Feldetrex Strategy December 12, 2014 ! Sco$ Ugras (Project Manager) ! Yann Bikard ! Krystle Karoscik ! Randy Lyde ! Jenny Russ ! Laavanya Sankaranarayanan ! Kiran Pookote (Director) 1 Penn Biotech Group Healthcare ConsulBng "We are a cross-‐disciplinary, graduate student run organiza6on at the University of Pennsylvania focusing on addressing the challenges and obstacles facing the life sciences industry. Our mul6disciplinary teams have worked successfully for both Fortune 500 and start-‐up companies, consul6ng on real life projects from Strategy to marke6ng, from Opera6ons to IP." 2 PBG: Premier Biomedical Team Name ScoF Ugras Project Manager Yann Bikard Team Member Email Bio • BA in Biology, UPenn • PhD Candidate, Biochemistry & Molecular Biophysics, UPenn [email protected] • PhD in Pharmacology and Medicinal Chemistry, University of Strasbourg • Research fellow, CHOP, University of Pennsylvania Biomedical Postdoctoral Program [email protected] Krystle Karoscik Team Member [email protected] • BA, PoliBcal Science and Neuroscience, Temple University • Masters Student, Cancer Biology, UPenn Randy Lyde Team Member [email protected] • BS in System Neuroscience, Temple University • PhD Candidate, Pharmacology, UPenn Jenny Russ Team Member [email protected] • PhD in Molecular Biology -‐ Max-‐Delbrueck-‐Center for Molecular Medicine and Humboldt Universitaet Berlin, Germany • Post-‐doc, Perelman School of Medicine, UPenn • B. Tech, Anna University, India • Masters Student, Molecular Biology, UPenn Laavanya Sankaranarayanan Team Member [email protected] Kiran Pookote Director • MBA Candidate, The Wharton School [email protected] • MPP Candidate, Harvard Kennedy School of Government 3 Final PresentaBon Outline I.  Midterm Summary and Final Goals II.  Fibromyalgia Overview III.  Fibromyalgia Primary Research IV.  Feldetrex Value Assessment for Fibromyalgia V.  Feldetrex Path to IND for Fibromyalgia VI.  CRPS Overview VII.  CRPS Primary Research VIII.  AlternaBve PotenBal IndicaBons IX.  Appendix 4 I. MIDTERM SUMMARY AND FINAL GOALS 5 Midterm Summary I.  Midterm: Market overviews of lead indicaBons: o 
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Fibromyalgia MulBple Sclerosis Neuropathy CompeBtor landscape for lead indicaBons IdenBfy potenBal orphan indicaBons for Feldetrex 6 Final Goals II.  Final: Fibromyalgia o 
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Overview CompeBtor Analysis Primary Research Value Assessment
Complex Regional Pain Syndrome (CRPS) o 
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Overview CompeBtor Analysis Primary Research 7 II. FIBROMYALGIA 8 Fibromyalgia – CharacterisBcs & Symptoms •  Chronic pain syndrome -‐ characterized by diﬀuse musculoskeletal achiness, sBﬀness, and exaggerated tenderness at 18 speciﬁed tender points •  Have lower pain threshold •  Disorder of Central Nervous System (CNS) •  Other symptoms: faBgue, joint sBﬀness, sleep disturbance, cogniBve dysfuncBon and other varied and ﬂuctuaBng clinical spectrum 9 Fibromyalgia -‐ Diagnosis •  Process of exclusion •  11/18 tender points1 •  ACR’s* diagnosBc criteria now account for chronic musculoskeletal pain, as well as faBgue, sleep problems, cogniBve disturbance and ﬂuctuaBons •  Remains undiagnosed in as many as 3 out of 4 people with the condiBon2 * American College of Rheumatology 1. 
2. 
10 Harth and Nielson, J Rheum, 2007 Arnold et al., Mayo Clin Proc, 2011 Fibromyalgia -‐ Causes •  Changes in the CNS that alter the processing of aﬀerent sensory input -‐ central sensiBzaBon •  Triggers include psychological and physical stress •  GeneBc polymorphisms in serotonergic and catecholaminergic processes appear to increase the risk of developing ﬁbromyalgia 11 Fibromyalgia -‐ PotenBal Mechanisms Mechanism DescripUon Central sensiUzaUon AmpliﬁcaBon of pain in spinal cord via spontaneous nervous acBvity; augmented sBmulus responses AbnormaliUes in descending inhibitory pain pathways DysfuncBons in brain centers (and/or pathways from these) that downregulate pain signaling in spinal cord Neurotransmi$er abnormaliUes Decreases Serotonin in CNS " aberrant pain signaling as well as decreased dopamine transmission Neurohormonal abnormaliUes DysfuncBon in hypothalamic-‐pituitary-‐adrenal axis, blunted corBsol responses and lac of corBsol diurnal variaBon, associated with FM Psychiatric comorbid condiUon Comorbid condiBons increased – depression, anxiety, PTS, somaBzaBon Adapted from : Abeles et al., Ann Int Med, 2007 12 Fibromyalgia -‐ Prevalence & Incidence •  2% of the US populaBon (~5 million adults) •  Worldwide prevalence ranges from 0.6% to 8.8% Prevalence RaUo (Male: Female 1:7) Males Females Incidence Rate (%) Incidence Rates in Women 8 18-‐29 years 70-‐79 years 6 4 2 0 Incidence rate (USA) Source : CDC – Fibromyalgia, :Queiroz, Curr Paid and Headache Rep, June 2013 13 Fibromyalgia -‐ A Secondary CondiBon Primary condiUon PaUents with ﬁbromyalgia (%) HyperprolacBnemia 71 Chronic FaBgue Syndrome 70 Systemic Lupus Erythematosus 65 Rheumatoid ArthriBs 57 Irritable Bowel Syndrome 32 HIV infecBon 29 Inﬂammatory Bowel Disease 27 PsoriaBc ArthriBs 24 HepaBBs C virus infecBon 16 Adapted from : Neumann and Buskila, Current Pain and Headache Reports, 2003 14 Fibromyalgia -‐ PaBent Costs •  Average yearly direct medical costs/person range from $3,400 to $3,600. •  Total annual costs (direct and indirect)/person = $5,945. •  Based on severity of disease, costs can increase by up to $2,924. Source : CDC 15 Fibromyalgia Treatments 1. 20) •  MedicaBons → reduce pain & improve •  Title s– leep
(Size Text (Size ) 18
Pain relievers. Over-‐the-‐counter: # Acetaminophen (Tylenol) # Ibuprofen (Advil, Motrin IB) # Naproxen (Aleve) Under prescripBon: #  Tramadol (Ultram, Conzip) AnU-‐seizure drugs. MedicaBons for epilepsy: # GabapenBn (Neuron6n, Gralise) → someBmes reducing symptoms. # Pregabalin (Lyrica) → 1st drug approved by FDA to treat ﬁbromyalgia. AnUdepressants. # DuloxeBne (Cymbalta) approved # Milnacipran (Savella) approved → ease pain and faBgue2. Under prescripBon: # Amitriptyline or FluoxeBne (Prozac) → promote sleep. Speciﬁc muscle relaxers. # Cyclobenzaprine → used oﬀ-‐label for ﬁbromyalgia treatment3. 16 1. hFp://www.mayoclinic.org / 2. Center for Advanced Health, 2013 3. MicroMedex. 5 Feb 2010. Fibromyalgia CompeBtor Landscape •  Total sales in U.S. → $1.7B (2011)7 Treatment Mechanism of AcUon Advantages LimitaUons Sales ($) Patent ExpiraUon $560M (USA, 2011, FM) 32% share of U.S. FM pa6ents7 5th top selling drug (general) Generic (December 2013) $105M (USA, 2013, total but almost only FM, $25.8M 2010) January, 2023 Management of FM DuloxeBne (Cymbalta) Serotonin and norepinephrine reuptake inhibitor Generic Mood and pain Does help?
Milnacipran (Savella) Serotonin and norepinephrine reuptake inhibitor Mood and pain Does help?
Pregabalin (Lyrica) -‐ GABA receptor agonist? -‐ $ Ca2+-‐dep. release of pro-‐nocicepBve NTs in the sp. cord Mood and pain Does help?
Cyclobenzaprine Muscle relaxant It works! -‐ anBcholinergic acBvity (average -‐ % norepinephrine release 7.6/10)3 1. Center for Advanced Health, 2013 2. Nat. Pain FoundaBon Survey for March 2014 1,2 60% no 1,2 68% no 61% no $450M (USA, 2011, FM) Patent upheld Bll 26% share of U.S. FM December 30, pa6ents7 2018 th
19 top selling drug (general) Used oﬀ-‐
label for FM4 $75M (50M tablets sold speciﬁcally for FM in 2010/ $1.5/tablet)5,6 1,2 3. hFp://www.drugs.com/ 4. MicroMedex. 5 Feb 2010. 17 Depends on formulaBon/ generic 5. hFp://seekingalpha.com/ 6. hFp://www.drugs.com/price-‐guide/ 7. hFp://decisionresources.com/ Fibromyalgia Agents in Development •  2 FM speciﬁc drugs in the pipeline1 Drug Sponsor Status Mechanism of acUon TNX-‐102 SL Tonix Pharm. Phase IIb data Sublingual cyclobenzaprine (new and beFer formulaBon) -‐ plans to pursue a Phase III trial based on improvements in several II endpoints -‐ will meet with FDA to discuss the primary endpoint for the trial -‐ Model: could capture 5% share at a cost of $6-‐7/pill ($2,500 / year by 2020) → $300M+ peak drug2 TD-‐9855 Theravance Inc. Phase II data Norepinephrine and serotonin reuptake inhibitor -‐ will complete a full analysis of the data and discuss with regulatory authoriBes before determining next steps, but that top-‐line data support further development of TD-‐9855 in the indicaUon 1. hFp://www.biocentury.com/ 2. hFp://seekingalpha.com/ 18 III. FIBROMYALGIA PRIMARY RESEARCH 19 Stakeholder Assessment – Current Treatment Overview for FM Interview Summary •  Interviewed three physicians who treat FM paBents •  PaBents ﬁrst visit doctor with chronic pain symptoms •  Treatment opBons include physical therapy and FDA approved drugs •  There is a lot of “inherent individual variaBon” in manifestaBons of symptoms •  There are some pediatric cases, with mean age at Bme of diagnosis being 17 “Treatment depends on the symptoms presented by the paBent” “FM is almost never the ﬁrst diagnosis…and based on symptoms we begin by targeBng the comorbidiBes” 20 “Prescribing cogniBve behavior therapy or physical therapy is common and it also works on almost everyone” Stakeholder Assessment – Current Treatment Overview for FM •  PaBent response to currently approved drugs is “fairly well”. Individual eﬃcacy is just “fair”. •  Major drawback of current medicaBon is that they “treat only the symptoms” –  “Every treatment opBons has its drawbacks -‐ there may be side eﬀects in some people, lack of eﬃcacy in others, for example, drugs that lower glutamate work only in a subset of the people. There needs to be a focus on actually understanding the mechanism of the disease” •  Incidence of ﬁbromyalgia diagnosis has increased in past few years because : –  “ExisBng FDA approved drugs” –  “AdverBsement campaigns (especially on TV) for current FDA approved drugs 21 Stakeholder Assessment – Unmet Needs for FM •  There is no drug that targets the actual condiBon •  The pathophysiology and mechanism of the disease is not understood, therefore current treatments target symptoms •  Current animal models only display the pain (by cold stress or hyperalgesia) but do not show other symptoms seen in FM paBents “Recent research on small ﬁber neuropathy (SFPN) has shown to be a promising causal route to study FM” “Drugs aﬀecBng the neurotransmiFer pathways seem to work, and further research in this [ﬁeld] may elucidate informaBon on mechanisms of FM” 22 “Some mechanisms play a beFer role in a subpopulaBon of FM paBents in terms of drug targets” IV. FELDETREX VALUE ASSESSMENT FOR FIBROMYALGIA 23 Fibromyalgia Market Size ProjecBons (1) > 5 million paBents with FM in the U.S. IntroducBon of 3 high-‐priced branded drugs with FDA-‐approved labeling for FM: ! Lyrica (Pregabalin) 2007 ! Cymbalta (DuloxeBne) 2008 ! Savella (Milnacipran)
2009 –  2011: Total. U.S drugs sales → $1.7B ! Lyrica $450M ! Cymbalta $560M ! Savella $35M >60% of market by sales hFp://seekingalpha.com/ hFp://sec.gov/ 24 Fibromyalgia Market Size ProjecBons (2) –  Present-‐2018: 4.2% annual growth –  2019: Due to generic erosion of Lyrica, total sales may decrease → TNX-‐102-‐SL could capture 5% share ($300M) Sublingual cyclobenzaprine ! May be an adjuncBve therapy ! Only opBon that is a sleep quality drug → What about TD-‐9855? Norepinephrine and serotonin reuptake inhibitor ! Same mechanism as Cymbalta and Savella 2011
! Lyrica 2014 ! Lyrica $450M ˃ $670M More than 20% annual growth sales for a drug approved in 2007 → FM has a long history of disease denial by the medical community, 1st drug approved was a major breakthrough for acceptance and diagnosis Lyrica: $2,400 / year → only a few U.S. FM paBents treated 1. hFp://www.prnewswire.com/ 2. hFp://www.sec.gov/ 25 25 Value Assessment – Key Points & AssumpBons Key Points and AssumpUons • 
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• 
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2011 (Best available data), Lyrica accounts for 26.5% of FM sales 2011: Total U.S. sales for FM drugs $1.7B Present -‐ 2018 assume 4.2% annual growth 2019, due to Lyrica going generic, assume 15% decrease in total sales 2019-‐2025 assume 4.2% annual growth Feldetrex IND approval 2015 Feldetrex NDA 2022 Feldetrex can capture 1-‐10% of market by 2030 26 26 Fibromyalgia Market ProjecBons ($Billions) 27 27 Feldetrex Value Assessment ($Millions) If Feldetrex can achieve 5% of FM market by 2025, this will result in $123M in sales 28 28 V. FELDETREX PATH TO IND FOR FIBROMYALGIA 29 InvesBgaBonal New Drug (IND) -‐ Timeline Research and Development in the Pharmaceu6cal Industry, 2006 30 What is an IND? •  An IND applicaBon is a request for exempBon from federal law –  It allows for shipping an unapproved drug across states •  Main Purpose –  Provide documentaBon that a new drug is safe and eﬀecBve to proceed to human clinical trials •  RegulaBons: –  Major regulaBng body is the Food and Drug AdministraBon (FDA) –  The Sponsor (Pharma Company) must follow the following rules before starBng clinical study with a new drug: •  21 CFR 312: Obtain IND number from FDA •  21 CFR Part 52: Provide IND number to IRB to obtain approval from IRB RegulaBons •  21 CFR Part 50: Obtain informed consent from paBent or their designee 31 Types of INDs Type of IND Non-‐Commercial (Physician) Emergency Use Commercial Use (PharmaceuBcal) Treatment 32 IND Requirements IND Requirements Commercial Treatment Emergency Form 1571 X X X Table of Contents X X X Introductory statement X X X General InvesBgaBon Plan X InvesBgaBonal Brochure X N/A N/A Clinical Protocol X Brief Clinical History Brief Clinical History Chemistry, Manufacturing, Control informaBon X X X Pharmacology and Toxicology X X X Pervious Human Experience X N/A N/A AddiBonal InformaBon X N/A N/A 33 Proposed Proposed Treatment plan Treatment plan Other General IND InformaBon •  Once the IND is submiFed it is assigned a number and sent to the appropriate reviewing commiFee. •  IND goes into aﬀect 30 days a€er FDA receives the IND unless FDA noBﬁes the sponsor otherwise. •  Drug cannot be administered unBl IND goes into eﬀect unless noBﬁed otherwise –  Emergency 34 When is an IND Not Needed? •  An IND is not needed when an approved drug is used in the course of medical pracBce (even for an indicaBon diﬀerent from the approved indicaBon) –  Oﬀ-‐Label •  However, and IND may be required when an approved product is used in a clinical invesBgaBon based on the use of the study informaBon or based on increased risk –  Ex: If sponsor wants to drug A to be indicated for something else ie. make it drug B new IND is required. •  Even when exempt from IND, IRB review and informed consent are required 35 Pre-‐IND MeeBng •  21 CFR 312.82(a) •  Major ObjecBves: –  To review and reach agreement on the design of animal studies needed to iniBate human tesBng –  To discuss the scope and design of Phase 1 tesBng, plans for studying the drug product in pediatric populaBons and best approach for presentaBon and forma•ng of data in the IND •  When and Why? – 
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Novel IndicaBon No current Guidance Documents Unique molecular enUUes, studies or indicaUons New sponsors or new to are area of drug development ProblemaBc Pharm/Tox Signals NME Avoid protocol changes 36 Animal Models of Fibromyalgia Fibromyalgia-‐like animal models InducUon Pathology Decrease in hindpaw and muscle Acid saline-‐induced Repeated muscle acid injecBons (pH4.0) given twice mechanical withdrawal threshold pain 2-‐5 days apart up to 4 weeks Hyperalgesic Hyperalgesia lasts 14 days as InjecBon of PGE2 a€er acute inﬂammatory insult Repeated muscle insult Priming opposed to hours in control FaBgue-‐enhanced FaBgue (2hr wheel run) + muscle insult (Saline pH5) muscle pain Cold Stress Stress Sound Stress Subchronic swimming stress Long-‐lasBng muscle hyperalgesia combined with whole body faBgue with no muscle damage Repeated cold stress. Mice kept in a cold room (-‐3 Mimics Chronic Widespread pain to +4 C) overnight for 3 days and transferred between normal room temp every 30 minutes lasBng 3 weeks during the day. 4 day sound stress. Mice placed 25 cm from speaker Increased and prolonged that emits pure tones, amplitudes vary randomly cutaneous hyperalgesia. from 20 to 110dB each minute lasBng 5 to 10 Sound stress has no eﬀect on seconds mechanical sensiBvity. Mice are forced to swim for 10 to 20 minutes for 3 days 37 Mice develop hyperalgesia to thermal sBmulus (decrease in force grip) up to 9 days Acid Saline-‐Induced Pain Model •  Non-‐inﬂammatory pain model induced by repeated intramuscular acid injecBons [two acid (pH 4) saline injecBons 2 to 5 days apart]. •  ProducBon of bilateral decrease in hindpaw and muscle mechanical withdrawal thresholds that last 4 weeks •  Enhanced visceral hyperalgesia and reduced physical acBvity (similar to FM) •  Pros: – 
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Produces chronic widespread pain condiBons Hyperalgesia develops similarly between male and female mice Many studies conducted using this model Similar results in rats and mice Model shows similar pharmacological management proﬁle to clinical treatment of FM •  Cons: –  Most previous studies conducted in male mice –  Unclear if there are comorbid symptoms 38 Example of Acid-‐Induced Experiment Drug AdministraBon or Control Acid AdministraBon Acid AdministraBon 0d 1d 2d 3d 4d 5d 6d 15m 30m 45m 60m Mechanical SBmulus Test -‐  All parameters of experiment will need to be opBmized based on pharmacodynamics and pharmacokineBcs of Feldetrex -‐  Based on results, concentraBon of drug, administraBon schedule, assay and readout frequency, route of administraBon, as well as other parameters may have to be adjusted 39 Pre-‐IND ConsultaBon Program •  Pre-‐IND advice may be requested for issues related to but not limited to: – 
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Design of nonclinical pharmacology Toxicology Drug acBvity studies Design and potenBal uses of any proposed treatment studies in animal models Data requirements for IND applicaBon IniBal drug development plans Regulatory requirements for demonstraBng safety and eﬃcacy •  To schedule Pre-‐IND consultaBon: Division of Anesthesia, Analgesia, and AddicBon Products Parinda Jani 301-‐796-‐1232 40 V. COMPLEX REGIONAL PAIN SYNDROME (CRPS) 41 CharacterisBcs of CRPS •  Chronic pain condiBon aﬀecBng mostly one limb (arms, legs, hands or feet), usually a€er an injury or trauma to that limb •  Characterized by prolonged or excessive pain as well as mild or dramaBc changes in skin color, temperature, and/or swelling in the aﬀected area •  CRPS-‐I: paBents without conﬁrmed nerve injuries •  CRPS-‐II: paBents with conﬁrmed nerve injuries •  Probably caused by damage to, or malfuncBon of, the peripheral and central nervous system Source: NINDS Source: www.diaXorney.com 42 Symptoms of CRPS “STAMP”
Sensory Trophic •  allodynia •  skin, hair, nail changes •  hyperalgesia •  hyperesthesia Autonomic •  swelling •  edema •  sweaBng Sources: www.rsds.org/3/clinical_guidelines/ www.schmerzpraxis-‐baden.ch hXp://en.wikipedia.org/wiki/Complex_regional_pain_syndrome 43 Motor Pain •  weakness •  contractures •  atrophy Allodynia -‐ sensaBon of pain from an innocuous sBmulus Algesia – sensiBvity to a painful sBmulus Esthesia – sensaBon to an innocuous sBmulus Causes of CRPS •  90% of cases triggered by a history of trauma or injury (fractures, sprains/
strains, so€ Bssue injury, limb immobilizaBon or surgical/medical procedures) •  Abnormal response that magniﬁes eﬀects of injury •  May be inﬂuenced by geneBcs: rare family clusters of CRPS •  Peripheral nerve abnormaliBes: -‐ small unmethylated and thinly methylated nerve ﬁbers -‐ contribute to inﬂammaBon and blood vessel abnormaliBes -‐ trigger abnormal neurological funcBon in spinal cord and brain •  Blood vessel abnormaliBes: -‐ dilate or leak ﬂuid " red, swollen skin -‐ starvaBon of muscle and deeper Bssues " muscle and joint pain and damage -‐ over-‐constricBon " cold, white, or bluish skin •  Immune system: high levels of cytokines " redness, swelling and warmth Source: NINDS 44 Diagnosis of CRPS – Budapest Criteria 1. Pain, ongoing and disproporBonate to any inciBng event 2. Symptoms: at least one symptom in three of the four* categories: • Sensory: reports of hyperesthesia and/or allodynia • Vasomotor: reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry • Sudomotor/edema: reports of edema and/or sweaBng changes and/or sweaBng asymmetry • Motor/trophic: reports of decreased range of moBon and/or motor dysfuncBon (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin) 3. Physical signs: at least one sign at Bme of evaluaBon in two or more categories: • Sensory: evidence of hyperalgesia and/or allodynia • Vasomotor: evidence of temperature asymmetry and/or skin color changes and/or asymmetry • Sudomotor/edema: evidence of edema and/or sweaBng changes and/or sweaBng assymetry • Motor/trophic: evidence of decreased range of moBon and/or motor dysfuncBon and/or trophic changes 4. No other diagnosis beFer explains the signs and symptoms *In clinical research se•ng: all four categories Source: www.rsds.org/3/clinical_guidelines/ 45 Incidence of CRPS • Incidence of 5.6 -‐ 26.2 per 100,000 paBents per year EsBmaBon for USA from data in NL based on a populaBon of 300,000,000: 150,000 – 250,000 people suﬀering from CRPS • Female to male raBo: 3.5 to 1 • Peak incidence is in people aged 55-‐75 • 6 years a€er onset: 30% of paBents completely recovered, 54% stable disease, 15% no improvement • 30% who worked before onset remain completely unable to work Sources: 1. Sandroni P. et al. CRPS-‐I: incidence and prevalence in Olmsted county, a populaBon-‐based study. Pain. 2003. 103(1-‐2):199-‐207. 2. Van Hilten JJ. Presented in conference at the Erasmus U Med Cent. RoFerdam, The Netherlands. 2007. 3. de Mos M, de Bruijn A, Huygen F, et al. The incidence of complex regional pain syndrome: A populaBon-‐based study. Pain. 2007. 129(1): 12-‐20. 4. hFp://www.pracBcalpainmanagement.com/pain/neuropathic/crps/overview-‐crps 5. hFp://www.medscape.com/viewarBcle/750778_2 46 Current Drugs Used for Treatment of CRPS AnB-‐inﬂammatory drugs: • nonsteroidal anB-‐inﬂammatory drugs (NSAIDs, e.g. ketoprofen) •  corBcosteroids • Cox-‐2 inhibitors (celecoxib, rofecoxib) • free-‐radical scavengers (vit. C) Immunomodulators: Opioids NMDA receptor antagonists • MK-‐801, ketamine, amantadine, dextromethorphan • Thalidomide, lenalidomide, etanercept and inﬂiximab AnB-‐hypertensives and α-‐adrenergic antagonists AnBconvulsants/neuromodulators: • Chlonidine, nifedipine, phenoxybenzamine, phentolamine • GabapenBn, phenytoin and other “membrane stabilizing” anBepilepBc drugs, and lamotrigine Calcitonin • Carbamazepine, oxcarbazepine Bisphosphonates Heterocyclic anBdepressants • Alendronate, clodronate, pamidronate, neridronate Source: www.rsds.org/3/clinical_guidelines/ and Varenna M. et al. Rheumatology 2012 47 Neridronate •  Aminobisphosphonate – inhibits farnesyl pyrophosphate synthase •  Intravenous or intramuscular administraBon •  Orphan drug designaBon by FDA for treatment of CRPS since March 2013 MulB-‐center, double-‐blind placebo-‐controlled trial tested eﬃcacy of neridronate in CRPS-‐I: •  Signiﬁcant improvement in neridronate treated group •  Open-‐extension phase for placebo group: results comparable to treated paBent group during blind phase •  1 year a€er end of study: none of the paBents had symptoms linked to CRPS-‐I PotenBal approval of neridronate by FDA: 2015 Sources: 1. Varenna M. et al. Rheumatology 2012 2. Ga^ D. et al. Therapeu6cs and Clinical Risk Management 2013 3. hFp://www.accessdata.fda.gov/scripts/opdlisBng/oopd/OOPD_Results_2.cfm?Index_Number=372412 4. hFp://www.rsdhope.org/neridronate-‐-‐-‐new-‐medicaBon-‐for-‐crps1.html 48 Market PredicBon for CRPS (Revenue 2005-‐2009) Year World (millions) USA (millions) 2005 $315 $110.25 2006 $344 $120.40 2007 $374 $130.90 2008 $394 $137.90 2009 $416 $145.60 Market growth predicBon: 7% (as of 2005 " best available informaBon) Source: Kalorama Informa6on 2005 49 Drugs in Clinical Trial for CRPS Treatment Source: clinicaltrials.gov 50 V. CRPS PRIMARY RESEARCH 51 CRPS – Primary Research Interview Summary !  Interviewed one physician who is the director of a pain center at an academic hospital !  He does not have exact numbers for how many paBents are diagnosed with CRPS, but esBmates no more than 5-‐10% of paBents. !  CRPS is an orphan disease, synonymous with Reﬂex SympatheBc Dystrophy. !  PaBents with CRPS o€en struggle with their pain for months before they are properly diagnosed. This is unfortunate since treatment outcomes are much beFer if treatment is started early. 52 CRPS – Primary Research !  First line of treatment depends on when the paBents are seen relaBve to the onset of treatment. If he sees them within 3 months of the onset of treatment, he oﬀers a combinaBon of injecBons, medicaBons, and physical therapy. First line medicaBons typically include gabapenBn and sodium channel anBseizure medicaBons. Physical therapy is criBcal. !  Treatment will change over Bme since blocks have a very limited role a€er 6 months. !  Currently, the best mechanism of acBon/medicaBon is gabapenBn, followed by pregabaline. !  He has not heard of anything promising with neridronate, but any alternaBve opBons for more eﬀecBve treatment could only help paBents. 53 Our RecommendaBon •  Based on symptoms and paBent populaBon CRPS is an interesBng candidate disease for Feldetrex •  Approval of neridronate by FDA is imminent: market monopoly for ~7 years " Not a suitable alternaBve for Feldetrex, thus we recommend other alternaBve indicaBons if Feldetrex is not approved for Fibromyalgia 54 V. ALTERNATIVE POTENTIAL INDICATIONS 55 Other PotenBal IndicaBons for Feldetrex •  Crohn’s Disease –  Inﬂammatory Bowel Disease where immune system aFacks the GI tract –  Abdominal pain, diarrhea, fever, and weight loss –  Prevalence: 6-‐9/10,000 •  Low Dose Naltrexone has already been shown to reduce: • 
–  Self reported pain –  ObjecBve markers of inﬂammaBon –  Disease severity Over 80 percent of study parBcipants exhibiBng improvement Source: 1. Smith JP et al (2007) Low-‐dose naltrexone therapy improves ac6ve Crohn’s disease. Am J Gastroenterol 102(4):820–828 2. Younger J et al (2014) The use of low-‐dose naltrexone(LDN) as a novel an6-‐inﬂammatory treatment for chronic pain 56 Other PotenBal Orphan IndicaBons for Feldetrex •  PolymyosiBs (PM) –  Chronic inﬂammaBon of the muscles –  Symptoms include pain, marked weakness and mass loss •  DermatomyosiBs –  Related to PM but also eﬀects the joints, esophagus, lungs, heart, and skin Source: 1. Smith JP et al (2007) Low-‐dose naltrexone therapy improves ac6ve Crohn’s disease. Am J Gastroenterol 102(4):820–828 2. Younger J et al (2014) The use of low-‐dose naltrexone(LDN) as a novel an6-‐inﬂammatory treatment for chronic pain 57 Other PotenBal Orphan IndicaBons for Feldetrex Orphan Diseases -‐ NP is a primary medical condiBon: Guillian-‐Barre Syndrome2 -‐ most common cause of pediatric motor neuropathy -‐ typical viral onset -‐ Cytomegalovirus -‐ 0.34-‐1.34 / 100,000 US pediatric populaBon -‐ 0.5-‐1.5 / 100,000 US adult populaBon -‐ 0.8-‐1.9 / 100,000 world populaBon3 -‐all paBents report some degree of pain -‐ geneBc peripheral nerve damage -‐ 70 diﬀerent types of CMT -‐ 40 / 100,000 US populaBon -‐ 2.8 million people worldwide -‐ all paBents report some degree of pain Charcot-‐Marie-‐Tooth4 -‐ most common inherited neurological disease 58 2. hFp://www.nih.gov/gbs 3. McGrogan et al 4. hFp://www.nih.gov/cmt QUESTIONS? 59 APPENDIX 60 MULTIPLE SCLEROSIS 61 MulBple Sclerosis (MS) – CharacterisBcs and Pathology •  Chronic disorder of the CNS: inﬂammaBon, demyelinaBon & degeneraBve changes •  Immune cells (T-‐cells, macrophages, microglia) aFack myelin sheath a€er passing through blood-‐brain barrier " holes in myelin, exposure of axons and decreased conducBon of nerve impulses Source: hXp://www.grassfactor.com/mul-‐case-‐study.htm Source: Na6onal MS Society 62 MS Symptoms Develop during acute exacerbaBons or as the cumulaBve result of mulBple lesions in the CNS Symptoms can include: FaBgue (most common), sensory complaints, tremors, balance/coordinaBon, depression, spasBcity, vision loss, cogniBve and emoBonal dysfuncBon, & bowel and bladder problems. •  Not all symptoms aﬀect all MS paUents •  No two persons have idenUcal complaints •  No one person develops all of the symptoms Type of symptoms depends on locaUon of lesions in CNS Source: MS Coali6on July 2014 63 EBology of MS The causes are enigmaUc: interplay between environment and geneUc factors Pathogens – molecular mimicry Chemicals Diet Geography Environmental factors Post genomic modiﬁcaUons MS Genes Genome allelic variaBons MonozygoBc twins 30% Linkage and associaBon studies Source: MS Coali6on July 2014 and Na6onal MS Society 64 Gene rearrangements SomaBc mutaBons Retroviral mRNA splicing Incidence of MS Worldwide incidence: 0.1% (Prevalence: 400,000 in US and 2.5 million worldwide) Women are aﬀected at least 2-‐3x more than men Caucasians are aﬀected more than other racial groups Predominant age: 20-‐40; wide disease onset with both pediatric onset & new onset in older adults 65 Clinical ClassiﬁcaBon of MS RRMS!
Relapsing-‐Reminng (RR): Most common, 80%. Deﬁned by relapses when symptoms become worse followed by parBal or complete recovery periods. Primary-‐Progressive (PP): RelaBvely rare, 10%. Slow but conBnuous worsening of disease from the onset. No disBnct relapses or remission. SPMS=PPMS Secondary-‐Progressive (SP): RPMS!
50% of people with RR develop SP within 10 years. IniBal period of RR disease, followed by a steadily worsening disease course; occasionally minor remissions. Sources: Na6onal Mul6ple Sclerosis Society; hXp://www.multsclerosis.org/progressiverelapsingmul6plesclerosis.html 66 Treatment ObjecBves for MS RRMS!
SPMS=PPMS Treatment objecUve: address the inﬂammatory component -‐  Prevent new aFacks -‐  Improve MRI outcome (reducBon of lesions) -‐  Slow disability progression Treatment objecUve: address the degeneraUve component -‐  Slow disability progression Sources: Na6onal Mul6ple Sclerosis Society; hXp://www.multsclerosis.org/progressiverelapsingmul6plesclerosis.html 67 Relapsing MS Treatment Overview FIRST-‐LINE THERAPIES • All approved for Relapsing MS • Disease modifying • Used as monotherapy CONCURRENT THERAPY • Short-‐term, high-‐dose cor4costeroid treatment • Standard through an acute relapse • Methylprednisolone • Prednisone • IFNβs • GlaUramer acetate • Monoclonal anUbody SECOND-‐LINE THERAPIES • First-‐line tx is not tolerated, non-‐
responders, or worsening relapsing disease • ChemotherapeuUcs Source: Hassain et al. Journal of Neuroimmunology 2014 and the The Na6onal MS Society 68 LimitaBons of Current Treatments •  IndicaBve therapies only available for relapsing-‐remi•ng MS •  Side eﬀects of ﬁrst line therapies: reacBons at injecBon site, ﬂu-‐like symptoms, asymptomaBc liver dysfuncBon •  Interferons: 34% of paBents develop auto-‐anBbodies that can reduce eﬃcacy •  ChemotherapeuBcs: serious side eﬀects like opportunisBc infecBons of the brain, leukemia and cardiac dysfuncBon •  No drugs available to prevent transiBon from relapsing to progressive MS Sources: UpToDate: Treatment of relapsing-‐remi^ng mul6ple sclerosis in adults 69 MS CompeBtor Landscape Total sales in U.S. → $7.1B (2013) Treatment Mechanism of AcUon Advantages Patent ExpiraUon Copaxone (glaBramer acetate)* Suppression of T cells in CNS 29% reducBon in relapse rate Jan 28 2017 Rebif / Avonex (interferon beta-‐1a)* T-‐cell inhibiBon 32% (SC)/18% (IM) reducBon in relapse rate Dec 31 2013 Betaseron / Extavia (interferon-‐beta-‐1b)* T-‐cell inhibiBon 34% reducBon in relapse rate Expired Tysabri (natalizumab) VLA-‐4 inhibitor 68% reducBon in relapse rate 2020 Novantrone (mitoxantrone) Type II topo-‐isomerase inhibitor 67% reducBon in relapse rate April 2006 Source: BCC Research 70 MS CompeBtor Landscape Treatment Mechanism of AcUon Advantages Patent ExpiraUon Ampyra (dalfampridine) Potassium channel blocker Improves walking by 32% Jan 22 2015 / Jan 22 2017 Gilenia (ﬁngolimod) S1P agonist 54% reducBon in relapse rate Feb 2019 Aubagio (teriﬂunomide) Dihydro-‐orotate dehydrogenase inhibitor 31% reducBon in relapse rate Oct 2014 Tacﬁdera (dimethyl fumarate) Nrf2 acBvator 44% to 53% reducBon in relapse rate March 27 2018 Siponimod (BAF312) S1P receptor modulator Phase III RRMS N/A Source: BCC Research 71 Sales of MS Disease-‐Modifying Drugs ($ millions) 2013
2018
First-‐line therapies* market share will drop from 60% to 25% by 2018 due to patent expiraBon Source: BCC Research 72 Global Market for MS Disease-‐Modifying Drugs GLOBAL FORECAST FOR MS DISEASE-‐MODIFYING THERAPIES BY REGION, THROUGH 2018 ($ MILLIONS) Region 2011 2012 2013 2018 United States 5,460.0 6,597.7 7,131.8 9,020.2 ROW 3,203.0 3,515.8 3,766.7 5,170.2 TOTAL 8,663.0 10,113.5 10,898.5 14,190.4 Note: ROW is EU5 +Japan+Other countries •  Price of treatments: US $30,000/year, ROW $14,000/year " one of the largest indicaBons by sales for several companies •  In US and EU 90% of paBents with MS treated with disease-‐modifying therapies " New MS agents: possess one or more unique qualiBes (improved eﬃcacy, tolerability or dosing) and can reach MS paBents whose treatments have failed due to lack of tolerability or of response Source: BCC Research 73 Reimbursement Environment •  MS products are facing more aggressive uBlizaBon management •  PaBent access for new MS therapies could be limited due to non-‐preferred status, high co-‐pay, or strict prior authorizaBon criteria Source: Aggarwal S & Topaloglu H (2013): Reimbursement and marketAccess of mul6ple sclerosis products in the United States, Value in Health16: A109. 74 Drugs in Development for MS Phase 1 Phase 1/2 Phase 2 Phase 3 Source: hXp://www.msdiscovery.org/ 75 NEUROPATHY 76 Neuropathy -‐ EBology •  DeﬁniBon: –  Damage or dysfuncBon of one or more peripheral nerves, resulBng in complex, chronic pain. –  Neuropathic pain (NP) is typically a secondary complicaBon in many underlying medical condiBons. –  90% of neuropathic pain is located in the peripheral nervous system (PNS). -‐10% in CNS -‐ex) opBc neuriBs in MS paBents -‐ex) lower back pain in FM paBents –  NP can be global (aﬀecBng the whole body) or local (concentrated in one area). –  Managed on an individual basis. 77 Primary Medical CondiUons Diabetes Neurologic Disorders Physical Trauma Viral InfecBon RepeBBve InfecBon Metabolic Problems Cancer Treatment HIV Excessive Vitamin B6 ConsumpBon Side Eﬀect of Some MedicaBons Neuropathy -‐ Incidence -‐NP as a secondary pain condiBon is diﬃcult to quanBfy – based on pain severity and locaBon¹ Incidence: MS (adults) -‐ Common MS symptom -‐ 1 out of 5 paBents at the Bme of diagnosis -‐ 20% of MS paBents are presenBng with pain at the Bme of their ﬁrst exam -‐ 63.5% of total MS cases in the US -‐ subsequent to iniBal diagnosis -‐ 29-‐86% of paBents worldwide develop NP – dependent on type of nerve damage Incidence: MS (pediatrics) -‐ Common symptom – slow progression to debilitaBng pain -‐ Current neuroimaging data will beFer predict NP Incidence: Fibromyalgia (adults) -‐ Uncommon – NP is typically widespread muscle pain in these paBents -‐ Early reports of Small Fiber Peripheral Neuropathy (SFPN) – potenBal market Incidence: Fibromyalgia (pediatrics) -‐ Uncommon in pediatric populaBon 1. hFp://www.neuropathy.org 78 2
Neuropathy – CombinaBon Treatment Current Treatments: – 
– 
– 
– 
– 
– 
– 
Disadvantages to current treatments5: NSAIDs Ion channel blocking drugs AnBconvulsants AnBdepressants AnBarrhythmic drugs SNRIs Opioids 1. Limited eﬃcacy 2. MulBple BtraBons or doses 3. Risk of abuse (opioids) 4. Cost (expensive) 5. Not all types of NP 5. Epidemiology 2011 79 CompeBtor Landscape of Top Agents -‐2013 total sales for each drug include all indicaBons, not only neuropathic pain. -‐CombinaBon therapy speciﬁc for neuropathic pain totaled ~$2.7 Billion USD in 2013.6 Treatment Mechanism of AcUon Advantages LimitaUons Sales ($) (US 2013) Patent ExpiraUon NeuronBn AnBconvulsant Global pain; epilepsy Side eﬀects; drug interacBons ~2.5B 2004 Lidoderm Analgesic Patch; direct Use; 1 patch for 12 hours ~918M 09/2013 Cymbalta SNRI Muscle relaxant Psych treatment ~5.2B 12/2013 Qutenza Analgesic Patch; direct Use; 1 patch for 12 hours ~80M 11/2016 Lyrica AnBconvulsant Severe nerve pain; epilepsy Allergic reacBons ~2.4B 12/2018 Nucynta Analgesic Dependency and abuse ~86M 06/2025 Rapid onset – 30min 6. DataMonitor R&D Trends
80 Neuropathy – Agents in Development Drug
Company
Mechanism
Phase
IndicaUon
ReUgabine
Valeant
K channel opener
Ph3
Eﬃcacy in epilepsy
SaUvex
GW Pharma
Cancer and MS pain
GRC-‐6211
Lilly/Glenmark
Cannabinoid-‐receptor Ph3
agonist
TRVP1 antag
Ph2
Ralﬁnamide Alipamide
ADX10059
Newron
Nav block MAOI
Ph2
NP condiBons
Addex
mGluR5 inhibitor
Ph2
Acute migraine
XP13512
Tezampanel NGX426
GSK
TorreyPines
Ph2
Ph2
RecruiBng Ph2
Ongoing
NDG8243
Merck/Neurogen
Pro-‐gabapenBn
AMPA/kinate antagonist
TRVP1 antag
Ph2
Postop dental pain
AZD 2066
TC6499
Astra Zeneca
GSK
mGluR5 inhibitor
Neuronal nicoBne receptor agonist
Ph1
Ph1
Ongoing
RecruiBng Ph1
NP
-‐Only one agent in development that speciﬁcally targets neuropathic pain.7
\ 81 7. www.clinicaltrials.gov Sources -‐ Fibromyalgia 1. 
2. 
3. 
4. 
5. 
6. 
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14. 
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J Manag Care Pharm (2012) 18(6):415-‐26 Ann Rev of FB MedicaBons -‐ Fiscal Year 2011 Frost and Sullivan: Assessment of the U.S. Fibromyalgia Market hFps://www.network-‐health.org/Providers/Policies-‐and-‐Manuals/coverage-‐
guidelines/Lyrica-‐(Pregabalin)-‐Coverage-‐Guidelines.aspx 17.  hFp://americannewsreport.com/naBonalpainreport/ﬁbromyalgia-‐drugs-‐
successes-‐or-‐failures-‐8823698.html 18.  hFp://www.sec.gov/Archives/edgar/data/1430306/000101376211002697/
exh9902.pdf 19.  hFp://seekingalpha.com/arBcle/2611035-‐tonix-‐pharmaceuBcals-‐phase-‐ii-‐phase-‐
iii-‐and-‐beyond-‐for-‐tnxminus-‐102?uprof=38&dr=1 84 Sources -‐ CRPS 1.  www.diaForney.com/rsd-‐complex-‐regional-‐pain-‐syndrome/ 2.  www.ninds.nih.gov/disorders/reﬂex_sympatheBc_dystrophy/
reﬂex_sympatheBc_dystrophy.htm 3.  www.rsds.org/3/clinical_guidelines/ 4.  www.schmerzpraxis-‐baden.ch 5.  en.wikipedia.org/wiki/Complex_regional_pain_syndrome 6.  Sandroni P. et al. CRPS-‐I: incidence and prevalence in Olmsted county, a populaBon-‐based study. Pain. 2003. 103(1-‐2):199-‐207. 7.  Van Hilten JJ. Presented in conference at the Erasmus U Med Cent. RoFerdam, The Netherlands. 2007. 8.  de Mos M, de Bruijn A, Huygen F, et al. The incidence of complex regional pain syndrome: A populaBon-‐based study. Pain. 2007. 129(1): 12-‐20. 9.  hFp://www.pracBcalpainmanagement.com/pain/neuropathic/crps/overview-‐crps 85 Sources -‐ CRPS 10. www.medscape.com/viewarBcle/750778_2 11. Varenna M. et al. Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-‐blind, placebo-‐controlled study. Rheumatology 2013, 52(3): 534-‐542. 12. Ga• D. et al. Clinical development of neridronate: potenBal for new applicaBons. TherapeuBcs and Clinical Risk Management 2013. 9: 139-‐147. 13. www.accessdata.fda.gov/scripts/opdlisBng/oopd/OOPD_Results_2.cfm?
Index_Number=372412 14. www.rsdhope.org/neridronate-‐-‐-‐new-‐medicaBon-‐for-‐crps1.html 15. Kalomara InformaBon 2005: Complex regional pain syndrome – A market brieﬁng. 2005. 16. clinicaltrials.gov 86 Sources -‐ MS 1.  hXp://www.grassfactor.com/mul-‐case-‐study.htm 2.  NaBonal MulBple Sclerosis Society: hFp://www.naBonalmssociety.org/ 3.  MulBple Sclerosis CoaliBon (2014): The Use of Disease-‐Modifying Therapies in Mul6ple Sclerosis: Principles and Current Evidence. hFp://www.ms-‐coaliBon.org/cms/index.php?
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disease. Am J Gastroenterol 102(4):820–828.
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88 Sources -‐ Neuropathy 1. 
2. 
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5. 
6. 
7. 
8. 
McGrogan et al. The epidemiology of Guillain-‐Barre syndrome worldwide. A systemaBc literature review. Neuroepidemiology. 2009;32(2). hFp://ghr.nlm.nih.gov/condiBon/guillain-‐barre-‐syndrome hFp://emedicine.medscape.com/arBcle/1180594-‐overview#a0156 hFp://www.neuropathy.org/site/DocServer/GBS-‐AlanBergerMD.pdf?
docID=1066 hFp://www.cmtausa.org/index.php?
opBon=com_content&view=arBcle&id=70&Itemid=28 hFp://www.ninds.nih.gov/disorders/charcot_marie_tooth/
detail_charcot_marie_tooth.htm Datamonitor. Epidemiology: Peripheral Neuropathic pain — A common co-‐morbidity for HIV, diabetes, and herpes zoster. HC00221–001 (October 2011). Datamonitor. R&D Trends: Neuropathic pain — Extensive and diverse pipeline driven by high unmet need. HC00064–006 (July 2011). 89