5th MS Research Day, June 14th 2014
New treatments in MS
What’s here and what’s nearly here
David Miller
Queen Square MS Centre
at UCL and UCLH
Course of MS and its treatment
Relapsing remitting
Secondary
progressive
Disability
Primary
progressive
Progressive
relapsing
Time in years
Aims of treatment
• Prevent relapses and associated disability
• Prevent progressive disability
• Reverse persistent disability
Aims of treatment
• Prevent relapses and associated disability √
• Prevent progressive disability X
• Reverse persistent disability X
Current treatments are for relapsing remitting MS
Relapsing remitting
Secondary
progressive
Primary
progressive
Progressive
relapsing
Time
Time in years
Problems measuring relapses
• Insensitive measure: “tip of the iceberg”
• Large and expensive treatment trials
• Trials don’t address very long-term effects
Relapsing remitting MS:
Monthly MRI: new lesions
10 new lesions per one relapse
New MRI lesions = good “surrogate” for
relapses in more than 50 MS trials
Decreasing
MRI lesions
Decreasing
relapses
Sormani et al Lancet Neurology 2013
Treatments work by impeding the immune
cells that cause new lesions and relapses
Immunomodulation
Immunosuppression
Less effective
More effective
Fewer side effects
More side effects
What’s here
• β-(beta)-interferons
–
–
–
–
Avonex
Rebif
Betaferon
Extavia
Injection into muscle once a week
Injection under skin 3 times a week
Injection under skin every second day
Injection under skin every second day
• Glatiramer acetate
– Copaxone
• Natalizumab
– Tysabri
• Fingolimod
– Gilenya
Injection under skin every day
Injection into vein once a month
Tablet once a day
ß-interferon
• Immunomodulation
• Reduces relapse rate by 30%
• Reduces new MRI lesions by 60%
• Good long term safety
Glatiramer acetate
• Immunomodulation
• Reduces relapse rate by 30%
• Reduces new MRI lesions by 40%
• Good long term safety
NHS “risk sharing scheme” for β-interferon &
glatiramer acetate
• Criteria for treatment
• Two relapses in two years
• Able to walk
• 6-year analysis = cost-effective
Natalizumab (Tysabri)
• Immunosuppression (novel)
– Prevents immune cells going from the blood to the brain
•
•
•
•
Reduces relapse rate by 70%
Reduced new MRI lesions by 90%
Reduces disability by 40%
Recommended by NICE for NHS (2007)
Blood-brain
barrier
Brain
Natalizumab: side effects
• Allergic reactions
• Progressive multifocal leucoencephalopathy (PML)
PML Risk Stratification*
JCAnti-JCV
Virus
Antibody
antibodyStatus
test
Negative
Positive
(50%)
Prior IS Use
1 in 1,429
1 in 556
No
1 in 10,000
1 in 189
Natalizumab
Exposure
1–24 months
0.1/1000
25–48 months
95% CI 0.01-0.35
1 in 164
49-72 months
(50%)
No Prior IS Use
Yes
Prior IS Use
0.7/1000
1.8/1000
95% CI 0.5-1.0
95% CI 1.1-2.7
5.3/1000
11.2/1000
95% CI 4.4-6.2
95% CI 8.6-14.3
6.1/1000
Insufficient data
95% CI 4.8-7.8
1 in 89
Data beyond 6 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody
positive patients with prior IS use and >48 months of natalizumab exposure.
*Based on natalizumab exposure and 343 confirmed PML cases as of 5th March 2013. Prior IS data in overall natalizumab-treated patients based on proportion of
patients with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML patients as of 5th March 2013. The analysis assumes that 55% of
natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test positive for anti-JCV antibodies prior to the onset and diagnosis of PML.
The estimate of PML incidence in anti-JCV antibody negative patients is based on the assumption that all patients received at least 1 dose of natalizumab . Assuming
that all patients received at least 18 doses of natalizumab, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.16/1000;
95% CI 0.02–0.56).
Biogen Idec, data on file.
NICE Criteria for natalizumab treatment
• 2 disabling relapses in 12 months + new MRI lesions
Fingolimod (Gilenya)
• Immunosuppression (novel)
– Traps immune cells in lymph nodes
• Reduces relapse rate by 50%
• Reduces new MRI lesions by 75%
• Reduces disability by 30%
• Recommended by NICE for NHS (2012)
Fingolimod: mechanism of action
(Sphingosine)
Fingolimod: side effects
•
•
•
•
•
Herpes infections (can be severe)
Heart block with first dose (ECG monitoring)
Blurred vision (swelling back of eye)
Abnormal liver function
High blood pressure
NHS England criteria for fingolimod
• Relapses on β-interferon or glatiramer acetate
• High PML risk on natalizumab
What’s nearly here
• Teriflunomide
– Aubagio
Tablet once a day
• Dimethylfumarate
– Tecfidera
Tablet twice a day
• Alemtuzumab
– Lemtrada
Injection into vein every day for 5 days
then again one year later for 3 days
Teriflunomide (Aubagio)
•
•
•
•
Immunomodulation
Reduces relapse rate by 30%
Reduces new MRI lesions by 50%
Recommended by NICE for NHS (2014)
Teriflunomide: side effects
•
•
•
•
Nausea, diarrhoea
Hair thinning
Abnormal liver function
Must avoid in pregnancy
NICE criteria for teriflunomide treatment
• Two relapses in two years
Dimethyfumarate (Tecfidera)
•
•
•
•
Immunomodulation
Reduces relapse rate by 50%
Reduces new MRI lesions by 75%
NICE appraisal: on-going
Dimethylfumarate: side effects
•
•
•
•
Flushing
Nausea, abdominal pain, diarrhoea
Abnormal liver function
Low white blood cell count
Alemtuzumab (Lemtrada)
• Immunosuppression
– Depletes immune cells from the blood
• Reduces relapses, disability and new lesions by 50%
compared to β-interferon
• Recommended by NICE for NHS (2014)
– Active relapsing remitting MS
Alemtuzumab: side effects
•
•
•
•
•
Infusion reactions
Infections (including herpes)
Overactive thyroid
Internal bleeding (low platelets)
Kidney failure (rare)
Effectiveness and risks of treatments
3.5
3
Natalizumab
Alemtuzumab
2.5
2
Fingolimod
Dimethylfumarate
1.5
Increasing
risks
1
β-interferon
Glatiramer acetate
Teriflunomide
0.5
0
0
0.5
1
1.5
2
2.5
3
Increasing effectiveness
3.5
Options for treating relapsing remitting MS
•
•
•
•
•
There will very soon be 10 different treatments
Their benefits and side effects vary
More benefit ≈ more side effects
Different treatments will benefit different people
Should be able to control relapses in most people
Future treatment of relapsing remitting MS
• More new treatments on the way
• Combination treatments
• Personalised treatment
• Long term benefit and safety