Teaching Course 6 Current Controversy in Management

Xavier Montalban

University of Toronto

St Michael’s Hospital

Toronto, Canada

Cemcat

Hospital Universitari Vall d’Hebron

Barcelona, Spain

Paris 2017

Teaching Course 6—Current Controversy in

Management: Interactive Case Discussion

Disclaimer

Dr. Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, GSK, Roche, Almirall, NMSS and MSIF. Editor for Clinical Cases for MSJ.

Case report

• 45 year old Caucasian gentleman living in Barcelona

• Smoker of 20 cig/day for the last 20 years

• No history of past neurological symptoms

• In April 2004, he was referred to our MS clinic because of a 6 months history of progressive weakness in his left lower extremity

Case report

Examination:

• Normal general physical examination

• Higher mental functions and cranial nerves were normal

• Moderate weakness in his left lower limb

• Bilateral extensor plantar response

• Bilateral altered touch sensation in his lower limbs specially in his left limb

• A clear sensory level was not found

Which is the right answer?

1. Myelopathy is the most probable cause of the symptoms

2. Several lesions distributed within the CNS can’t be ruled out

3. Although there is no clear sensory level myelopathy can’t be ruled out

4. An spinal MR is the most appropriate test to be performed

5. All answers are correct

Which is the right answer?

• Myelopathy is the most probable cause of the symptoms

• Several lesions distributed within the CNS can’t be ruled out

• Although there is no clear sensory level myelopathy can’t be ruled out

• An spinal MR is the most appropriate test to be performed

• All answers are correct

MR showed several lesions sugestiveof demyelination

A diagnosis of PPMS was suspected

Primary Progresive Multiple Sclerosis

Defined by steady progressive from onset, without distinct relapses, in

neurological function over months to years

Represents 10-15% of all MS cases

Slight gender bias (F/M: 1.1-1.3 to 1)

Greater mean age at onset (40 vs 30 years)

Almost never seen in childhood

Clinical features very different from those of acute relapsing MS

80-85% spastic paraparesis (no clear sensory level)

10-15%: progressive cerebellar ataxia, and cognitive, brainstem

or visual symptoms

Diagnostic challenge

More difficult to achieve (diagnosis of exclusion)

Spinal cord MRI, and CSF analysis highly informative

Which is the right answer?

1. MR is specific enough to be pathognomonic of MS

2. Patient’s clinical history, neurological examination and the results of the MR are diagnostic of MS

3. A CSF tap is not recommended

4. Brain MR is not indicated

5. Other aetiologies should be ruled out

Which is the right answer?

1. MR is specific enough to be pathognomonic of MS

2. Patient’s clinical history, neurological examination and the results of the MR are diagnostic of MS

3. A CSF tap is not recommended

4. Brain MR is not indicated

5. Other aetiologies should be ruled out

Rule out other diagnosisPrimary Progressive MS

Dural fistula

Meningiomatosis

Multifocal white matter lesionsSpecific diagnosis in young adults

SUSACCADASIL Fabry PACNS Neurosarcoidosis

Lyme disease Multiple sclerosisFat embolism

1 2 3 4 5

6 7 8

Rice et al. JNNP 2013

Differential Diagnosis of PP multiple sclerosis

•Degenerative disorders:ALS•Compressive:

•Tumors•Chiari type I

•Hereditary:•HSP, SCA•Leukodystrophies

•Metabolic:•Vitamins B12, E•Copper•Hypothyroidism•Toxic: phenytoin, nitricooxide•Alcohol

•Infective/inflammatory•HIV•Syphilis•Prions•Vasculitis•Sarcoid•Lupus•Brucellosis

•Paraneoplastic•Idiopathic

Diagnostic criteria 2010: PPMS

DIS: ≥ 1 T2 lesion in ≥ 1 topography

juxta infraPV

DIS: ≥ 2 T2 spinal cord lesions

Positive Brain MRI

Positive Spinal cord MRI

1.- Positive CSF evidence

2.- Positive Brain MRI

3.- Positive spinal cord MRI

• Progressive syndrome for > 1 year

• Other progressive conditions excluded

• Two out of three:

This consensus-based recommendation is justifiedby comparing diagnostic criteria for PPMS and bya subsequent reanalysis of these data (X.Montalban, personal communication).

MR showed few lesions sugestive of demyelination

Case report

• CSF analyses showed no cells. Protein and glucose levels were normal. IgG index was 1.2. IgG oligoclonal bands were detected.

• Blood tests showed negative results for Borrelia, Treponema, HIV, toxoplasma and auto-antibodies. B12 levels were normal.

• Normal VEP

Diagnostic criteria 2010: PPMS

DIS: ≥ 1 T2 lesion in ≥ 1 topography

juxta infraPV

DIS: ≥ 2 T2 spinal cord lesions

Positive Brain MRI

Positive Spinal cord MRI

1.- Positive CSF evidence

2.- Positive Brain MRI

3.- Positive spinal cord MRI

Progressive syndrome for > 1 year

Other progressive conditions excluded

Two out of three:

This consensus-based recommendation is justifiedby comparing diagnostic criteria for PPMS and bya subsequent reanalysis of these data (X.Montalban, personal communication).

×

Case report

• CSF analyses showed no cells. Protein and glucose levels were normal. IgG index was 1.2. IgG oligoclonal bands were detected.

• Blood tests showed negative results for Borrelia, Treponema, HIV, toxoplasma and auto-antibodies. B12 levels were normal.

• Normal VEP

• Patient was treated with i.v. steroids for 5 days with some but incomplete recovery of the motor function

Which would you do first?

1. Treat him with alemtuzumab

2. Treat him with siponimod

3. Treat him with fingolimod

4. Recommend giving up smoking

Which would you do first?

1. Treat him with alemtuzumab

2. Treat him with siponimod

3. Treat him with fingolimod

4. Recommend giving up smoking

Healy B Arch Neurol,2009

Smoking: effect on the conversion from relapsing- remitting to secondary progressive MS

Never-smokers

Ex-smokers

Current-smokers

Smoking

Manouchehrinia A Brain 2013

Time of smoking cessation and disability progression

Smoking

Smoking cessation even after the onset of the disease will have a positive impact on disease progression

Case report

• After initial incomplete recovery the motor deficit gradually worsened over 4 years and the patient had difficulties in walking more than 500 m without help or resting

• The patient was seen at our center for a 3 weeks worsening in the difficulty in walking

• A new MR was performed and 2 Gd enhancing lesions were observed (one in the brain and the other in the spinal cord)

Which is the right answer?

1. Patients with PPMS have no attacks during their

follow up

2. Patients with PPMS have no Gd enhancing lesions

3. Patients with PPMS and attacks during the follow

up are classified currently as Progressive Relapsing

MS

4. All the answers are wrong

Which is the right answer?

1. Patients with PPMS have no attacks during their

follow up

2. Patients with PPMS have no Gd enhancing lesions

3. Patients with PPMS and attacks during the follow

up are classified currently as Progressive Relapsing

MS

4. All the answers are wrong

18 out of 42 patients (42%) with early

PPMS had at least one enhancing

lesion on their baseline scan

Enhancing lesion volume and number

of lesions are similar to those seen in

RRMS

Number of enhancing lesions

associated with younger age (r=0.5,

p=0.003) and higher T2 load (r=0.5,

p=0.02) (and higher degree of

disability)

Institute of Neurology, University

College London, UK

Early PPMS study. Brain Enhancement

Ingle, JNNP 2005

Brain 1999

A substantial minority (28%) of the PP-multiplesclerosis cohort had a distinct relapse evendecades after onset of progressive deterioration.

PPMS and inflammation

CIS RRMS

Non active

Active*Non

activeActive

* CIS becomes RRMS if patient experiences subsequentactivity and fulfills current MS diagnostic criteria

Lublin FD, et al. Neurology 2014

PROGRESSIVE DISEASE

Active and with

progression

Active and without

progression

Non active and with

progression

Non active and withoutprogression

PPMS SPMS

2013 clinical phenotypes revisions

Case report

• Different treatment options with DMA were discussed with the patient:

Which is the right answer?

1. Ocrelizumab is approved in US for patients with

PPMS

2. Patients with PPMS must be treated with DMA

3. Most of the trials in patients with PPMS have been

positive

4. There isn’t any hint of efficacy coming from any

PPMS trial

Which is the right answer?

1. Ocrelizumab is approved in US for patients with

PPMS

2. Patients with PPMS must be treated with DMA

3. Most of the trials in patients with PPMS have been

positive

4. There isn’t any hint of efficacy coming from any

PPMS trial

Case report

• Different treatment options with DMA were discussed with the patient:

• One trial with rituximab showed in a subgroup of patients a positive effect

• One trial has been positive (ocrelizumab)

• Ages Eligible for Study: 25 Years to 65 Years• Diagnosis of PPMS (according to the 2005 Revised

McDonald criteria)• Time since first reported symptoms between 2 and 10

years• Evidence of clinical disability progression in the 2

years prior to Screening• Disability status at Screening:

– EDSS score of 3.5-6.0 inclusive– pyramidal functional system score of 2 or more– 25'TWT less than 30 seconds

• 969 patients enrolled

Oral fingolimod (FTY720)

INFORMS® trial - Inclusion criteria

Primary Progressive - INFORMS

Lublin et al. Lancet 2016

Inclusion criteria:Diagnosis of PPMS (McDonald 2005)

≥1 year of disease progression plus two of three criteria: positive brain MRI; positive spinal cord MRI; or positive CSF

Age 25–65 yearsEDSS 3.5–6.0pyramidal FS≥2, 25TWT <30 secDisease duration 2 – 10 years≥0.5 EDSS increase in prior 2 years

Primary outcome: fingolimod vs placebo on delaying time to 3-mo CDP on novel composite endpoint of meeting any of 3 criteria

• Increase from baseline EDSS (if baseline score ≤5.0, or by 0.5 point if baseline score ≥5.5

• ≥20% increase of from baseline 25-Foot-Timed-Walk• ≥20% increase from baseline 9-Hole Peg Test

Primary Progressive - INFORMS

Main secondary outcome: fingolimod vs placebo on delaying time to 3-mo CDP on conventional endpoint of meeting increase from baseline EDSS (if baseline score ≤5.0, or by 0.5 point if baseline score ≥5.5)

Lublin et al. Lancet 2016

CD20 as a Target

• CD20, a phosphorylated protein

(297 amino acids, 33–35 kDa)

– Highly expressed on the

surface of pre-B through

memory B cells, but is not

expressed on stem cells or

plasma cells

– Expressed in B cells in lesions

of acute and progressive forms

of MS (PPMS, SPMS)

– Stable, does not get secreted

or shed, and does not

internalize on antibody binding

PPMS = primary progressive MS; SPMS = secondary progressive MS.

Johnson P, Glennie M. Semin Oncol. 2003;30(1 suppl 2):3–8; Waubant E. Int MS J. 2008;15(1):19–25; Meinl E, et al. Ann Neurol. 2006;59(6):880–92; Magliozzi R, et al. Brain. 2007;130(pt 4):1089–104;

Frischer JM, et al. Brain. 2009;132:1175–896; Magliozzi R, et al. Ann Neurol. 2010;68(4):477–93; Winiarska M, et al. Front Biosci. 2011;16:277–306

CD20

cytoplasm

Confidential — For internal use only. Do not copy, distribute or use without prior written consent

Efficacy And Safety of Ocrelizumab in Primary Progressive Multiple Sclerosis – Results of the Placebo-controlled, Double-blind, Phase III ORATORIO

Study

X Montalban, B Hemmer, K Rammohan, G Giovannoni, J de Seze, A Bar-Or, DL Arnold, A Sauter, A Kakarieka, D Masterman, P Chin, H Garren, J Wolinsky,

on behalf of the ORATORIO clinical investigators

NCT01194570

31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis 2015

Platform presentation number 228

Ocrelizumab

ORATORIO® - Inclusion criteria

Adult patients, 18-55 years of age

Primary Progressive Multiple Sclerosis (according to revised McDonald criteria)

Expanded Disability Status Scale (EDSS) 3 to 6.5 points

Disease duration from onset of MS symptoms < 15 years if EDSS > 5.0, < 10 years if EDSS >/= 5.0

736 patients recruited

ORATORIO: Phase III study in primary progressive MS (PPMS) Study Design

• Diagnosis of PPMS (2005 revised McDonald criteria)1

• Age 18–55 years

• EDSS 3.0–6.5

• CSF: elevated IgG index or >1 oligoclonal bands

• No history of RRMS, SPMS, or PRMS

• No treatment with other MS DMTs at screening 2

:1 R

and

om

isat

ion

#

*Patients received methylprednisolone prior to each ocrelizumab infusion or placebo infusion. †The blinded treatment period may be extended until database lock.#2:1 randomisation stratified by age (≤45 vs >45) and region (US vs ROW).‡Continued monitoring occurs if B cells are not repleted.

Primary endpoint: Significant reduction in 12-week CDP

24% reduction in risk of CDP

HR (95% CI): 0.76 (0.59, 0.98); p=0.0321

Time to 12-week Confirmed Disability Progression

n

Placebo 244 232 212 199 189 180 172 162 153 145 136 120 85 66 46 30 20 7 2

Ocrelizumab 487 462 450 431 414 391 376 355 338 319 304 281 207 166 136 80 47 20 7

Montalban X, et al. ECTRIMS 2015. Platform presentation 228.

Secondary endpoint: Significant reduction in the rate of whole brain volume loss

n

Placebo 203 200 150

Ocrelizumab 407 403 325

17.5% reduction vs placebo

p=0.0206*

Percent Change of Whole Brain Volume from Week 24 to Week 120

-1.1%

-0.90%

Montalban X, et al. ECTRIMS 2015. Platform presentation 228.

Significant reduction in risk of 12-week confirmed disability progression

Overall Study Population

Placebo(N=244)

Ocrelizumab(N=488)

HazardRatio

95% CI

n Events n Events

Overallpopulation

244 96 487 160 0.76 (0.59, 0.98)

≥T1 Gd+

lesions 60 27 133 43 0.65 (0.40, 1.06)

No T1 Gd+

lesions183 68 350 115 0.84 (0.62, 1.13)

24% reduction in risk of CDP

HR (95% CI): 0.76 (0.59, 0.98);

p-value (log rank)=0.0321*

(n=488)

7

Inflammation is a common and frequent phenomenon even in clinically “pure” progressive patients

Neuroprotective plus anti-inflammatory strategies seem to be necessary which means adding more difficulties to trials

Recruitment in phase 3 PC trials in progressive MS increasingly difficult in western countries

Biomarker (probably MR) for phase 2 trials is desperately needed

New trial designs

Something escapes from our understanding (INFORMS)

Conclusions

Case report

• The patient decided not to be treated and continue to progressively worsening over the following 4 years.

• Patient needed two canes to walk 200 meters with difficulty, spasticity was a problem due to painful spasms of the extremities and also contributed to walking problems

• The patient reports that he smokes marihuana occasionally to ameliorate spasticity symptoms with irregular results

1. Treat patient with nabiximols

2. Treat patient with fampridine

3. Treat patient with oral baclofen and/or tizanidine

4. Recommend to continue with smoking cannabinoids

Which is the wrong answer?

1. Treat patient with nabiximols

2. Treat patient with fampridine

3. Treat patient with oral baclofen and/or tizanidine

4. Recommend to continue with smoking cannabinoids

Which is the wrong answer?

Smoking cannabis is not a good option

• Herbs: Smoked Cannabis

– Insufficient evidence

– Data are inadequate to support or refute use of smoked cannabis for spasticity, pain, balance/posture, or cognition in MS (Level U).

• A population-based cohort study examined men (n = 49,321)

• cannabis smoking was significantly associated with more than a twofold risk (hazard ratio 2.12, 95 % CI 1.08-4.14) of developing lung cancer over the 40-year follow-up period, even after statistical adjustment for baseline tobacco use, alcohol use, respiratory conditions, and socioeconomic status

Calleghan RC et al. Cancer C Control 2013

Smoking cannabis is not a good option

Spasticity management. Team approach

PT

Standing, Positioning, Stretching,

exercise programme, Splinting,

FES, Monitoring treatment

PWS / Carer

Monitor aggravating factors

Exercise / stretching

Monitor drug effectiveness

DR

Timing of assessments

& treatments

Drug prescribing & evaluating

OT

Adaptations

Wheelchair

Positioning

Splinting

Role / function

Nurses

Skin, Bladder, Bowel

Education

Positioning

LOW quality

Imprecision of results

Problems in randomization

Lost to follow-up of an important proportion of patients

No safety issues evaluated

From evidence to recommendations

Physiotherapy based in active and passive exercises with stretching, used alone or in combination with other antispastic treatments can help management of the patients symptoms.

WEAK

Physiotherapy

Safety

From evidence to recomendations

Oral baclofen

LOW qualityHeterogeneity in patients included

Blinding was not completely effective overestimate treatment effects

No sample size calculations

Side-effects such as drowsiness, weakness, paraesthesiae and dry mouth were common and limit the dose tolerated. Baclofen side effects were fewer and better tolerated than those caused by diazepam.

Safety

In patients with spasticity the treatment with oral baclofen is recommended

WEAK

TizanidineMODERATE quality

Conduct of the studies was robust

No sample size calculations

Well tolerated, most frequent side-effects drowsiness and a dry mouth. No difference between tizanidine and baclofen in terms of frequency and severity of side-effects

Safety

From evidence to recomendations

In patients with spasticity and no improvement or poor tolerance to oral baclofen, it can be replaced by tizanidine

WEAK

Nabiximols

HIGH qualityConduct of the studies was robust

No heterogeneity

Well tolerated, most frequent side-effects were dose-related psichotropic effects of cannabis such as dizziness and administration site reactions

Safety

From evidence to recommendations

In patients with spasticity and lack of clinical improvement or poor tolerance to other medications, treatment with Nabiximols is recommended. If no improvement is achieved in the short term, discontinuation must be considered. STRONG

Management

“Based on this review, we are unable to make any newrecommendations on the use of adrenaline for the treatment ofanaphylaxis.”

...but, please, use it!!!

Case report

• Patient was treated with baclofen starting with 10 mg twice a day and increasing the dose progressively until reaching 25 t.i.d. Some improvement was observed but not to a satisfactory degree .

• Nabiximols was tried for 4-6 weeks increasing the dose progressively up to 6 sprays per day. A further improvement was observed with a decrease in the number and intensity of painful spasms (>20% improvement in a VAS). Gait did not improve

Case report

• Patient continued worsening and referred that reaching the toilette from the living room (just about 10m) was very difficult.

Which would you do?

1. Recommend multidisciplinary approach

2. Continue treatment with antispastic drugs

3. Treat patient with fampridine

4. All the above

Which would you do?

1. Recommend multidisciplinary approach

2. Continue treatment with antispastic drugs

3. Treat patient with fampridine

4. All the above

1. Harris Interactive. Experiences with Multiple Sclerosis (MS): Perspectives of People with MS and MS Care Partners [poll]. March 25, 2008.2. LaRocca NG. Patient 2011; 4: 189–201.

3. van Asch. Eur Neur Rev 2011; 6 (2): 115–120.

Walking impairment in MS

• Walking integrates multiple functional systems, including motor (pyramidal and extra pyramidal), sensory (proprioception), cerebellar and vestibular

• Over 60% of people with MS report difficulty walking 1

• 70% of patients who have walking difficulty say it is the most challenging aspect of their MS 2

• As MS progresses, walking impairments become more severe and may have a greater impact on patients’ lives 3

67

• Treatment with fampridine is restricted toprescription and supervision by physiciansexperienced in the management of MS

• It is indicated for the improvement of walking in adult patients with multiplesclerosis with walking disability (EDSS 4-7)

• Initial prescription should be limited to 2 weeks of therapy as clinical

benefits should generally be identified within 2-weeks after starting

fampridine

• A timed walking test, e.g. the Timed 25 Foot Walk (T25FW), is

recommended to evaluate improvement after two weeks. If no

improvement is observed, the drug should be discontinued

• It should be discontinued if benefit is not reported by patients

Walking impairment in MS

Case report

• Patient continued worsening and referred that reaching the toilette from the living room (just about 10m) was very difficult.

• Fampridine was tried and a significant improvement of the Timed 25 Foot Walk and in the MSWS-12 was observed.

• Patient is now being treated in our centre by a multidisciplinary team

Learning objectives

• To review the current diagnostic criteria of PPMS

• To review the new MS phenotype classification

• To understand the current controversy surrounding management of risk factors

• To review the use of therapies