The CMD genes ~ The CMD to LGMD spectrum CMDLGMD Ullrich CMD (col6a1, col6a2, col6a3) Bethlem myopathy Merosin deficient CMD (LAMA2) Dystroglycanopathies: FKRP, fukutin, POMT1, POMT2, POMGnT1, LARGE Syndromic: WWS, MEB, Fukuyama LGMD2K, LGMD2I, LGMD2L, LGMD2N SEPN1 Alpha 9 integrin Lamin A/C

Congenital Myopathy- RYR1 There is an overlap between congenital muscular dystrophy and congenital myopathy. CMD subtype: SEPN1 or Rigid Spine Muscular Dystrophy can look exactly like Ryanodine Receptor congenital myopathy on biopsy and clinical picture A decision to include Congenital Myopathy- RYR1 in the CMDIR, as no exisiting registry, similar clinical needs and overlapping targets in calcium handling. We welcome the RYR1 families!

Why do we care about Clinical Trial Readiness?

Being ready means: 1. We maximize our chances of getting a good drug to and through clinical trial. 2. We are able to measure an effect that the FDA accepts and is meaningful to our community.

Why do trials fail to reach clinically significant endpoints or show a benefit in outcome measure?

The drug has no effect, not the intended effect or the size of the effect is not measurable. The community was not “ready” to go to clinical trials. no biomarkers not rigorous enough preclinical testing not enough known about the drug’s effect in the population outcome measures that pick up big not subtle changes unable to reach a statistically significant number of participants to show smaller effect rate of disease progression in participants too variable

Therapeutic intervention failure identify a tight cohort identify clinically meaningful endpoints validate outcome measures identify biomarkers identify clinical trial design How do we measure functional gains in strength? Current motor scales and timed tests Effort dependent, how do the scales work in the setting of contractures Longitudinal natural history

Cure CMD Initiatives to Address Clinical Trial Readiness SubjectSpeaker CMD Standard of CareAnne Rutkowski, Cure CMD Chairman CMDIRAmi Mehta, Lead Genetic Counselor CMDIR CMD BioBankTara Schimdlen, Genetic Counselor, NIGMS Repository at Coriell CMD Outcome MeasuresEunice Kim, Cure CMD Vice Chair CMD Natural History studyCarsten Bonnemann, MD, NINDS Cure CMD SMAB Chairman

Update on CMD Care Guidelines Led by Dr. Ching Wang, Dr. Thomas Sejersen and Cure CMD CMD Standard of Care Committee (80 international subspecialists) CMD Clinician survey, subspecialist specific CMD Family Standard of Care survey CMD Care Guidelines Workshop, Brussels Nov 2009 Revisions CMD Care Guidelines. Submitted for Publication After publication, distribution of Care Guidelines Next step…..CMD Family Friendly Care Guidelines

Why are CMD Care Guidelines important? 1. Assist doctors who have never seen a CMD patient offer a standard approach to work up (diagnosis), referrals to subspecialists and an understanding of care issues 2. This results in more PRO-ACTIVE CMD medical care in the global community. 3. Assists families and affected individuals be informed about appropriate care and anticipate upcoming care issues 4. An important part of CMD clinical trial readiness

Future directions 1. Publication and adoption of CMD Care guidelines (physician and lay friendly versions) 2. Identification of different medical practices that might benefit people with CMD if adopted on a broader scale 3. Identification of areas of uncertainty in CMD medical practice, develop hypothesis, fund clinical trials to determine best practices that improve and save lives.

What do we all want? A scientific investment that delivers a drug to slow disease progression, buys time, and improves quality of life Earlier diagnosis with genetic confirmation (if possible) Less variable, more proactive medical care from the global medical community with an emphasis on multidisciplinary care