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EMSP Annual Congress
Brussels, 12. Mai 2011
New treatments for spasticity and other symptoms Norbert Goebels, MD
Department of Neurology
Düsseldorf, Germany
Multiple Sclerosis Therapy Immunmodulation-> Treatment of the underlying "autoimmune disease": -> Investment into the future Symptomatic Therapy Therapy of the symptoms of the disease: ->"immediate (?) relief from symptoms" Multiple Sclerosis: Scope of Symptoms • Blurred vision • Concentration • Reduced colour • Visual field deficit • Articulation • Articulation • Eye movements •Tremor, vertigo • Sensory symptoms • Spasticity • Palsy • Sphincter dysfunction • Sexual dysfunction And many others, often nonspecific symptoms! Ten most common MS Symptoms Sherrat et al. 1980 Aminopyridine-MOA Korenke et al., 2008 Early Studies II Stefoski et al. 1987 P-Kinetics of unsustained Formulation Stefoski et al. 1987 P-Kinetics of unsustained Formulation Bever et al. 1990 Dalfampridine (Biogen-Idec / Acorda) • 4-aminopyridine, sustained release (SR) • Modifies axonal function -> Duration of action potential increases • 10 mg Dalfampridine 2x/d (N=119) vs. Placebo (N=120) • Timed 25 ft walk test Andrew D. Goodman, MD, Annals of Neurology 2010 Phase III Trial: Extended Release Oral Dalfampridine in Multiple Sclerosis (MSF204) Andrew D. Goodman, MD et al, Annals of Neurology 2010 Primary Outcome: Percentage of Timed-Walk Responders (Pooled) Across trials, approximately 38% of patients treated with PR-fampridine showed a
consistent increase in walking speed (timed-walk responders)
MS-F203 Goodman et al. Lancet 2009; MS-F204 Goodman et al. Ann Neurol 2010. Biogen Idec data on file.

PR-Fampridine Shows Consistent Effects Regardless of MS Type Treatment Group by Disease Type
PRMS=progressive-relapsing MS.
MS-F203 Goodman et al. Lancet 2009; MS-F204 Goodman et al. Ann Neurol 2010. Biogen Idec data on file. Phase 3 Studies: Most Frequent Adverse Events (AEs) Urinary tract infection
Upper respiratory tract infection
Back pain
Balance disorder
Studies MS-F203 and MS-F204: all AEs seen in >5% of PR-fampridine–treated patients.
MS-F203 Goodman et al. Lancet 2009; MS-F204 Goodman et al. Ann Neurol 2010. Biogen Idec data on file. Quantitative Benefit-risk Profile for PR-Fampridine Favoring
PR-Fampridine 10 mg
T25FW responders
Improvement in
MSWS-12 overall score
Improvement in LEMMT
Improvement in Ashworth
score (spasticity)
≥20% Improvement in
T25 walking speed
CGI Score ≤3
at end DB period
Average SGI score
over DB period ≥6
CNS excitation
Urinary tract infection
–150 –100 –50
Risk Difference and 95% CI (of 1000 Patients)
DB=double-blind; CNS=central nervous system.
Biogen Idec, data on file.
€ Fampridine $ Retail-Price Dalfampridine (AMPYRA ®) in the USA: 12.672,- USD / year (= 7,2 g) 7,2 g 4-Aminopyridin: 22,83 € (30,50 $) Ten most common MS Symptoms

The stretch-reflex arc in MS spasticity "disordered sensorimotor control resulting from an upper motor neuron lesion, presenting as inter- sustained involuntary activation of muscles." Stevenson VL. Clin Rehab 2010 description: tightening of muscles that feels like leg stiffness, jumping of legs, a repetitive bouncing of the foot, muscle cramping in the legs or arms, legs going out tight and straight or drawing up". Rizzo et al. Mult Scler 2004 MS spasticity: causes • Result of myelin and nerve fibre degradation • MS plaques inhibit supraspinal control of reflex • ->Impairment of functional movements of muscles of the extremities and of the trunk. • Progressive damage -> loss of inhibition and a disruption of the stretch-reflex arc Bavikatte & Gaber Br J Med Pract 2009; 2: 29-34; Springhouse. Handbook of signs and symptoms. LWW, 2005. MS spasticity severity (% from US survey of > 20000 patients)
Rizzo et al. Mult Scler 2004; 10: 589-95. MS spasticity: symptom rating scales The most frequently used have been: • Ashworth Scale/Ashworth (modified) Scale • Numerical Rating Scale (NRS) • Multiple Sclerosis Spasticity Scale (MSSS) • Daily mean spasm score • Tardieu Scale (rarely used today) MS spasticity: conclusions • Spasticity is one of the most disabling symptoms associated with MS. • Like all MS symptoms, spasticity occurs as a result of myelin and nerve fibre degradation. • The Ashworth scale is the most widely used rating scale for assessing the degree of spasticity. • The NRS is a valid and sensitive diagnostic tool for determining the severity of spasticity.

Management of spasticity in MS patients Symptomatic Therapy for Spasticity (1) Treatment of contributing factors  (Urinary tract) Infections  (Infected) decubitus ulcer  Beta-Interferon associated increase of spasticity Symptomatic Therapy for Spasticity (2) • Multimodal rehabilitation including intense physiotherapy to reduce the extent of motor deficits • Passive movement of major joints (motordriven bicycle) • If possible: Aerobic Fitnesstraining • Important: Sufficient Intensity and frequency Medication:
Substance (Drugname)
Side effects
Baclofen (e.g. Lioresal) Fatigue, nausea, confusion, ataxia Tizanidin (e.g. Sirdalud) Hypotonia, dry mouth, nausea Gabapentin (e.g. Neurontin) 300 – 2400 (3600) mg/d Vertigo, fatigue, weakness Symptomatic Therapy for Spasticity (3) • Oral anti-spasticity agents (z.B. Baclofen/Lioresal®, Tizanidin/Sirdalud®) • cave: weakness • Increase dosage slowly (start with e.g. 3x2.5 mg Lioresal, 3x1 mg Sirdalud), -> maximum dosage according to effect, combine if necessary • Botulinumtoxin A (z.B. Botox®) • Intrathecal Baclofen ("Lioresal pump") • Intrathecal Triamcinolon (Volon A) Cannabis Medical use of cannabis • Cannabis has a long-history of use as both a medicine and as a recreational drug. • Medically, street cannabis has been used to utilise it's antispastic, muscle relaxant and pain relief • In a UK survey of persons using cannabis medically (mostly smokers) between 1998 and 2002, almost 75% indicated that it was better or somewhat better than their previous treatment for MS or various pain states. Ware et al. Int J Clin Pract 2005;59: 291-95. Street cannabis: concerns/limitations • Legal issues. • Street cannabis lacks standardization and purity • In Tetrahydrocanabinol (THC, psychoactive cannabinoid) and low levels of Canabidiol CBD (antipsychotic cannabinoid) were reported . • Largely smoked and this increases the risk of lung cancer, heart disease, etc. • Smoked cannabis has variable pharmacokinetics, causing very high THC peaks, which lead to psychoactivity and other adverse events. Chong et al. Mult Scler 2006; 12: 646-51.; Wade et al. Mult Scler 2006; q12: 639-45.; Aldington et al. Eur Resp J 2008; 31: 280-86.; Potter et al. J Forensic Sci 2008; 53: 90-4. The endocanabinoid system • 1990 breakthrough in the field of canabinoid research: CB1 receptor was discovered by Matsuda et al. • 1992 Discovery of anandamide (endocanabinoid) by Devane et al. • 1993 Discovery of CB2 receptor by Munro et al. • During the last 10 years the antispastic and analgesic effects of cannabinoids were investigated New target for the regulation of physiological functions Experimental studies showed, that the endocanabinoid system significantly changes in processes of spasticity.

The protein sequences of CB1 and CB2 receptors CB1 receptors: hippocampus, basal ganglia, cortex, cerebellum,hypothalamus,
pituitary, limbicstructure and gastrointestinal tract. CB2 receptors: immune cells and tissues and bone.
Endocannabinoids act as retrograde neuromodulators CB: Cannabinoid; EC: Endocannabinoid; NT: Neurotransmitter Cannabinoids: mechanism of action 1. A nerve impulse reaching the synapse stimulates the release of neurotransmitters (the yellow molecules). These cross the synapse and bind to receptors on the post- synaptic cell, initiating a series of events. 2. One of these events is the release of endocannabinoids (the red molecules) which are released locally, crossing the synapse in the opposite direction of the nerve impulse. 3. The endocannabinoids bind to pre-synaptic CB1 receptors (the light blue receptors) neurotransmitters, neurotransmitters are inhibitory (e.g., GABA) or excitatory (e.g., glutamate). This is an example of negative feedback system. 4. Phytocannabinoids mimic the action of these endocannabinoids. In this way, they are able to augment the effect that endocannabinoids have in regulating the transmission of impulses from one nerve to another. CNS forum. Cannabinoid receptors 2009. Biozzi mice with chronic relapsing EAE CB1 agonists ameliorate spasticity *p < 0.001 compared with baseline Collin et al. 2007 Rationale for the development of the standardised fix combination THC/CBD • To produce a standardised medicinal product based upon the main active constituents of Cannabis sativa, tetrahydrocannabinol (THC) and cannabidiol (CBD). • Formulated to ensure purity and stability. • To administer in a way (oromucosal) which provides a satisfactory pharmacokinetic profile avoiding the high plasma levels and risks associated with • To benefit from the synergistic interaction between CBD and THC, with a reduction in psychoactivity and enhanced cannabinoid-mediated clinical effects. Perez Drugs of Today 2006; 42: 495-501; Potter et al. J Forensic Sci 2008; 53: 90-4. Standardized fix combination of THC/CBD • Oromucosal spray contains two canabinoids, which act synergistically: • 1) Tetrahydrocanabinol (THC) • 2) Canabidiol (CBD) • THC is a CB1- and CB2-receptor agonist • CBD is a CB1- receptor antagonist and prevent the psychoactive effects of THC THC and CBD: synergy (complementary effects) Russo & Guy Med Hypotheses 2006; 66: 234-46. Standardised fix combination THC/CBD: Composition and production • First-in-class endocannabinoid system modulator comprising THC + CBD. • Cannabinoid-based medicine derived from Cannabis • Prepared from 2 cloned chemovars of C. sativa to ensure standardisation and quality. • 10ml amber vials with a pump for oromucosal Standardised fix combination THC/CBD manufacturing: sophisticated cultivation Maximum plasma THC levels with the standardised fix combination THC/CBD and Street Cannabis (smoked) Standardised fix Standardised fix combination THC/CBD combination THC/CBD steady state dose Guy & Stott In Parnham et al. (eds) Milestones in drug therapy: cannabinoids as therapeutics, 2005. Clinical Overview (Phase III) Author/publ. year Patients n = Primary endpoint Results Score of five MS- 1. endpoint: not sign.; symptoms: spasticity, 2. endpoint: spasticity spasms, bladder, alone: significant tremor, pain (VAS) 189 / 12 centers spasticity (NRS) statistically significant Pivotal study II spasticity (NRS) spasticity (NRS) statistically significant Time to failure of favour of THC/CBD Incidence of AEs comparable to short term studies Severity of worst Dosage & severity constant -> longterm efficacy Standardized fix combination THC/CBD: third pivotal clinical trial Published (abstract available and full text pending)
EU (multicentre) A 2-phase study: Phase A- single- blind response assessment and Phase B- a randomised, placebo-controlled, double-blind, paral el group study To assess the efficacy and safety of the standardised fix combination THC/CBD vs. placebo in patients with MS spasticity • N = 572 MS adult patients • MS with spasticity and an inadequate response to drug therapy • Single-blind the standardised fix combination THC/CBD for 4 week, with initial responders (improving 20% or more from baseline NRS score) randomised to the standardised fix combination THC/CBD or placebo for 12 more weeks • Participants continued with current therapies throughout the study •14 day follow-up after controlled period of 12 weeks Change in Spasticity numerical rating scale (NRS) score outcome Secondary • Improvement in NRS responses of 30% or more and 50% or more • Modified Ashworth scale of spasticity • Timed 10-metre walk and motricity index • Spasm frequency and sleep disruption • Barthel ADL index • Carer's global impression of change (CGIC) • Quality of Life Novotna et al. Eur J of Neurology 2011 Standardised fix combination THC/CBD*: third pivotal clinical trial: two-phase study design Phase A (n=572)
Phase B (n=241)
12 weeks THC/CBD*
12 weeks Placebo
Novotna et al. Eur J of Neurology 2011 Standardized fix combination THC/CBD*: third pivotal clinical trial results: NRS resolution from phase A responders Novotna et al. Eur J of Neurology 2011 Standardised fix combination THC/CBD third pivotal clinical trial: Well-being and quality of life (QoL) • Barthel activities of daily living (ADL) (p = 0.0067). • Physician, carer and patient global impression of change (p = 0.0045, p = 0.0053 and p = 0.0234, respectively). • Sleep disruption NRS (p <0.0001). • Spasm frequency (p = 0.0046). • QoL EQ-5D (0.48 to 0.57; +19%). • QoL SF-36 Role Physical 0-100 (35.1 to 48.1; +37%). Ambler et al. Mult Scler 2009; 15: S258; Montalbán & Wright Mult Scler 2009; 15: S272. Standardised fix combination THC/CBD: adverse events (AEs) • During the first 4 weeks of exposure dizziness (14-32%) and fatigue (12-25%) were the most common AEs. • Usually mild to moderate and resolved quickly. • When the recommended gradual "up titration" schedule was introduced the incidence of AEs was reduced. • In clinical trials the rates of withdrawal due to AEs was • The standardised fix combination THC/CBD does not exhibit the side effects typically associated with recreational cannabis use. Wade et al. Mult Scler 2004; 10: 434-41; Wade et al. Mult Scler 2006; 12: 639-45; Collin et al. Eur J Neurol 2007; 14:290-96. Collin et al. Mult Scler 2007; 13: S129; Ambler et al. Mult Scler 2009; 15: S258. Standardised fix combination THC/CBD: AEs listed in the SmPC MeDRa System Organ Class disorders
Very common
≥1/100 to <1/10
Infections and infestations Metabolism and nutrition Anorexia (including ↓appetite), ↑ appetite Depression, disorientation, dissociation, Amnesia, balance disorder, attention problems, memory impairment, somnolence, dysarthria, dysgeusia, lethargy Ear and labyrinth Cardiac Vascular Respiratory, thoracic, mediastinal Gastrointestinal Constipation, diarrhoea, nausea, dry mouth, glossodynia, vomiting, mouth ulcers, oral discomfort/pain, General disorders and admin site Application site pain, asthenia, feeling abnormal/drunk, malaise Injury. Poisoning and procedural Treatment-related neurological AEs Standardised fix combination Placebo (n = 853) THC/CBD (n = 921) Disturbance in attention Memory impairment Coordination abnormal Cognitive disorder Depressed consciousness [From the standardised fix combination THC/CBD integrated safety analysis (Sept 1, 2007) from non-cancer studies.] NB. These data do not include results from the third pivotal clinical trial which used the "up-titration" schedule and was associated with a significantly lower incidence of AEs. Cognitive and Neuropsychiatric Effects • Cognitive impairment occurs with the standardised fix combination THC/CBD, but in the majority of instances the symptoms were mild-to-moderate. • Psychiatric AEs were also reported for the standardised fix combination THC/CBD , but they were mostly of mild-to-moderate severity. • There is no evidence from RCTs that the standardised fix combination THC/CBD poses any long-term or irreversible neuropsychiatric or cognitive risk to patients [From the standardised fix combination THC/CBD integrated safety analysis (May 11, 2007)] Potential for abuse • The standardised fix combination THC/CBD does not exhibit the psychostimulant effects typically associated with recreational cannabis use. • Intoxication was reported to be very low during the course of short- and long-term studies. • No association with signs of drug tolerance and in a long-term trial the mean dosage decreased slightly. • No consistent withdrawal syndrome has been observed, and there is no evidence of drug misuse or abuse. • Lower abuse potential than equivalent doses of dronabinol, which itself is considered to have minimal abuse potential, in 23 abuse-prone recreational marijuana users. Wade et al. Mult Scler 2006;12: 639-45; Collin et al. Eur J Neurol 2007; 14:290-96; Schoedel et al. 2010. Indication of standardized fix combination THC/CBD Add-on treatment, for symptom improvement in patients
with moderate to severe spasticity due to multiple
sclerosis (MS), who have not responded adequately to other anti-spasticity medication Standardised fix combination THC/CBD clinical efficacy: conclusions • Results from well-controlled RCTs provide conclusive evidence of the efficacy of the standardised fix combination THC/CBD in MS-related spasticity. • Randomized withdrawal of the standardised fix combination THC/CBD treatment provided definitive proof of long-term efficacy. • The standardised fix combination THC/CBD not only reduced the symptoms associated with MS-spasticity, it also increased the ability of the patient to perform certain tasks and improved the perception of patients and their carers regarding functional status. Standardized fix combination THC/CBD Approval expected in: • Standardised fix combination THC/CBD well tolerated • Dizziness and fatigue are the most common AEs • Most AEs are mild to moderate • Only few withdrawals due to unwanted effects. • Fix combination THC/CBD does not appear to pose risks of long-term or irreversible neuropsychiatric or cognitive impairment • Famprine increases mobility in 1/3 of patients, currently not approved in EU, expensive


Biochemical Journal Immediate Publication. Published on 12 Apr 2006 as manuscript BJ20060409 The life-extending gene Indy encodes an exchanger for Krebs-cycle Felix Knauf1,2, Nilufar Mohebbi1, Carsten Teichert1, Diana Herold1, Blanka Rogina3, Stephen Helfand3, Maik Gollasch1, Friedrich C. Luft1 and Peter S. Aronson2* 1Franz Volhard Clinic at the Max Delbruck Center, HELIOS Kliniken – Berlin, Medical Faculty of the Charité, Humboldt University, D-13125 Berlin, Germany

Why aircraft disinsection?Norman G. Gratz,1 Robert Steffen,2 & William Cocksedge3 A serious problem is posed by the inadvertent transport of live mosquitoes aboard aircraft arriving from tropicalcountries where vector-borne diseases are endemic. Surveys at international airports have found many instances oflive insects, particularly mosquitoes, aboard aircraft arriving from countries where malaria and arboviruses areendemic. In some instances mosquito species have been established in countries in which they have not previouslybeen reported. A serious consequence of the transport of infected mosquitoes aboard aircraft has been thenumerous cases of ‘‘airport malaria'' reported from Europe, North America and elsewhere. There is an importanton-going need for the disinsection of aircraft coming from airports in tropical disease endemic areas intononendemic areas. The methods and materials available for use in aircraft disinsection and the WHOrecommendations for their use are described.