What s New in Multiple Sclerosis and Parkinson Disease?

Transcription

1 What s New in Multiple Sclerosis and Parkinson Disease? Eric S. Farbman, MD University of Nevada School of Medicine Division of Neurology Director of Movement Disorders Center

2 Disclosures Member of Parkinson Study Group (PSG) Member of Huntington Study Group (HSG) These are consortiums of academic groups We are doing research studies as part of both Barely make enough money to cover the study costs

3 Autoimmune disease of central nervous system Primarily attacks white matter of the brain and spinal cord Cause unknown but likely a combination of genetic, environment, infectious factors Four main types, with accumulation of disability Multiple Sclerosis

4 Multiple Sclerosis History 1868: JM Charcot Examined a young woman with a tremor he had never seen before, slurred speech, abnormal eye movements. When she died, he examined her brain and found the characteristic plaques of MS He wrote a complete description of the disease, including changes in the brain Baffled by cause and treatment

5 Multiple Sclerosis Late 19 th Century 1873 Dr. Walter Moxon sees MS in England 1878 Dr. Edward Seguin sees MS in the U.S. By the end of the century, much of what can be determined by careful observation was known More common in women than in men Not directly inherited Produces many different neurological symptoms Not known to be an auto-immune disease, because at the time the existence of the immune system was unknown!

6 Multiple Sclerosis 20 th Century 1916 James Dawson, MD described inflammation around blood vessels, damage to myelin 1919 abnormalities in spinal fluid noted 1947 Elvin Kabat, MD identified oligoclonal bands (immunologic proteins) in spinal fluid, providing a way to diagnose MS, and also demonstrating that the immune system is connected

7 Multiple Sclerosis Treatment History 1969 Patients who were having MS attacks were given ACTH which proved superior to placebo in speeding recovery In subsequent years this was replaced by high dose IV steroid therapy (which is still used today) Better medications were introduced for spasticity, bladder management, fatigue, sexual problems, and neuralgias and pain.

8 Multiple Sclerosis Disease Modifiers 1990s saw the introduction of medications to treat the actual disease, not just symptoms Beta interferons believed to slow progression via anti-inflammatory properties Glatiramer acetate uncertain method of action, but may shift T h cells to inflammation suppresors, and it may act as decoy in response against myelin Mitoxantrone cancer agent shown to be useful in secondary progressive MS, which was unique

9 Multiple Sclerosis MRI The big leap forward occurred with the introduction of MRI Gave physicians a way to view the disease Gave researchers faster way of testing drugs When MRI was introduced, it shortened the time from first symptom to diagnosis from 7 years to 6 months!

10 Multiple Sclerosis What s Next? Oral agents Main disease modifying medications (Interferon beta-1a, Interferon beta-1b, Glatiramer acetate are all injections More effective agents Reduction in relapses of the current agents range from about 33% -40% depending on article Would like to be able to stop disease Would like something for primary progressive MS

11 MS Treatments--Natalizumab mab against α4-integrin (CD49) Believed to work by preventing activated lymphocytes from crossing BBB Initially approved by FDA in 2004 but was withdrawn because of increased risk of PML Re-introduced in 2006 with careful monitoring Risk of PML is greatest in those who are JC virus + JC virus -: 1 in 25,000 over 3 years vs. 1 in 1000 Reduces relapses by 68% vs. placebo

12 MS Treatment Fingolimod First FDA approved oral disease modifying agent It is a sphingosine 1-phosphate receptor modulator which sequesters lymphocytes in lymph nodes In pivotal trial, annual relapse rate was half that of interferon (0.16 vs 0.33) and greater relapse freedom over the year (83% vs. 69%) Sounds great, but

13 Prior to starting fingolimod Ophthalmology appointment to check for macular edema Bloodwork to check blood counts, LFTs Need to have antibodies to varicella virus (chicken pox); if negative, need to be vaccinated Need to have first dose observation, usually 6 hours, to watch for bradycardia In the trial there were reports of skin cancer EMA recommends stronger cardiac safety warnings

14 MS Treatment--What s Coming? Dimethyl fumarate Submitted to FDA for approval on February 28, 2012 Already approved in Europe to treat psoriasis May have several pathways of action Switch T-helper cells from T H 1 to T H 2 Inhibit expression of proinflammatory cytokines (IL12,IL6) Inhibit expression of adhesion molecules Good safety profile Flushing GI side effects

15 Teriflunomide Active metabolite of leflunomide, a drug used to treat rheumatoid arthritis Thought to work by blocking primidine synthesis which alters DNA T-cell replication Prevents rapidly dividing cells which reduces circulating T and B cells Thought to prevent interaction of T cells with APCs Safety profile: No serious opportunistic infections Known teratogenicity so women are advised to avoid pregnancy while on this and for two years after cessation

16 MS Treatments Other agents Almetuzumab mab against CD52, found on mature lymphocytes Shows significantly reduced disability Shows 55% reduction in relapse rate Safety: Some other autoimmune syndromes, ITP Daclizumab mab against high-affinity IL2 receptor (which is present on activated, but not resting, T cells) Reduction of enhancing lesions (1.32 vs 4.75) Safety: cutaneous events and high-grade infections

17 MS Treatments Perspective Cladribine Immunosuppressant whose active metabolite leads to apoptosis of lymphocytes Shown to be effective in RRMS Not approved because of concerns about sustained immunosuppression and associated cancer risk Laquinimod Promotes anti-inflammatory cytokine profiles Met secondary endpoints (reduction of brain loss, reduction of brain lesions on MRI) Did not meet 1 o endpoint of reducing relapse rate

18 Still looking Primary Progressive MS

19 Parkinson Disease Idiopathic degeneration of neurons in substantia nigra causing loss of dopamine. Mean onset age: 55 M:F 3:2 Prevalence: 160/100,000 50,000 new cases annually Lab values: all normal

20 Cardinal Symptoms of PD Resting tremor: 5Hz, pill-rolling, asymmetric Rigidity increased resistance to passive movement, often w/cogwheeling Bradykinesia/Hypokinesia Loss of automatic movements (i.e. armswing), masked facies, festinating gait, freezing Postural Instability Difficulty rising from a chair Falling backwards

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22 James Parkinson and the Shaking Palsy 1817: Published his now classic monograph Called it paralysis agitans Detailed account of resting tremor and festinating gait Description of the disease is based on only six cases, some of which he only noticed casually in the street

23 Charcot and Parkinson Disease Characterized the tremor Resting nature and its frequency No head involvement Movement suppresses (in beginning) Bradykinesia (slowness of motion) Rigidity not commented on by Parkinson, Charcot knew it was different than that seen in stroke Stance, posture, and gait issues First to call it Parkinson s disease

24 Carbidopa/Levodopa Gold standard Dopamine does not cross blood-brain barrier; levodopa does All patients with PD will respond to this If a patient derives no or only minimal benefit from levodopa, the patient likely has one of the Parkinson-plus syndromes, essential tremor, or some other condition

25 Complications of Carbidopa/Levodopa Wears off; as time goes by, a dose that previously lasted 8 hours will gradually last less and patient will need more medicine, have more on/off fluctuations Dyskinesias--chorea, dystonia of limbs, often from excess levo-dopa. Usually affects family more than patient, but can be socially upsetting.

26 As the Disease Progresses, the Therapeutic Window Narrows Plasma Levodopa Concentrations Smooth, extended response Diminished duration Shorter, unpredictable response Absent or infrequent dyskinesia Increased incidence On time with increased dyskinesia of dyskinesia

27 Parkinson Disease Medications Carbidopa/Levodopa COMT inhibitors Amantadine Dopamine agonists Anti-cholinergics MAO b -inhibitors

28 Parkinson Disease What s Next? Better way of diagnosis Non-oral agents Non-dopaminergic agents Agents that last longer without fluctuations Treatments for non-motor symptoms We have fairly good medicines for tremors, rigidity, bradykinesia It is increasingly realized that the non-motor symptoms play a large role in disability Pain Sleep issues Balance Dizziness/Lightheadedness Constipation

29 Parkinson Disease Diagnosis Generally a clinical diagnosis In 2011 a SPECT scan was approved in the U.S. Ioflupane (I 123 ) has a high binding affinity for presynaptic dopamine transmitters Can help differentiate essential tremor from Parkinson disease Will not differentiate between Parkinson disease and Parkinson-plus disorders

30 Parkinson Disease Rotigotine Transdermal (patch) dopamine agonist Provides a slow, constant supply over 24 hours Initially approved in 2007, withdrawn in 2008 Not taken off the market because of safety reasons Taken off because of problems with the delivery, with crystals forming on outside of the patch New formulation approved in April, 2012 Novel mechanism of delivery of PD medicine

31 Parkinson Disease IPX066 Novel formulation of carbidopa/levodopa Works quickly (like current immediate release) Lasts longer with a steady plasma concentration (unlike current continuous release) May benefit patients with dyskinesias More efficacious than placebo in early Parkinson dx Provided more sustained clinical benefit with fewer doses than immediate-release CD/LD Filed with the FDA in February, 2012

32 Parkinson Disease: Adenosine A 2A Receptor Antagonists Agents that are similar to caffeine Modulate dopaminergic effects on striatal dysfunction associated with motor disability Should increase effect of levodopa without a resulting increase in dyskinesias First agent brought to FDA in 2007 received a Not Approvable letter in 2008 Other agents currently in trials

33 Parkinson Disease: Longer lasting agents without fluctuations

34 PD The Surgical Option Only after maximal medical treatment Must be dopa-responsive Very good for rigidity, dyskinesias, tremor Not good for postural instability Operation of choice: deep brain stimulation at STN or GPi

35 Effects of Surgical Targets

36 PD Deep Brain Stimulation

37 Apomorphine First documented in 1951 to be beneficial for Parkinson patients Effects were primarily on tremor and rigidity At the time, its method of action was unknown In the original studies it was given orally Caused extreme nausea, postural hypotension Extremely short duration of action Years later it was determined to be a dopamine agonist, and non-oral routes were discovered

38 Apomorphine (continued) Currently approved as a subcutaneous injection to treat off episodes Often used emergently as 90% of patients receive benefit faster than 20 minutes Approved in Europe, and being investigated in the United States as an infusion Studies show significant reductions in off time and fluctuations, and significant increase in on time No worsening of psychiatric status Some nausea and orthostatic hypotension Itchy nodules at injection site but no cutaneous necrosis

39 Levodopa/Carbidopa Intestinal Gel Infusion of levodopa directly into the duodenum Appears to optimize levodopa treatment while eliminating or at least reducing dyskinesias Already approved in Europe; in trials in U.S. A significant number of individuals have benefitted from long-term treatment duration (> 10 years) Daily dosage is stable Main side effects deal with the pump and the tubing

40 Parkinson Disease LCIG

41 PD Treating the Non-motor Symptoms Oftentimes the more disabling symptoms One such symptom is lightheadedness Currently Droxidopa is a medication approved in Japan to treat orthostatic hypotension Droxidopa is a norepinephrine precursor Recently filed for FDA approval Demonstrated statistical significance in primary endpoint, measurements that looked at symptoms of neurogenic orthostatic hypotension FDA asked company for more data; trials continue

42 So what s new in MS and PD? There have been some new medications and diagnostic tools in the last few years There are potentially revolutionary new medications that will become available soon that are very different than any of our current treatments However, there have been some recent missteps involving can t miss agents Nevertheless, it is an exciting time to be a clinical neurologist!