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New Ideas and Dilemmas from Recent Clinical Research in Muscle Diseases

New Ideas and Dilemmas from Recent Clinical Research in Muscle Diseases. Richard J. Barohn, M.D. Gertrude and Dewey Ziegler Professor of Neurology Chair, Department of Neurology University of Kansas Medical Center Kansas City, Kansas KUMC Neurology/Neurosurgery Grand Rounds December 21, 2012.

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New Ideas and Dilemmas from Recent Clinical Research in Muscle Diseases

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  1. New Ideas and Dilemmas from Recent Clinical Research in Muscle Diseases Richard J. Barohn, M.D. Gertrude and Dewey Ziegler Professor of NeurologyChair, Department of Neurology University of Kansas Medical Center Kansas City, Kansas KUMC Neurology/Neurosurgery Grand Rounds December 21, 2012

  2. Idiopathic Inflammatory Myopathies • Dermatomyositis (DM) • Polymyositis (PM) • Autoimmune Necrotizing Myopathy • Inclusion Body Myositis (IBM)

  3. PM/DM/NM Drug Therapy • 3rd Line • Rituximab* • Cyclophosphamide • Etanercept* (Amato) • Tacrolimus (Oddis) • Cyclosporine • Acthar • 4th Line / Experimental • Chlorambucil • Infliximab • Toclizumab • Abatacept • Alemtuzimab • 1st Line • Prednisone • IV methylprednisolone • 2nd Line • Methotrexate • Azathioprine* • IVIG* • Mycophenolate mofetil *RCT

  4. Randomized, Pilot Trial of Etanercept in DermatomyositisMuscle Study Group (Amato, et al)Neurology 2011 • Etanercept = tumor necrosis factor α inhibitor • NIH funded; 16 subjects: 11 ETAN/5 PLAC • ETAN 50 mg subQ weekly x 52 weeks • All on PRED at least 2 mo • After ETAN vs. PLAC, PRED taper • Results: All 5 PLAC relapsed (med 148 days) • 5/11 ETAN tapered off PRED • 6/11 ETAN failures (med 358 days)

  5. Randomized, Pilot Trial of Etanercept in Dermatomyositis (cont.)Muscle Study Group (Amato, et al)Neurology 2011 • Avg PREDdose after week 24: • PLAC – 29.2 mg/day • ETAN – 1.2 mg/day • Other outcome measures: no diff • MMT, MVIC, IMACS, MITAX, MYOACT, HAQ, SF36, INQOL, CK • No AE/SAE diffs • Conc: ETAN may have steroid sparing in DM • Needs further study • Lessons: PRED taper & dose good for endpoint • Small, underpowered trial can be positive – if lucky!

  6. Randomized, Placebo-phase Trial of Rituximab in the Treatment of Refractory Adult & Juvenile DermatomyositisOddis et al, 2011 • NIH funded • Rituximab – B cell depleting agent • 195 pts (76 PM, 76 DM, 48 JDM) • Refractory to PRED and other oral IS • 2 groups: • RITUX early – RITUX wks 0/1; PLAC wks 8/9 • RITUX late – PLAC wks 0/1; RITUX wks 8/9 • Primary endpoint: time to DOI • DOI = >20% improv in 3/6 core measures & no >2 CSMS worsening by >25% • Secondary - time to 20% imp MMT - % DOI week 8

  7. Randomized, Placebo-phase Trial of Rituximab in the Treatment of Refractory Adult & Juvenile Dermatomyositis (cont.)Oddis et al, 2011 • Dose – adults 1.5 gm/m2; child 575 mg/m2 • Core set measures – MMT; patient & MD VAS; HAQ; CK; extraneuromuscular disease/activity score • Results: DOI time: 20.0 wks early group; 20.2 wks late group • Time to 20% imp MMT: no diff • % meeting DOI @ 8 wks: Ritux 15%; Plac 20.6% • AE inf reactions – Ritux 15%; Plac 5.3% • Lessons: Trial design – overestimated how fast Ritux worked • Placebo effect – underestimated • ? instruments

  8. Statin-associated Autoimmune Necrotizing MyopathyDimachkie et al, 2011 • DEF: NM after statin use, but weakness progressing >2 months • Retrospective chart review over the last 10 years at U. Kansas Medical Center • 138 with idiopathic inflammatory myopathy • 30 with biopsy proven NM: • 18 (60%) had history of statin intake • 2 (6.7%) had associated malignancy • 10 (33.3%) had idiopathic NM • Out of the 18 patients on statins : • 7 toxic NM • 11 SANM

  9. Statin-associated Autoimmune Necrotizing Myopathy (SANM)

  10. Inclusion Body Myositis Clinical Features • frequently misdiagnosed as PM • insidious onset and slowly progressive (average duration of symptoms prior to dx is 6 yrs) • males affected more than females • usually develops over the age of 50 to 60 years (most common myositis in patients presenting over the age of 50 years) • Typical phenotype: • wrist/finger flexors • Knee extensors

  11. Treatment for IBM SUMMARY • No convincing evidence drug Rx significantly improves IBM • A small number of patients may have transient improvement or stabilization • However, all patients ultimately deteriorate over time • Empiric trial can be offered if patient is aware of realistic results and side effects • Other option - No drug Rx • Other option – Investigational Rx trials

  12. Pilot Study of Arimoclomol in IBM Cl OH O N N • Derivative of Bimoclomol, developed by CytRx, a potent co-inducer of Heat Shock Proteins • Stabilizes Heat Shock Transcription Factor-1 (HSF-1) • This increases levels of HSP70 and HSP90 • Interacts with acidic membrane lipids to stabilize plasma membranes • Interacts with cardiolipin in mitochondria • May stabilize membrane • May inhibit apoptosis • Safe in 3 month ALS trial N O (Muscle Nerve 2008;38:837)

  13. Pilot Study of Arimoclomol in IBM • To assess the safety and tolerability of arimoclomol 100 mg PO TID administered for 4 months in subjects with IBM • 2 sites: KUMC & UCL-ION MRC • Each site enrolled 12 subjects, n=24 • Randomization 2/1 • Provide data for future multi-center, randomized, placebo-controlled efficacy study • Problem – unclear if small biotech company will move drug forward

  14. Arimoclomol in IBMIBMFRS IBMFRS declines by an average 2 points per year The IBMFRS is a useful outcome measure for future IBM research Arimoclomol is well tolerated in this study population

  15. Duchenne Muscular Dystrophy • Corticosteroid therapy • Treatment of boys with nonsense stop-codon mutations • Gentamicin • PTC 124 (Ataluren) • Exon skipping therapy

  16. Prednisone Treatment for DMD • Mendell and CIDD group – 1989 • Prednisone delayed wheelchair use • Boys placed on prednisone 0.75 mg/kg/day • 30 lb / 15 kg boy = approx. 10 mg/day • We recommended prednisone to most families when boys are ambulatory and beginning to fall • Potential side effects: • Weight gain • Mood changes/insomnia • Osteoporosis • Less often: diabetes, high blood pressure, cataracts Lesson: sometimes old drugs work if studied well!

  17. Corticosteroids in DMD & Potential Alternatives to Prednisone • Deflazacort • Intermittent prednisone dosing Blinded Trial to Find Optimum Steroid Regimen for DMD • New trial just funded by NIH – Drs. Griggs & Bushby • Boys randomized to 3 groups • Pred 0.75 mg/kg/d • Pred 0.75 mg/kg/d: 10 days on/10 days off • Deflazacort 0.9 mg/kg/day • KUMC/CMH is a site

  18. Laboratory Evaluation to Establish Duchenne Muscular Dystrophy • Molecular genetic testing • 70% deletions • 10% duplications • By PCR • 20% point mutation/splicing errors • Require gene sequencing • Muscle biopsy for immunostaining and/or Western blot Conclusion: 1st do deletion/duplication testing. If neg, do biopsy or sequencing

  19. Duchenne vs. Becker’s • Duchenne Disruption of amino acid reading frame • Out-of-frame mutation • No dystrophin • Becker’s Preservation of amino acid reading frame • In-frame mutation • Dystrophin abnormal but present

  20. Reading Frame • THE BIG RED DOG RAN AND SAT • THE BIR EDD OGR ANA NDS AT • = Duchenne (more severe) Muscular Dystrophy • THE DOG RAN AND SAT • = Becker (less severe) Muscular Dystrophy

  21. Normal Flow of Genetic Information Results in Full-Length Protein Production Normal Protein Synthesis NormalStop Codon Ribosomes Amino acid Dystrophin mRNA Full-length Dystrophin

  22. Nonsense Mutation Halts the Flow of Genetic Information and Results in Truncated Protein Production Incomplete Protein Synthesis NormalStop Codon Nonsense(Premature Stop) Codon Dystrophin mRNA Truncated Dystrophin • For DMD/BMD, nonsense mutations are causative in ~15% of patients

  23. Gentamicin Treatment of DMD Jerry Mendell, MD, PI/Richard Barohn, MD, Co-IAnnals of Neurology 2010;67:771-780 • 2 sites: OSU and KUMC • Background: • Gent treatment increased dystrophin in MDX mice • Initial 14-day infusion study decreased CK • 9 boys received Gent IV weekly • 4 boys received Gent 2 times a week • Monitered for hearing and kidney toxicity • Results: • CK often decreased • Dystrophin often increased in muscle biopsy • No definite clinical benefit noted • No side effects • Lessons/problem: • Proof of concept • Weekly IV limitation

  24. YIELD Ataluren Has Been Designed to Overcome Nonsense Mutations Ataluren FacilitatedProtein Synthesis NormalStop Codon Nonsense(Premature Stop) Codon Dystrophin mRNA Full-length Dystrophin • A nonsense mutation must be present for ataluren to be active • Gene sequencing can be used for patient selection

  25. A Phase 2b Registration-Directed Study of Ataluren in Boys with DMD/BMD is Ongoing Double-blind Placebo-controlledStudy Open-labelExtension Study • Eligibility Criteria: • Ambulatory boys 5 yo with nonsense-mutation DMD/BMD Ataluren20, 20, 40 mg/kg • Primary Outcome Measure: • 6-minute walk distance N=55 Ataluren10, 10, 20 mg/kg Ataluren 20, 20, 40 mg/kg R/S N=55 Placebo N=55 48 Weeks • Visits: • Every 6 weeks • Primary goal: To demonstrate a ≥10% improvement in 6MWD (ataluren vs placebo) • Establishes a regulatory path forward for drugs being developed for DMD/BMD

  26. Ataluren Trial Update • Low dose group had better 6MWT than high dose & PLAC • Wk 48: low dose group • 29.7 meters greater • Open-label extension in progress • PTC presenting data to FDA • Lessons: • Bell shaped curve response • ? Makes sense • Pre and post biopsy difficult

  27. 1. American Association of Neuromuscular & Electrodiagnostic Medicine. Muscle Nerve. 2009;40(1):149-160. 2. Kishnani PS, et al. Genet Med. 2006;8(5):267-288. Pompe Disease: Definition • Pompe disease • A genetic lysosomal storage disorder characterized by the absence or marked deficiency of the lysosomal enzyme acid a-glucosidase (GAA)1: • Glycogen accumulates in muscle cells; • Which in turn causes progressive degeneration of skeletal, including respiratory, and cardiac muscle, depending on patient age • Classified as infantile-onset or late-onset, although disease onset presents as a continuous spectrum2

  28. Chart printed with permission: American Association of Neuromuscular & Electrodiagnostic Medicine. Muscle Nerve. 2009;40(1):149-160. Limb-girdle syndrome* Dyspnea secondary to ventilatory muscle weakness Physical examination, EMG, serum CK, and FVC seated and supine Above findings suggestive of a specific alternate diagnosis Above findings suggestive of Pompe disease or a nonspecific myopathy Consider alternate diagnosis Blood-based GAA enzyme activity assay† Muscle biopsy‡ Normal GAA enzyme activity Reduced GAA enzyme activity Findings suggestive of Pompe disease Findings suggestive of an alternate diagnosis Confirm reduction of GAA enzyme activity in a second sample: lymphocytes, fibroblasts, or muscle (if available) AND/OR GAA gene sequencing GAA enzyme activity assay in muscle or blood Reduced GAA enzyme activity Normal GAA enzyme activity Positive Negative Consider alternate diagnosis Pompe disease confirmed Reassess patient and consider muscle biopsy *Proximal muscle weakness with or without respiratory symptoms.† Dried blood spot or whole blood sent to laboratory for spotting. ‡ Some patients may have already had a muscle biopsy performed.

  29. rGAA is Beneficial in Patients with the Most Rapid Disease Progression (Early Onset) 20 mg/kg qow Dose: 20 or 40 mg/kg qow Myozyme Duration: 1 Year 1 Year

  30. van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, Herson S, Kishnani PS, Laforet P, Lake SL, Lange DJ, Leshner RT, Mayhew JE, Morgan C, Nozaki K, Park DJ, Pestronk A, Rosenbloom B, Skrinar A, van Capelle CI, van der Beek NA, Wasserstein M, Zivkovic SA. • N Engl J Med. 2010 Apr 15;362(15):1396-406. A randomized study of alglucosidasealfa in late-onset Pompe's disease

  31. LOTS Study Design Randomized, double-blind, placebo-controlled, 12-month trial; (extended to 18 mo) 20 mg/kg every other week 90 patient planned enrollment 2:1 drug to placebo assignment Co-primary end points 6MWT FVC upright Secondary end points QMT leg score Short Form-36 physical component summary (SF-36 PCS) score 6-month FVC analysis 6-month walk test analysis All patients begin active treatment after 26th infusion prior to unblinding A Placebo-Controlled Study of Safety and Effectiveness of Myozyme in Patients With Late-Onset Pompe Disease. http://clinicaltrials.gov/ct2/show/NCT00158600?term=AGLU02704&rank=2. Accessed September 29, 2009.

  32. Co-Primary Endpoint: 6MWT MZ +25.13 m PL -2.99 meters LME* p value=0.0464 GEE p value=0.0326 * With robust variance estimation Baseline Mean (SD) % Predicted (SD) Week 78 Mean (SD) % Predicted (SD) Myozyme 332.2 m (126.7) 50.7% (18.7) Myozyme 362.7 m (145.3) 57.6% (21.9) Placebo 317.9 m (132.3) 48.7% (20.4) Placebo 312.7 m (147.2) 49.9% (22.8)

  33. Co-Primary Endpoint: Forced Vital Capacity (cont’d) MZ +1.20% predicted PL -2.20% predicted LME* p value=0.0041 GEE p value=0.0019 * With robust variance estimation Baseline Mean (SD) Week 78 Mean (SD) Myozyme 55.4% (14.4) Myozyme 56.7% (16.4) Placebo 53.0% (15.7) Placebo 51.1% (15.8)

  34. Enzyme Replacement Studies for Pompe • Lessons Learned: • Are PLAC trials in fatal diseases indicated? • Is modest effect on adults worth great $ • Is 6MWT as important as quality of life or strength endpoints?

  35. Phase II Therapeutic Trial of Mexiletine in Non-Dystrophic Myotonia Richard Barohn, Brian Bundy, Yunxia Wang, Laura Herbelin, Jaya Trivedi, Michael Hanna, Dipa Raja Rayan, Shannon Venance, Emma Ciafaloni, Mohammad Salajegheh, Giovanni Meola, Valeria Sansone, Alice Zanolini, Jeffrey Statland, Robert Griggs, CINCH Study Group Supported by FDA-OPD RO1 FD 003454 & RDCRN/NIH U54 NS059065-05S1 IND #77,021

  36. Mexiletine in NDM Two-Period Crossover Design Mexiletine 200mg tid N =29 Placebo Wash- out Period NDM N = 59 Week: 1 2 3 4 6 7 8 9 N =30 Placebo Mexiletine 200mg tid Indicates the weeks to include for the primary endpoint analysis

  37. Outcome Measures • Primary Outcome: • Stiffness: self-reported using an Interactive Voice Response Diary (IVR) • Telephone call in daily • Rate stiffness, weakness, fatigue and pain on 0-9 scale • Secondary Outcome: • Pain, Weakness, and Fatigue– IVR • Clinical Myotonia Assessment • Quality of life as measured by INQoL, SF36 • Quantitative measure of hand grip myotonia • Measurement of CMAP after short and long exercise • Grading of Myotonia on Needle EMG

  38. CONSORT Information • Enrollment N = 62 • Ineligible N = 3 • Prolonged QT:1 • Elevated ALT:1 • No myotonia seen on clinical exam:1 • Randomized N = 59 (December 23, 2008 to January 25, 2011) • Received Mexiletine followed by Placebo N = 29 • Received Placebo followed by Mexiletine N = 30 • Dropouts:4 • Migraines:1 • Gastric discomfort:1 • Noncompliance: 2 • Genotype • Na – 21 (35.6%) • Cl – 34 (57.6%) • ? - 4 (6.8%)

  39. Interactive Voice Response Diary • Primary outcome: • Mexiletine significantly improved stiffness on the IVR • Secondary measures • Mexiletine also significantly improved pain, weakness, and tiredness on the IVR

  40. Handgrip Evaluation: all subjects • The population average is driven by chloride subjects (34/55) whose dominant trend is warm up • Mexiletine significantly decreased the average time to open the fist after forced closure

  41. EMG: Myotonia Grade • Approximately 70% of subjects demonstrated grade 3 myotonia on electromyography during placebo • Mexiletine significantly shifts the myotonia grade to lower grades in both muscles tested

  42. JAMA 2012;308(13):1357-1365

  43. Conclusion • Mexiletine improved stiffness, pain, weakness and fatigue in NDM patients measured by IVR and quality of life measured by SF-36 • Stiffness scores: the largest treatment mean difference • Most frequent side effect • GI: 9/59 (15%) reported • Other outcome measures currently being analyzed • Lessons: • Investigator-initiated rare disease research can be done in multi-site consortium • Patient reported outcome measures can be primary endpoint • Generic drug availability can be problematic

  44. Status of Mexiletine • Cardiology rarely uses now • 2 generic companies • TEVA (US) • Boehringer (Europe) • Pharmacies find it hard to keep in stock • We applied for orphan drug status 7/2010 • ? Possibility of getting current generic companies or new companies interested in labeling indication • ? Re-purposing mexiletine

  45. Conclusion • KUMC involved in numerous cutting edge clinical trials • Novel drugs • Re-purposed drugs • Fertile research field for students, residents, fellows, faculty • Utilize infrastructure of Frontiers/CTSA • Requires a large TEAM!

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