pd treatment: unmet clinical need
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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, GermanyTRANSCRIPT
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