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

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

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 1974. Inconsistency of dosage was seen among and within different countries.

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) But more cataracts!

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)

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 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

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.

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

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

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

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

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

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?