Disease State Primer: Neuropathic Painlumleian.com/files/6013/8013/2260/2012_Lumleian... · •Ralfinamide (Newron): Nav 1.7 antagonist Statistical Challenges •~30% placebo response

Q2 2012 Update

Disease State Primer: Neuropathic Pain

2

Table of Contents

Slide Number

I. Introduction • Who is Lumleian and what is a disease state primer?

• What is our perspective on Neuropathic Pain?

• 3 – 6

• 7 – 9

II. Disease Overview and Care Paradigm • What is Neuropathic Pain?

• Presentation, diagnosis, classification

• Epidemiology by geography and patient segment

• Current care paradigm and clinical evidence

• Emerging care paradigm

11 • 12

• 13

• 15

• 17 – 23

• 24

III. Clinical Development Pipeline • Disease mechanism overview

• Clinical development pipeline mapping

• Sodium Channels

• Trp Channels

• Cannabinoid

• Vesicular release

• NGF Antagonist

• Other mechanisms (opioid receptors, P2X3, NE reuptake

inhibition , Anti-TNFα, calcium channel blockade, combinations)

26 – 27 • 28 - 30

• 31 – 37

• 38 – 41

• 42 - 44

• 45 - 47

• 48 – 50

• 51 – 53

• 54 - 68

IV. Commercial Landscape • Global, US, EU, Japan market size and growth by brand

• Wall Street consensus forecasts for pipeline assets

• US growth decomposition: Rx volume, pricing, product mix

• US promotional spending, marketing mix and brand messaging

70 • 71 – 74

• 75

• 76 – 78

• 79 – 85

V. Appendix • Table of Acronyms

• More about Lumleian

• 87 – 88

• 89 – 91

3

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.

• Data Mining

- Regulatory filings

- Scientific literature

- Patent filings

- Company filings

and press releases

• Secondary Data

- Industry pipelines

- Wall Street analysis

- US TRx, pricing,

promotional spend

• Primary Research

- Key opinion leaders

- Practicing physicians

- Reimbursement

Expertise Based

Teams

• Experience

- Academic faculty

- Bio-pharmaceutical

- Equity research

- Strategy consulting

• Expertise

- 30+ clinicians

and Ph.D. scientists

• Analytics

- 5 Ph.D. economists

and statisticians

Universal

Information

Real-Time

Knowledge

• Disease State Primers

- Disease overview

and care paradigm

- Clinical development pipeline

- Commercial landscape

• Functional Drill Downs

- In licensing assessments

- Early and late stage

- Preliminary due dilligence

- Real-time clinical data

• Proprietary Analytics

- Asset valuation

- Epidemiologic forecasts

- Industry benchmarks

• Drug Development

and commercial

- Patient segment valuations

- Promotional response models

• Healthcare professional

and direct to consumer

• Academic and

Research Institutions

- Portfolio optimization

• Early stage

- Out licensing strategy

• Asset valuation

• Transaction support

• Royalty monetization

• Bio-pharmaceutical Companies

- Asset valuation

- Clinical strategy

- In licensing strategy

• Early and late stage

- Portfolio optimization

• Early and late stage

- Preliminary due dilligence

• Life Science Investors

- Asset valuation

- Clinical strategy

- In licensing strategy

Life Science

Client Base

Decision

Support

4

Notes: 1These are a representative sub-set of the publicly available data sources

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.

Data Mining

and Analytics

• Company presentations

• Earnings announcements

• Equity research coverage

• Investor relations transcripts

• Clinical trials

• Conference presentations

• Gene ontology

• Industry pipeline databases

• NIH grants

• Scientific literature & citations

• Business development transactions

• Venture capital investments

• Disease profiles

• Industry publications

• Sales and Rx data

• Treatment algorithms

• Advisory committee transcripts

• FDA and EMA filings

Scientific

& Clinical:

Financial:

Academic

Tech Transfer:

Competitive

Landscape:

• Early stage technologies

• Intellectual property filings

Business

Development:

Regulatory:

• Leverage data mining

technology to access

novel data sources

• Standardize, collate,

and link data sources

• Execute Lumleian’s

proprietary analytical

models

Universe of Public

Information1

• 30+ clinicians and

Ph.D. scientists

- Focused by area

of expertise

• 5 Ph.D. economists

and statisticians

Expert Validation

and Decision Support

5

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

• Clinical strategy

• Portfolio optimization

- Pre-Clinical

- Clinical

• Transaction support

- In licensing

- Out licensing Disease

State Primers

Proprietary

Analytics

• Asset valuation

• Epidemiologic forecasts

• Industry benchmarks

- Commercial

- Clinical Development

• Patient segment

valuations

• Promotional

response models

- Healthcare professional

- Direct to consumer

• Royalty monetization

Functional

Drill Downs

• Real-time clinical

data

- Trial strategies

- Results

• In licensing

assessments

- Pre-clinical

- Clinical

• Preliminary

due dilligence

- Scientific

- Clinical

- Commercial

• Disease overview

and care paradigm

• Clinical development

pipeline

• Commercial

landscape Customized

Standardized

6

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

What is a Lumleian’s disease state primer?

7

Executive Summary: Neuropathic Pain

• The global

Disease

Overview and

Care Paradigm

• 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

touch/movement or uncomfortable altered sensations

• Associated with significant loss of quality of life such as major depression, sleep interruption, immobility, social isolation

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

Clinical

Development

Pipeline

• 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

• Targets with increasing interest include certain ion channel family subtypes (eg. Ca2+, Na+, Trp) due to their restricted

activity, favorable tolerability and efficacy

• NGF antibodies are progressing in Phase II for severe cancer-related pain with favorable results; however long-term safety

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

Commercial

Landscape

• The NP market is expected to grow from $2.4billion to $3.6billion in 2020.

8

What are the key questions for 2012?

Key Questions

• 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

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?

Lumleian’s

Perspective

• 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

- 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

- 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

9

0

1

2

3

4

5

Level of Unmet Need Likelihood of Technical Success Regulatory Impetus Commerical Attractiveness Required Investment

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.

Average

Neuropathic Pain: Relative Attractiveness of Greenfield Investment in Late Stage Clinical Development

High

Low

Neuropathic

Pain

Required

Investment

Phase III Investment

• ~2,100 patients in 13

phase II trials

• Requires >4-6wks

• 30% placebo responders

Commercial Spend

• Average $14M/month for

Brand spending

• Where are dollars focused: - 42% Healthcare professional

- 58% Direct to consumer

Phase IV Investment

• ~22,000 patients in 34

Phase IV trials

• 57 sites

Level of

Unmet Need

Clinical Unmet Need

• ~30% of NP are un- or

underdiagnosed

• Reasonable expectation

of 30-50% pain reduction

Global Epidemiology

• ~4-8% World Wide

• Expected to incr. with

disease prevalence

Disease Burden

• ~$3.7 billion in lost

productivity in just DPN

• 3x increase in annual

health care cost

• > prevalence over 45 yrs

Mortality Statement

• Associated with primary

disease, not a mortality

cause

Commercial

Attractiveness

Market Size

• $2.4billion

Condition Statement

• Chronic: >10yrs

• Common comorbidity of

age-related diseases

Global Epidemiology

• 57.8million WW ‘10

• 69.5million WW ‘25

Market Expansion

• Diabetes

Generic Penetration

• US Rx: 61% Generic

• Upcoming LOE

Cymbalta (06/13),

Lidoderm (09/13)

Competitive Launches

• 49

Payor (Rx)

• Medicaid/3rd party/cash

Likelihood of

Technical Success

Etiology Statement

• Identifiable targets

• Modest reliability of

animal models

• Translatability between

pre-clinical to man is

poor

Historic Ph. III /IIIB

Failures

• Aprepitant (Merck):

Substance P antagonist

• Ralfinamide (Newron):

Nav 1.7 antagonist

Statistical Challenges

• ~30% placebo response

• Clear outcome

measures

Target Patient

Populations

• DPN, PHN, CIPN, FM

Regulatory

Environment

Clinical Unmet Need

• ~50% treated respond

adequately to available

therapies

Historical Precedents

• Safety has been a

primary concern and

hurdle for NP

treatments

• Many late state assets

are approved for other

indications seeking

market expansion

Advocacy

• IASP

• Motivating education

and access to

medication

10

Table of Contents

Slide Number



• 3 – 6

• 7 – 9






11 • 12

• 13

• 15

• 17 – 23

• 24



• Sodium Channels

• Trp Channels

• Cannabinoid


• NGF Antagonist



26 – 27 • 28 - 30

• 31 – 37

• 38 – 41

• 42 - 44

• 45 - 47

• 48 – 50

• 51 – 53

• 54 - 68





70 • 71 – 74

• 75

• 76 – 78

• 79 – 85



• 87 – 88

• 89 – 91

11

What is

Neuropathic

Pain?

• 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

- Between 50-100% of those affected by NP develop depression as well as interference with mobility, sleep and

enjoyment of life

• Neuropathic pain can develop without any obvious underlying cause but is most commonly a consequence

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

What is the

disease burden?

• 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

- US prevalence is ~21M and incidence of ~1.0M in 2010

• 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

What is today’s

care paradigm?

• 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

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

- 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

emerging care

paradigm?

• Looking forward Lumleian foresees step-wise improvement in the care paradigm, including: - Greater awareness of the presenting symptoms and treatment paradigm

- Personalized treatment paradigm given heterogeneous NP populations and treatment responsiveness

- Development of peripherally restricted, tolerable therapeutics

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)

Estmates based on sum of actual numbers translated from percentage estimates of NP prevalence amongst each disease state

Executive Summary: Disease Overview and Care Paradigm

12

Yes No

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)

What is Neuropathic Pain?

Description

• Painful stimuli is transmitted to the brain via the spinal cord by the usually

well-controlled, peripheral C- and A-fibers

• Neuropathic pain is the continued perception of pain in spite of the

resolution of an identifiable cause

- C- and A-fibers (slowly and rapidly conducting) develop inappropriate firing

properties

- Maladaptive interpretation of normal stimuli at PNS and CNS

• Can be idiopathic in origin (i.e. CRPS or trigeminal neuralgia) or co-morbidity

of identifiable disease (i.e. HZ, HIV, cancer, diabetes)

Etiology

• NP is associated with disease, dysfunction or lesion of the PNS or/and CNS

- Involve alterations in activity, processing or inhibition of painful signals

- Associated with hyperactivity of some neurons or lack of activity of others

- Inappropriate maintenance of NP by neuro-immune system

- Genetic alterations may predispose people to developing NP

Symptom

Progression

• Initially presents as normal, protective pain for some (e.g. shingles, surgery,

trauma), in others (e.g. diabetes, chemotherapy), begins as loss or gain of

positive symptoms such as tingling, burning, extreme sensitivity to touch or

changes in temperature

• NP persisting longer than 6 months is classified as chronic

• Associated with wasting, sleep disturbances, severe depression, anxiety, job

loss, isolation, social and psychological impairments

Disease

Burden

• NP affects approximately 10% of US/global population (may be higher

depending on classification of disorder)

• The average health care cost is $17,555/yr vs. $5,715/yr1

• Complicated due to poor diagnostics, confusion or dismissal of symptomology

• US $40 billion per annum in health care, disability and related costs

2. Is Neuropathic Pain a primary cause of

mortality?

7. Where is Neuropathic Pain treated,

commonly?

Yes No

Out

Patient

Inpatient

Hospital

Long Term

Care

Symptom

Relief

Disease

Treatment

Disease

Cure

3. Is Neuropathic Pain an acute or chronic

disease?

Acute Chronic

6. Which specialties treat Neuropathic Pain,

commonly?

5. What is Neuropathic Pain’s treatment goal?

8. Who pays for Neuropathic Pain care (Rx),

commonly?

3rd party Cash Medicaid

PCP Neurology Pain

Specialist

4. Is Neuropathic Pain a communicable

disease?

Yes No

1. Is Neuropathic Pain’s etiology well

understood?

Yes No

9. Does Neuropathic Pain impact a special

population?

Notes: 1Most recent information is from 2000

http://www.who.int/mental_health/neurology/neurodiso/en/index.html

13

Criteria Diagnostic

test

Ranked

Scale Unlikely NP

Acute, inflammatory pain

Probable NP Chronic, distressing-type

pain

Definite NP Chronic pain, presents with

associated disease

Pain in an

area that

makes

sense

VAS 0-11 • 0-3/11 • >3/11 • >3/11

SF-MPQ

Word value(0-

45) Intensity

(0-5)

• Throbbing, wrenching, dull

• 3 intensity

• Same as probable

DN4 (0-10) • 4/10 • Same as probable

LANSS (0-24) • 12/24 • Same as probable

Patient

description

• Resolved or acute

• 4 times/week

• 3-6 months

• Continuous

• >6 months

Medical

history

Drug abuse,

psychological

state

• Present or former disease

associated with NP

• Heavy alcohol use

• Use of illegal drugs

• Poor coping skills

• Present or former disease

associated with NP

• Positive history with pain in

neuroanatomically probable area

Neurologi

cal exam

Description of

pain or

spontaneous

sensations

VAS (0-11)

• Unremarkable

• No sensory loss

• VAS with exam 3/11

• Probable pain descriptors

• Decreased sensibility in painful

area

• Present or former disease known to

cause nerve lesion

• Nerve lesion confirmed

• VAS with exam >3/11

Exam

confirmin

g cause

Physiological

changes in skin,

CNS or PNS

• No changes associated with NP • Alterations in skin (color, hair,

scarring)

• Abnormal EMG (sensitive to large

nerve conductance)

• Clinical biochemistry

• CT/MRI (tumors or herniated disc)

• Positive results from all four

general tests

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)

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.

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

14

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)

Current Neuropathic Pain pharmacological treatment paradigms place emphasis on increasing

tolerability of pain allowing for normal psycho-social functioning (i.e. pain reduction to

15

0.9

1.7

0.5 0.5

0.0

0.4

0.8

1.2

1.6

2.0

US EU JP RW

20.1 24.8

19.9 23.0

1.3

1.4 16.1

21.1 57.4

70.4

0

30

60

90

2010 2025

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) ;

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.

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.

Moderate

Neuropathic Pain Global Prevalence (M) US Prevalence of Common NP Conditions (M)

4.2 7.0 3.7

5.2 4.4

12.8 9.6

18.0

5.7

8.2

27.6

51.1

0

10

20

30

40

50

60

2010 2025

CAGR

(‘11-’25)

PHN

Epidemiologic Studies: Solid bars Lumleian Estimate: Hashed bars

2010 Neuropathic Pain Global Incidence (M)

• Age: Patients at 70yrs are ~1.3x more likely to develop NP

than at 50yrs

• Genetics: Variation in ion channels responsible for threshold

determination may make certain individuals more or less

susceptible to developing Neuropathic Pain

• Life Style: Heavy smoker, alcoholism, chronic illegal drug use,

low physical activity

• Surgery types: Mastectomy, amputations, rhizotomy

• Drug treatment: Chemotherapeutics, anti-retrovirals

• Sex: Women are ~1.6x more likely to develop and increases

with specific types (ie. fibromyalgia, vulvodynia)

• Psychological: Severe depression, poor coping skills

Risk Factors

EU:

4-17%

JP:

RW:

CAGR

(’11-’25)

4-8%

US/CA:

9%

2%

1%

WW:

DPN

Cancer associated

NP

Low Back Pain w/

Radiculopathy

Other

16

Sources: CDC.Gov – Herpes 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)

Notes: # Herpes Zoster unique as an acute disorder with resolution of symptoms in

17

Diagnosis (Current)

• Diagnosis is based on matching positive or negative symptoms

with underlying diseases and excluding all other possible

causes for pain

• Traditional sensory signs: spontaneous pain,

thermal/mechanical hyperalgesia or allodynia

Diagnosis:

1st line:

Clinical Trials/Other:

Treatment (Current)

• Expectations are to:

- Reduce VAS pain score by 30-50%

- Improve sleep

- Reduce associated depression

- Improve quality of life

• If improvements are noted - attempt to decrease dose

• Pain treatments must be titrated at start

• 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

which are associated with significant CNS effects

- Tramadol or morphine/oxycodone is usually relegated to a

third line monotherapy

• Further consultations with:

- Psychologists: behavioral/cognitive therapy and associated

depression

- Nutritionists/dieticians for alterations in diet

- Physiotherapy: improve mobility

- Alternative therapies: sought by ~20% of NP patients

If trigeminal neuralgia –

carbamazepine

Neurontin/Lyrica OR

Cymbalta OR

Amitriptyline

Cannabinoids

Alternative Therapies

Clinical Trial Enrollment

Positive NP diagnosis

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

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.

Prognosis (Current)

• Patients are regularly assessed for drug-associated

adverse events

• Patients can experience some recovery at 10 years

Switch to different

class of 1st line drugs Add alternative 1st line

Add Tramadol 3rd line:

Expert referrals:

Switch to opioids

Neuropathic Pain Treatment Paradigm

2nd line:

Psychology

Nutritionist

Physiotherapy

Pain Clinic

Lidoderm or Qutenza at

any time

18

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

Dosing

Safety

Mechanism

of Action

Efficacy

Generics

• Ion channel blockade

‐ E.g.a2d-calcium channel

ligand

‐ Prevents propagation of

action potential and

release of excitatory

neurotransmitters

• Oral

Anticonvulsant

(ie. Lyrica, Neurontin)

• Fall/balance impairment

• Depression

• Erectile dysfunction

• Weight gain

• Peripheral edema

• No (Lyrica)

• Yes (Neurontin ,Tegretol,

Lamictal)

• Inhibition of noradrenaline

and/or serotonin reuptake

of descending inhibitory

pain control

• Antagonism of NMDA

receptors

• Oral

TCA

(ie. amytriptyline)

• Glaucoma

• Orthostatic symptoms

• Cardiac disease

• Hypertension

• Fall/balance impairment

• Suicidal ideation


• Weight gain

• Yes

• Perpetuates continued

inhibitory activity

• Non-selective sodium

channel blocker

• Prevents action

potential in all

sensory, motor,

autonomic fibers

• Patch

Topical Analgesic

(ie. Lidoderm)

• Dermatological

reactions

• No

• Prevents action

potential in all sensory,

motor, autonomic fibers

• Increase availability of

serotonin and noradrenaline

in descending inhibitory

pathways

• Oral

SNRI

(ie. Cymbalta)

• Liver insufficiency


• No (Cymbalta, Savella)

• Yes (Effexor)

• Perpetuates continued

inhibitory activity

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.

• Attenuates hyperactivity of

nociceptive afferents

Brands

• Lyrica (pregabalin)

• Neurontin (gabapentin)

• Tegretol (carbamazepine)

• Lamictal (lamotrigine)

• Elavil (amitriptyline)

• Pamelor (nortriptyline)

• Norpramin(desipramine)

• Imipramine

• Cymbalta (duloxetine)

• Effexor (venlafaxine)

• Savella (milnacipran)

• Lidoderm (5% lidocaine)

19

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

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

(Generic)

• Oral (25,50,75,100,150,200,225,300 mg) - US Patent exp date: Dec 30 2018

• Oral (100, 300, 400, 600, 800mg) - 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

(including off-label

uses)

• Moderate to Severe Neuropathic Pain(~6.5/10) - Indicated for: DPN, SCI, fibromyalgia, PHN

- Used for: phantom limb pain, neuropathic cancer

pain, post-stroke pain, painful polyneuropathy

- SSI vs. placebo in NP associated with PHN, SCI,

fibromyalgia, ranging from 26-48%

- Efficacious in reducing sleep disturbances

- NNT: DPN (~3.9), PHN (4.9)

• Moderate to Severe Neuropathic Pain(~6.5/10) - Indicated for: PHN

- Used for: DPN, painful polyneuropathy, amputation,

neuropathic cancer pain, SCI

- SSI vs. placebo in NP associated with PHN ~30%

- Efficacious in reducing sleep disturbances

- NNT: DPN (8.1, PHN (5.5)

Adverse Events

(Discontinuations %)

• Worsening of preexisting tumors (0.66%),

ophthalmological effects (0.8%), peripheral

edema (0.6%), weight gain (1.1%), dizziness

(6.1%), somnolence (3.3%)

• ~15% of trial participants will withdraw for the

following adverse events

- Worsening of preexisting tumors, ophthalmological

effects, dizziness, somnolence, behavioral changes

Lumleian

Commentary

• There is still a significant percentage of non-

responsive patients and significant CNS

adverse events

• Negative results obtained for HIV-NP

• Higher selectivity than Neurontin (lower dose)

• Efficacy in generally similar to Lyrica though TID dosing

and side effects are a disadvantage

• Gabapentin is available as generic

• Has approximately equal indication profile to Lyrica

http://www.uspto.gov/

20

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

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

reuptake inhibitor

• Serotonin/norepinephrine reuptake inhibitor

Sponsor • Sandoz, Mylan Pharm., Mutual Pharm. • Eli Lilly

Formulation

(Generic)

• Tablets (10,25,50,75,100,150mg)

• Injection (10mg/ml) - Generic

• Delayed release capsules (20, 30,60 mg) - US Patent expires June 2013

Dosing • Tablet: 25mg QD at night; titrated 25mg QD as

tolerated to max 150mg

• Capsules: 30-60mg QD

Indications

(including off-label

uses)

• Moderate to Severe Neuropathic Pain - Indicated for: DPN, PHN

- Used for: post-surgical, post-stroke

- Usually requires a delay of 3-4wks

- Avg 90mg maintenance had SSI vs. placebo in NP

associated with PHN (34%)

- NNT: DPN (1.3-3.4), PHN (~2.5), central pain (1.7)

• Moderate Neuropathic Pain - Indicated for fibromyalgia, DPN, chronic muscoskeletal pain

- Initial 30mg titrated to 60mg for fibromyalgia and 60mg

starting dose for diabetic neuralgia

- DPN: ~60% patients experience 30% pain score reduction

- Fibromyalgia: ~40% patients experienced a 30% pain score

reduction

- NNT: DPN (5.2)

Adverse Events

(Discontinuations %)

• Suicidal thoughts, dry mouth, sedation,

constipation, weight gain, postural hypotension

in elderly, not to be used in conjunction with

SSRI

• Tablet: Suicidal thinking/behavior in adults (1.8%),

hepatotoxicity (1.32%), worsening of glycemic control,

nausea (3.5%), dizziness (~2%) somnolence (1.1%),

headache (1.2%) dry mouth, constipation, insomnia,

Lumleian

Commentary

• Care should be exercised in patients with

cardiac problems

• Recent data indicate use for combination

therapy with gabapentin reducing mood

interference

• Has approximately the same efficacy as Lyrica, used

alternatively or in conjunction with Lyrica

• Has a good safely profile and unlike other SNRIs, useful

in fibromyalgia but less effective than TCA

21

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

(Generic)

• Tablets (200mg) and (100, 200, 400mg)-XR

• Chewable (100mg)

• Suspension (100mg/5mg) - Generic

• Topical patch (700mg) - Also available as gel

Dosing • Tablet: starting 100mg BID incr 100mg BID to

1200mg

• Suspension: 50mg QID incr 50mg QID to 1200mg

• Topical: 1patch BID max 3 patches BID. Usually

efficacious at 3 patches

Indications • Moderate Neuropathic Pain - Indicated for: Trigeminal Neuralgia

- Efficacious in ~70% patients determined by 50% pain

score reduction for reduction pain severity, painful

spontaneous paroxysms

- NNT for: Trigeminal Neuralgia (1.5)

• Moderate Neuropathic Pain - Indicated for: PHN

- Use for: PDN, low back pain with NP

- Initial 10mg-75mg/day titrated to 150mg

- Efficacious at 2wks in ~50% patients determined by

30% pain score reduction

- Diabetic neuropathy - 52%,

- NNT for: PHN (4.4)

Adverse Events

(Discontinuations)

• Dizziness, drowsiness, unsteadiness, nausea,

vomiting, blood problems, skin disorders, suicidal

thoughts, not to be used in conjunction with TCAs

• Topical: Skin erythema, rash, allergic reactions

Lumleian

Commentary

• Primary indication for trigeminal neuralgia

however, side-effects can be dose-limiting

• Is useful primarily for PHN; however Qutenza is a

significant competitor

• Addition to gabapentin significantly increased

efficacy where pain is localized

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

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

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.

22

Sources: Ultram FDA label information

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

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

(Generic)

• Tablet-ER (100, 200, 300mg)

• 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

(Discontinuations)

• Respiratory depression, ataxia, sedation, constipation, seizures, nausea, orthostatic

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

23

Source: Product prescription information; Company press release

Dosing

Sponsor

Mechanism

of Action

Relative

Generic

Availability

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.

Description

Formulation

• Mu-opioid agonist with

norepinephrine reuptake

inhibition

• 50mg TID titrated daily to

max 700mg/day

Nucynta (tapentadol)

• Combination opioid/SNRI

increases potency thereby

increasing dose with

decreased side-effect

profile

• No (exp Aug 2022)

• Tablets (50, 75, 100mg)

• Tramadol (Ultram)

• Janssen Pharmaceuticals/

Grunenthal GmbH

• Launched 2009 (US) 2010

(EU) 2011 (CDN)

• a2d-calcium channel ligand

• 300mg QD to max 1800mg

Gralise (Gabapentin)

• New formulation

• Extended release to

increase compliance

• 10hr release

• No

• Tablets (300, 600mg)

• Depomed

• Launched 2011 (US)

• Neurontin (gabapentin)

• CB1 agonist (cannabis

extract)

• Once every 4hrs to avg

maintenance of 5 spray/day

• 1spay = 100ml

Sativex

(nabiximols)

• Only analgesic indicated for

MS pain/spasms

• First-in-class

• Is an investigational drug in

the US as an add-on therapy

• No

• Spray: (25mg/ml D9-THC,

25mg/ml cannabidiol)

• Bayer/GW Pharma

• Approved 2005 (CDN, Spain,

UK, New Zealand)

• Cesamet, medical marijuana

• TrpV1 agonist

• Reduction in available

nociceptive afferents

• Patch: (179g capsaicin)

Qutenza (8% capsaicin)

• No (exp 2016)

• 1x every 3mths

• Apply for 60min max

4patches

• Long lasting effects

• Painful for some

• Lidoderm

• NeurogesX/Astellas Pharma

• Launched 2009 (US) 2010

(EU)

24

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

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.

Future

Diagnosis

• 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: - Ion channel genetic alterations lead to loss or amplification of pain sensation

- 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

Future

Treatment

• 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

ion channel antagonists e.g. tanezumab (Pfizer) and XEN-402 (Xenon)

• 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)

25

Table of Contents

Slide Number



• 3 – 6

• 7 – 9






11 • 12

• 13

• 15

• 17 – 23

• 24



• Sodium Channels

• Trp Channels

• Cannabinoid


• NGF Antagonist



26 – 27 • 28 - 30

• 31 – 37

• 38 – 41

• 42 - 44

• 45 - 47

• 48 – 50

• 51 – 53

• 54 - 68





70 • 71 – 74

• 75

• 76 – 78

• 79 – 85



• 87 – 88

• 89 – 91

26

Sources: Lumleian estimates based on publicly available data from bio-pharmaceutical companies (financial statements, investor presentations,

pipeline presentations, analyst day transcripts); 3rd party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; TrialTrove

Executive Summary: Clinical Development Pipeline

What is in the

industry’s

clinical

development

pipeline?

• 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

indications progressed furthest in the pipeline although a development program may be ongoing for other

indications: - 7 in Phase IV, 13 in Phase III, 34 in Phase II, and 11 in Phase I

• Neuropathic Pain presents with varying pathology in individual disease subsets: - 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

What is the

evidence for late

stage assets?

• 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

- Lyrica has had mixed results in the effort to expand NP indications

• Cannabinoid: Top line safety data for Sativex released from post-marketing results in Canada and EU,

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

27

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.

Unmet Need

• 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

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

• Synergistic Effects: opportunity exists for drugs that are known to exhibit synergistic effects with current

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

Large

Opportunity

28

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

Mechanism of Action for Receptor/Sequestering

Agents Phase III/IV

(N = 6)

Phase II

(N = 18)

Phase I

(N = 5)

NGF (N=5)

Anti-NGF (N = 3) 3

TrkA antagonist (N = 1) 1

TrkA agonist (N = 1) 1

Opioid (N=3)

ORL-1, MOR agonist (N = 1) 1

Pre-proENK gene therapy (N = 1) 1

OR ligand (N = 1) 1

Serotonergic (N=1) 5HT-1A agonist (N = 1) 1

SNRI (N=4) 5HT reuptake inhibitor &

NA reuptake inhibitor (N=4) 2 2

Cytokine/

chemokine (N=2)

Anti-TNFa (N = 1) 1

CCR2B antagonist (N = 1) 1

Cannabinoid (N=5) CB1 agonist (N = 3) 2 1

FAAH inhibitor (N = 2) 2

Other receptor

inhibition (N=9)

Orexin, p38 MAPK, H3, erythropoietin,

triple reuptake, aldose reductase,

angiotensin II, clostridial

endopeptidase, HSP90/JNK, a2-AR

(N = 9)

8 1



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:

• NGF sequestration has

demonstrated reduction in

pain scores

• Three humanized mAbs in

Phase II

• Alternative approaches

include TrkA antagonism

Opioids:

• Efficacious in reducing some

elements of NP

• Typically used as add-on

therapy with current

development attempting to

overcome abuse and

addiction issues

SNRI:

• Generally shown solid results

in clinic

• Ongoing trials are focused on

expanding indications

TNFa:

• Humira is in late-stage trial

for NP indication

Cannabinioids:

• Currently in use in EU and

Canada

• In late stage trials for US

29

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

Mechanism of Action Ion Channel Ligands

Phase

III/IV

(N = 6)

Phase II

(N = 7)

Phase I

(N = 7)

Sodium Channel

(N=9)

Nav 1.7 antagonist (N=6) 2 4

Nav 1.1, 1.2, 1.3

antagonist (N=2) 2

Nav 1.3, 1.7 (N=1) 1

TRP channels

(N=4)

TrpV1 agonist (N= 2) 1 1

TrpV3 antagonist (N=1) 1

TrpA1 antagonist (N=1) 1

Calcium channel

(N=5)

a2d Ca2+ channel ligand

(N=2) 1 1

Ca2+ channel antagonist

(N=1) 1

Cav 2.2/3.2 (N=2) 1 1

P2X3 antagonist (N=1) 1

Glutamatergic (N=1) 1



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.

Sodium channel:

• Selective Nav 1.7 antagonists have

generated good data in select NP

indications

Trp channels:

• Peripheral restriction is associated with

reduced side-effect profile

• Large body of basic research is yielding

fruitful new targets

Calcium channels:

• Lyrica indication expansion trials are

included

• However, other selective calcium

channel blockers are in Phase I/II trials

P2X3:

• Restricted to subtype of peripheral C-

fibers

Glutamatergic:

• Key excitatory neurotransmitter

(glutamate) in PNS and CNS

30

Other MOA NP Pipeline: Current (N = 16)

Mechanism of Action Mixed and Other

Phase

III/IV

(N =8)

Phase II

(N = 8)

Phase I

(N = 0)

Mixed (N=7)

CYP450 inhib, NMDA,

VGSC, Kv antagonist (N=1) 1

NMDA antagonist, Kv

agonist (N=2) 1 1

D1/4/5, 5HT, a1/2AR, H1,

mAchR antagonist (N=1) 1

Opioid receptor agonist,

SNRI (N=1) 1

TCA+NMDA antagonist

(N=1) 1

Dopamine antagonist +

GABA agonist (N=1) 1

Mesenchymal precursor cells (N=1) 1

Unknown/unidentified (N=5) 5

Varicella-zoster vaccine (N=1) 1

Vesicular release (N=2) 2



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.

Mixed:

• Newer therapeutic formulations have

taken into account the mixed nature and

higher efficacy of combination therapy

• Phase II success is capitalizing on this

observation

• Trends include enhancing inhibition

through either the descending inhibitory

system or preventing excitatory signals

simultaneously with blocking excitation

Other:

• Stem cell and vaccine development

• Development of varicella vaccine should

reduce post-herpetic neuralgia incidence

by preventing resurgence of latent virus

Vesicular release:

• The large body of late-stage success is

primarily Botox

• Other approved drugs in this class are

being investigated

31



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

4 6

1

19

1

3 1 1 1

2 1

1 1 2

1

10

1

1 1

1

1 1 1 1 2

19

10

6 6

4

2 2 2 2 2 2 2 2 2 2

0

5

10

15

20

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

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

NP-associated indications

32

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

Mechanism of Action Phase III/IV (N = 7) Phase II (N = 18) Phase I (N = 4)

NGF (N=5)

Anti-NGF (N = 3) • ABT-110 (Abbott)

• Fulranumab (J&JPRDLLC)

• Tanezumab (Pfizer)

TrkA antagonist (N = 1) • CT-327 (Creabilis)

TrkA agonist (N = 1) • DA-9801 (Dong-A)

Opioid (N=3)

ORL-1, MOR agonist (N = 1) • GRT-6005(Forest/Grunenthal)

Pre-proENK gene therapy (N = 1) • NP-2(Diamyd)

OR ligand (N = 1) • KP-201 (KemPharma)

Serotonergic

(N=1) 5HT-1A agonist (N = 1) • Befiradol (Pierre Fabre)

SNRI (N=4) 5HT reuptake inhibitor &

NA reuptake inhibitor (N=4) • Cymbalta (Eli)

• Savella (Forest)

• TD-9855 (Theravance)

• Beloxepine (Cubist Pharm)

Cytokine/

chemokine

(N=2)

Anti-TNFa (N = 1) • Humira (Abbott)

CCR2B antagonist (N = 1) • AZD-2423 (AstraZeneca)

Cannabinoid

(N=5)

CB1 agonist (N = 3) • Sativex (GW)

• Cesamet (Valeant/other) • Marinol (Echo)

FAAH inhibitor (N = 2) • V-158866 (Vernalis)

Other receptor

inhibition (N=9)

Orexin, p38 MAPK, H3,

erythropoietin, triple reuptake,

aldose reductase, angiotensin II,

clostridial endopeptidase,

HSP90/JNK, a2-AR (N = 9)

• ARA-290 (Araim)

• EMA-401 (Spinifex)

• Ranirestat (Eisai/Dainippon)

• SXN-100323 (Allergan)

• ABT-652 (Abbott)

• MK-6096 (Merck)

• AEG-33773 (Aegera)

• ARC-4558 (Arcion)

• SEP-432 (Sunovion)



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.

33

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

Mechanism of Action Phase III/IV (N = 6) Phase II (N = 9) Phase I (N = 5)

Sodium Channel

(N=9)

Nav 1.7 antagonist (N=6)

• CNV-1014802

(Convergence) • XEN-402 (Xenon)

• PF-05089771 (Pfizer) • PF-05150122 (Pfizer) • PF-05186462 (Pfizer) • PF-05241328 (Pfizer)

Nav 1.1, 1.2, 1.3 antagonist

(N=2)

• Stedesa (BIAL) • Lamictal (GSK)

Nav 1.3, 1.7 (N=1) • Tectin (Wex)

TRP channels

(N=4)

TrpV1 agonist (N= 2) • Qutenza (Astellas) • Civamide (Winston)

TrpV3 antagonist (N=1) • GRC-15300 (Sanofi)

TrpA1 antagonist (N=1) • GRC-17536 (Glenmark)

Calcium channel

(N=5)

a2d Ca2+ channel ligand (N=2) • Lyrica (Pfizer) • DS-5565 (Daiichi)

Ca2+ channel antagonist (N=1) • Sensodyne (SantoSolve)

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)



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.

34

Other MOA NP Pipeline: Current (N = 16)

Mechanism of Action Phase III/IV (N =7) Phase II (N =9) Phase I (N = 0)

Mixed (N=7)

CYP450 inhib, NMDA, VGSC, Kv

antagonist (N=1)

• Neurodex (Avanir)

NMDA antagonist, Kv agonist (N=2) • CNSB-015 (Relevare) • Flupirtine (Meda)

D1/4/5, 5HT, a1/2AR, H1, mAchR

antagonist (N=1)

• Seroquel (AZ)

Opioid receptor agonist, SNRI (N=1) • Nucynta (Grunenthal)

TCA+NMDA antagonist (N=1) • AmiKet (EpiCept)

Dopamine antagonist + GABA

agonist (N=1) • Xyrem (Jazz Pharm)

Mesenchymal precursor cells (N=1) • Mesenchymal precursor cell

(Mesoblast)

Unknown/unidentified (N=5)

• ASP-3652(Astellas) • AGN/EHT-0001 (BMS) • BMS-954561 (BMS) • GRT-6010 (Grunenthal) • Carisbamate (J&J)

Varicella-zoster vaccine (N=1) • Varivax (Merck)

Vesicular release (N=2) • Botox (Allergan) • Keppra (UCB)



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.

35

Indication Phase III/IV (N = 10) Phase II (N = 20) Phase I (N = 0)

Cancer-related

(N=5)

• Nucynta (opioid+SNRI) • Sativex (CB1) • Tectin (Nav1.7) • CNSB-015 (NMDA+Kv)

• NP-2 (opioid) • Fulranumab (NGF) • Tanezumab (NGF) • CNSB-015 (NMDA+Kv)

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

Diabetic Neuropathy

(N=20)

• Qutenza (TrpV1) • Nuedexta (mixed) • Stedesa (Na channel) • Ranirestat (aldose) • Nucynta (mixed) • Lamictal (Na channel) • Sativex (CB1) • Botox (Vesicular release) • Cesamet (CB1)

• ABT-639 (Cav3.2) • ABT-652 (H3) • ARA-290 (erythropoeitin) • AZD-2423 (CCR2B) • BMS-954561 (unknown) • DS-5565 (Ca channel) • GRC-17536 (TrpA1) • ARC-4558 (a2-AR)

• DA-9801 (NGF) • GRT-6005 (opioid) • Carisbamate (unknown) • MK-6096 (orexin) • Befiradol (serotonin) • GRC-15300 (TrpV3) • Amiket (TCA+NMDA) • AEG-33773 (HSP/JNK) • Stedesa (Nav 1.1-3)

Back

pain

(N=4)

w/o radiculopathy

(N=2)

• Nucynta(mixed)

• ABT-110 (NGF) • Botox (Vesicular release) • Savella (SNRI) • Tanezumab (NGF)

• CNV-1014802 (Na channel) • Mesenchymal cells (stem

cells)

w/ radiculopathy

(N=1)

• Lyrica (Ca channel) • Enbrel (TNFa) • 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.

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.

36

Indication Phase III/IV (N = 8) Phase II (N = 7) Phase I (N =11)

Fibromyalgia (N=4)

• Xyrem (Dopamine) • Seroquel (mixed) • Keppra (Vesicular release)

• Botox (Vesicular release) • Stedesa (Na channel) • Flupirtine (NMDA+Kv)

HIV-related (N=0) • CNSB015 (NMDA+Kv)

Interstitial cystitis (N=3)

• Humira (TNFa) • Tanezumab (NGF) • AF-219 (P2X3) • ASP-3652 (unknown)

MS (N=3)

• Cesamet (Cb1) • Cymbalta (SNRI)

• Neurodex (Cyp450/NMDA) • Marinol (CB1)

Neuropathic Pain

(N=15)

• Seroquel (mixed) • Qutenza (TrpV1) • KP-201 (Opioid)

• AGN-0001 (unknown) • CT-327 (NGF) • Keppra (Vesicular release) • GRT-6010 (unknown)

• CNV-2197944

(Cav2.2) • Beloxepin (SNRI) • IPI-940 (FAAH) • PF-05089771 (Nav1.7) • PF-05150122 (Nav1.7)

• PF-05241328 (Nav1.7) • PF-05186462 (Nav1.7) • TD-9855 (SNRI) • V-158866 (FAAH) • SEP-432 (TRI) • AV-101 (NMDA)

NP(N=1) Idiopathic • Savella (SNRI)

Burn • Lyrica (Ca channel)


pipeline presentations, analyst day transcripts); 3rd party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; CenterWatch


more than one indication




37

Indication Phase III/IV (N = 5) Phase II (N = 6) Phase I (N = 0)

Post-herpetic neuralgia

(N=6)

• Varivax (vaccine) • Stedesa (Na channel)

• SXN-100323 (endopep.) • BMS-954561 (unknown) • Carisbamate (unknown) • XEN-402 (Nav1.7)

• Tanezumab (NGF) • Sensodyne (Ca channel) • EMA-401 (angiotensin) • Civamide (TrpV1 • AmiKet (TCA+NMDA)

Post-stroke

(N=1)

• Botox(Vesicular release)

Spinal cord injury

(N=0)

• Lyrica (Ca channel) • Botox (Vesicular release) • Befiradol (Serotonin)

Trigeminal neuralgia

(N=1)

• Lamictal (Na channel) • CNV-1014802 (Na channel)

Post-

traumatic

(N=3)

General (N=1) • AZD-2423 (CCR2B)

Amputation

(N=1)

• Sensodyne (Ca channel)

TKA (N=1) • Lyrica (Ca channel)

Chronic pelvic pain

(N=0)

• Cymbalta (SNRI) • Botox (Vesicular release) • Savella (SNRI)


pipeline presentations, analyst day transcripts); 3rd party equity research reports; Bio-Pharma Insight; Clinical Trials.gov; CenterWatch


more than one indication




38

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 ;

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

Mechanism

• Selective blockade of neuronal

hyperexcitability - Reduces release of neurotransmitters in spinal

cord to halt signal propagation

Potential

Considerations

• Alteration in expression may be disease

specific

• Caution exemplified by recent failure of

Ralfinamide (Newron), a mixed ion channel

including Nav1.7 antagonist, which failed to

show efficacy in low-back pain associated with

a neuropathic component - However this was in contrast to positive Phase II

with mixed NP patients

Phase III • Stedesa (BIAL Group) • Tetrodotoxin (Wex Pharmaceuticals) • Lamictal (GSK)

Phase II • CNV-1014802 (Convergence Pharmaceuticals) • XEN-402 (Xenon)

Pipeline

http://www.jci.org/articles/view/43158http://www.jci.org/articles/view/43158http://www.jci.org/120/11

39

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

Commentary:

• Top-line results suggests moderate efficacy (NNT=4) and it appears to be well tolerated

• 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

BID, 30 μg BID, 30 μg TID, and 30 μg QID

• Induction: 30μg BID 4days

Duration: • Induction: 4 days

• Follow up: 11 days

• Induction: 4 days

• Follow-up: Days 5, 8 & 15

End-Points: • Primary: Reduction in pain intensity

• Secondary endpoints: estimate duration of response

and QoL improvement

• Primary: Improvement of pain intensity or use of analgesics

and improvement in QoL

• 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

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.

40

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

Commentary:

• Lamictal has generally not demonstrated significant improvement over existing SoC

• 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

neuropathies associated with HIV infection

• Moderate to Severe NP (>4/10) associated with either Type

I or II diabetes for greater than 6mths and less than 5yrs

Target Enrollment: • Neurotoxic: N=62 (Lamictal) N=30 (Placebo)

• Non-neurotoxic: N=88 (Lamictal) N=47 (Placebo)

• Intent to treat: N=679

• Safety: N=706

Randomization: • Randomized by neurotoxic ART stratum, double-blind,

placebo-controlled, parallel design

• Placebo-controlled, randomized, double blind

Dosing: • Induction/dose escalation: 25mg

• Maintenance: 400mg/day (non-enzyme modifiers) or

600mg/day (drug enzyme modifiers)

• Analgesics were maintained throughout

• Induction/dose escalation: 25mg

• Maintenance: 200mg, 300mg, 400mg daily

• Acetaminophen only used as rescue analgesic

Duration: • Induction: 7 weeks

• Maintenance: 4 weeks

• Induction: 7 weeks

• Maintenance: 12 weeks

End-Points: • Primary: mean change in avg pain vs baseline (using

Gracely Pain Score)

• Secondary: Other demonstrations of symptom relief

• Primary: Mean daily pain intensity vs baseline NPS

• 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

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.

41

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

Commentary:

• Top-line results suggests efficacy at the highest dose and it appears to be well tolerated

• 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

Nav1.7

• Moderate to Severe pain >4/10 post-herpetic neuralgia

Target Enrollment: • N = 4 • N=70

Randomization: • Randomized, double-blind, placebo-controlled,

crossover, each participant randomized to receive

placeboactive or activeplacebo

• Randomized, crossover, double-blind, placebo-controlled

Dosing: • Test: 400mg XEN-402 (XPF-001) BID capsule

• No use of existing medication

• Rescue: 3g/day acetaminophen

• 8% XEN-402 (XPF-002) application BID topical

Duration: • Treatment: 2 consecutive days

• Washout: 2 day

• Placebo: 2 consecutive days

• Baseline (1-4 wks)

• Treatment (4-12 wks)

End-Points: • Change of intensity of inducible pain 2hrs post-pain

induction

• Change in mean p

Documents

Disease State Primer: Neuropathic Painlumleian.com/files/6013/8013/2260/2012_Lumleian... · •Ralfinamide (Newron): Nav 1.7 antagonist Statistical Challenges •~30% placebo response