Dr T Willis Paediatric Neurologist, RJAH and BCH. Dr D Willis Severn Hospice, Telford.

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1 Duchenne Muscular Dystrophy a severe muscle wasting disease Dr T Willis Paediatric Neurologist, RJAH and BCH. Dr D Willis Severn Hospice, Telford.

2 Duchenne Muscular Dystrophy Caused by an out of frame mutation in the dystrophin gene Absence of dystrophin in muscle fibres Progressive symmetrical muscular weakness Proximal > distal Calf hypertrophy Symptoms < 5 years Wheelchair < 13 years (without treatment) Respiratory and Cardiac involvement Behavioural problems/asd Learning difficulties prevalence 1/3500 newborn boys

3 Muscular Dystrophy Genetic defect Loss of membrane integrity Elfux/influx of Proteins/growth factors Muscle fibres hypertrhophy Fibrosis Necrosis Loss of muscle mass

4 Duchenne Muscular Dystrophy: current treatments Pharmacological treatments Treatment of complications Respiratory care Cardiac management Orthotic and orthopaedic approach Bone health and management Psychological support

5 Duchenne Muscular Dystrophy: current treatments Pharmacological treatments Treatment of complications Respiratory care Cardiac management Orthotic and orthopaedic approach

6 Duchenne Muscular Dystrophy: current treatments Pharmacological treatments Corticosteroids Prednisolone/Prednisone 0.75mg/kg/day Deflazacort 0.9mg/kg/day

7 (Cochrane review, AAN, ENMC) Manzur et al. Glucocorticoids dor Duchenne muscular dystrophy Cochrane Database Syst Rev Delays loss of ambulation to age years Facilitates development of additional skills e.g. Jumping, hopping running, riding a bike Reduces likelyhood of spinal surgery from 90% to 10% Maintains respiratory function delaying need for assistive ventilation

8 Duchenne Muscular Dystrophy: Side effects: Weight gain Behaviour problems Cushingoid appearance Vertebral fractures Short stature Delayed puberty Cataracts Hypertension GI bleeding Diabetes Impact of steroids Are significant Require proactive management Behavioural guidance Prophylaxis/treatment of osteoporosis Regular follow up (BP, glycosuria, eye check, physical exam)

9 Muscular Dystrophy: current treatments Pharmacological treatments Treatment of complications Respiratory care Cardiac management Orthotic and orthopaedic approach

10 Muscular Dystrophy: current treatments Pharmacological treatments Treatment of complications Single most important impact Respiratory care on Cardiac natural management history of DMD Orthotic and orthopaedic approach

11 Duchenne Muscular Dystrophy: Respiratory care 1)Timely and appropriate assessment Regular (6 months- yearly) FVC check Overnight studies- oxygen 2) Prevention 3) Active interventions Ventilatory support (NIV, BiPap) Cough Assist Machine

12 Muscular Dystrophy: current treatments Pharmacological treatments Treatment of complications Respiratory care Cardiac management Orthotic and orthopaedic approach Feeding management

13 Duchenne Muscular Dystrophy: Cardiac treatment 1) Timely and appropriate assessment ECG and Echo At diagnosis Before any surgery Every two years to age 10 Annually after age 10 2) Prevention ACE-inhibitors Steroids? 3) Active management ACE-inhibitors + beta-blockers

14 Respiratory support is proven to improve life expectancy with maintenance of a good quality of life Cardiac surveillance and treatment is likely to have similar benefits DMD is a treatable disease Predictable complications in different systems Steroids prolong ambulation and delay the onset of other complications In conjunction with physiotherapy regimes

15 Modification of the mutation (Exon skipping, stop codon suppression) Gene transfer Cell therapies Upregulation of alternative proteins Increase in muscle bulk Addressing downstream pathology

16 DNA RNA Gene Addition e.g. microdystrophin via viral vector. Cell therapy. Modify RNA e.g. exon-skipping Protein Modify translation e.g. gentamycin PTC 124 (ataluren) Genetic therapies

17 Types of mutations associated with DMD Large deletions and duplications Splice site mutations Small deletions and insertions Nonsense mutations From Roberts at al, 1994 Missense mutations Most mutations disrupt the open reading frame leading to a failure to fully translate the mrna and produce a functional protein

18 LGMD2D Gene therapy clinical trial Mendell et al, 2010

19 Potential to improve muscle regeneration and restore dystrophin but will not make new muscle per se 1990s myoblast transplants unsuccessful Trembley (Canada) continuing with a Phase 1/2 clinical trials with local delivery to a specific muscle. Mesoangioblast trial run by Guilio Cossu in Italy Stem cell trials (Phase 1/2) ongoing in Turkey and India. Cardiosphere derived cells delivered via intracoronary infusion (Capricor, USA, Phase 1/2)

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22 Two chemistries taken to clinical trial 2OmePS and PMO. Evidence of clinical benefit arresting the progression of the disease for boys eligible for exon 51 skipping. Other exon targets current in clinical trial (44, 45, 53). Other antisense reagents: Cell penetrating peptides linked to PMO TricycloDNA oligonucleotides

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24 ataluren discovery Phase 2b (007) 174 nmdmd patients Phase 3 (020) 220 nmdmd patients Phase 1 62 healthy males Phase 2a (004) 38 nmdmd patients Initial natural history publications EMA DMD draft guidelines EMA approval of ataluren years of research & development 750+ healthy volunteers/patients exposed/treated and ~900 patient-years of treatment Safety profile: Generally well tolerated Phase 2a: Dystrophin expression demonstrated Phase 2b: Clinically meaningful benefit in 6MWT/Natural History data Phase 3: ACT DMD fully enrolled with data expected Q EMA granted marketing authorisation approval for ambulatory nmdmd patients aged 5 years and older July

25 ~13% of boys have DBMD due to a nonsense mutation Nonsense (Premature Stop) Codon Normal Stop Codon Dystrophin mrna Incomplete dystrophin Slide 25

26 ~13% of boys have DBMD due to a nonsense mutation Nonsense (Premature Stop) Codon Normal Stop Codon Dystrophin mrna Ataluren induces full-length protein production Incomplete dystrophin Nonsense (Premature Stop) Codon YIELD Normal Stop Codon Dystrophin mrna Slide 26 Fulllength dystrophin

27 Up-regulation of utrophin to treat DMD. Increasing muscle mass. Inhibiting the pathological process. Improving the blood supply to muscles Nutritional supplements. All the above use compounds that can be delivered systemically thus offering the promise of treating all affected muscles. Many compounds are already in use in man.

28 Finite number of springs Section through a muscle fibre Finite number of binding sites Fewer springs Still functional but lower weight capacity Muscle fibre membrane Costamere Contractile apparatus Contraction and relaxation stress transmitted through costamere anchor sites Less dystrophin (Becker) Still functional but lower stress tolerance No springs Structural failure Dystrophin or Utrophin No dystrophin (Duchenne) Structural failure

29 Utrophin similar to dystrophin but does not localise nnos Expression of utrophin developmentally precedes dystrophin SMT C1100 : Utrophin Inducer for DMD Currently in Phase 1b clinical trial (Summit). Can correct mdx mouse Biglycan: Stabilises utrophin at the muscle membrane (Tivorsan)

30 Corticosteroids current standard of care where tolerated but have significant side effects Potential alternatives (most act by inhibiting NFkB): Halofugionone (HT-100 Phase ½, Akashi Therapeutics) CAT-1000 (Phase ½, Catabasis) VBP-15 (about to enter trial, ReveraGen) Nemo-binding domain (NBD) peptide And others..

31 Myostatin is a negative regulator of muscle mass Release of soluble form of the Activin IIB receptor to block myostatin signaling (Acceleron - ACE-031). Trial stopped because of bleeding. Antibody to block myostatin binding. Pfizer PF (phase 1/2). Adnectin to block myostatin. Bristol-Myers Squib BMS (Phase 1/2) Other strategies: Propeptide blocker, Inhibition of myostatin production (sirna)

32 New therapies for DMD: translational research Many different treatment strategies exist Many different companies undertake efforts to develop successful treatment for DMD To date, still no treatment available on the market Although new research into possible molecular treatments for DMD is at an exciting stage, currently compliance with internationally agreed standards of care remain the highest priority in prolonging survival and increasing quality of life

33 Addressing the lack of trial culture in NMD Patient identification importance of national and international registries Managing expectations - the ethical environment for trials High technology and high costs Working with pharmaceutical companies

34 Precise molecular diagnosis Understand the natural history of the condition Define outcome measures Consistency of care and management (Standards of care) Awareness that DMD is a systemic disease and very much an adult disease

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39 Paed vs adult Hospices not taking them Discuss pall care at diagnosis? It s a different disease now

40 Pain is an issue in the late stage Control Negotiation is a large part of the consultation process Right to have family is an issue- more than my experience of normal pall care

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