensus Forecast ($B) Updated: 08/01/12

$0.8 $0.6 Ranirestat $0.5 $0.4 $0.3 Nucynta

$0.1 $0.1 Horizant $0.0 10A 11A 12F 13F 14F 15F 16F Wall Street Consensus Forecast: Hashed bars

Global GSK’s Horizant Global JNJ’s Nucynta Equity Research Forecasts ($B) Equity Research Forecasts ($B)

16F Consensus: $0.12B 16F Consensus: $0.12B

$0.20 (Adjusted for NP only) $0.20 (Adjusted for NP only) Thousands $0.10 Thousands $0.10

$0.00 $0.00 12F 13F 14F 15F 16F 12F 13F 14F 15F 16F Notes: These forecasts are not representative of Lumleian’s viewpoint; Ad-hoc Lumleian develops its own forecasts for clients based on its proprietary analytics and research;

Sources: Consensus estimates based on publicly available equity research forecasts that have been updated in the past 12 months (since 08/01/11); Consensus estimate is the ‘straight line’ average with each bank’s forecast weighted equally 75 In Q2 ’12 US NP retail revenue increased by ~15.7% compared to Q2 ’11, driven by a ~8.0% increase in days of therapy, a ~10.6% increase in price per day, and a 4.6% decrease in product mix, indicating a strong growth in Rx volume and price, but a small shift of the therapies toward to cheaper generic drugs.

Decomposition of Q2’12 US NP’s Retail Revenue Growth (over Q2’11) Updated: 08/01/12 20% +10.6% +15.7% -2.9%

10% +8.0%

Days of Price per day Product Retail Therapy (Independent of Mix) Mix Revenue

Jun’12 vs. Jun’11 3.6% 9.3% -3.3% 9.7% Jul’11-Jun’12 vs. 8.6% 8.4% -2.8% 14.2% Jul’10-Jun’11

Notes: Revenues include both branded and generic products; YTD growth compares 2011 vs. 2010; QTD growth compares the 3months 10/11-12/11 vs. the 3 months 7/11-9/11; MTD compares the month 12/11 vs. the month 12/10

Sources: SDI (IMS) retail sales and prescription data 76 In the US, the prescription market for NP increased ~8.1% annually over last 5 years, which is dominated by anticonvulsants with ~72% share in Q2 ’12, where generic gabapentin kept obtaining share from Lyrica. Antidepressants account for ~22% share of the Rx, but lost 2.6 percent share to anticonvulsants over last 5 years.

US NP’s Prescription Share (TRx) Share Change Rx Volume Updated: 08/01/12 Share (% points) Growth 100% Tramadol ’12-Q2 1 yr 3 yr 5 yr 1 yr 5 yr Lidoderm TCAs Total TRx 7.0% 8.1% Savella Anticonvulsant 72.4% 0.9 0.8 3.8 8.3% 9.3% 75% Cymbalta Lyrica 18.5% -1.7 -6.7 -5.7 -2.1% 2.4%

Gabapentin 51.8% 2.3 7.6 10.3 12.0% 13.0%

Gralise 0.4% 0.4 0.4 0.4 50% Carbamazepine 1.7% -0.1 -0.5 -1.2 0.4% -2.6% Antidepressant 22.1% -0.9 -0.5 -2.6 2.9% 6.6% Gabapentin Cymbalta 11.8% 0.0 -1.3 -1.6 7.2% 5.5% 25% Savella 2.9% -0.5 2.6 2.9

TCAs 7.4% -0.4 -1.8 -4.0 1.0% -0.8% Lyrica Other 5.4% 0.0 -0.4 -1.2 6.7% 5.4% 0% Lidoderm 2.8% -0.1 -0.8 -1.6 3.0% -1.3%

Tramadol 2.7% 0.1 0.4 0.4 10.7% 12.1%

Solid color: Branded drug; Hashed color: Generic drug

Notes: Patient share includes both branded and generic products; Share Change compares the share for ’12-Q2 vs. 1 yr, 3 yr, and 12 yr ago; YTD growth compares the patient share for HY12vs. the patient share for HY11; QoQ growth compares the patient share for the 3months 04/12-06/12 vs. the 3 months 04/11-06/11 Sources: SDI (IMS) Oncology Tracker data 77 The average price for NP drugs was $2.85 per day in Jun’12, which increased ~5.8% over last 12 months. Steady increasing trend was observed for branded drugs, whereas a temporary decline for Lyrica and Lidoderm happened around Nov’11, likely due to the new launch of Gralise for PHN. Generic drugs kept price lower than $1 per day to grab share in Rx market.

US NP’s Cost per Day of Therapy

Cost per Day Change in Cost per Day $12 Updated: 08/01/12 1mon 3mon 12mon Jun’12 (Jun’12 vs. (Jun’12 vs. (Jun’12 vs. May’12) Mar’12) Jun’11) Weighted Avg $2.85 0.0% -0.6% 5.8% Total Lyrica $6.71 0.1% 0.0% 8.0%

Gabapentin $0.96 -0.2% -1.4% 1.0%

$6 Gralise $5.23 5.7% 15.7%

Carbamazepine $1.57 0.6% 0.9% 7.2%

Cymbalta $7.10 0.3% 0.4% 18.3%

Savella $4.58 0.7% 8.3% 15.9%

TCAs $0.19 -0.5% -0.1% 2.9% $0 Lidoderm $10.63 -0.4% -0.2% 4.3%

Tramadol $0.72 -0.3% -2.4% -6.4%

Notes: Prescription includes both branded and generic products; Cost change compares the price change for 12/11 vs. 1 month, 3 months, and 12 months ago Sources: SDI (IMS) retail sales and prescription data 78 In Apr ’12, healthcare professional (HCP) spend was $38.5M, and accounts for ~42.2% of $97M total promotional spend, where Cymbalta, Savella and Lyrica built up ~85% share of entire HCP spend; direct to consumer (DTC) spend has been dominated by Cymbalta and Lyrica with ~63% and ~25% share of voice, respectively.

Total Promotional Spend ($M) Updated: 08/01/12

$140 $97.0M (04/12) Share of CAGR Wallet $70 DTC Apr ’12 3MR HCP 42.2% -2.3%

HCP DTC 57.8% -8.5% $0 M J J A S O N D J F M A 2011 2012

Healthcare Professional Spend ($M) Direct to Consumer Spend ($M)

$54.9M

$38.5M Share of Share of

$60 CAGR $80 (04/12) CAGR (04/12) Voice Voice

HCP Apr ’12 3MR DTC Apr ’12 3MR Millions Lyrica 25.4% 8.8% Millions Lyrica 24.9% -12.3% $30 Gralise 5.9% 8.3% $40 Gralise 2.1% -14.0% Cymbalta 46.9% 2.1% Cymbalta 63.2% -3.1% Savella 13.2% -10.0% Savella 5.4% -12.8% Lidoderm 7.7% -39.4% Lidoderm 4.1% -34.5% $0 Qutenza 0.2% -88.5% $0 Qutenza 0.2% -86.7% M J J A S O N D J F M A M J J A S O N D J F M A Neurontin 0.2% 58.2% Neurontin 0.2% 2011 2012 2011 2012 NPS 0.5% 226.5%

Note: Healthcare Professional (HCP) spend includes marketing to physicians, nurse practitioners, physician assistants through marketing & event promotions, journals, and online promotions; Direct to Consumer (DTC) includes marketing channels in television, radio, newspapers, magazines, outdoor advertisements, and internet; 3 month rolling (3MR) compares spend for the 3 months 2/12-4/12 vs. the 3 months 11/11-1/12; The promotional spend for a certain drug covers all indications. Sources: SDI (IMS) Promotion Audits 79 The promotional spend for Lyrica was $24.4M in April ’12, of which $14M were spent on DTC promotion. DTC messages emphasized on the self- awareness of the pain symptoms in diabetes and fibromyalgia patients.

5/11 & 7/11 - What's causing 9/11 - Diabetes damages nerves, but you can do something your chronic widespread 04/12 & 02/12 about that shooting, burning, pins-and-needles pain. Get muscle pain? The answer may Diabetes damages specific treatment for your unique pain. Lyrica can help. be over-active nerves. nerves which may cause Fibromyalgia is chronic shooting, burning, pins widespread muscle pain. and needles pain. Lyrica can provide significant Lyrica is believed to relief from Fibromyalgia work on these damaged pain. Relief can start here. nerves. Get specific 2/12--Lyrica is believed to treatment to scale back calm these nerves. In some this pain. Lyrica is FDA patients it works in as early DTC approved to treat 6/11 & 8/11 - What's as the first week diabetic nerve pain. causing your chronic $40 Total Promotional Spend ($M) widespread muscle pain? The answer may be over- active nerves. $24.4M CAGR Fibromyalgia is chronic $20 widespread muscle pain DTC Apr-12 3MR thought to be caused by HCP $10.4M 8.8% over-active nerves. Lyrica HCP can provide significant $0 DTC $14.0M -12.3% relief. www.lyrica.com M J J A S O N D J F M A Share of HCP 26.0% 26.6% 26.5% 25.9% 25.8% 22.7% 24.2% 22.9% 24.4% 24.0% 30.0% 25.4% voice DTC 30.1% 26.6% 24.2% 30.4% 32.1% 23.7% 29.1% 27.1% 34.3% 32.8% 29.5% 24.9%

10/11 & 3/12 - While 05/12 there are many diabetes When a hug hurts, complications, painful Lyrica can make a DPN is one they can't ignore. Help manage your difference in patients’ painful Diabetic reducing Peripheral Neuropathy fibromyalgia pain. with Lyrica. LYRICA LYRICA

Notes: Updated: 08/01/12; 3 month rolling (3MR) compares spend for the 3 months 2/12-4/12 vs. the 3 months 11/11-1/12; The promotional spend for a certain drug covers all indications. Sources: SDI Promotion Audits, 80 The promotional spend for Cymbalta was $54.6M in April ’12, the largest amount among all NP drugs, of which $35.4M were spent on DTC. DTC messages introduced the approval in low back pain, while the HCP messages emphasized on the Cymbalta’s multiple indications for chronic pain treatment.

3/11 - Are you living with chronic osteoarthritis pain or chronic low back 3/12 - Spanish pain? Cymbalta is now approved by the FDA for the management of chronic musculoskeletal pain in people with chronic osteoarthritis pain and chronic low back pain. www.cymbalta.com $54.6M CAGR (Apr-12) 3MR Total Promotional Spend ($M) $80 HCP $19.2M 2.1% DTC $35.4M -3.1%

$40 DTC

HCP $0 12/11 - 4 chronic pain M J J A S O N D J F M A conditions. 3 FDA- approved indications. HCP 42.4% 46.8% 52.1% 51.9% 48.2% 50.8% 41.2% 42.2% 44.0% 44.9% 42.0% 46.9% More ways Cymbalta Share of can help. CYMBALTA voice DTC 58.1% 61.4% 66.7% 58.3% 57.9% 64.1% 59.0% 57.9% 53.2% 58.2% 58.6% 63.2%

5/11 - I will make 5/11, 7/11 & 8/11 - each visit as 10/11- Today a Cymbalta has informative for you as non-NSAID, non- demonstrated possible. Approach my narcotic, once- predictable job from an daily analgesic, utilization, empathetic point of FDA approved for 3 remaining view. Remember to indications across consistent from always say "thanks". I 4 different chronic Jan. 2007- will support your goal pain conditions can March 2011. of doing what's best be found in 1 CYMBALTA for your patients. medication. CYMBALTA CYMBALTA

Notes: Updated: 08/01/12; 3 month rolling (3MR) compares spend for the 3 months 2/12-4/12 vs. the 3 months 11/11-1/12; The promotional spend for a certain drug covers all indications. Sources: SDI Promotion Audits 81 The promotional spend for Savella was $8.4M in April ’12, of which $5.4M were spent on HCP promotion. HCP messages focused on the symptom relief for fibromyalgia.

Total Promotional Spend ($M) $20

$8.4M CAGR $10 (Apr-12) 3MR DTC HCP $5.4M -10.0% HCP DTC $3M -12.8% $0 M J J A S O N D J F M A Share of HCP 20.1% 16.0% 14.5% 12.9% 15.0% 13.8% 14.9% 15.6% 16.2% 17.3% 12.8% 13.2% voice DTC 8.0% 7.5% 5.2% 5.7% 6.9% 6.1% 5.0% 6.5% 5.7% 4.8% 6.1% 5.4%

06/11 & 08/11 For the management of fibromyalgia. Savella relieves symptoms of fibromyalgia. SAVELLA

Notes: Updated: 08/01/12; 3 month rolling (3MR) compares spend for the 3 months 2/12-4/12 vs. the 3 months 11/11-1/12; The promotional spend for a certain drug covers all indications. Sources: SDI Promotion Audits 82 The promotional spend for Lidoderm was $5.5M in April ’12, of which $3.1M were spent on HCP promotion. HCP messages focused on the education to about PHN diagnosis, and mentioned the Lidoderm monotherapy and combination with oral analgesics as treatment for PHN.

Total Promotional Spend ($M) $10

$5.5M CAGR $5 (Apr-12) 3MR DTC HCP $3.1M -39.4%

HCP DTC $2.3M -34.5% $0 M J J A S O N D J F M A

Share of HCP 10.0% 8.2% 6.4% 7.0% 10.3% 6.9% 12.9% 12.0% 8.7% 7.0% 6.0% 7.7% voice DTC 2.8% 3.7% 3.2% 4.3% 3.1% 3.8% 6.1% 5.5% 3.7% 2.7% 4.1% 4.1%

5/11 & 10/11 - An insightful and informative 6/11 - Could your 11/11 &12/11 - Lidoderm is indicated for relief of webcast series. The challenges of postherpetic patients have PHN? Don't 12/11-Lidoderm is indicated for relief of pain pain associated with post-herpetic neuralgia. neuralgia in the long-term care setting. let your patients be associated with post-herpetic neuralgia. Apply Apply only to intact skin. Start. Start with LIDODERM among the 80% who are only to intact skin. Start. Start with Lidoderm Lidoderm alone or with oral analgesics for your misdiagnosed. LIDODERM alone or with oral analgesics for your patients with patients with PHN pain. LIDODERM PHN pain. LIDODERM

Notes: Updated: 08/01/12; 3 month rolling (3MR) compares spend for the 3 months 2/12-4/12 vs. the 3 months 11/11-1/12; The promotional spend for a certain drug covers all indications. Sources: SDI Promotion Audits 83 The promotional spend for Gralise was $3.7M in April ’12, of which $2.4M were spent on HCP promotion. HCP messages introduced the new approved indication for PHN and the new gastroretentive technology.

Total Promotional Spend ($M) DTC $5.0 $4.0 $3.0 DTC $3.7M CAGR (Apr-12) 3MR $2.0 HCP HCP $2.4M 8.3% $1.0 DTC $1.2M -14.0% $0.0 M J J A S O N D J F M A

Share of HCP 0.0% 0.0% 0.0% 0.0% 0.1% 4.5% 6.3% 5.6% 5.5% 6.6% 6.7% 5.9% voice DTC 0.0% 0.0% 0.0% 0.0% 0.0% 2.4% 0.8% 2.4% 2.5% 1.5% 1.7% 2.1%

04/12 - Gralise: Watch how patented Gastroretentive technology works.

04/12 - Management of 10/11 - Introducing 10/11 - This is what a day spent dealing with Postherpetic Neuralgia: Gralise, a once-daily Gralise PHN pain can look like. Give your patients with once-daily Gabapentin formulation 05/12 - 24-Hour tablets -- a new option PHN the full day with new once-daily Gralise. using Gastroretentive technology. treatment option for in postherpetic GRALISE GRALISE neuralgia (PHN) Postherpetic therapy. GRALISE Neuralgia: Gralise, once daily Gabapentin.

Total Promotional Spend ($M) $2

$0.2M CAGR $1 (Apr-12) 3MR DTC HCP $0.1M -88.5% HCP DTC $0.09M -86.7% $0 M J J A S O N D J F M A Share of HCP 0.7% 1.9% 0.5% 1.4% 0.0% 0.8% 0.0% 1.6% 0.7% 0.0% 0.0% 0.2% voice DTC 0.7% 0.9% 0.7% 1.2% 0.0% 0.0% 0.0% 0.6% 0.5% 0.0% 0.0% 0.2%

11A 2011 Actual CSF Cerebrospinal Fluid IR Immediate Release 11F 2011 Forecast CT X-ray Computed Tomography JNJ Johnson and Johnson 5-HT 5-Hydroxytryptamine D Dopamine JNK C-Jun N-terminal Kinase ABT Abbott Douleur Neuropathique en 4 JP Japan DN4 aLBPI Average Low Back Pain Intensity questions Leeds Assessment of Neuropathic LANSS AR Adrenergic Receptor DPN Diabetic Peripheral Neuropathy Symptoms and Signs AZN AstraZeneca DTC Direct to Consumer LLY Eli Lilly B Billions ELN Elan LoE Loss of Exclusivity BAX Baxter ENK Enkephalin M Millions BID Bis in Die (Twice daily) EU European Union mAchR Muscarinic Acetylcholine Receptor BMS Bristol-Myers Squibb FAAH Fatty Acid Amide Hydrolase MAPK Mitogen-Activated Protein Kinase CA Completer Analysis FDA Food and Drug Administration mg Milligrams Modified Intention to Treat CAGR Compound Annual Growth Rate FMS Fibromyalgia Syndrome MITT CB1 Cannabinoid Receptor 1 GE General Electric MoA Mechanism of Action Magnetic Resonance Imaging CCR2B Chemokine (C-C motif) Receptor GI Gastrointestinal MRI CDN Canadian GSK GlaxoSmithKline MRK Merck Clinician’s Interview-Based H3 Histamine Receptor MS Multiple Sclerosis CIBIC Month to Date Impression of Change HCP Health Care Professional MTD Chemotherapy-Induced Peripheral HIV Human Immunodeficiency Virus MYGN Myriad Genetics CIPN Neuropathy HSP Heat Shock Protein N Number CNS Central Nervous System HZ Herpes Zoster NA Noradrenaline CRPS Complex Regional Pain Syndrome

87 Table of Acronyms (2 of 2)

NGF Nerve Growth Factor Q3 Third Quarter TCA Tricyclic Antidepressants NIH-Chronic Prostatitis Symptom Q4 Fourth Quarter Total Knee Arthroplasty NIH-CPSI TKA Index QD Quaque Die (Once Daily) TN Trigeminal Neuralgia N-Methyl D-Aspartic Acid NMDA QoL Quality of Life TNFa Tumor Necrosis Factor alpha Number Needed to Treat NNT QTD Quarter To Date TRGT Targacept Neuropathic Pain NP RCT Randomized Control Trial Trk Tropomyosin Receptor Kinase Neuropsychological Test Battery NTB ROI Return on Investment Trp Transient Receptor Potential Novartis NVS RW Rest of World TRx Total Prescriptions Orally Disintegrating Tablet ODT Rx Prescription US United States Opioid Receptor OR SAE Serious Adverse Events VAS Visual Analogue Scale Primary Care Physician PCP Short Form McGill Pain VGSC Voltage Gated Sodium Channel SF-MPQ Positron Emission Tomography Questionaire PET WW World Wide Pfizer Serotonin Norepinephrine PFE XR Extended Release SNRI Ph. Phase Reuptake Inhibitor Yrs. Years Doctor of Philosophy Sanofi-Aventis Ph.D. SNY YTD Year to date PHN Post-Herpetic Neuralgia SOC Standard of Care PiB Pittsburg Compound B SS Statistically Significant PNS Peripheral Nervous System Statistically Significant SSI PPN Painful Peripheral Neuropathy Improvement PRN Pro re nata (As needed) Selective Serotonin Reuptake SSRI Q1 First Quarter Inhibitor Q2 Second Quarter TAE Treatment-related Adverse Events

88 As a leadership team, we designed Lumleian’s business model based on our collective experience in: academic R&D, bio-pharmaceutical industry, equity research and strategy consulting …

• Frank Deane, Ph.D. is a Director of Decision Science and Founder of Lumleian. Frank has over ten years experience working with life science companies and concurrently holds an appointment in the department of strategy at the Carroll School of Management, Boston College, where he teaches ‘Strategic Issues in Pharma and Bio-Tech,’ to MBA students. Prior to founding Lumleian, Frank was a director with Leerink Swann and a case team leader with Bain, where he gained substantial operational experience growing and operating a diverse set of businesses. Frank entered consulting after spending three years in the bio-pharmaceutical industry with Eli Lilly, supporting portfolio optimization and business unit strategic planning. He began his career, as a quantitative risk analyst working at BlackRock. Frank earned a Ph.D. in econometrics from the Krannert School of Management at Purdue University, where his dissertation focused on applying game theory and statistical modeling to optimize pharmaceutical sales and marketing resources. Frank has a bachelor of arts in economics from Princeton University. • Mark Hochstetler, MBA is a Director of Decision Science at Lumleian. Mark has over ten years experience working with life science companies. Prior to joining Lumleian, Mark served as the CFO at OPK Biotech, which focuses on developing oxygen therapeutics for the treatment of anemia, ischemia, and trauma. Before segueing to industry, Mark spent 5 years as a strategy consultant and equity research analyst at Leerink Swann, where he covered: Array, Arqule, Ariad, Celgene, Chelsea, Cougar, Cubist, Genentech, GTx, Hana, Idenix, InterMune, Kosan, Millennium, MGI Pharma, Onyx, Poniard and Vertex. Mark earned an MBA from Duke University’s Fuqua School of Business with a concentration in health sector management. Mark has a bachelor of arts in political science from Stanford University.

• Sarah Haigh Molina, Ph.D. is a Manager of Decision Science at Lumleian, where she leads the Academia and Non- profit practice. Sarah has over ten years experience working and researching in the life sciences. Prior to joining Lumleian, Sarah was an Assistant Professor of Medicine at Boston University School of Medicine where she served as the Director of High-throughput Screening. Before returning to academia, Sarah was US Operations Manager at Molecular Cytomics. Sarah earned a Ph.D. in biology from York University, an MBA from Boston University with a concentration in entrepreneurship, and a bachelors of science in biochemistry from Dundee University.

89 … Having lived the client experience, we know quality is paramount, and pioneered our approach with quality and process efficiency as dual mantras.

• Jean Kung, M.Eng., MBA as Manager of Process Efficiency and Quality Control oversees day-to-day operations and finances at Lumleian and has over five years experience working in the life sciences. Jean designed the process by which Lumleian efficiently and effectively creates and quarterly updates its disease state primers and serves as the final point of quality control. Prior to joining Lumleian, Jean served as a contract project manager to various life science clients. Before entrepreneurship, Jean was a clinical research associate at Health Policy Associates and a researcher at the Harris Orthopedic Biomaterials and Biomechanics Laboratory, Massachusetts General Hospital. Jean earned a masters of science in biological engineering from Cornell University and an MBA in the Health Sector Management Program from Boston University with a concentration in operations and technology management. Jean has a bachelor of science in biological engineering, also from Cornell University.

• Qingwei Sun, M.Eng., MS as a Decision Science Analyst oversees secondary data collection, synthesis and analysis and designed analytical methodologies fundamental to Lumleian’s knowledge management platform. KM database. Using meta-analysis method, he aggregates the clinical and commercial data required to generate Lumleian’s disease state primers. His work has wide application in product development, portfolio management, and investment strategy for both large pharmaceutical companies and emerging bio-techs. Qingwei, who is fluent in Chinese and Japanese, leads our work with Asian clients. Qingwei joined Lumleian after obtaining a Master of Science degree from Harvard School of Public Health. He earned both Bachelor and Master of Engineering degrees from Kyoto University, Japan, concentrating in materials science.

• Mike Onore, B.Sc. is an Decision Science Analyst at Lumleian. Before joining Lumleian, Mike worked as a research assistant at Levitan & Associates, a management-consulting firm specializing in the energy industry. While at Levitan, he used econometric analysis on regional market data to forecast wholesale energy prices, and analyzed plant level emissions statistics for clients’ litigation strategy support. He has also worked as a business analyst in the Project Management Office of John Hancock Mutual Fund Product Support, where he enhanced automation throughout the department, including a vendor cost summary and an annual automated activity report. He earned a Bachelor’s of Science in Economics from Northeastern University, with a thesis on the cost effectiveness of municipal policy strategies for incentivizing bike travel as a modal choice for Boston’s commuters.

90 We recruit decision scientists explicitly for their expertise and relevant experience across the gamut of major therapeutic areas and disease states.

• Whitney Amyot, Ph.D. as Decision Scientist focusing on infectious disease leverages her expertise in scientific investigation and infectious disease to support primary and secondary research for strategic decision making with biopharmaceutical clients and investors. She has more than ten years of experience in scientific research, including positions at Atlanta’s Veteran Affairs hospital and in the pharmacology department at Emory University School of Medicine. In her current role Whitney provides a broad knowledge base to ensure Lumleian is up to date on current discovery and clinical trends. Whitney earned a Ph.D. in Molecular Microbiology from Tufts University Sackler Graduate School of Biomedical Sciences where her dissertation focused translocation in the becterium Legionella pneumophila. Whitney has a Bachelor of Science degree in Biology from Emory University.

• Alice S. Kaanta, Ph.D. as Decision Scientist focusing on oncology is responsible for leading a team of decision scientists in reviewing the scientific, clinical and regulatory landscape in numerous oncology indications. Alice has over ten years of experience in scientific research, in both academia and industry, where her primary focus has been on cancer research. Alice earned her Ph.D. in Biological and Biomedical Sciences from Harvard University. At Harvard, Alice worked in the Brugge Lab studying the regulation of pro- apoptotic Bcl-2 family member Bim in breast cancer progression and in the Neel lab where she identified and characterized a novel multi-potent mammary progenitor with pregnancy-specific activity. Alice earned dual bachelor of science degrees in Biology and Physics from the Massachusetts Institute of Technology.

• Jennifer Peleshok, Ph.D. is a Decision Scientist focusing on pain management. Jennifer has nine years of experience in scientific research in academia and industry with a focus on nerve growth factor (NGF) in both cancer and chronic pain. Jennifer earned her PhD in Pharmacology and Therapeutics from McGill University (Canada). At McGill, Jennifer worked in the lab of Dr. Ribeiro-da-Silva examining the role of peripheral innervation in animal models of chronic pain with attention to the role of NGF. During this time, she collaborated with numerous industry partners on their pain programs, including AstraZeneca and Pfizer.