PD Treatment: unmet clinical need Vienna, April 2011 Heinz Reichmann, MD, PhD, FAAN, FRCP Department of Neurology University of Technology Dresden, Germany Dresden Opera House

Two Contrary Quotations Parkinson’s disease doesn’t kill you, it takes your life away English Parkinson Lay Organisation There is no other neurodegenerative disease which could be treated better than Parkinson’s disease Heinz Reichmann, Physician, University of Dresden, Germany

Unmet clinical needs from a patient‘s perspective Etiology Why have I got this disease? Have I done something wrong? How can I stop the progression?

a-Synuclein–positive Lewy bodies in Host Substantia nigra and Grafted Dopaminergic Neurons. Li J-Y et al.Nature Medicine (2008), 14.

Olanow CW & Prusiner SB (2009)

Unmet clinical needs from a patient‘s perspective Disease course How can I avoid that other people notice my impairments? How can I stay stable and ambulant? How can I avoid motor fluctuations How can I deal with psychiatric problems? How can I deal with disturbances of the autonomic nervous system? How can I deal with pain, hyposmia, vision and sleep problems?

Key issues in the medical management of PD: a physician‘s perspective Early disease Establish symptomatic control Avoid motor complications Modify progression Advanced disease Maintain symptomatic control Control motor complications Control non-motor complications

Advantages of early treatment Reverse dopaminergic symptoms Maintain QoL Maintain symptom control Support compensatory mechanisms Slow progression There are numerous advantages to the patient if treatment is initiated early. For example, early treatment may reverse dopaminergic symptoms, maintain symptom control, and may even support the compensatory mechanisms involved in maintaining the dopaminergic symptoms despite the progressive loss of dopaminergic neurones in the substantia nigra. Furthermore, early treatment may allow patients to maintain their quality of life and could lead to a slower progression of the disease. 9

Neuroprotection “Interventions that produce enduring benefits by favorably influencing underlying etiology or pathogenesis and thereby forestalling onset of illness or clinical decline” Shoulson, Mov Disord 1998 In early disease, there also remains the issue of the need for a treatment that modifies disease progression. This slide shows a quote from a paper that Ira Shoulson published in 1998. It is a definition of what neuroprotection should be in PD or any neurodegenerative disorder. The term ‘neuroprotection’ should be applied to interventions that influence the underlying aetiology. It could be argued that, if such drugs really do have an influence on the underlying aeitology, that these interventions should – if they are to be called neuroprotective – somehow delay the onset of illness, or they should at least delay the clinical decline.

James Parkinson on Neuroprotection “... there appears to be sufficient reason for hoping that some remedial process may ere long be discovered, by which, at least, the progress of the disease may be stopped.” J. Parkinson, 1817

Neuroprotection trials in Parkinson’s disease – pitfalls Symptomatic effects of intervention Non-linear clinical scales Definition of primary endpoints Onset of study Inhomogeneous study population Duration of study The search for neuroprotective drugs has been one of the major challenges, not only in treatment, but also in the design of clinical trials. Trial designs are required that would be able to show that a given drug intervention would actually meet the definition of neuroprotection. This slide shows some of the pitfalls encountered in the design of clinical trials attempting to show neuroprotective properties of PD therapies. There are trial design issues such as the presence of confounders, for example, with drugs that have symptomatic efficacy. Study designs of a potentially neuroprotective agent have attempted to overcome the issue of confounding symptomatic efficacy be utilising a wash-out period at the end of the treatment intervention. Then, there is the question of how long the wash-out period would need to be in order to be sure that no symptomatic effect remains. Even if the length of wash-out period could be established – say two or three months – there has to be a consideration of whether this would be tolerated by patients and whether it would be feasible using the scales required for clinical trials. In particular, the UPDRS has raised some issues. This is a non-linear scale and, therefore, there is an issue surrounding the best end-point to use in order to show neuroprotection, and the study duration required. Thus, it is not an easy task to assess the disease-modifying efficacy of a drug.

The ADAGIO Study with Rasagiline Figure 3. Changes in Scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) in the Four Study Groups. The mean (±SE) change from baseline in the UPDRS score in the efficacy cohort for the second and third primary end points for patients receiving rasagiline at a dose of 1 mg per day (Panel A) and those receiving 2 mg per day (Panel B) are shown. The dashed lines indicate placebo, and the solid lines indicate rasagiline. Olanow et al. NEJM 2009

The ideal drug to treat Parkinson’s disease Need Current availability Symptomatic efficacy + Long-term benefit +/- Well-tolerated +/- Long duration of action +/- Simple titration and dosing -/+ No motor-complications +/- Disease-modifying efficacy +/- Please could you explain the -/+ for ‘simple titration and dosing? This slide summarises the current position with respect to availability of the ideal drug/drugs to meet the therapeutic needs in PD. Ideally, in early disease, drugs with symptomatic efficacy are required, and it can be concluded that a range of possible options are available. In addition, however, there is a requirement for drugs that provide enduring efficacy. This need is only partially met, for example by drugs – such as levodopa – which continue to be effective long-term in PD, but disappointingly at the cost of development of fluctuations. Other drugs lose their benefit over time, and so this leaves an ambiguous situation with respect to the ideal drug for long-term benefit. Many of the currently available drugs are well tolerated in many PD patients. However, none meet the ultimate goal of being perfectly tolerated by all patients. Thus, again, improvements with respect to tolerability are required. Drugs with a long duration of action are needed. This issue concerns the role of drugs with short-lived duration of action and consequent pulsatile dopamine receptor stimulation which leads to the development of dyskinesias. Drugs with a long duration of action are available but, ideally, what is required is a drug that has a very long duration of action that would also be very simple to dose – once daily, or even less. This would be of enormous benefit to patients, and is certainly an area for improvement. Drugs are required that are free of long term side effects in terms of motor complications. Some progress has been made in this respect, for example with the dopamine agonists, but this need has not been completely met. The ultimate, and as yet unfulfilled, need is to have a drug that modifies disease progression.

Avoidance motor complications in RCTs of early PD monotherapy <.02 (n = 208) (n = 211) 0 1 2 3 4 5 Years * Risk of developing motor complications over 5 years: cabergoline* versus levodopa Cabergoline delays onset of motor complications *All cabergoline-treated patients with early Parkinson’s disease, including those with levodopa supplementation. Rinne UK, et al. Drugs 1998; 55 (Suppl 1): 23-30. P < 0.001 Therapy Levodopa (N=146) Pergolide (N=147) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time (months) 3 6 9 12 15 18 21 24 27 30 33 36 Survival Distribution Function Time to onset of positive UPDRS Part IV A, question 32 (presence of dyskinesia) Time to onset of dyskinesia: Kaplan-Meier plot 0.00 0.20 0.40 0.60 0.80 1.00 1 2 3 4 5 Years Survival distribution function * *Low denominator beyond this time point 143 73 125 67 111 62 101 56 85 45 179 89 Hazard ratio 2.82 95% CI [1.78, 4.44] p<0.0001 UPDRS item 32 & AE information [Prof. Quinn, London, UK] Ropinirole (N=179) L-dopa (N=89) Dyskinesias: all patients regardless of L-dopa supplementation Pramipexole* is associated with a lower risk of developing motor complications compared with levodopa (2 years’ results) 10 20 30 40 50 60 200 400 600 800 Days from randomisation Patients with motor complications (%) P <.001 Levodopa Pramipexole However, the objective of delaying the onset of motor complications is not fully resolved. Even although there is a reduced risk for dyskinesias and motor fluctuations when treatment with a dopamine agonist is initiated instead of levodopa, over the years, in all these trials, patients subsequently went on to develop complications even if they had been started on a dopamine agonist. Thus, the therapeutic need to control or to prevent motor complications is met, in part. But, as treatment continues, and as disease progresses, patients on dopamine agonists will need supplemental levodopa. Although at lesser rates, patients will still develop motor complications in terms of dyskinesias and fluctuations. *All pramipexole-treated patients, including those with levodopa supplementation. Parkinson Study Group. JAMA 2000; 284: 1931-1938.

Continuous dopaminergic stimulation: dopamine agonists Oral dopamine agonists with long elimination half-life Subcutaneous infusion of apomorphine Transdermal application

Progression of PD complications N=368 patients from DATATOP treated with levodopa New onset of motor and non-motor complications over 2 year follow-up ‘wearing-off’ 52% ON–OFF 9% dyskinesias 14% FoG 29% confusion 7% dementia 3% As disease progresses, the development of motor complications related to levodopa drug treatment is not the only problem. This slide shows a summary of results from the DATATOP trial, published by the Parkinson Study Group. A sub-cohort of patients were re-randomised at the end of the original phase of the study, and were followed for a further 2 years. Incidences of the development of motor and non-motor complications over a short period of 2 years were observed. This was a large group of patients receiving levodopa treatment. With ongoing levodopa treatment, 50% of patients developed ‘wearing-off’, and 14% experienced new dyskinesias over this 2-year period. Over as short a period as 2 years, there were also other new-onset problems, such as freezing of gait (FOG), which was quite frequent (29%). These gait problems, and freezing in particular, are significant in PD. Shoulson et al. Ann Neurol 2002; 51:604-612 FoG = freezing of gait

Prevalence of parkinsonian signs and associated mortality in a community population of older people N=159 No parkinsonism N=301 Parkinsonism with no gait disturbance N=36 Parkinsonism with gait disturbances Some studies have found that the presence of gait problems/disorders was a predictor of mortality. This slide shows results of a community-based survey of the elderly in Manhatten, New York. It indicates that, among parkinsonian patients (all kinds of parkinsonisms are grouped together) in this study, those patients with gait disturbances had a reduced probability of survival. Thus, the development of problems such as gait disorders and, of course, also cognitive disorders such as dementia, is an issue for the long-term prognosis of PD. Bennett et al. New Eng J Med 1996; 334:71-76

Complications of disease progression in Parkinson’s disease Levodopa-related motor complications Response fluctuations Dyskinesias Disease-related motor complications Freezing Postural imbalance Dysarthria and dysphagia Non-motor complications Neuropsychiatric morbidity Sleep disorders Autonomic dysfunction Regardless, of the current treatment options, and even if new drugs become available that will modify disease progression, it will remain the case that PD continues to be a progressive disorder. This slide illustrates the various complications of disease progression of advanced PD. Irrespective of the treatment approach, complications of advanced disease arise. These complications occur eventually, regardless of how treatment is started. Ultimately, a certain percentage of patients will develop motor complications – including disease-related, rather than treatment-related motor complications, such as the increase in prevalence of gait disorder or postural imbalance – and, of course, non-motor complications. Thus, there continue to be significant challenges facing optimal treatment of PD.

Invasive Treatment

Non-motor features of Parkinson’s disease Neuropsychiatric: depression anhedonia / apathy fatigue anxiety frontal-executive dysfunction dementia psychosis Hyposmia Sleep disorders: insomnia daytime sleepiness RBD Autonomic dysfunction: orthostatic hypotension constipation urogenital dysfunction Dementia is a main challenge area within the non-motor features of PD. In the long term, with advancing neurodegeneration in PD, dementia is seen in up to 40% of patients. However, there are also other neuropsychiatric problems, such as depression, anxiety, psychosis, sleep disorders, and autonomic dysfunction. Considering the current pharmaceutical armamentarium for these non-motor features of PD, this is a depressing scenario. Reichmann H, Neurodeg.Disord.2010;7:284-290

The PRIAMO Study Barone P et al. (2009)

Impairment of Qualtiy of Life in PD Schrag et al. J Neurol Neurosurg Psychiatry 2000;69:308–12.

Starkstein SE et al. Mov Disord 2009;24:1211-1216 ) Starkstein SE et al. Mov Disord 2009;24:1211-1216

Starkstein SE et al. Mov Disord 2009;24:1211-1216

Prevalence of Depressive Disorders and Symptoms in Parkinson’s Disease Major depressive disorder Clinically relevant depressive symptoms Population Number of studies Prevalence General population 4 8.1 5 10.8 General practice - 2 42.3 Outpatient setting 11 24.0 25 40.4 Inpatient setting 1 21.7 3 54.3 Nursing home 32.7 Values vary widely due to: Different diagnostic approaches Different cohorts Few data on incidence Mostly publications on prevalence in tertiary care centers Average prevalences Major Depressive D 17% Minor Depressive D 22% Dysthymia 13% Clinical relevant depressive symptoms 35 % Prevalence rates of depressive disorders in PD vary widely across studies. Differences in diagnostic approaches and cohorts are likely explanations. A recent review found major depressive disorder in 17% of PD patients, minor depression in 22% and dysthymia in 13%. Clinically significant depressive symptoms, irrespective of the presence of a DSM defined depressive disorder, were found in 35%.1 The PRODEST-PD study (PROfile of DEpressive SympToms in Parkinson’s Disease), a recent large multicenter study, found major depression in 9.2% of PD patients.2 References Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 2008;23(2):183-9. Barone P, Goetz CG, Houben JJ, et al. PRODEST--Depressive symptoms in Parkinson’s disease: Effect of antidepressant treatment on symptom items of depression. Poster presented at the 60th AAN Annual Meeting, Chicago, IL, USA, April 12-19, 2008, P05.145. Reijnders JS, et al. Mov Disord 2008;23(2):183-9.

Dementia, Depression and Psychosis in German PD patients (n=1,326) 70.0 67.4 Dementia: 40.4 % Depression: 37.2 % Psychosis: 20.4 % Prevalence < 65 Years 66-75 Years > 76 Years 60.0 50.0 44.5 40.0 37.3 34.9 33.7 32.0 30.0 18.6 20.0 17.0 10.4 10.0 0.0 Dementia Depression Psychosis Riedel O, et al. J Neurol 2008;255:255-64.

Pramipexole Was Superior to Placebo in Reducing PD-Related Depressive Symptoms Geriatric Depression Scale (GDS) Total Score after 12 Weeks -4,0 -3,0 -2,0 -1,0 0,0 Change in GDS Total Score P = 0.03 Baseline Geriatric Depression Scale (GDS) scores showed a reduction in depressive symptoms in the active treatment group that was apparent from Week 5. Adjusted mean changes in GDS total scores after 12 weeks were -1.7 in the placebo group and -2.5 in the pramipexole group. The treatment difference of -0.8 (95% CI: -1.5, -0.1) had a significant P-value of 0.0346.1 Reference Barone P, Poewe W, Tolosa E, et al. Efficacy of double-blind, placebo-controlled pramipexole against depression in Parkinson’s disease, MDS 13th International Congress, Paris, France, June 7-11, 2009, Poster Mo-248. Pramipexole (n = 139) Placebo (n = 148) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (Weeks) Barone P, et al. Lancet Neurol 2010. Epub ahead of print.

Nortriptyline Is Superior to Paroxetine CR in Depressed PD Patients -2 -4 -6 HAM-D change -8 -10 Placebo Nortiptyline -12 Paroxetine In a randomized controlled trial on 52 PD patients with depression, nortriptyline—a norepinephrine and serotonin reuptake inhibitor—was superior to placebo with a response rate of 53% (placebo 24%). Nortriptyline was superior to the selective serotonin reuptake inhibitor (SSRI) paroxetine CR. Paroxetine CR was not superior to placebo. Responders were defined as having a ≥50% improvement on the Hamilton Depression Rating Scale.1 Combined noradrenergic and serotonergic reuptake inhibition may be more effective in treating depression in PD than SSRI. Reference Menza M, Dobkin RD, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009;72:886-92. -14 2 4 6 8 Weeks from baseline Depression in PD was improved significantly with nortriptyline Menza M, et al. Neurology 2009;72:886-92.

The senses and intellect are uninjured

Epidemiology of Parkinson Dementia About 40% of PD patients suffer from dementia PD patients have a six fold increased risk for dementia 10 20 30 40 50 60 70 80 90 Year 8 Year 12 Year 16 % PD-patients with dementia 3 Key point: Dementia is commonly associated with PD. Dementia is a common occurrence in PD, although epidemiological reports vary widely due to differing methods of cognitive assessment, definitions of dementia and study populations. Dementia associated with PD has an average prevalence of up to 40% in cross-sectional studies.1 The prevalence of dementia is up to six times higher in patients with PD than that in age-matched healthy controls. As shown in the slide, which presents 8-year longitudinal data from PD patients without dementia at baseline in whom the prevalence of dementia was prospectively studied, the condition had a prevalence approaching 80%.2 1Cummings JL. J Geriatr Psychaitry Neurol 1988;1:24–36; 2Aarsland D et al. Arch Neurol 2003;60:387–92. Aarsland D et al. Arch Neurol 2003;60:387–92 Emre M. Lancet Neurol 2003;2:229–37

EXPRESS Extension-Study Week 0-24 Week 25-48

EXPRESS Study and Extension Study Double-blind phase Open-label extension (all patients receiving rivastigmine) -4 -3.5 Improvement -3 -2.5 Rivastigmine Placebo Change from baseline, NPI-10 -2 -1.5 -1 -0.5 Baseline Week: 0 16 24 48 Rivastigmine, n = 179 177 178 171 Placebo, n = 99 99 97 96

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