UK clinical perspective on treatment reviews of multiple

sclerosis therapiesAlasdair Coles

Neurologist, Cambridge, UK

Disclaimer

• Investigator on many Genzyme studies of alemtuzumab treatment of multiple sclerosis.

• Received honoraria and travel assistance for speaking on alemtuzumab from Genzyme.

• Received grant support from Genzyme.

• My institution (University of Cambridge) has received gifts from Genzyme.

19 year old female law student and marathon runner

History18 months: ataxia, diplopia and headache 10 months: numb right big toe, tripping 4 months: burning sensation on right

shoulder1 month: diplopia, vertigo, numb right leg

for 2 weeks

EDSS 1.0

A marathon runner

A marathon runner

19 year old law student

Treatment

Started on interferon beta-1a SC.

2 months later: ascending numbness, weak legs then arms, then difficulty breathing, admitted to intensive care with quadraparesis. Steroids and plasma exchange. Good improvement over 6 weeks.

EDSS 2.5

A marathon runner

A marathon runner

RES: “rapidly evolving severe multiple sclerosis”• ≥ 2 disabling relapses in the previous year

AND• ≥ 1 gadolinium-enhancing lesions on brain

MRI Licensed indication for natalizumab in many regions

HAD: “high disease activity despite interferon-beta” • ≥ 1 relapse in the previous year on interferon-

beta• ≥ 1 gadolinium-enhancing MRI lesions or at

least nine T2-hyperintensive lesions on cranial MRI

Approved indication for fingolimod in many regions

What category of multiple sclerosis does she have according to NICE?

What evidence can guide switching from interferon to another drug ?

No RCT has compared switching to fingolimod versus natalizumab.

Sources of other evidence may be:• “real-life” databases• Indirect treatment comparison

“Real-life” databases: MSBase

Proportion of patients whose disability improves after

switching

Kalincik Ann Neurol. 2015 Mar;77(3):425-35

Natalizumab

Fingolimod

Indirect treatment comparison: relapse-free outcome

Genzyme, Manufacturer’s

submission to NICE 2014

A comparison of alemtuzumab, interferon beta-1a SC, teriflunomide and fingolimod in HAD

Genzyme, Manufacturer’s

submission to NICE 2014

Indirect treatment comparison of treatments of high disease activity

despite interferon-beta

Incre

asin

g e

fficacy

Increasing burden of treatment(worse safety, more difficult administration)

Interferon-beta

Natalizumab JC+

Mitoxantrone

Fingolimod

Dimethyl fumarate

Autologous stem cell transplantation

Glatiramer

Sketch of disease-modifying therapies in 2015/6

Daclizumab

Modified from Hauser S, ANN NEUROL 2013;74:317–327

Laquinimod

Alemtuzumab

Natalizumab JC neg

Rituximab / ocrelizumab

Teriflunomide

Azathioprine

Treatment AMildly effective, mildly toxic

Disease active

Escalation Strategy

Disease suppressed Disease still active

Treatment BMore effective, more toxic

Disease suppressed Disease still active

Treatment CMost effective, most toxic

Incre

asin

g e

fficacy

Increasing burden of treatment(worse safety, more difficult administration)

Interferon-beta

Natalizumab JC+

Mitoxantrone

Fingolimod

Dimethyl fumarate

Autologous stem cell transplantation

Glatiramer

First, second and third line therapies

Laquinimod

Alemtuzumab

Natalizumab JC neg

Rituximab / ocrelizumab

Teriflunomide

Third line

Second line

First line

Daclizumab

Treatment CMost effective, most toxic

Disease active

Induction Strategy

Disease suppressed Disease still active

Treatment C again or…..AMildly effective, mildly toxic

Disease suppressed Disease still active

Incre

asin

g e

fficacy

Increasing burden of treatment(worse safety, more difficult administration)

Interferon-beta

Natalizumab JC+

Mitoxantrone

Fingolimod

Dimethyl fumarate

Autologous stem cell transplantation

Glatiramer

High and low risk treatments

Daclizumab

Laquinimod

Alemtuzumab

Natalizumab JC neg

Rituxmab / ocrelizumab

Teriflunomide

“Dangerous”

“Aggressive”

“Safe”

19 year old female law student and marathon runner

Attitude to illness: Very concerned to maintain intellectual level and run good marathon times.

Attitude to risk: “I am a high risk, high gain person”

Elected to receive alemtuzumab (in the UK)Received two cycles in 2003 and 2004.Since then has had one relapse and this triggered a further cycle of alemtuzumab. Continues to run marathons.

Back to our case

“Alemtuzumab is recommended as a possible treatment for people with active relapsing–remitting multiple sclerosis.”• European Medicines Agency, 2013

“We are very pleased to be able to recommend alemtuzumab for adults with relapsing-remitting multiple sclerosis. Evidence has shown that alemtuzumab is more effective and less expensive than current similar treatments for those with severe relapsing-remitting MS• National Institute for Health and Care Excellence

Chief Executive, Sir Andrew Dillon , 2014

UK approved use of alemtuzumab

Conclusion

• Rigid derivation of treatment guidelines from randomised controlled trials leads to unforeseen consequences.

• Indirect treatment comparisons and “real-lef” database studies answer questions not resolvable by RCTs

• Safety- conscious investigators and pharma tend to promote an escalation approach, which misses the opportunities of induction treatment.

• Detailed guidelines fail reduce the opportunity for physicians to adapt advice for individual patient factors, such as approach to risk.