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

Idiopathic Inflammatory Myopathies

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

3rd Line• Rituximab*• Cyclophosphamide• Etanercept* (Amato)• Tacrolimus (Oddis)• Cyclosporine• Acthar

4th Line / Experimental• Chlorambucil• Infliximab• Toclizumab• Abatacept• Alemtuzimab

**RCT

Randomized, Pilot Trial of Etanercept in Dermatomyositis

Muscle 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)

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!

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

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

Statin-associated Autoimmune Necrotizing Myopathy

Dimachkie 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

Grable-Esposito et al. 2010 Dimachkie et al. 2011

Cases 25 11

Mean age of onset(yrs) 64.7 55

♀ / ♂ 1.1/1 2.6/1

Phenotype Proximal arm and leg Proximal leg mainly

Bulbar symptoms 3 2

Post-statin D/C weakness for > 1month >2 month

Mean CK 8203 5700

Autoimmune d/o & Abnormal labs

Hashimoto thyroiditisANA (2)

-Jo1 (1), ANA (1) and RF

# RX with immunosupressants 22 10

Statin-associated Autoimmune Necrotizing Myopathy (SANM)

Inclusion Body MyositisClinical 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 IBMSUMMARY

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

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

NO N

Cl OH

(Muscle Nerve 2008;38:837)

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

Arimoclomol in IBMIBMFRS

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IBM

FR

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0 1 2 3 4 5 6 7 8 9 10 11 12month

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

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 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

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

• DuchenneDisruption of amino acid reading frame

• Out-of-frame mutation• No dystrophin

• Becker’sPreservation of amino acid reading frame

• In-frame mutation• Dystrophin abnormal but present

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

Normal Protein Synthesis

Full-length Dystrophin

Ribosomes

Amino acid

NormalStop

Codon

Dystrophin mRNA

Normal Flow of Genetic Information Results in Full-Length Protein Production

Incomplete Protein Synthesis

Truncated Dystrophin

Nonsense(Premature Stop) Codon

NormalStop

Codon

Nonsense Mutation Halts the Flow of Genetic Information and Results

in Truncated Protein Production

Dystrophin mRNA

For DMD/BMD, nonsense mutations are causative in ~15% of patients

Gentamicin Treatment of DMD Jerry Mendell, MD, PI/Richard Barohn, MD, Co-I

Annals of Neurology 2010;67:771-7802 sites: OSU and KUMC

Background: Gent treatment increased dystrophin in MDX miceInitial 14-day infusion study decreased CK9 boys received Gent IV weekly4 boys received Gent 2 times a weekMonitered for hearing and kidney toxicity

Results:CK often decreasedDystrophin often increased in muscle biopsyNo definite clinical benefit notedNo side effects

Lessons/problem:Proof of conceptWeekly IV limitation

YIELD

Ataluren Facilitated Protein Synthesis

Full-length

Dystrophin

NormalStop

Codon

Nonsense(Premature Stop)

Codon

Ataluren Has Been Designed to Overcome Nonsense Mutations

Dystrophin mRNA

A nonsense mutation must be present for ataluren to be active Gene sequencing can be used for patient selection

Ataluren10, 10, 20 mg/kg

A Phase 2b Registration-Directed Study of Ataluren in Boys with DMD/BMD is Ongoing

Open-labelExtension

Study

Double-blind Placebo-controlled

Study

Ataluren20, 20, 40 mg/kg

Placebo

Ataluren 20, 20, 40 mg/kg

R/S

48 Weeks

Eligibility Criteria:• Ambulatory boys 5 yo with nonsense-mutation DMD/BMD

Primary Outcome Measure:• 6-minute walk distance N=55

N=55

N=55

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 Trial Update

Low dose group had better 6MWT than high dose & PLAC

Wk 48: low dose group29.7 meters greater

Open-label extension in progress PTC presenting data to FDALessons:

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

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.

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

*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.

ParameterAGLU01602 (n=18)

< 6 months at ERT

AGLU01702 (n=21)

6-36 months at ERT

Alive100% 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 72% 48%20 or 40 mg/kg qow 20 mg/kg qowDose:

rGAA is Beneficial in Patients with the Most Rapid Disease Progression (Early Onset)

Myozyme Duration: 1 Year 1 Year

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 alglucosidase alfa in late-onset Pompe's disease

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.

Co-Primary Endpoint: 6MWT

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Weeks from Baseline

Myozyme Placebo

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)

MZ +25.13 m

PL -2.99 meters

LME* p value=0.0464GEE p value=0.0326* With robust variance estimation

Co-Primary Endpoint: Forced Vital Capacity (cont’d)

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Weeks from Baseline

Myozyme

Placebo

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)

MZ +1.20% predicted

PL -2.20% predicted

LME* p value=0.0041GEE 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

NDMN = 59

1 2 3 4 6 7 8 9Week:Wash-outPeriod

Placebo

PlaceboN =29

N =30

Two-Period Crossover Design

Indicates the weeks to include for the primary endpoint analysis

Mexiletine 200mg tid

Mexiletine 200mg tid

Mexiletine in NDM

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

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

EndpointTreatment

Effect Estimate

95% Confidence

IntervalP-value

IVR—Stiffness -2.69 -3.26, -2.12 <0.001

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

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 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 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

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!