Findings from the DuchenneConnect Registry: Using Your Data to Be:er Understand Duchenne

Transcription

1 Findings from the DuchenneConnect Registry: Using Your Data to Be:er Understand Duchenne Stanley F. Nelson, MD Center for Duchenne Muscular Dystrophy Professor Human Gene<cs, Pathology and Laboratory Medicine, and Psychiatry

2 Duchenne/Becker muscular X linked disease dystrophy Duchenne described ~150 years ago Becker described about 50 years ago One of the first cloned disease genes DMD in 1987 One of the most common gene<c disorders: About 12,000 in US Minimal known effec<ve therapies Difficult to perform clinical trials

3 Laminin/Agrin OUTSIDE MUSCLE γ Sarcoglycan- SSPN subcomplex β α δ α SSPN β Dystroglycan subcomplex MUSCLE CELL SURFACE Inside MUSCLE α β1 nnos Syntrophins Actin

4 Improvements in care have reduced mortality of DBMD over past 20 years (US) Age at death Data from Kenneson, et al 2010

5 What is helping to treat DMD Suppor<ve Care: respiratory/pt Cardiac care for heart failure Medica<ons Steroids ACE Inhibitors (like lisinopril) Are there other factors? What role do an<- oxidants/vitd/nutri<onal supplements play? Can we explore this without long/small clinical trials?

6 FEW DMD pa<ents have par<cipated in clinical trials

7 DuchenneConnect Registry: Do we know that the data are typical? Duchenne Dele<on - Small muta<on 3% Duplica<on 10% Dele<on 74% Nonsense 8% Splice site 3% Fig 12. Muta<on types reported by par<cipants with Duchenne.** Duplica<on (small muta<ons), Inser<on/dele<on, Inser<ons and Other account for less than 3% of muta<on types reported. DuchenneConnect DMD Mutation Spectrum Published DMD Mutation Spectrum 1. Similar mutation spectrum 2. Similar age of diagnosis (4.8y V 4.9y(MDSTARNET)) 3. Similar age at WC use (10.43y v 10.3y)) Relative to published data

8 How can we use the DuchenneConnect data to assess therapeu<c benefit of drugs/supplements? Use Age at Wheelchair use as measure of severity: Correlate each drug/supplement usage with severity Assess if combina<ons are correlated with severity Interpret poten<al for treatment benefit from single drugs and combined agents Advantages: Largest cohort for such interpreta<ons, assesses actually used treatments Disadvantages: Not <ghtly controlled, unknown drug doses/<ming

9 Duchenne Connect N=2285 Duchenne Muscular Dystrophy N=1396 Country Diagnosis Becker Muscular Dystrophy N=128 Other (Uknown, Carrier,At risk) N= 761 US N=972 *Other oecd N=229 Non oecd N= 195 Mean Age of Diagnosis 4.12 yrs N=963 Mean: 4.02 yrs N= yrs N=185 FEMALE /UK CARDIOMYOPATHY MEDICATION (i.e. Perindopril) Mean Age at Wheelchair: N=384 STEROID USE (Deflazacort, Prednisone) Remove non-wc user (n=711) Remove outliers (N=69) VITAMINS AND SUPPLEMENTS (Vitamin D, Calcium, Coenzyme Q,..)

10 Wide varia<on in age at wheelchair use provides ability to determine effect of drugs Age at start of Wheelchair use (OECD Countries with DMD Diagnosis, N=384) MEAN AGE: years Age When Wheelchair Bound

11 DC data observe steroids EFFECT

12 Steroids KNOWN to improve muscle functon: Meta- analysis of prior placebo controlled studies demonstrate effectveness of chronic steroids From Manzur, Kuntzer, Pike and Swan Cochrane Database of Systematic Reviews January 2008

13 Iden<fying effects of other treatments based on age of Wheelchair Bound CARDIOMYOPATHY MEDS **Perindopril or similar N=197 Never used Steroids N=124 Previously used Steroids N=110 Mean Age at Wheelchair: N=384 STEROID USE Currently using deflazacort N=76 Currently using prednisone N=75 SUPPLEMENTS Vitamin D N=88 Vitamin C N=32 Calcium N=76 Vitamn E N=15 Crea<ne monohydrate N=7 Coenzyme Q10 N=39 Magne- sium N=11 Melat onin N=7 Protan dim N=5 Vitamin A N=5 SUPPLEMENTS Calcium N=53 Vitamin D N=54 Coenzyme Q10 N=22 Vitamin C N=12 Crea<ne monohydrate N=6 Vitamin E N=6 Protandim N=5

14 Many children are on ACEI due to observed beneficial effect in cardioprotecton of perindopril (Duboc et al, 2005/2007) 10 year follow up of boys with Duchenne Core result is fewer boys with LVEF<45% at 5y and larger frac<on alive at 10 yrs. 8/29 (28%) have LVEF<45% in PLACEBO group 2/28 (7%) have LVEF <45% in PERINDOPRIL group

15 Do ACE Inhibitors impact severity of skeletal muscles in DMD? *ACEI category includes: Aceon (Perindopril) Captopril (Capoten) Enalapril (Vasotec) Lisinopril (Prinivil, Zestril) Losar<n (Cozaar) Ramipril (Altace) Never Used Steroids Number Observa<ons Taking ACEI Not Taking ACEI ACEI vs No ACEI P-value= Current Steroid User Mean Wheelchair Age (years) Number Observa<ons Mean Wheelchair Age (years) Number Observa<ons Mean Wheelchair Age (years) Taking ACEI Not Taking ACEI Amongst steroid users: ACEI vs No ACEI P-value=

16 Different ACE Inhibitors correlate with age at wheelchair use similarly All ACE Inhibitors: 11.08y Losartan (Cozaar): 11.42y Lisinopril (Zestril): 11.1y No significant difference: both are correlated with longer ambulation

17 Correlation of Supplements/Drugs with Age of Wheelchair Use

18 None 9.6y

19 Inferred Regimen Deflazacort/prednisone ACE Inhibitor Vitamin D Calcium CoEnzyme Q10 Vitamin C Crea<ne An<oxidant

20 What else might be contribu<ng to Other gene variants? disease severity? Wheelchair Age of Steroids vs those with No Supplements* Age steroids no supplements

21 Can we observe other effects?: Steroids and Duchenne: Scoliosis reduced in literature Clinical Paper

22 Observed percentage of post ambulatory boys with DMD who need scoliosis surgery

23 Concluding remarks Register at Duchenneconnect.org More complete par<cipa<on improves ability to provide compara<ve data More complete par<cipa<on lessens poten<al sampling bias: BUT ALMOST 10% of all US affecteds included Need to improve integra<on with other country registries, harmonize data accrual and simplify parent par<cipa<on More collected informa<on may improve confidence in data by clinicians to help guide prac<ce parameters Registry data provides a dimension of clinical informa<on difficult to collect in clinical trials and individual physician prac<ces

24 CONTACT INFORMATION For ques<ons about the DuchenneConnect registry, contact Ann Mar<n: Telephone: (201) htp:// You can also contact DuchenneConnect with gene<c counseling and research ques<ons. Contact Dr. Nelson at Or through the CDMD:

25 Acknowledgements Holly Peay Vanessa Miller Ann Martin Advisors UCLA Ascia Eskin (P30 Informatics/Genomics Core: NIAMS Center Grant Sandy Dai/Ake Lu Rita Cantor Cheri Silverstein

26 M. Carrie Miceli, Ph.D. MIMG Stanley Nelson, MD Human Genetics Melissa Spencer, Ph.D. Neurology Linda Baum, M.D. Ph.D., Pathology Rachelle Crosbie, Ph.D. Physiology April Pyle, Ph.D. MIMG Ron Victor, MD, Cedars Sinai Medical Center Gail Thomas, PhD, Cedars Sinai Medical Center Perry Sheih, MD, PhD, Department of Neurology Kristina Kam, Pediatric Nurse Practitioner, Dept. of Pediatrics Nancy Halnon, MD,, Pediatric Cardiology Miriam Ischander, MD, Pediatric Pulmonology William Oppenheim, MD Dept. of Orthopedics Hillary Zeberman, MSW, Medical Social Worker Eileen Folwer, PhD, Prof, Physical Therapy, Dept of Orthopedics

27 Frac<on of DMD Pa<ents able to walk: effect of steroids (n=1089 pa<ents) Never taken Steroids Current Steroid Users

28

29

30 Summary of Supplements/drugs in 384 DMD pa<ents aver WC age mean age at wc number observa<ons Ace Inhibitors steroids VitaminD Calcium CoenzymeQ VitaminC VitaminE Magnesium Crea<neMonohydrate 12 9 Melatonin 11 8 Protandim L.Arginine GreenTeaExtract VitaminA_Beta.Carotene B.50Complex 11 3 GrapeSeedExtract HGH 13 3 Juven L.Carni<ne Selenomax 9 1 No supplements/drugs reported: 9.6 y 136

31

32