1. ACTION DUCHENNE INTERNATIONAL CONFERENCE
2015
Steroids in Duchenne muscular dystrophy
The use of steroids in DMD.
FOR-DMD steroid trial, does it still matter?
Research update on steroids
Dr Henriette van Ruiten
Clinical Research Associate
The John Walton Muscular Dystrophy Research Centre
Newcastle upon Tyne

2. Duchenne Muscular Dystrophy (DMD)
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

3. Current treatments Pharmacological treatments
Treatment of complications
Respiratory care
Cardiac management
Orthotic and orthopaedic approach
The benefits of steroids in DMD were first suggested in Inconsistency of dosage was seen among and within different countries.

4. 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

5. 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)

6. 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.

7. Steroids – which? Deflazacort: Only available in tablets
Not available in all countries, more expensive
Daily deflazacort is ? fewer side effects (weight gain)
But more cataracts!

8. Steroids – which is best?
No consensus which steroid regime is best
Prednisone daily
Deflazocort daily
Prednisone 10 days on/10 days off
Prednisone weekend doses
Prednisone 10mg/kg (we)

9. 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

10. 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

11. Steroids – balance between benefits and risk

12. 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 than boys not on steroids (Treat NMD data)
Improve upper arm function
Important for feeding, driving wheelchair, self care and using phones/computers
Stabilisez resp function – improves vital capcity
Steroids strengthen axial muscles (delay spinal surgery)
Data Treat NMD regustry: steroid users are 5x more liley to walk than non steroid users at age 12-17
Boys not on steroid slose ability to walk between age 9-10

13. 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
ON steroid FVC continues to increase with age,
Not on steroids it declines.

14. Side effects of steroids
Considerable but predictable
Side effects:
Behaviour problems
Weight gain
Cushingoid appearance
Vertebral fractures
Immunosuppression
Short stature
Delayed puberty
Cataracts
Hypertension
GI upset
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
Short stature: Don’t advocate use of growth hormone
Puberty delay – testosterone is very successful and
GI upset: avoid ibuprofen

15. 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.

16. 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.

17. 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)

18. 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!
Message is not to stop stroids – benefots continu beyone loss of ambulation

19. 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

20. Research update 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

21. Research update Initial results: Phase 2 (boys with DMD)
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

22. 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

23. Thank you
Any questions?