Disease State Primer: Neuropathic Pain. Q Update

Transcription

1 Disease State Primer: Neuropathic Pain Q Update

2 Table of Contents I. Introduction Who is Lumleian and what is a disease state primer? What is our perspective on Neuropathic Pain? II. III. IV. 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 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) 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 V. Appendix Table of Acronyms More about Lumleian Slide Number

3 What are the key questions for 2012? Key Questions Lumleian s Perspective 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? 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 3

4 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) Epidemiologic Studies: Solid bars ( 11-25) WW: RW: JP: EU: US/CA: 4-8% 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 1% 2% 9% 4-17% 2010 Neuropathic Pain Global Incidence (M) US EU JP RW Risk Factors US Prevalence of Common NP Conditions (M) ( 11-25) Moderate 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 % 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): (2009) ; Other PHN DPN Lumleian Estimate: Hashed bars 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 Low Back Pain w/ Radiculopathy Cancer associated NP 4

5 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. Diagnosis: 1 st line: 2 nd line: 3 rd line: Clinical Trials/Other: Expert referrals: Neuropathic Pain Treatment Paradigm Add alternative 1 st line Add Tramadol Positive NP diagnosis Neurontin/Lyrica OR Cymbalta OR Amitriptyline Cannabinoids Alternative Therapies Clinical Trial Enrollment Psychology Nutritionist Physiotherapy Pain Clinic Switch to different class of 1 st line drugs Switch to opioids If trigeminal neuralgia carbamazepine Lidoderm or Qutenza at any time 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 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 2 nd line medication initiated upon 1 st line failure or intolerance Opioid based medications are occasionally added to 1 st 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 Prognosis (Current) Patients are regularly assessed for drug-associated 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 5

6 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. Phase III Phase II Pipeline Stedesa (BIAL Group) Tetrodotoxin (Wex Pharmaceuticals) Lamictal (GSK) CNV (Convergence Pharmaceuticals) XEN-402 (Xenon) Physiology Pathophysiology Hypothesized Mechanism Potential Considerations 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 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 Selective blockade of neuronal hyperexcitability - Reduces release of neurotransmitters in spinal cord to halt signal propagation 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 Source: Pain as a channelopathy Ramin Raouf, Kathryn Quick, John N. Wood Published in Volume 120, Issue 11 J Clin Invest. 2010; 120(11): ; Newron Press Release May 6, 2010 ; 6

7 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 Gabapentin Gralise Carbamazepine Cymbalta Savella Amitriptyline Nortriptyline Lidoderm Qutenza 58% 41% 100% 11% 19% 100% 13% 9% 22% 100% Uses for NP Tramadol 2% 0% 20% 40% 60% 80% 100% Sources: SDI (IMS) PDDA

8 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) $5.0 $4.2 $3.9 $3.4 $2.8 $2.5 Updated: 08/01/12 $4.0 $3.9 $3.9 Pipeline RW JP EU Recent and Anticipated New Product Launches - Global Cypress s Savella (Fibromyalgia, 01/09) Neurogesx s Qutenza (PHN, 11/09) Depomed s Gralise (PHN, 01/11) JNJ s Nucynta ( 12) Eisai s Ranirestat ( 14) $0.0 10A 11A 12A/F 13F 14F 15F 16F Actual: Solid bars Consensus Wall Street Forecast: Hashed bars Global & Pipeline 11 Sales ($B) 10 11A 11-12F 13 16F $ % 12.9% -2.5% US $ % 11.9% -16.1% EU $ % 11.6% 0.3% JP $ % 21.5% 12.2% RW $ % 3.5% 1.6% US Recent and Anticipated Line Extensions GSK s Horizant (PHN, 06/12) PFE s Lyrica (NP associated with spinal cord injury, 06/12) Recent and Anticipated Loss of Exclusivity US: Cymbalta (06/13), Lidoderm (09/13) 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, analyst day transcripts); 3 rd party equity research reports; Bio-Pharma Insight 8

9 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 $70 DTC $97.0M (04/12) Share of Wallet Apr 12 3MR $0 HCP M J J A S O N D J F M A HCP 42.2% -2.3% DTC 57.8% -8.5% Healthcare Professional Spend ($M) Direct to Consumer Spend ($M) $60 $30 $0 $38.5M (04/12) Share of Voice Lidoderm 7.7% -39.4% Qutenza 0.2% -88.5% $0 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% NPS 0.5% 226.5% HCP Apr 12 3MR Lyrica 25.4% 8.8% Gralise 5.9% 8.3% Cymbalta 46.9% 2.1% Savella 13.2% -10.0% $80 $40 $54.9M (04/12) Share of Voice DTC Apr 12 3MR Lyrica 24.9% -12.3% Gralise 2.1% -14.0% Cymbalta 63.2% -3.1% Savella 5.4% -12.8% Lidoderm 4.1% -34.5% Qutenza 0.2% -86.7% Neurontin 0.2% 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