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MultipleSclerosis:Current&Emerging Treatments Personalized Strategies Dr. Suhail Al-Shammri Associate Professor& Head Division of Neurology, Mubark Al.

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Presentation on theme: "MultipleSclerosis:Current&Emerging Treatments Personalized Strategies Dr. Suhail Al-Shammri Associate Professor& Head Division of Neurology, Mubark Al."— Presentation transcript:

1 MultipleSclerosis:Current&Emerging Treatments Personalized Strategies Dr. Suhail Al-Shammri Associate Professor& Head Division of Neurology, Mubark Al Kabir Hospital

2 Overview The diagnostic criteria of multiple sclerosis( MS) Classification of idiopathic inflammatory demyelinating disorders Clinical course of MS Current and emerging MS therapies

3 Idiopathic CNS Demyelinating Diseases Typical CNS demyelinating Diseases: – Radiologically isolated syndrome (RIS) – Clinically isolated syndrome (CIS) – Relapsing –remitting multiple sclerosis (RRMS) – Secondary progressive MS (SPMS) – Primary progressive MS (PPMS)

4 Atypical CNS Demyelinating Diseases Acute disseminated encephalomyelitis (ADEM) Acute hemorrhagic leukoencephalitis (AHLE) Tumefactive MS Balo’s concentric sclerosis Marburg

5 Radiologically Isolated Syndrome (RIS) – No typical symptoms of CNS demyelination – No formally accepted diagnostic criteria – MRI : Typical MS lesions – CSF abnormalities – Clinical MS Attack: – 35% over 5 years – MRI progression: 59-83% in 2 years – DMT is initiated only in case of clinical/MRI progression Okuda DT et al, Neurology2011:76()8,

6 Diagnostic Criteria for MS An effort to make the diagnostic process more objective Formal criteria were devised to codify the typical MS features into indisputable diagnostic criteria The primary driving force is identification of patients for research trials. ”a consensus on which patient has MS” Criteria are designed to be specific There are patients with MS who do not meet those criteria “A patient has MS when an an experienced neurologist says he or she has MS”

7 Schumacher Criteria Onset of symptoms between 10 and 50 years Objective abnormalities on neurologic examination The signs and symptoms indicate CNS white matter damage The lesions are disseminated in space ( 2 or more separate lesions) The lesions are disseminated in time (2 attacks at least 1 month apart) No better explanation

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9 The Mc Donald Criteria ‘the world consists of three types of person: those who have multiple sclerosis; those who do not; and those who might’. Polman CH et al,Ann Neurology, 2001 Episodes from history Objective clinical signsAdditional data needed from MRI or clinical follow up 2 attacks 1 attack Progressive course over 1 year 2 lesions 1 lesion 2 lesions 1 lesion None DIS DIT Both DIS&DIT DIS demonstrated by 2 : 1- MRI brain 2. MRI cord 3. CSF oligoclonal bands

10 Dissemination in Space Polman CH et al, Ann Neurol 2011; 69:292–302

11 Dissemination in Time Polman CH et al, Ann Neurol 2011; 69:292–302

12 MRI Brain DIS

13 MRI Cervical spine: DIS

14 MRI Brain T2WI

15 MRI Brain Enhanced T1WI:DIT

16 CASE On 18/3/08 patient complained of ocular pain on moving the left eye with blurred vision. 2 days later she developed left frontal headache. Seen by the ophthalmologist who diagnosed her as optic neuritis and advised to be on neurobion. She had several attacks of Rt. Upper limb heaviness in the last 2 years, each was lasting for a week. Her cousin has MS.

17 CASE : Examination Her vision was 20/200 in the left eye and 20/40 in the right eye. There was a central scotoma, and red and blue colors were less intense in the left eye. RAPD on the left Left fundus: disc is congested and swollen. Central Scotoma Treated with pulse IV methylprednisolone for 3 days and improved followed by short prednisolone taper

18 Case 1: Fundoscopy

19 Case : MRI Brain

20 Case 2: MRI Spine

21 Case : CSF Oligoclonal bands

22 Clinically Isolated Syndrome (CIS) Single characteristic clinical attack of CNS demyelination: – Optic neuritis – Acute partial myelitis – Brain stem syndrome – Cortical

23 Clinically Isolated Syndrome (CIS) MRI: – Low risk: 1 or no other asymptomatic brain lesion – High risk: 2 or > asymptomatic lesions Treatment approved for high risk patients – IFN-B, GA reduces second attack: ARR 15%

24 Baseline MRI and Risk of CDMS for Monofocal onset CIS (BENEFIT Placebo N=93)

25 CHAMPSCHAMPS2ETOMSBENEFIT25 Unifocal/multifocal/ No pt Unifocal/ 383 UnifocalUnifocal+ multifocal /309 Unifocal/ 487 IFN-BAvonex+Pulse MP AvonexRebifBetasron Dose/30µg/im/weekly30µg/IM/ weekly 22µg/SC/ Weekly 250µg/SC/EOD Duration/years3522 Pre-MRI T2 load2or>4 or >2 OR> %CDMS,P value35 VS50, p= VS 49, P= VS 45 P= VS 45 (69%/85% +MRI effectYesYes, P=0.001 Yes, P=0.001

26 TOPIC Primary end point: Conversion to CDMS (as defined by the occurrence of a relapse) Key inclusion criteria: Patients 18 to 55 years of age with a first acute/subacute neurologic event consistent with demyelination. MS symptom onset within 90 days of randomization. Screening MRI scan with 2 T2 lesions 3 mM diameter that are characteristic of MS. Screened (N=846 ) Placebo (n=197) Teriflunomide 7 mg (n=205) R Long-Term Extension Teriflunomide 14 mg (n=216) 108-Week Treatment Phase Randomized n=618 Miller A. Plattform presentation ECTRIMS 2013

27 Primary / Key Secondary Endpoint Primary Endpoint: Time to Clinically Definite MS (CDMS) 43% Safety / Tolerability: Adverse events observed in the trial were consistent with previous clinical trials with Aubagio. Miller A. Plattform presentation ECTRIMS % p= % p= Gd-enhancing T1 Lesions)

28 CIS: When To Initiate Therapy? Patients with normal MRI or with fewer than 2 – Low risk of developing early clinical attacks – Clinical and MRI monitoring – Without immediately commencing immunotherapy (DMT) Those with abnormal MRI with2or> lesions consistent with MS or with evidence of intrathecal synthesis of antibodies should be considered for DMT, Patients with atypical clinical or MRI presentation require further diagnostic evaluation.

29 Relapsing-Remitting MS Subacute repeated onset of CNS dysfunction with resolution ( sometimes incomplete, over days to weeks) Revised McDonald criteria MRI: Periventricular, brainstem, juxtacortical prominent T2, often Gad enhancing lesions, T1 hypointense (black holes) T reatment: Interferon-B, Glatiramer acetate, natalizumab, mitoxantrone

30 Features Consistent With MS Relapses and remissions Age Onset between ages 15 and 50 Optic neuritis Lhermitte's sign Internuclear ophthalmoplegia Fatigue Uhthoff's phenomenon

31 Features Inconsistent With MS Steady progression Onset before age 10 or after age 50 Cortical deficits such as aphasia, apraxia, alexia, neglect Rigidity, sustained dystonia Convulsions Early dementia Deficit developing within minutes

32 Secondary Progressive MS Majority of RRMS many years following onset Progressive impairment (spastic gait disturbance) between or in absence of attacks No clear effect of DMT without ongoing attacks or inflammation Role of DMTs in SPMS patients: – with ongoing relapses – Substantial ongoing accrual on new MRI inflammatory lesions

33 Primary Progressive MS Presents with progressive myelopathic gait, cerebellar ataxia or cognitive impairment without clear history of any clinical attacks Clinical progression must be for at least 1 year and accompanied by a combinstion of brain&spinal abnormalities and/or CSF anormalities consistent with MS Lack of clinical attacks/ relative paucity of MRI lesions No approved DMTs

34 Multiple Sclerosis (MS) Multiple Sclerosis is the commonest disabling neurological condition to afflict young adults MS is an autoimmune disease triggered by environmental agents acting in a genetically susceptible people Auto-aggresive autoimmune attack on the myelin sheath and other components of CNS Current&emerging DMTs are based in the above paradigm Is MS a primary neurodegenerative disease

35 MS: Pathology

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37 Demographic Characteristics of Multiple Sclerosis in Kuwait Total recruited patients in study: 195 Gender Distribution N(M/F): 195(76/119) Cross sectional or retrospectively included patients:134 Newly diagnosed drug naïve patient:65 SD±10.3

38 Clinical Characteristics of Multiple Sclerosis in Kuwaiti Population Presenting symptoms

39 PRESENTING SYMPTOMS IN MSTotal % SENSORY LOSS IN LIMBS30.7 VISUAL LOSS15.9 MOTOR WEAKNESS14.2 DIPLOPIA6.8 GAIT DISTURBANCE4.8 INCOORDINATION2.9 SENSORY LOSS-FACE2.8 LHERMITTE’S1.8 VERTIGO1.7 BLADDER SYMPTOMS1 AUTE TRANSVERSE MYELOPATHY0.7 PAIN0.5 OTHERS2.5 POLYSYMPTOMATIC13.7

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41 Medication details in studied Kuwaiti MS patients

42 MS Therapy: Deciding on which Medication Determine Therapeutic Goals – To reduce clinical relapse – To reduce accumulation of new MRI lesions –  new T2 lesions –  Gadolinium-enhancing lesions –  black holes –  Brain and spinal cord atrophy Reduce short-term relapse related disability

43 How To Determine of The Goals are Met? Compare with baseline relapse rate – Recall bias – Regression to the mean Assessment of improvement or stability in neurological impairment – Assess functional ambulatory limitation May indicate progression MRI ongoing/new inflammatory activity – Serial MRI to assess radiologic stability, worsening or improvement- q12-24 month except

44 How To Determine of The Goals are Met? If goals of DMT or symptomatic treatment are being met  no change in DMT unless problems with medication tolerability A detailed evaluation of common and idiopathic side effects will be required – Switching of medication based on adherence and tolerability ma be needed

45 What if Goals are not being Met If pre-therapy relapse rate is not improved – A therapeutic switch may be indicated Relapse rate is incomplete indicator of ongoing inflammatory disease activity – Cranial and spinal MRI May show therapy resistant inflammatory disease Guide switch to a more potent anti-inflammatory medication Clinical attack or definitive worsening disability is may lacking

46 Case 2 Mr. A.M.J is a 33 years old Kuwaiti male, diagnosed to have MS in In Jan 2008, he developed diplopia, followed by paresthesia in feet, ascending to abdomen, chest and forearms. These symptoms persisted By June 2008, he was ataxic and on a wheel chair, when he sought medical advice MRI was consistent with MS Marked imrovement was noted in sensory symptoms after pulse steroids.

47 Case 2 His symptoms showed a rapid progression, by Sept 2008, he had optic neuritis, sphincteric disturbance, and positive Lhermitte’s sign. In Oct 2008, he started to take Rebif. His disease remained stable, with no new relapses and no new lesions on MRI till In April 2011, he went for CCSVI treatment and discontinued Rebif without our knowledge or advice.

48 CASE 1 Lhermitte’s sign was positive Cranial nerves were normal No motor weakness Mild sensory deficit for light touch and vibration on left side Plantars were flexor bilaterally Romberg’s sign was mildly positive Moderate left sided dysmetria, with tandem ataxia EDSS :2; AI :1.

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51 Case 1: MRI Cervical spineTWI

52 Case 2 In August 2011 he reported dizziness, ataxia and diplopia He was treated with pulse steroids with marked recovery. He was clinically stable, and was advised to restart Rebif. In Jan 2012, EDSS:1, AI:0. MRI in June 2012 showed new cerebellar lesions, with no enhancement. In Oct 2012, he came in with a mild relapse and was treated with pulse steroids. An MRI in Dec 2012 showed worsening lesion load, and he was advised to start Tysabri after JCV serology. He started Tysabri in Dec 2012, and till 5 months post Tysabri, there were no active lesions.

53 Case 2 In Sept 2013, patient came with another severe relapse, with homonymous hemianopia, sphincteric problems, gait ataxia, and sensory disturbance. Treated with pulse steroids with partial improvement in urinary symptoms and ataxia, but not in visual symptoms.

54 Case 2: MRI Brain 2

55 Case 2: MRI Cervical spine 2

56 Case 2 MRI showed marked worsening, with tumefactive enhancing lesions A CSF study was done, which was normal, negative for JCV. Considering this as a failure of Tysabri, it is planned to treat him with Rituximab

57 Is Clinical Worsening due to Attack related Disease or Progression? If it is due to non-inflammatory MS progressive disease – Neurodegenerative MS – ?subclinical ( and sub-radiologic) inflammation unresponsive to current DMTs – Switching to alternative MS therapy is futile Escalating therapy If clinical impairment is strongly associated with ongoing relapses or marked new inflammatory MRI activity

58 Existing & Emerging MS therapies Modified from P. Vermersch Phase I Phase II Phase III Marketed Interferons Antiproliferative agents Cytolytic mAbs Symptomatic Tx Vaccine, tolerization Lymphocyte trafficking Immune regulation Other Idebenone BIIB033 Fingolimod Firategrast Siponimod ONO-4641 CS-0777 ELND-002 Tysabri Daclizumab Laquinimod BG12 NI-0801 AZD5904 GRC4039 CCX-140 AIN457 Cladribine Nerispirdine Ofatumumab Belimumab Ampyra Ocrelizumab Sativex Alemtuzumab Copaxone IPX-056 RPI-78M LY Novantrone Rebif Betaferon Pixantrone Peg IFN  (BIIB017) ATX-MS-1467 PI2301 RTL1000 Copaxone generics x2 Azathioprine Teriflunomide LV Copaxone Avonex = Oral administration = Injectable Extavia Ponesimod

59 IFNβ-1b SC qod GA SC qd IFNβ-1a IM qwk Mitox IV q 90 d wks IFNβ-1a SC tiw Natalizumab IV q 4 wks Fingolimod 0.5 mg gd Teriflun PO qd Laquin PO Daclizumab SC BG-12 PO bid Alemtuz IV The Changing Landscape of MS Disease Modifying Treatment Of Approved and Emerging Therapies

60 How are MS medication is selected? Injectable interferon-β and glatiramer acetate remain the first line DMT for many clinicians – Their side effects are manageable with minimum of serious side effects First line DMTs are effective in reducing clinical attacks and new MRI lesions

61 Injectable therapies Oral therapies Consider side effects BG 12 Fingolimod Terflunomide Oral therapies Consider side effects BG 12 Fingolimod Terflunomide Natalizumab Glatiramer Interferon β Relapsing inflammatory MS clinical course First line First line? Severe relapsing inflammatory MS/JCV negative Inadequate response/inj intolerance Inadequate response/oral intolerance Parallel switch Inadequate response/JCV negative

62 Drawback of injectable Medication Interferon-β – “Flue-like illness” often transient – Liver enzyme monitoring – Rarely depression Glatiramer acetate – Flushing, eosinophilia, rare allergic reaction, injection-site reactions (skin liopatrophy) – Conbination therapy+interferon-β1a IM/weekly and glatiramer acetate does not appear to be significantly more efficacious than monotherapy Lublin FD et al, Ann Neurology 2013

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68 BG-12 Phase III trials

69 BG-12  Integrated analysis Compared with PBO, BG mg BID and TID significantly reduced ARR, risk of relapse, adjusted ARR requiring steroids, disability progression, and MRI outcomes. Demonstrated consistent benefits on clinical efficacy across prespecified subgroups of RRMS pts with varied baseline demographics and disease characteristics Overall incidence of AEs, SAEs, and discontinuations due to AES similar across tx groups; flushing and GI events most common AEs

70 Nrf2 - Detox Enzymes - Antioxidant Enzymes - NADPH Generating Enzymes - GSH Biosynthesis Enzymes - Chaperones - Ubiquitination/Proteasome Cell and Tissue Protection NF  B - Proinflammatory cytokines - Leukocyte adhesion molecules - Lymphocyte activation Inflammation, Tissue Damage Nrf2 Pathway May Induce a Cytoprotective Response and Inhibit NF  B Mediated Inflammation BG-12

71 DEFINE Trial BG12 240mg bid vs tid: Primary endpoint - Relapses p< % 52.7%

72 DEFINE: MRI p< % p< % Placebo BG12 bid BG12 tid

73 BG-12 (dimethyl fumarate, DMF): CONFIRM — Annualized Relapse Rate

74 Laquinimod Small molecule

75 Sensitivity analyses using different statistical methods (Poisson regression, negative binomial, ANCOVA) yielded similar magnitudes of effect, statistically significant LAQUINIMOD 0.6mgPLACEBO % Reduction p= Annualized Relapse Rate Comi G. et al. Oral laquinimod reduced relapse rate and delayed progression of disability in Allegro, a placebo-controlled phase III trial for RRMS. Presented at the Late-Breaking Science Session of the 63rd Annual Meeting of the American Academy of Neurology; April 9-16, 2011; Honolulu, HI Laquinimod: Annualized Relapse Rate

76 30% Reduction p= % Reduction p= LAQUINIMOD 0.6mg PLACEBO GdE-T1 Lesions New-T2 Lesions CUMULATIVE NUMBER OF GdE-T1 LESIONS (MONTHS 12 & 24) CUMULATIVE NUMBER OF NEW-T2 LESIONS (MONTHS 12 & 24) LAQUINIMOD 0.6mg PLACEBO Comi G. et al. Oral laquinimod reduced relapse rate and delayed progression of disability in Allegro, a placebo-controlled phase III trial for RRMS. Presented at the Late-Breaking Science Session of the 63rd Annual Meeting of the American Academy of Neurology; April 9-16, 2011; Honolulu, HI Laquinimod: Reduction in MRI Activity

77 Daclizumab Anti-CD25 mAb

78 Daclizumab Effects similar in patients with highly active MS compared with pts with less aggressive disease prior to tx initiation Treatment resulted in significant increase in number of pts who were disease- activity free following 1 year of tx in SELECT trial Patients had reductions in % change in volume of T1-hypointense and T2-hyperintense lesions over 52 wks of treatment vs increases in PBO group

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80 S1P receptor modulators/ agonists In phase 2b study, ponesimod significantly reduced inflammatory MRI activity at all doses tested, with a significant dose response; lower ARR also observed with ponesimod compared with PBO, and was generally well tolerated Primary endpoint met in phase 2 DreaMS trial: ONO-4641 demonstrated significant efficacy on all key MRI measures of disease activity at all 3 doses compared with PBO, and was generally well tolerated Compared with PBO, reduction in mean CUAL observed as early as month 1 for siponimod 0.25 mg/day and 2.0 mg/day, and in all doses at month 2 in phase 2 BOLD trial; effect maintained at each month up to month 6; similar pattern for new/enlarging T2 lesions for all siponimod doses at month 2 and maintained at each month up to month 613

81 Glatiramer acetate Compared with PBO, GA 40 mg SC TIW significantly reduced: ARR by 34.4.% (P <.0001) Cumulative # GdE lesions by 44.8% (P <.0001) Cumulative # new/enlarging T2 lesions by 34.7% (P <.0001) Safety profile consistent with GA 20 mg/day SC

82 Teriflunomide Pyrimidine Synthesis Inhibitor (anti- metabolite)

83 Teriflunomide Compared with PBO, 7 mg/day and 14 mg/day teriflunomide significantly reduced ARR by 22.3% and 36.3%, respectively (P =.0183 and P =.0001, respectively) Compared with PBO, 14 mg/day teriflunomide significantly reduced 12-wk CDP (HR =.685; P =.0442) Both teriflunomide doses generally well tolerated; safety profile consistent with prior studies Update from TEMSO trialMean reductions in lymphocyte and neutrophil observed in TEMSO were small in magnitude and were reversible after treatment discontinuation or on treatment in some cases; no other clinically significant complications to blood cytopenias reported

84 a) Adjusted for Expanded Disability Status Scale (EDSS) score strata at baseline and takes duration of treatment into account.ARR, annualised relapse rate; RRR, relative risk reduction Teriflunomide Adjusted a annualized relapse rate RRR: 31.2% p= RRR: 31.5% p= TEMSO: Relapse Rate

85 Number at risk Placebo 7 mg teriflunomide 14 mg teriflunomide Disability progression (%) Week Placebo vs 7 mg: HRR 23.7% p= Placebo vs 14 mg: HRR 29.8% p= % 21.7% 20.2% Placebo 7 mg teriflunomide 14 mg teriflunomide TEMSO: EDSS progression (3 month confirmed)

86 TENERE: Annualized relapse rate The ARR in the 14 mg teriflunomide group was not statistically different from the ARR in the Rebif® group The estimated ARR was higher in the 7mg treatment group Rebif® N= Genzyme, Press release, Cambridge, MA – December 20, 2011

87 FINGOLIMOD Sphingosine-1- Phosphate (S1P) Receptor Agonist

88 Fingolimod Treatment with fingolimod 0.5 mg: – Significant benefits on relapse-related outcomes within first 3 months and on volume loss over 6 months compared with PBO in FREEDOMS and FREEDOMS II studies; concordant results from 2 large phase 3 trials, along with phase 2 data, allow better definition of expectations regarding time lag between initiation and effects of fingolimod treatment Fingolimod treatment initiation effects in pooled population from FREEDOMS, FREEDOMS II (vs PBO), and TRANSFORMS (vs IM IFN à- 1a) a transient, mostly asymptomatic decrease in heart rate; symptomatic bradycardia and Mobitz I and 2:1 AVBs were dose- dependent; AVB first occurrences most common <6 h post-dose5 Analysis of TRANSFORMS trial demonstrated advantage of switching to fingolimod over remaining on IFN à-1a IM with regard to time to relapse in RRMS6

89 LN T-cell FTY720-P Prevents T-cell invasion of central nervous system S1P receptor Sphingosine-1-phosphate (S1P) receptor modulator Internalises S1P 1, blocks lymphocyte egress from lymph node (LN) while sparing immune surveillance by peripheral memory T-cells FTY720 traps circulating lymphocytes in peripheral lymph nodes Multiple sclerosis FTY720 Fingolimod: Mechanism of Action

90 FREEDOMS (Fingolimod) Annualized Relapse Rate Annualised relapse rate Placebo (n = 418) Fingolimod 0.5 mg (n = 425) Fingolimod 1.25 mg (n = 429) -54% vs placebo p < % vs placebo p < ITT population; negative binomial regression model adjusted for treatment group, country, number of relapses in previous 2 years and baseline Expanded Disability Status Scale (EDSS) as covariates

91 *Analysis performed using a negative binomial regression model adjusted for treatment group and country **Analysis performed using rank ANCOVA adjusted for treatment group, country and number of lesions at baseline Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging Fingolimod 0.5 mg (n = 370) Fingolimod 1.25 mg (n = 337 ) (13.2) 2.5 (7.2) 2.5 (5.5) Placebo (n = 339) # new/enlarging T2 lesions at month 24 from baseline* Fingolimod 1.25 mg (n = 343 ) Mean (SD) lesion number Placebo (n = 332) Fingolimod 0.5 mg (n = 369) 0.2 (1.1) 1.1 (2.4) 0.2 (0.8) # T1 Gd+ lesions at month 24** p < FREEDOMS (Fingolimod) MRI Lesion Activity

92 FREEDOMS (Fingolimod) Disability (Disability) Progression Placebo Fingolimod 0.5 mg Fingolimod 1.25 mg Patients with 3-month confirmed EDSS progression (%) Days on study Fingolimod 1.25 mg vs placebo, HR = 0.68, p = Fingolimod 0.5 mg vs placebo, HR = 0.70, p = HR, hazard ratio


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