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DUODOPA® Feb.05 1 DUODOPA® product and system Feb.05 2 Parkinson’s Disease Feb.05 3 DUODOPA® • An innovative treatment – A NEW and UNIQUE mode of therapy – For a limited group of patients suffering from Advanced Parkinson’s Disease • Orphan condition – DUODOPA® is indicated for ADVANCED levodoparesponsive Parkinson’s Disease patients with severe motor fluctuations and dyskinesias – A rare clinical profile ► DUODOPA® is an Orphan Drug Feb.05 4 Advanced Parkinson’s Disease is an ORPHAN condition The Orphan condition must affect less than 5 in 10 000 (0,05%) persons in the community < 230 000 persons in Europe Epidemiology PD prevalence : 0.1 % to 0.2 % European Population (25 EU states) Parkinson’s Disease Population 690 000 10 % of prevalence Advanced PD with Severe Motor Fluctuations 69 000 patients 460 000 000 Ref : F.Stocchhi & al Strategies for treating patienst with advanced PD with disastrous Fluctuations an Dyskinesias.Cl. Neuropharmacology. 1997 Vol.20, N°2, pp.95-115 Feb.05 5 Advanced PD Patients • Patients significantly limited in their activities despite treatment with available anti-Parkinson drugs • Motor complications such as “wearing-off” effect, “on-off” phenomena, and dyskinesias • Stage 3 or 4 (Hoehn & Yahr rating scale) – advanced stage, severely disabling disease – both sides of the body affected, patients still able to walk and stand alone but unable to complete day-to-day tasks – usually cannot live on their own and require substantial help Ref : MM.Hoehn,MD,and Melvin D.Yahr, MD Parkinsonism : onset, progression, and mortality Neurology/Vol17/May 1967 : 427-442 Feb.05 6 Progression of Parkinson’s Disease Response to treatment with Levodopa • Levodopa : the most effective agent for symptomatic treatment of Parkinson’s Disease ► still considered the “gold standard” of therapy • Long term administration of oral Levodopa ► development of motor complications : “on-off” phenomena – dyskinesia ► limits patients’ ability to fully benefit from levodopa Feb.05 7 Progression of Parkinson’s Disease Response to treatment with Levodopa Freedom from symptoms ADVANCED PARKINSON STAGE Response to treatment Dyskinesia ”The good years” Increased symptom variation “On-off” Disease progression ~ 0-4 Feb.05 ~ 4-7 ~7-10 ~ >10 Years 8 Locus Niger Feb.05 9 How do motor complications occur? • Related to the progression of the disease ► continuous death of dopaminergic neurons ► reduced dopamine storage capacity • With time, after a certain threshold of degeneration the therapeutic window of levodopa plasma concentration becomes increasingly narrow Feb.05 10 Progression of Parkinsons disease Therapeutic Window ~ 0-4 Early phase ”the good years” Ability to store dopamine Threshold for morning dose only = Normal mobility = Parkinsonism Feb.05 ~ 4-7 Wearing-off Short off-periods ~ 7-10 Wearing-off with dyskinesias Predictable fluctuations with peak-dose dyskinesias ~ >10 Time (years) On-off fluctuations Unpredictable fluctuations Very narrow therapeutic window Defined therapeutic window = Dyskinesia 2 11 Intermittent Dopaminergic Stimulation Levodopa uptake is in the upper part of the small intestine dopamine depletion + short half-life of levodopa + variable absorption of oral levodopa due to erratic gastric emptying Feb.05 ► variability in levodopa plasma concentrations below or above the window ▼ “pulsatile” Dopaminergic Stimulation 12 Continuous Dopaminergic Stimulation - CDS By delivering a predictable and constant infusion of levodopa ▼ Stable levodopa plasma concentrations ▼ Continuous Dopaminergic Stimulation ▼ Reduced motor fluctuations More continuous benefits for patients from levodopa therapy Feb.05 13 DUODOPA® Reduces both motor fluctuations and dyskinesia by providing CDS with levodopa ▼ New and effective alternative for Advanced Parkinson’s Disease patients Feb.05 14 Galenic formulation issue Poor solubility of levodopa : - large infusion volume of levodopa solution - not possible in practice ► need for special formulation DUODOPA® a highly concentrated Intestinal gel formulation of Levodopa / Carbidopa H2O 3000 ml Feb.05 Levodopa 2.000 mg Carbidopa 500 mg Gel 100 ml 15 Duodopa® versus Oral Levodopa Pharmacokinetic profiles Concentration-time curves. All test days for one patient n°14 Patient 14 Sinemet plasma levodopa Baseline Test day 1 Test day 2 Test day 3 8 7 7 6 6 5 5 4 4 3 3 2 2 1 1 0 D 8 9 10 M 11 D 12 13 Time Test day 4 Test day 5 Test day 6 8 g/ml g/ml Patient 14 Duodopa plasma levodopa 0 DM 14 15 16 17 M 8 9 10 11 M 12 13 14 15 16 17 Time Results from clinical study NPP-001-99 Feb.05 16 09 :0 0 08 :0 0 Feb.05 4 3 3 0 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 17 :0 0 4 17 :0 0 5 16 :0 0 5 16 :0 0 6 15 :0 0 6 15 :0 0 7 14 :0 0 7 14 :0 0 17 :0 0 16 :0 0 15 :0 0 14 :0 0 0,5 13 :0 0 0,5 13 :0 0 1,0 13 :0 0 1,0 12 :0 0 1,5 12 :0 0 1,5 12 :0 0 2,0 11 :0 0 2,0 11 :0 0 2,5 11 :0 0 Sinemet depot 10 :0 0 2,5 10 :0 0 3,0 10 :0 0 3,0 09 :0 0 3,5 09 :0 0 1 08 :0 0 17 :0 0 16 :0 0 15 :0 0 14 :0 0 13 :0 0 12 :0 0 11 :0 0 10 :0 0 09 :0 0 08 :0 0 Patient 7 3,5 09 :0 0 2 08 :0 0 17 :0 0 16 :0 0 15 :0 0 14 :0 0 13 :0 0 12 :0 0 11 :0 0 10 :0 0 09 :0 0 08 :0 0 Patient 14 0,0 08 :0 0 17 :0 0 16 :0 0 15 :0 0 14 :0 0 13 :0 0 12 :0 0 11 :0 0 10 :0 0 Patient 16 Levodopa levels in plasma (2) Duodopa® 0,0 2 1 0 17 Duodopa® versus Oral Levodopa Plasma levodopa concentrations - Five Patients cases Results from clinical study NPP-001-99 Feb.05 18 Clinical development Concept test 1991-92 A first test to evaluate the underlying concept of Duodopa®. NPP-001-1992 A study of the clinical effect of continuous intraduodenal infusion of a stabilized suspension of levodopa/carbidopa on patients with on-off phenomena. Long-term study-1998 A follow-up on long-term utility of Duodopa treatment. NPP-001-1999 A comparison of the plasma levodopa variability during continuous intraduodenal infusion of a levodopa/carbidopa and oral levodopa/carbidopa in patients with advanced Parkinson’s disease. NPP-002-2000 A retrospective study investigating how long patients treated with Duodopa® had received their medication. NPP-001-2002 (DIREQT) A study of the effect on motor fluctuations and on Quality of Life aspects. NPP-002-2002 An assessment of safety as well as global efficacy and variability in dose requirements. Feb.05 19 Publications on Duodopa® Bredberg et al. Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson's disease. Eur J Clin Pharmacol 1993; 45: 117-122. Nilsson et al. Long-term intraduodenal infusion of a water based levodopacarbidopa dispersion in very advanced Parkinson's disease. Acta Neurol Scand 1998; 97: 175-183. Nilsson et al. Duodenal levodopa infusion in Parkinson’s disease – longterm experience. Acta Neurol Scand 2001; 104: 343-348. Nyholm et al. Optimizing levodopa pharmacokinetics – intestinal infusion versus oral sustained-release tablets.Clin Neuropharm. 2003; 26:156-163 Nyholm et al. Duodenal levodopa infusion monotherapy versus oral polypharmacy in advanced Parkinson disease. Neurology 2005; 64:216-223 Feb.05 20 Duodopa® benefits and risks • Efficacy on core symptoms of Parkinson’s Disease similar to levodopa oral formulation • Additional benefits due to Continuous Dopaminergic Stimulation : ► Control of the « ON-OFF » fluctuations ► By maximizing the functional « ON-time » during the day with less « OFF » episodes and less « ON-time » with dyskinesia • Adverse event profile similar to oral Levodopa / Carbidopa • No unexpected tolerability or safety issues ► Only minor problems due to the Duodopa® delivery system • No death related to the treatment Feb.05 21 Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson’s disease NEUROLOGY Jan.25th 2005; 64:216-223 • Objective : – to compare daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in patients with advanced PD for Motor Fluctuations and QoL • Methods : – – – – Randomized, controlled, multi-center study 24 patients enrolled (6 women & 19 men) Cross over study design (3weeks + 3weeks) Video scoring of motor function by blinded assessors on a global treatment response scale (-3 to 0 to +3) – Patient self-assessment with electronic diary Feb.05 22 Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson’s disease NEUROLOGY Jan.25th 2005; 64:216-223 • Results with Duodopa® – Median percentage of ratings in functional «ON» interval (-1 to +1) increased from 81 to 100% (p<0.01) – Decrease in «OFF» state and no increase in dyskinesia (p<0.01) – Median UPDRS score decreased from 53 to 35 in favor of Duodopa (p<0.05) – Quality of life improved: PD Questionnaire-39 and 15D Quality of life Instrument (p<0.01) – Adverse events similar for both treatments Feb.05 23 DUODOPA® in clinical practice Feb.05 24 ® DUODOPA • Intestinal Gel – Concentrated suspension of levodopa/carbidopa (2g / 0.5g for 100 ml) – Same ratio 4:1 as common oral formulations – Cassette of 100ml • Levodopa 20 mg/ml • Carbidopa 5 mg/ml – Box with 7 cassettes • Portable pump – Specially designed – Programmable to allow individualized dose regimen infusion – Security features available : • Specially designed software • Alarms • Controlled programming Feb.05 25 DUODOPA® Treatment TEST PERIOD Temporary Nasoduodenal tube to test the clinical response Feb.05 PERMANENT Treatment Permanent catheter implanted into the duodenum via a Percutaneous Endoscopic Gastrostomy (PEG) 26 DUODOPA® TEST PERIOD (1) • Temporary treatment ► 3 to 5 days duration • Evaluation of positive clinical response • Dose titration • Fine tuning to individual needs • Steps as little as 2 mg of levodopa • Pump acceptability and handling Feb.05 27 ® DUODOPA TEST PERIOD (2) • Adjustable dose Schedule – Morning bolus dose • To rapidly reach a steady state of plasma concentration – Maintenance infusion rate • During the day (over 16 hours) • Exceptionnally during 24 hours – Extra doses • As little as 2 mg of levodopa • Can be self administered by the patient when needed Feb.05 28 ® DUODOPA PERMANENT Treatment • Continuous intra-intestinal infusion – Through a permanent catheter implanted into the duodenum via a Percutaneous Endoscopic Gastrostomy (PEG) under local anesthesia • Monotherapy – For most patients on a long term treatment • Individual adaptation of dose – Fine tuned titration – Morning and extra doses and infusion rate adjustable in steps of 2 mg Feb.05 29 ORPHAN EUROPE Services • Material for Duodopa® system : – – – – Nasointestinal tube PEG tube / Inner tube Pump delivery and service Holster, vest or belt…. ► provided free of charge by ORPHAN EUROPE • Additional services : – Educational support (patient, family, caregivers… ) – Hospital staff support Feb.05 30 DUODOPA® Patients Feb.05 31 DUODOPA® Patient profile How to select the first patient to build up experience : - Severe motor fluctuations - Tried different oral drug combinations - Clear response to levodopa ► good “ON” period - Preferably no dementia - Preferably no depression - No age limit restrictions Feb.05 32 DUODOPA® Swedish experience General profile of the Duodopa® patients • Number of treated patients : ► ~ 100 • Age : – 49-82 years old – most of them were between 55 and 70 years old when they started • Prior treatment duration with various combinations of PD therapies before Duodopa® ► 10-15 years • Average duration with Duodopa® treatment : ► ~ 4 years Feb.05 33 Case Study – Swedish patient History of the disease Born in 1951 Professor of Physics in Uppsala University First Symptoms of PD in 1991 : 40 years old In 1999 :Unpredictable motor complications « ON » periods of good quality with levodopa Different Treatments 1991-2000 : Oral treatments with levodopa /selegiline/cabergoline In 2000 : Included in a trial with Duodopa® via nasoduodenal tube. He was well–controlled but at the end of the study ► Reluctant to a permanent infusion system ► He refused a DBS afraid of risks associated with Neurosurgery ► He came back to previous oral treatments In 2001 : increasing motor fluctuations ► Levodopa combined with Apomorphine infusion In 2002 : He is included in a new trial with Duodopa® on Monotherapy Then he chose the permanent treatment with DUODOPA® since March 2003 Feb.05 34 Case Study – Swedish patient Follow-up On monotherapy with DUODOPA® he improved considerably Patient fully satisfied with his new treatment and very well equilibrated. Only minor motor fluctuations observed He is still under monotherapy during the day (6 am to 10 pm), he takes oral levodopa during the night but no other medications He can now work on a 75 % basis. … and he goes to his work by bike! Feb.05 35 Conclusion • Unmet medical need fulfilled : ► Continuous Dopaminergic Stimulation achievable with Levodopa as Monotherapy • Patient’s positive response is confirmed before permanent treatment (Test period) • Individualized treatment : ► adjustable in steps of 2 mg (0.1ml) ► efficient ► safe • Improved Quality of life Feb.05 36 BACK-UP Feb.05 37 Case Study – German patient n°1 History of the disease Born in 1936 - Female 1973-1995 : Symptoms of PD 1995 : Diagnosis of PD (59 years old) 2003 : Severe motor complications « ON » periods of good quality with levodopa Different Treatments 1973-1995 : psychopharmaceutical drugs 1995-2004 : oral treatments : combination of Levodopa and dopaminergic agonists 2004 : Heavy fluctuations – switch within 15 min from -3 to +3 Very short normal « ON » phases in a day DBS and Apomorphin refused by the patient Nov 2004 : DUODOPA® implementation Follow up Increased « ON » periods, with clear clinical improvements Patient very satisfied : fantastic improvement of her daily live Feb.05 38 Case Study- German patient n°2 History of the disease Born in 1941 – Male – Architect 1985 : First symptoms of PD (48 years old) Since 2003 : Severe motor complications and psychotic symptoms though oral treatments Some « ON » periods of good quality with levodopa Different treatments 1985 - 2004 : Oral treatments : combination of Levodopa, dopaminergic and agonists COMT inhibitors DBS refused by the patient Dec 2004 : DUODOPA® implementation Follow up Increased « ON » periods, about 95% compared to previous treatment Only 2 or 3 short “OFF” periods per day well controlled with extra doses No psychotic symptoms any more Patient extremely satisfied Feb.05 39 DIREQT Duodopa® Infusion - Randomised Efficacy and Quality of life Trial • Duodopa® monotherapy vs any combination of conventional medication • 24 patients, 5 centres in Sweden • Video recordings, ”blinded” scoring • Efficacy and Quality of Life - electronic home diary Nyholm et al., 2005 Feb.05 40 DIREQT – Study design Black boxes = duodenal levodopa/carbidopa gel infusion monotherapy. White boxes = conventional combination pharmacotherapy. Arrows pointing downwards indicate video recordings every 30 min. for 8 hrs. Figures indicate weeks. Nyholm et al., 2005 Feb.05 41 Treatment response scale Video Scoring Percentage of recordings in grouped intervals of the Treatment Response Scale -3 to -2 = severe OFF to moderate OFF -1 to +1 = mild OFF, normal, mild dyskinesia (”functional ON”) +2 to +3 = moderate dyskinesia; severe dyskinesia Feb.05 42 Video Scoring • Video recording every 30 min from 8 am to 5 pm (18 points) 4 tasks: – – – – Piano playing Alternate hands movement Getting up from a chair Walking • Motor abilities evaluated by investigator on the rating scale • Rating from video scoring shows that patients treated with DUODOPA® spent more time in “normal” motor state on infusion and less time in both “OFF”state and “hyperkinetic” state -3 Severe parkinsonism -2 Parkinsonism -1, 0, +1 “On” +2 +3 Feb.05 “OFF” State “Normal” motor State Dyskinesia Severe dyskinesia “Hyperkinetic” State 43 Dose rating scheme Tablets 9/5 2002 R-M G +3 +2 +1 0 -1 -2 -3 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Morning dose Speed Extra dose Other treatment Tablet treatment Feb.05 44 Dose rating scheme Duodopa® 15/5 2002 R-M G +3 +2 +1 0 -1 -2 -3 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Morning dose 2 ml 40 mg Speed 34 1.7mg/h ml/h 12 mg 0.6 ml Extra dose 16 0.8mg ml Other treatment Duodopa® : Levodopa 20 mg/ml - Carbidopa 5 mg/ml Feb.05 45 DUODOPA® Gel formulation Advantages Problems with existing Levodopa formulations Solved by DUODOPA® formulation Limited solubility, large volumes (1-2 mg/ml =1000 - 2000 ml to cover a daily need of 2000 mg) 20 mg/ml covers a daily need of 2000 mg in a 100 ml cassette. Poor stability of solution in room temperature and light, supply needs to be changed during the day Good long-term stability in refrigerator, the content of one cassette is stable for a whole day at room temperature. Large infusion pumps Portable specially designed pump, weights about 18 oz. (510g) including a full cassette. Feb.05 46 DUODOPA® storage condition • Deep frozen at end of manufacture ► Can be stored for 2 years in freezer at – 20°C • At the pharmacy storage and patient’s house ► Must be kept refrigerated between 2°C to 8°C • 15 weeks shelf-life when stored in refrigerator • The gel suspension in 1 cassette is stable 24 hours at room temperature Feb.05 47 Advantages of Problems with Oral Levodopa/Carbidopa ® DUODOPA Solved by the DUODOPA® administration Fluctuating pharmacokinetics due to erratic gastric emptying, i.e. “pulsatile” dopaminergic stimulation Smooth pharmacokinetics due to constant infusion to the site of absorption, i.e. Continuous Dopaminergic Stimulation Extra tablet doses of 50-100 mg may add to the previous dose, due to delayed gastric emptying, forming high peak concentration and severe dyskinesia Extra doses of e.g. 10 mg, adjustable in steps of 2 mg, do not produce any marked peaks in the concentration curve, i.e. the patient turns “ON” without dyskinesia Individualized therapy is difficult with The morning dose and extra doses tablet strengths of 50-200 mg are adjustable in steps of 2 mg and the infusion rate in steps of 2 mg/hr Feb.05 48