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

• 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)

Current treatments

Pharmacological treatments

Treatment of complications

Respiratory care

Cardiac management

Orthotic and orthopaedic approach

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

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)

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.

Steroids – which?

Deflazacort:• Only available in tablets• Not available in all countries, more expensive• Daily deflazacort is ? fewer side effects (weight

gain)

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

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

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

Steroids – balance between benefits and risk

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

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

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

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.

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.

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)

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!

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

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

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

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

Thank you

Any questions?