Advanced Therapies for Motor Symptoms in PD. Matthew Boyce MD

Transcription

1 Advanced Therapies for Motor Symptoms in PD Matthew Boyce MD

2 Medtronic Education Teva Speakers Bureau Acadia Speakers Bureau Disclosures

3 Discuss issues in advanced PD Adjunct therapies to levo-dopa Newer formulations of levo-dopa Objective

4 Rigidity Bradykinesia Tremor Gait issues Freezing, shuffling Dyskinesia/dystonia Motor Features

5 ELLDOPA Trial

6 Lang AE, and Lozano PD Medication AM. Treatment: Parkinsons Some Disease. Potential Flows Second of two Monotherapy-MILD parts. (Review) N Eng JN of Medicine 1998; MODERATE 339; SEVERE MILD/MODERATE MAO-B Levodopa COMT Dopamine Agonist (decrease Levodopa) Anti cholergernic COMT Levodopa Older patients Amantadine MAO-B Dopamine Agonist (2x) Levodopa Anti cholergernic COMT Levodopa Younger patients Amantadine MAO B- Rasagiline Dopamine Agonist Levodopa Levodopa Dopamine Agonist MAO-B COMT Anti cholergernic Amantadine After 5 years of treatment with Levodopa Use- Dyskinesia and Motor Fluxuations develop in ~50% of patients. * Lang (1998) * Dyskinesia incidence increases with levodopa use Adapted from Lang AE, and Lozano AM. Parkinsons Disease. Second of two parts. (Review) N Eng JN of Medicine 1998; 339;

7 Dopamine agonists MAOI COMT Inhibitors Apokyn Amantadine, ADS-5102 Adjuct Therapies

8 Xadago (Safinimide) MAOb-I FDA approved March 2017 Off time reduced by hour with similar increase in good on time compared to 0.6 hours with placebo Gocovri - ER Amantadine FDA Approved Aug mg amantadine taken once at bedtime 37-48% vs % reduction in UDysRS 3.6 and 4.0 hour increase in functional time daily vs. a 0.8 and 2.1 hour increase Adjunct Therapies

9 2006 AAN Practice Guidelines on treatment of motor fluctuations and dyskinesia Conclusions. Entacapone (two Class I studies) and rasagiline (two Class I studies) are established as effective in reducing off time. Pergolide (one Class I study), pramipexole (one Class I and one Class II study), ropinirole (two Class II studies), and tolcapone (two Class II studies) are probably effective in reducing off time. Apomorphine subcutaneously injected (one Class II study), cabergoline (two Class III studies), and selegiline (one Class II study, one Class III study) are possibly effective in reducing off time. Based on four Class III studies, sustained release carbidopa/levodopa does not decrease off time compared to immediate release. Amantadine is possibly effective for reducing dyskinesia (one Class II) Adjunct Therapies

10 Sinemet CR Rytary L-dopa Intestinal Gel, Duopa CVT-301 (Inhaled) Pump-patch, liquid L-dopa Levo-dopa

11 Rytary

12 APEX-PD Rytary in L-dopa naïve patients ADVANCE-PD Rytary vs IR CD/LD in advanced PD Ascend-PD Rytary vs CD/LD/ENT in advanced PD Rytary

13 APEX-PD RCT, double blind, fixed dose vs placebo Titrated to 145, 245, or 390 TID Primary endpoint, change in UPDRS II and III Improvement was 11.7, 12.9, and 14.9 points for the three dosages and 0.6 points for placebo Rytary

14 ADVANCE-PD RCT, double blind, parallel group 3 week optimization of IR CD/LD then 6 week dose conversion period all open label to determine optimum dosing Random assignment to Rytary vs IR for 13 weeks PD duration 7.4 years, mean off time 5.97 hours Mean daily dose Rytary 2:1 over IR CD/LD Rytary 3.6 doses/day vs IR CD/LD 5.2 doses/day Extra 1.2 hour reduction in off time Rytary

15 ASCEND-PD RCT, double blind, crossover in patients on CLE with 2.5 h/d off time 6 week open label dose conversion period Randomized, two 2 week crossover treatment periods separated by 1 week open label rytary washout period LD dosage 1723 mg (Rytary) vs 652 mg (CLE) 3.5 doses vs 4.7 doses 3.8 h vs 5.2 h, mean daily off time, with increase in on time without troublesome dyskinesia Significant patient preference for Rytary 52.5% vs 27.4% Rytary

16 Conversion from IR C/L Take 24 hr amount of IR and double it, divide that by 3-4 doses to roughly approximate the dose of Rytary Can err on the low side and use 95 mg capsules to further adjust Once on stable dosing convert to the lowest daily quantity of capsules Rytary

17 Adverse events Nausea Dizziness Falls Insomnia Dyskinesia Rytary

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19 Duopa

20 Continuous infusion of carbidopa/levodopa via a pump delivered through a J-PEG 20/5 mg/ml levo-dopa/carbidopa An initial MORNING DOSE is delivered followed by a continuous infusion over 16 hours Patients can have an EXTRA DOSE at set intervals Duopa

21 Procedure JPEG placed by gastroenterology, surgery, IR Programming Can be done in the hospital or clinic Calculate morning dose Morning (l-dopa x 0.8)/20 mg/ml = X ml, then add 3ml Calculate continuous dose Remaining l-dopa dose for the day/ 20 mg/ml Then divide by 16 hours = X ml/hr Set an extra dose Start with 1ml, increase by 0.2 ml increments Q2h Duopa

22 2014 double blind, double-dummy 12 week trial showed 4 hour reduction in off time compared to 2.1 hour improvement with IR C/L Olanow CW Lance Neurol month, open-label results 354 patients, Fernandez HH Mov Disorders AE while common (92%) were generally transient 32.4% had SAE (device insertion, abdominal pain) 7.6% discontinued due to any AE Off time reduced by 4.4 hours and was sustained On time without troublesome dyskinesia increased 4.8hours 78% were much or very much improved on CGI-I Duopa

23 Effect on dyskinesia Antonini A, Mov Dis 2015 Post-hoc analysis of 12 week double blind and 54 week open label study looking at patients with initial TSD of at least 1 hr/day Double blind Reductions in Off time as well as reductions in On time with TSD and increase in On time without TSD Not significantly different then IR group but trended better Open label Off time 36% to 14 % On time with TSD 21% to 10% On time without dyskinesia 22% to 50% Effect of Duopa on Nonmotor symptoms, open label 60 weeks study Standaert DG Mov Dis Clin Prac 2017 Reduced NMSS by 17.6 ± of the 9 domains were reduced through to week 60 Sleep/fatigue, attention/memory, GI, sexual function, misc Duopa

24 CVT-301 Inhaled levodopa Apomorphine subcutaneous pump Solubilized levodopa methylester salt via subcutaneous pump, neuroderm Near Future

25 THANK YOU