PD Treatment: unmet clinical need
Vienna, April2011 Heinz Reichmann, MD, PhD, FAAN, FRCP Department of Neurology University of Technology Dresden, Germany Dresden Opera House Two Contrary Quotations
Parkinsons disease doesnt kill you, it takes your life away English Parkinson Lay Organisation There is no other neurodegenerativedisease which could be treated better than Parkinsons disease Heinz Reichmann, Physician, University of Dresden, Germany Unmet clinical needs from a patients perspective
Etiology Why have I got this disease? Have I done something wrong? How can I stop the progression? a-Synucleinpositive 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 patients 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 physicians 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 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 reasonfor hoping that some remedial processmay ere long be discovered, by which,at least, the progress of the disease maybe stopped. J. Parkinson, 1817 Neuroprotection trials in Parkinsons 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 Parkinsons 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 Parkinsons disease
NeedCurrent 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