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Treatment principles

Treatment principles. Parkinson’s disease. Current treatments and medications. Levodopa. Levodopa (L-dopa) is the naturally occurring ‘L-isomer’ of the amino acid dihydroxy- phenylalanine (an isomer is a chemical with the same formula but a 3-dimensionally different structure) 1

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Treatment principles

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  1. Treatment principles Parkinson’s disease

  2. Current treatments and medications

  3. Levodopa • Levodopa (L-dopa) is the naturally occurring ‘L-isomer’ of the amino acid dihydroxy-phenylalanine (an isomer is a chemical with the same formula but a 3-dimensionally different structure)1 • Levodopa is transported into the brain across the blood–brain barrier, where it is the precursor to several neurotransmitters, including dopamine2 • To preserve levodopa for the brain, by preventing the conversion of levodopa to dopamine outside the brain (which may be associated with peripheral dopaminergic effects such as nausea and vomiting), levodopa is prescribed with a ‘peripheral’ dopa decarboxylase inhibitor2,3 • Levodopa, once converted to dopamine in the brain, increases the levels of dopamine, counteracting the pathologically low levels of the neurotransmitter in the PD brain1,2,4 • Levodopa treatment needs to be tailored to the needs of the individual patient3 O HO OH H NH2 HO 1. Hornykiewicz. J Neurol 2010;257(Suppl 2):S249–252; 2. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014;3. Jankovic & Aguilar. Neuropsychiatr Dis Treat 2008;4(4):743–757; 4. Trenkwalder et al. Neurology 2019;92(13):e1487–e1496

  4. DOPAMINE L-DOPA (+ DDI) DOPA MAO-A DDC DOPAMINE Mechanism of action of levodopa plus a peripheral dopa decarboxylase inhibitor Click to watch the animation Blood–brain barrier DDC Short burstsof drug release COMT 3-OMD DAT HVA Rapid inactivation HVA DOPAC D2 D5 D1 D3 D4 Post-synaptic neurones MAO-B Glial cell

  5. Strengths and limitations of levodopa Short half-life (~1 hour)1 1 Gold standard, the most effective symptomatic therapy in PD4,5 1 Only a small percentage of oral levodopa reaches the brain1 2 Strengths Limitations Early wearing-off leading to reduced quality of life2,3 Acceptable tolerability profile5 3 2 Levodopa Motor fluctuations and dyskinesia will develop over long term treatment3,4 4 Improvements in quality of life seen in short term6 3 1. Nutt & Fellman. ClinNeuropharmacol 1984;7(1):35–49; 2. Chapuis et al. MovDisord 2005;20:224–230; 3. Freitas et al. SeminNeurol 2017;37(2):147–157; 4. Hametner et al. J Neurol 2010;257(Suppl 2):S268–S275;5. Ferreira et al. Eur J Neurol 2013;20(1):5–15; 6. Sethi. Neurologist 2010;16(2):76–83

  6. Change in levodopa response over time – ‘wearing-off’ Advanced PD1,2(short duration of clinical response) Moderate PD1,2(diminished duration of clinical response) Early PD1,2(smooth, extended duration of clinical response) • Levodopa therapy can be complicated by the development of motor complications, which include dyskinesias and motor fluctuations; this typically occurs after several years of treatment1-3 • There is evidence that motor fluctuations and dyskinesias are not associated with the duration of exposure to levodopa therapy, but rather to disease progression itself3 • The initial long duration response to a dose of levodopa (gold line on graph) becomes progressively shorter, and periods in which the patient responds to the drug become complicated by involuntary dyskinetic movements1,2 Window of good treatment responsea Clinical effect 2 4 6 Time (hours) Levodopa dose aThe window of good treatment response narrows as patients with PD progress to the more advanced stages 1. Adapted from: Obeso et al. Neurology 2000;55(4 Suppl):2. Adapted from: S13; Schapira et al. Eur J Neurol 2009;16(9):982–989; 3. Cilia et al. Brain 2014;137(Pt 10):2731–2742

  7. Dyskinesia and motor fluctuations Risk of dyskinesia Blood concentration of levodopa Good symptom control Clinical response Risk of akinesia Wearing-off/delayed ON Wearing-off/delayed ON Nocturnal akinesia Early morningakinesia Time Dose • Dose • Dose • Dose Adapted from: Stacy. NeurolClin 2009;27(3):605–631; Chapuis et al. MovDisord 2005;20(2):224–230

  8. Other medications used in the treatment of Parkinson’s disease (I) Dopamine agonists (DAs)1 • DAs mimic the action of dopamine by activating dopamine receptors • DAs are useful as monotherapy in earlier stages of PD, and are also useful as adjunctive treatment in patients experiencing motor fluctuations1,2 • DAs can cause/contribute to a variety of side effects, including nausea, psychosis and ‘impulse control disorders’ (e.g., hypersexuality, pathological gambling, binge eating, and compulsive buying)1,3 Dopamine and DAs at the synapse4 1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014;2. Fox et al. Mov Disord 2018;33(8):1248–1266; 3. Apomorphine. SPC. 2018;4. Lundbeck Institute Campus. https://institute.progress.im/en/image-bank

  9. Other medications used in the treatment of Parkinson’s disease (II) Monoamine oxidase type B (MAO-B) inhibitors1,2 • MAO breaks down dopamine • MAO-B inhibitors have shown efficacy in patients with PD as monotherapy or as adjunct therapy MAO-B inhibitor mechanism of action at the synapse3 MAO-B=monoamine oxidase type B 1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014;2. Fox et al. Mov Disord 2018;33(8):1248–12663. Lundbeck Institute Campus. https://institute.progress.im/en/image-bank

  10. Other medications used in the treatment of Parkinson’s disease (III) Catechol-O-methyltransferase (COMT) inhibitors1 • COMT breaks down levodopa • To increase the amount of levodopa that gets to the brain, COMT inhibitors are used to decrease the metabolism of levodopa • COMT inhibitors increase the half-life of levodopa by up to about 50% • In some countries, a COMT inhibitor is available with levodopa/decarboxylase inhibitor as a combination tablet, easing the patient’s pill burden COMT=catechol-O-methyltransferase 1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014; 2. Lundbeck Institute Campus. https://institute.progress.im/en/image-bank

  11. Other medications used in the treatment of Parkinson’s disease (IV) Non-dopaminergic agents • Anticholinergic therapies have been shown to be useful in the symptomatic treatment of PD1-3 • Excessive activation of glutamate receptors is thought to at least partly explain levodopa-induced dyskinesias – drugs with actions on the glutamate system have been shown to treat the symptoms of PD1 • Other agents targeting other neurotransmitters are currently under investigation1,2 1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014;2. Stayte & Vissel. Front Neurosci 2014;8:113;3. Fox et al. Mov Disord 2018;33(8):1248–1266

  12. Holistic medicine and the multi-disciplinary approach The multi-disciplinary approach1 • Management by medication alone cannot fully address the symptoms of PD1 • The guidelines for the treatment of PD outline a variety of non-pharmacological approaches which can be usefully employed:2 • Physiotherapy – to improve gait, balance, aerobic capacity, flexibility, and fitness • Occupational therapy – to help maintain functioning, and work, family, and other social roles • Speech and language therapy – teaching strategies to optimise clarity of speech, and improve safety of swallowing • Integrated models of multi- and inter-disciplinary patient care are needed to ensure good quality healthcare delivery1 Neurology Occupationaltherapy Speechtherapy Socialwork Physical therapy Patient 1. Prizer & Browner. J Parkinsons Dis 2012;2(2):79–86; 2. NICE guideline CG35, 2006

  13. Exercise and Parkinson’s disease • Non-pharmacological treatment options are a valid part of the treatment paradigm of PD1,2 • Exercise programs and physiotherapy have been extensively studied in patients with PD1,2 • Rehabilitation through physical therapy has a variety of goals and methods that generally promote benefits in mobility, posture, and balance in individuals with PD1 • Example interventions include treadmill, resistance, and balance training, and dance therapy1 • One meta-analysis compared physiotherapy with no intervention in patients with PD:3 • Walking speed was significantly improved in the physiotherapy group (p<0.001) • UPDRS Motor score improved with physiotherapy (p<0.001) • Exercise can modify long-term motor symptoms and physical functioning in patients with PD, potentially increasing the efficacy of pharmacological treatment and delaying disease progression4 UPDRS=Unified Parkinson’s Disease Rating Scale 1. Borrione et al. World J Methodol 2014;4(3):133–143; 2. Oliveira de Carvalho et al. ClinPract Epidemiol Ment Health 2018;14:89–98;3. Tomlinson et al. BMJ 2012;345:e5004; 4. Mak et al. Nat Rev Neurol 2017;13(11):689–703

  14. Treatment principles in the advanced stages of Parkinson’s disease • After long-term levodopa therapy, some patients develop motor complications, which comprise ON–OFF motor fluctuations and dyskinesia1 • In the advanced stages, numerous non-motor symptoms will emerge which are more troublesome to the patient and respond only partially, if at all, to drugs2 • The oral delivery of drugs may be problematic in patients with PD; specifically, the involvement of the gastrointestinal system complicates the intestinal absorption of drugs3 • Improved levodopa delivery strategies being explored:2 • Transdermal – through the skin, e.g., a patch • Pulmonary – breathed into the lungs, e.g., an inhaler • Percutaneous – directly into the intestine, e.g., intestinal infusion 1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014;2. Jenner. TranslNeurodegener 2015;4:3;3. Chaudhuri et al. Parkinsonism RelatDisord 2016;33(Suppl 1):S2–S8

  15. Deep brain stimulation – the surgical approach

  16. Deep brain stimulation • Deep brain stimulation (DBS) involves the surgical implantation of one or more electrodes into specific areas of the brain; these electrodes modify or disrupt abnormal patterns of brain signalling1 • DBS is often successful, with dramatic improvements in motor symptoms and reductions in motor complications reported after the surgery1 • As with any surgical technique, there are risks; depending on the placement of the electrodes, DBS can lead to e.g. motor problems, cognitive dysfunction and mood and behavioural abnormalities2,3 1. Hickey & Stacy. Front Neurosci 2016;10:173;2. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014;3. Haubenberger & Hallett. N Engl J Med 2018;378(19):1802–1810

  17. Where to target – the globus pallidus pars interna (GPi) versus the subthalamic nucleus (STN) • There is an ongoing discussion concerning the relative efficacy of stimulating the globus pallidus interna (GPi) versus the subthalamic nucleus (STN) in treating PD1 • Strong clinical evidence supports the improvement of motor and non-motor complications and quality of life, with some data suggesting that GPi DBS might be less effective than STN DBS2,3 • However, neither GPi nor STN stimulation provides control of non-dopaminergic symptoms (e.g., levodopa-unresponsive gait and balance impairment, and cognitive decline)2 • Other areas of the brain are under investigation, such as the ‘pedunculopontine nucleus’, with the aim of finding a brain region which, when stimulated by DBS, would lead to reduction of non-dopaminergic symptoms2 1. Pouratian et al. DegenerNeurolNeuromuscul Dis 2012;2012(2);2. Castrioto & Moro. Expert Rev Neurother 2013;13(12):1319–1328;3. Odekerken et al. Neurology 2016;86(8):755–761

  18. The clinical efficacy of deep brain stimulation • The ideal candidate for DBS is a patient:1,2 • With idiopathic PD • Who is responding well to levodopa • With motor fluctuations or dyskinesias despite well optimised levodopa therapy, or suffers from refractory tremor • With no cognitive decline, no psychiatric or behavioural issues, and no major comorbidities (non-levodopa-responsive symptoms, such as poor cognition, postural instability, dysarthria, and dysphagia, do not improve with DBS, and can even get worse) • Roughly a third of DBS failures are attributed to inappropriate patient selection2 • When used in patients with PD, DBS results in significant improvements in ON-time and a reduction in dyskinesias2 • In some key clinical trials, DBS treatment of patients with PD leads to improvements in measures of quality of life2,3 • Whilst effective for the cardinal symptoms of PD, DBS can occasionally negatively impact some of the axial symptoms of PD (e.g., gait, balance, or speech)2,3 1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014;2. Pouratian et al. DegenerNeurolNeuromuscul Dis 2012;2012(2);3. Anderson et al. Parkinsons Dis 2017;2017:5124328

  19. Disease modification

  20. The ‘holy grail’ – a disease-modifying drug • One of the greatest unmet needs in the treatment of PD is a disease-modifying therapy that reduces the rate of neurodegeneration seen in PD, or stops the process altogether1,2 Disease modification in PD3,4 Cure Maintenance of function Progressive loss of function Slowing of disease progression Treatment Symptomatic benefit Untreated Time 1. Kalia et al. Mov Disord 2015;30(11):1442–1450; 2. Lang & Espay. Mov Disord 2018;33(5) 660–677;2. Adapted from: Lang. Nat Med 2010;16(11):1223–1226; 3. Adapted from: Van Dam & De Deyn. Nat Rev Drug Discov 2006;5(11):956–970

  21. Immunotherapeutic approaches targeting α-synuclein Possible α-synuclein targets for development of therapies for PD1-4 • Given the central role that α-synuclein plays in the pathology of PD, there has been much interest in this protein as a potential drug target1,2 • α-synuclein is a naturally occurring protein, with important functions at the synapse – fully disrupting all the α-synuclein in the brain would be problematic1 • Strategies are under investigation that target many stages of the α-synuclein pathological process1-4 Neuron 3 1 1 α-synuclein Antibody • Targeting extracellular α-synuclein – with antibodies that would prevent cell-to-cell transmission of α-synuclein • Targeting multimerization of α-synuclein – to prevent the α-synuclein combining to form fibrils • Targeting intracellular α-synuclein – to restore proper α-synuclein handling inside the neuron, it might be possible to enhance signalling or breakdown processes (e.g., autophagy) within the cell 1 Neuron α-synuclein fibrils 2 2 3 Lewy body Targeting α-synuclein for the treatment of PD is a suitable direction, but more studies are needed1 1. Dehay et al. Lancet Neurol 2015;14(8):855–866; 2. Sardi et al. Mov Disord 2018;33(5):684–696;3. Brundin et al. Mov Disord 2015;30(11):1521–1527; 4. Harikrishna Reddy et al. Pharmacology 2014;93(5–6):260–271

  22. Other targets for disease modification Leucine-rich repeat kinase 2 (LRRK2)1 • Mutations in the gene LRRK2 are the most common genetic cause of PD (LRRK2 is a protein kinase that modifies other proteins) • Because of this link, drugs that act as inhibitors of the LRRK2 kinase are being investigated Glucocerebrosidase (GBA)2 • Mutations in GBA confer a risk of PD • Preliminary research has suggested that increasing GBA enzyme activity can reduce α-synuclein levels • Trials are underway of treatments that act as molecular chaperones, increasing the activity of the GBA protein Glucagon-like peptide 1 receptor (GLP-1)3 • Drugs which activate GLP-1 are thought to mediate inflammation – a key process in neurodegeneration • Early trials of GLP-1-targeting drugs in patients with PD gave promising results, with results lasting 12 months after the last injection Nicotine and caffeine receptors1 • Tobacco smoking is linked to a reduced risk of PD – but is not a treatment option! • A protective effect of caffeine consumption in reducing the risk of PD has been shown in several studies1,4 • Trials have investigated the effects of nicotine patches on the progression of PD, but more work is needed • There have been some positive results from clinical trials of caffeine in PD 1. Kalia et al. MovDisord 2015;30(11):1442–1450; 2. Balestrino & Schapira. Neuroscientist 2018;24(5):540–559;3. Brundin et al. Mov Disord 2015;30(11):1521–1527;4. Ascherio & Schwarzschild. Lancet Neurol 2016;15(12):1257–1272

  23. Gene- and cell-based therapies

  24. Gene therapy • Gene therapy is the use of genetic material (DNA or RNA) as an agent to alter cellular/biological function and treat disease – either to correct a genetic flaw or to introduce new genes1 • This can be done in two different ways:1 • Ex vivo – where the manipulation is performed outside of the body, in cell culture • In vivo – where the manipulation is performed within the body • There are many potential candidates for gene therapy, including the LRRK2 gene, the Parkin gene and the SCNA gene1 • There are many potential risks of gene therapy:1 • Uncontrolled overproduction of the targeted protein, resulting in adverse effects • ‘Insertional mutagenesis’, where the introduced gene inserts into the host genome at a site promoting cancer • Induction of an autoimmune and inflammatory response • The serious risk of insertional mutagenesis can be controlled by the use of ex vivo methods, and the careful selection of the method of insertion within the genome1 A successful gene therapy would slow or halt the progression of PD1,2 DNA=deoxyribonucleic acid; RNA=ribonucleic acid; SCNA=synuclein alpha gene 1. Allen & Feigin. Neurotherapeutics 2014;11(1):60–67; 2. Coune et al. Cold Spring HarbPerspect Med 2012;2(4):a009431

  25. The potential of stem cell therapies • The potential power of stem cells is that they can come from the patient, and can become many different types of cell depending on the stimulation to which they are exposed1,2 • However, along with the ethical concerns connected with certain stem cells, when tested in clinical trials, stem cell therapies have shown a large variation in efficacy for relieving the symptoms of PD1 • There are several types of stem cells that are being researched for their potential in the treatment of PD:2 • Embryonic stem cells – cells derived from the inner cell mass of early-stage embryos • Induced pluripotent stem cells – adult cells that are taken and ‘reprogrammed’; they can potentially become any cell type of the body • Mesenchymal stem cells – ‘multipotent’ cells derived from the bone marrow; they can be ‘reprogrammed’ to become neurons • Expanded neural precursor cells – precursor cells from the brain can be used to generate dopamine neurons for transplantation • Induced neurons – these are neurons that are produced by ‘reprogramming’ standard cells, such as the cells of the extracellular matrix and connective tissue Although a potentially powerful therapy, the size and durability of any therapeutic effect of cell therapies would need to be weighed against the cost2 1. Zhu et al. Int J Neurosci 2016;126(11):955–962; 2. Barker et al. Nat Rev Neurol 2015;11(9):492–503

  26. The future of treatment for Parkinson’s disease The current treatment paradigm1,2 • When symptomatic therapy is indicated, patients can be initiated on levodopa, a dopamine agonist, or an MAO-B inhibitor • As the disease advances, symptomatic monotherapy can be augmented with the use of combination therapy, e.g., levodopa combined with a dopamine agonist and/or an MAO-B inhibitor • Some patients with more advanced PD can benefit significantly from device-aided therapies, such as deep brain stimulation, or continuous infusions of dopaminergic agents • Non-motor symptoms should be treated as they emerge, with symptomatic therapies • In addition to medical treatments, there should be an emphasis on non-pharmacological therapies, e.g., physical exercise and speech therapy What does the ideal future hold? Individuals with genetic PD receive gene therapy to restore the correct genes and prevent the onset of PD Individuals who would go on to develop PD are identified early and treated with drugs that prevent the onset of motor symptoms Individuals who do develop motor symptoms are given cell-based therapies that replace the damaged neurons and restore the patient’s functioning MAO-B=monoamine oxidase type B 1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014; 2. Fox et al. Mov Disord 2018;33(8):1248–1266

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