action duchenne international conference 2015 steroids in duchenne muscular dystrophy 1.the use of...
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ACTION DUCHENNE INTERNATIONAL CONFERENCE
2015
Steroids in Duchenne muscular dystrophy
1. The use of steroids in DMD.2. FOR-DMD steroid trial, does it still matter?3. Research update on steroids
Dr Henriette van RuitenClinical Research Associate The John Walton Muscular Dystrophy Research CentreNewcastle upon Tyne
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• Affects 1 in 3500 newborns
• In UK,
• 100 boys are born with DMD each year
• There are 2500 patients with DMD
• Caused by mutation in the dystrophin gene,
• Absence of dystrophin in muscle fibres
• Clinically characterised by progressive muscle wasting
Duchenne Muscular Dystrophy (DMD)
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Current treatments
Pharmacological treatments
Treatment of complications
Respiratory care
Cardiac management
Orthotic and orthopaedic approach
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Pharmacological treatments
Steroids• Also called corticosteroids or
glucocorticoids. • Man made version of hormones normally
produced by the adrenal glands• Steroids are mainly used to reduce
inflammation and suppress immune system
• Used in conditions such as asthma, arthritis, eczema etc)Why are steroids used in DMD?
• Only medication currently available for all which slows the decline in muscle strength in DMD
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Steroids – history of use
First report on steroids in DMD
• In 1974 Drachman et all. (Lancet) first prescribed steroids to 14 boys with DMD in USA.
• Recorded an improvement in motor power and muscular activities in 8 out of 14 boys.Steroids in the UK:
• Part of routine care in the last 15 years
• “Gold Standard” for treatment of DMD as per Standard of care guidelines (Bushby et al, 2009)
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Steroids – which?
Steroids used in DMD are prednisolone and deflazacort.
Prednisolone• Available in both tablet and liquid form• Daily prednisolone more effective than
intermittent in improving muscle strength (North Star data)
• Intermittent prednisolone has less side effects.
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Steroids – which?
Deflazacort:• Only available in tablets• Not available in all countries, more expensive• Daily deflazacort is ? fewer side effects (weight
gain)
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Steroids – which is best?
No consensus which steroid regime is best
Deflazocort daily
Prednisone weekend doses
Prednisone 10mg/kg (we)
Prednisone daily
Prednisone 10 days on/10 days off
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Steroid – prescription chaos
Worldwide 105 clinics which prescribe 29 different steroid regimes
In the UK prednisolone is most commonly prescribed with 50:50 split between daily and intermittent regimes. Minority prescribe deflazacort.
Current trial FOR DMD – to end the prescription chaos
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FOR DMD STUDY (www.for-dmd.org)
International study (US, Canada, UK, Germany, Italy)
This study compares three ways of giving steroids to young boys (age 4-7) with DMD
Steroids studied: Prednisolone daily 0.75mg/kg Prednisolone (0.75mg/kg) 10 days on/10 days off Deflazacort daily 0.9mg/kg
Aim: to determine which increases muscle strength the most and which has the fewest side effects
End date is September 2016
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Steroids – balance between benefits and risk
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Benefits of Steroids
Early increase in motor skills and energy,
Delay loss of milestones
Boys on steroid are 5x more like to walk at age 12-17 than boys not on steroids (Treat NMD data)
Improve upper arm function
Important for feeding, driving wheelchair, self care and using phones/computers
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Benefits of steroids
Strengthen muscles in the back
Reduces likelihood of spinal surgery from 90% to 10%
Strengthen breathing muscles
Steroids improve vital capacity (FVC)
Low FVC linked to need for breathing support
Protect the heart
However, response to steroids is variable
Approx 1-2% of boys do not respond to steroids
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Side effects: Behaviour problems Weight gain Cushingoid appearance Vertebral fractures Immunosuppression Short stature Delayed puberty Cataracts Hypertension GI upset
Side effects of steroids
Are significant Require proactive
management
• Behavioural guidance• Prophylaxis/treatment of
osteoporosis• Regular follow up (BP,
glycosuria, eye check, physical exam)
• Flue jabs• Avoid live vaccines
Considerable but predictable
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Starting steroids
Around the plateau phase of motor function. This usually happens around the age of 4-5yrs old.
With time steroid dose is adjusted according to benefits and side effects
Try and prevent/treat side effects before reducing dose
In older less ambulant boys steroids may still be of benefit; eg in improving upper body strength, reducing the risk of scoliosis and stabilizing respiratory function.
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General advice on taking steroids
Before taking steroids: check chickenpox immunity, bone scan and an eye check.
Once the steroids have been started: regular review for monitoring of side effects, and a regular bone scan
Do not stop steroids suddenly, must be reduced gradually.
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Emergencies in boys with DMD on steroids
If vomiting or unable to take steroids – contact GP or the muscle team. Your son may need to be given steroids by injection.
Always carry your steroid warning card
Information about emergency management for boys with DMD is available from AD (Action Emergency pack) and Parent Project (Emergency information card)
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When to stop steroids
The age to stop steroids needs to be decided individually. It may be necessary to change or stop the steroids because of side effects. In other situations, they can be used for many years, beyond the age at loss of ambulation.
Never stop steroids suddenly!
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Research update
FOR DMD trial - update Recruitment target = 225 boys End of recruitment is august 2016 Current no of boys enrolled = 156 Boys can be in exon skipping trial AND FOR DMD Results expected 2018 Results will provide evidence based guidance on
best steroid treatment in DMD Standardise steroid treatment Important for current and future clinical trials
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Starting steroids early (< age 4): Merlini et al 2012 Prolongs ambulation compared to starting steroids
later.
Next generation steroids: VBP15 – Dr Eric Hoffman USA Replacement drug for steroids. New drug with a
similar mode of action but without side effects In addition it has been shown to stabilise the
structure of muscle cells
Research update
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Research update
Initial results: Preclinical: beneficial in mice (better than
prednisolone) Phase I: results awaited
Phase 2 (boys with DMD) Phase 2a: In USA, steroid naïve boys Phase 2b: In Europe
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Summary
At the moment steroids are the only “treatment” available for all boys with DMD.
The benefits are indisputable however they come at a cost.
FOR DMD study: to provide an “evidence based” guidance on steroid treatment.
Next generation steroids – very promising
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Thank you
Any questions?