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
Idiopathic Inflammatory Myopathies
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Dermatomyositis (DM)
Polymyositis (PM)
Autoimmune Necrotizing Myopathy
Inclusion Body Myositis (IBM)
PM/DM/NM Drug Therapy
 1st
Line
• Prednisone
• IV methylprednisolone
 2nd
•
•
•
•
Line
Methotrexate
Azathioprine*
IVIG*
Mycophenolate mofetil
*RCT
3rd Line
• Rituximab*
• Cyclophosphamide
• Etanercept* (Amato)
• Tacrolimus (Oddis)
• Cyclosporine
• Acthar
 4th Line / Experimental
• Chlorambucil
• Infliximab
• Toclizumab
• Abatacept
• Alemtuzimab
Randomized, Pilot Trial of Etanercept in
Dermatomyositis
Muscle Study Group (Amato, et al)
Neurology 2011
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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)
Randomized, Pilot Trial of Etanercept
in Dermatomyositis (cont.)
Muscle Study Group (Amato, et al)
Neurology 2011
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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!
Randomized, Placebo-phase Trial of
Rituximab in the Treatment of Refractory
Adult & Juvenile Dermatomyositis
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Oddis 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
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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
Randomized, Placebo-phase Trial of Rituximab
in the Treatment of Refractory Adult
& Juvenile Dermatomyositis (cont.)
Oddis et al, 2011
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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
Statin-associated Autoimmune
Necrotizing Myopathy
Dimachkie et al, 2011
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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
Statin-associated Autoimmune
Necrotizing Myopathy (SANM)
Grable-Esposito et al. 2010
Dimachkie et al. 2011
25
11
Mean age of onset(yrs)
64.7
55
♀/♂
1.1/1
2.6/1
Proximal arm and leg
Proximal leg mainly
3
2
> 1month
>2 month
8203
5700
Hashimoto thyroiditis
ANA (2)
Jo1 (1), ANA (1) and RF
22
10
Cases
Phenotype
Bulbar symptoms
Post-statin D/C weakness for
Mean CK
Autoimmune d/o &
Abnormal labs
# RX with immunosupressants
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
Treatment for IBM
SUMMARY
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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
Pilot Study of Arimoclomol in IBM
Cl
OH
N
O
N
N
O
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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
(Muscle Nerve 2008;38:837)
Pilot Study of Arimoclomol in IBM
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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, placebocontrolled efficacy study
Problem – unclear if small biotech company will move drug
forward
25
15
20
IBMFRS
30
35
Arimoclomol in IBM
IBMFRS
0
1
2
3
4
5
6
month
7
Month 0 is the baseline. The thick line denotes the mean
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
8
9
10
11
12
Duchenne Muscular Dystrophy
1.
Corticosteroid therapy
2.
Treatment of boys with nonsense stop-codon
mutations
– Gentamicin
– PTC 124 (Ataluren)
3.
Exon skipping therapy
Prednisone Treatment for DMD
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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!
Corticosteroids in DMD &
Potential Alternatives to Prednisone
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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
Laboratory Evaluation to Establish
Duchenne Muscular Dystrophy
1. Molecular genetic testing
•
•
70% deletions
10% duplications
 By PCR
• 20% point mutation/splicing errors
 Require gene sequencing
2. Muscle biopsy for immunostaining and/or Western blot
Conclusion: 1st do deletion/duplication testing. If neg,
do biopsy or sequencing
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
Reading Frame
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THE BIG RED DOG RAN AND SAT
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THE BIR EDD OGR ANA NDS AT
 = Duchenne (more severe) Muscular Dystrophy
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THE DOG RAN AND SAT
 = Becker (less severe) Muscular Dystrophy
Normal Flow of Genetic Information
Results in Full-Length Protein Production
Normal Protein Synthesis
Normal
Stop
Codon
Ribosomes
Amino acid
Dystrophin mRNA
Full-length
Dystrophin
Nonsense Mutation Halts the Flow
of Genetic Information and Results
in Truncated Protein Production
Incomplete Protein Synthesis
Nonsense
(Premature Stop) Codon
Normal
Stop
Codon
Dystrophin mRNA
 For DMD/BMD, nonsense mutations are causative in ~15% of patients
Truncated
Dystrophin
Gentamicin Treatment of DMD
Jerry Mendell, MD, PI/Richard Barohn, MD, Co-I
Annals 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
Ataluren Has Been Designed to
Overcome Nonsense Mutations
Ataluren Facilitated Protein Synthesis
Nonsense
(Premature Stop)
Codon
Normal
Stop
Codon
YIELD
Dystrophin mRNA
 A nonsense mutation must be present for ataluren to be active
 Gene sequencing can be used for patient selection
Fulllength
Dystrophi
n
A Phase 2b Registration-Directed Study of
Ataluren in Boys with DMD/BMD is Ongoing
Double-blind
Placebo-controlled
Study
Eligibility Criteria:
• Ambulatory boys 5 yo
with nonsense-mutation
DMD/BMD
Open-label
Extension
Study
Ataluren
20, 20, 40 mg/kg
Primary Outcome Measure:
• 6-minute walk distance
N=55
Ataluren
10, 10, 20 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
Ataluren
20, 20, 40 mg/kg
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
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
Characteristic
Infantile-Onset
Late-Onset
Onset
Birth*
After 1 year of age1; can present as late as the
2nd to 6th decade of life2
Progression
Rapid1
Slower but relentless1
Muscles affected
Cardiac2
Skeletal, including respiratory1
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.
*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.
Chart printed with permission: American Association of Neuromuscular & Electrodiagnostic Medicine. Muscle Nerve. 2009;40(1):149-160.
rGAA is Beneficial in Patients with the Most Rapid
Disease Progression (Early Onset)
Parameter
AGLU01602 (n=18)
< 6 months at ERT
AGLU01702 (n=21)
6-36 months at ERT
Alive
100% at 18 months age
( risk of death by 98%)
76% after 1 year of ERT
( risk of death by 78%)
Alive & Invasive Ventilator
Free
83% at 18 months age
69% after 1 year of ERT
Reversal of cardiomyopathy
(decrease in LV mass index)
100%
83%
Measurable Motor Gains
Dose:
Myozyme Duration:
72%
48%
20 or 40 mg/kg qow
20 mg/kg qow
1 Year
1 Year
A randomized study of alglucosidase alfa in
late-onset Pompe's disease
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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.
LOTS Study Design
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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.
Co-Primary Endpoint: 6MWT
Change in Mean Distance Walked (meters)
35
30
MZ +25.13 m
25
20
Myozyme
15
Placebo
10
5
0
PL -2.99 meters
0
10
20
30
40
50
-5
Weeks from Baseline
60
70
80
90
LME* p value=0.0464
GEE p value=0.0326
* With robust variance estimation
Baseline
Myozyme
Placebo
Mean (SD)
% Predicted (SD)
332.2 m (126.7)
50.7% (18.7)
317.9 m (132.3)
48.7% (20.4)
Myozyme
Placebo
Week 78
Mean (SD)
% Predicted (SD)
362.7 m (145.3)
57.6% (21.9)
312.7 m (147.2)
49.9% (22.8)
Co-Primary Endpoint: Forced Vital
Capacity (cont’d)
5
Change in Mean % Predicted
4
3
2
MZ +1.20% predicted
1
Myozyme
0
0
10
20
30
40
50
-1
60
70
80
90
Placebo
PL -2.20% predicted
-2
-3
-4
-5
Baseline
Myozyme
Placebo
Mean (SD)
Week 78
Mean (SD)
55.4% (14.4)Myozyme 56.7% (16.4)
Weeks from Baseline
53.0% (15.7)Placebo
51.1% (15.8)
LME* p value=0.0041
GEE p value=0.0019
* With robust variance estimation
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?
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
Mexiletine in NDM
Two-Period Crossover Design
N =29
NDM
N = 59
Week:
N =30
Mexiletine 200mg tid
1
2
Placebo
3
4
Placebo
Washout
Period
6
7
8
9
Mexiletine 200mg tid
Indicates the weeks to include for the primary endpoint analysis
Outcome Measures
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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
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%)
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
Treatment
Effect
Estimate
-2.69
95%
Confidence
Interval
-3.26, -2.12
IVR—Pain
-1.48
-2.03, -0.94
< 0.001
IVR—Weakness
-1.16
-1.77, -0.54
< 0.001
IVR—Tiredness
-0.90
-1.49, -0.31
0.004
Endpoint
IVR—Stiffness
P-value
<0.001
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
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
JAMA 2012;308(13):1357-1365
Conclusion
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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
Status of Mexiletine
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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
Conclusion
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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!