ECTRIMS burning debate pk coyle
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Transcript of ECTRIMS burning debate pk coyle
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