People in Wheelchairs Should Be

Included in Progressive MS Trials: No

Consultant: Accordant, Bayer, Biogen, Genentech/Roche, Mallinckrodt, Novartis, Sanofi/Genzyme, Serono, Teva

Research: Actelion, Genentech/Roche, Novartis, Opexa

Background

Rationale

Recommendations

MS therapeutics is in a Renaissance era

14 distinct agents, encompassing 9 distinct

mechanisms of action

for relapsing forms of MS

First line injectables

IFNβ-1b 250 mcg SC every other day (Betaseron;

Extavia)

IFNβ-1a 30 mcg IM weekly (Avonex); 44 (22) mcg

SC 3x weekly (Rebif)

pegylated IFNβ-1a 125 mcg SC Q14 days (Plegridy)

glatiramer acetate 40 mg SC 3x weekly, 20 mg SC

daily (Copaxone), 20 mg SC daily (Glatopa)

First line orals

fingolimod 0.5 mg daily (Gilenya)

teriflunomide 14 mg (7 mg) daily (Aubagio)

dimethyl fumarate 240 mg twice daily (Tecfidera)

Second line infusions/injectables

natalizumab 300 mg IV Q28 days (Tysabri)

alemtuzumab 12 mg IV in two annual 5/3 day

cycles (Lemtrada)

daclizumab 150 mg SC monthly (Zinbryta)

mitoxantrone 12 mg/m2 IV Q3 months (max

140 mg/m2) (Novantrone)

Wheelchair bound MS people have EDSS ≥7

Score Definition

7Wheelchair bound (unable to walk >5 meters)Wheels self, transfers alone

7.5Wheelchair bound (no more than few steps)May need aid to transfer, possible motorized wheelchair

8 Bed or chair bound; retains many self care functions

8.5 Bed bound; retains some self care functions

9 Bed bound; needs assistance; can communicate and eat

9.5Totally dependent; unable to communicate or eat/swallow

≥98% have progressive MS

Hard to get accurate numbers

<20% of all MS

This severe population appears to be decreasing

(in treatment era)

Progression is age linked (midlife/menopause)

50 year follow up of Gothenburg incidence

cohort (N=305)

median time to EDSS 7 was 48 years (vs. 26 years to

EDSS 6)

in RR, SP, CIS subset (N=254) 13% non-ambulatory,

31% died from MS

*J Neurol 2015;262:1148; Brain 1989;112:133; NEJM 2000;343;14302015; 161:51

Lyon MS database (N=1,844)

median time to EDSS 7 (≤10 meters) 33.1 years in

relapsing cohort, 13.4 years in PPMS cohort

London, Canada MS database (N=1,099)

EDSS 8 (bed patient) reached at median 46.4 years

Conclusion from natural history studies:

wheelchair bound MS people are often decades

into their disease

*J Neurol 2015;262:1148; Brain 1989;112:133; NEJM 2000;343;14302015; 161:51

Current and past practice has been to routinely exclude non-ambulatory MS people from pivotal clinical trials

Nothing has changed to rethink this

This is because this small MS population has significant prior CNS damage, loss of CNS reserve, more confounding comorbid issues, and less function to assess and lose

In fact, a very strong case can be made in the modern era to continue this practice

No DMTs documented for progressive MS (and

no CNS repair strategies)

However phase III trials in secondary

progressive MS (SPMS) (siponimod) and primary

progressive (PPMS) (ocrelizumab) reported

meeting their primary outcome

SPMS trial entered EDSS 3 to 6.5; 1 outcome

time to confirmed 3 month EDSS progression

( 1 point EDSS 3-5; 0.5 point EDSS 5.5-6.5)

PPMS trial entered EDSS 3 to 6.5; 1 outcome

time to confirmed 3 month progression

Both of these trials excluded wheelchair bound

MS

Wheelchair bound MS patients can certainly enter

many types of trials

These include natural history, symptom

management, CNS repair, QOL, rehabilitation trials

Perhaps even phase I/II progressive DMT trials

1 outcome MRI (atrophy)

They should not enter pivotal phase III DMT trials

cannot risk compromising results

More deconditioned

More comorbidities/complications

Poorer symptom management

Less preventative health care

Literature search found 16 low grade studies

some trends for improvement, but no high grade

evidence

summary: no conclusions can be drawn for benefit

Canadian study (N=743 MS people) looked at

exercise participation in ambulatory vs. non-

ambulatory MS

disability/non-ambulation was strong predictor of

exercise *Int J Rehab Res 2012;35:281; Peer J 2015;3:e1158; 161:51

N=41 MS patients admitted to inpatient rehabilitation

21 ambulatory, 20 wheelchair bound

16/21 (76%) of ambulatory patients achieved 100% mobility goals

Only 41 (20%) wheelchair bound achieved 100% mobility goals

Wheelchair bound MS had double the length of stay

*Neurorehabilitation 2012;30:97

Prospective study of N=198 MS patients

comorbid issues (HBP, dyslipidemia, asthma,

psoriasis, eczema, anemia) in MS vs. general

population

obesity, dyslipidemia associated with level of

disability

Comorbidities associated with greater disability

at diagnosis

*Neuroepidemiology 2016;46:106; Neurology 2009;72:117

N=132 consecutive late stage MS attending

rehabilitation center

87 women, 43 men

mean age 58, disease duration 18.7 years

9.6 hours bedridden, 14.3 hours wheelchair

only 25 had residual ability to walk alone or with

help

DVT in 58 (44%)*Thromb Res 2010;125:315

N=129 patients admitted to specialist inpatient rehab unit

mean age 56

PPMS 42%, SPMS 58%

EDSS <6 11%, 6-7 46%, ≥8 43%

Symptom treatment unsatisfactory for spasticity (46%), pain (28%), bladder (23%), emotional disturbance (14%)

Conclusion: poor symptom management in advanced MS

*ACTA Neurol Scand 2016;DOI:10.1111/ane.12631

N=47 women with EDSS ≥7

Mean age 56.8 years, disease duration 20 years

Rate of mammography, PAP smears,

colonoscopy

Conclusion: advanced MS people have markedly

preventative health care

*Int J MS Care 2015;17:200

Evaluated 58 prospective candidate outcomes in progressive MS trials (8 clinical, 1 electrophysiologic, 1 OCT, 7 MRI volumetric, 9 quantitative T1 MRI, 32 DTI MRI)

Used machine learning to come up with 4 clinical measures disability score (CombiWISE)

EDSS, Scripps neurologic rating scale, 25 FTW, 9 HPT

outperformed MRI (including brain atrophy) measures

Clinical deterioration outcomes argue for most functional progressive MS patients

*Front Neurol 2016;7:131

Pivotal trials require 1 clinical outcome

Effective DMT will slow (not stop) progression

difficult to show

You need sufficient measurable outcomes to document a placebo difference

wheelchair bound MS people cannot be assessed for 25 FTW; they cover a very limited portion of EDSS

People typically older, longer disease duration, more disabled than in CIS/relapsing trials

they carry associated baggage of immobility, 2complications, comorbidity, age, more complications

You need people with more CNS reserve, less

global injury, less comorbidity, and more to lose

You need to enter more exclusive “pristine pure”

population: to assure you don’t miss a treatment

effect

It is important to enter a population where you

are most likely to see a benefit

cannot risk trial failure because you entered a

suboptimal population

For pivotal phase III progressive MS DMT trials keep the current cap at EDSS <7

this is to maximize ability to see an impact over a finite period

Any approved progressive MS DMTs must be available to wheelchair bound MS people who have CNS function to lose

CNS repair trials can certainly be open to wheelchair bound MS people