1. Randomized Controlled Trials of Methotrexate & Mycophenolate in MG
Richard J. Barohn, MD
Gary Gronseth, MD
Chair, Department of Neurology
Vice Chair, Department of Neurology
Gertrude and Dewey Ziegler Professor of Neurology
University Distinguished Professor
Vice Chancellor for Research
University of Kansas Medical Center
Kansas City, KS

2. Mycophenolate Mofetil (CellCept)
Mechanism: select/rev cytostatic eff on T&B cells
Early Studies
Ciafaloni 2001
8/12 (67%) improved in 2 mos
Chaudhry 2001
50% of 20 MG pts improved in 6-12 mos
Cos 2000
59% of 29 MG pts improved in 6-12 mos
Meriggioli et al 2003
85 pts-73% imp
Blinded RCT-14 pts/5 months Rx
MM-QMG imp 2.5
Plac-QMG imp 0.24 (p=0.30)

3. Mycophenolate Mofetil Rand/Control Trials in MG
Sanders & colleagues (MSG Neurology 2008;71:394)
Investigator initiated funded by FDA-ODG
Must be AChR-Ab pos
No prior IS Rx
2.5 gm MM vs. plac
All placed on pred 20
1o – QMG 3 mos
2o – MMT, MG-ADL
AChR-Ab, SFEMG
80 subjects
Aspreva sponsored-138 subjects (Sanders et al Neurol 2008;71:400)
Can already be on prednisone
9 month trial

4. Mycophenolate Mofetil Rand/Control Trials in MG
Sanders & colleagues (MSG Neurology 2008;71:394)
Aspreva sponsored-138 subjects (Sanders et al Neurol 2008;71:400)
RESULTS FOR BOTH:
NO SIGNIFICANT DIFFERENCE!

5. Mycophenolate Mofetil Rand/Control Trials Why Negative?
Drug does not work
Prednisone improved all pts and masked MM effect
Studies were not long enough
Endpoints were not good enough
Non-homogenous populations enrolled

6. Phase II Trial of Methotrexate in MG Barohn and Muscle Study Group FDA OPD R01 FD003538/IND #101,306
A randomized, double-blind, placebo-controlled study
50 patients
25 receiving MTX; 20mg/week
25 receiving placebo/12 mo study
Hypothesis – adding MTX therapy will improve the MG manifestations so that prednisone dose can be reduced and clinical measures of MG severity will improve
The primary measure of efficacy will be the 9-month prednisone area under the curve (AUC)
Secondary: QMG, MG ADL, MG Comp, MG QOL15
20 sites – KUMC, UTSW, UTSCSA, UC-Irvine, OSU, U. North Carolina, U. Virginia, UCSF – Fresno, U. Miami, U. Indiana, MGH, CPMC, U. Iowa, Toronto, Phoenix, Methodist, NM Center Houston, Penn State, U. Florida, U. Toronto
Conclusion: NEGATIVE STUDY
Pasnoor M, He J, Herbelin L, Burns TM, Nations S, Bril V, Wang AK, Elsheikh BH, Kissel JT, Saperstein D, Shaibani JA, Jackson C, Swenson A, Howard JF, Goyal N, David W, Wichkund M, Pulley M, Becker M, Mozaffar T, Benatar M, Pazcuzzi R, Simpson E, Rosenfeld J, Dimachkie MM, Statland JM, Barohn RJ, The Methotrexate in MG Investigators of the Muscle Study Group. A Randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology. 2016; 87: PMCID:PMC

7. Neurology Jul 5;87(1):57-64.
PMID:
PMCID: PMC

8. MG MTX trial: Primary outcome Prednisone area under the curve
Intent-to-treat analysis using multiple imputation method
Mean Prednisone dose in :
Methotrexate group: ±
Placebo : ±
P-value : 0.14
Average daily prednisone dose
Methotrexate group: ± 9.54
Placebo group: ± 7.82

9. MG MTX Trial: Secondary Outcome Measures
Methotrexate Mean change
Placebo mean change
Difference between Placebo and MTX
P value
QMG
-1.6 ±3.5
.28 ± 4.5
1.88
0.08
MGMMT
-5.6 ± 4.6
-3.7 ± 7.7
1.9
0.14
MGQOL
-4.3 ±9.2
-4.8 ± 11.4
0.5
0.38
MGADL
-1.4± 2.3
-0.26± 2.9
1.14
0.059
MG Composite
-4.8 ±4.4
-2.5± 5.4
2.3
0.052
*Intent-to-treat analysis using multiple imputation

10. MG MTX Trial: Is it “Negative”? Why?
MTX/MMF do not work
Prednisone probably works too well
Difficult to do studies with patients on prednisone
Underdose methotrexate
High number of PBO drop outs
Not enough patients (underpowered)
Statistical handling of dropouts

11. MG MTX Trial: Is it “Negative”? Why?
Prednisone probably works too well
Maybe hard to do MG studies with patients on prednisone
Methotrexate does not work
Underdose methotrexate
High number of PBO drop outs
Not enough patients (underpowered)
Statistical handling of dropouts

12. My Rx Recommendations - prior to 2007 My Rx Recommendations – 2016
Myasthenia Gravis
My Rx Recommendations - prior to 2007
1st Line: Tensilon
Mestinon
Prednisone
Thymectomy
2nd Line: Azathioprine
Mycophenolate Mofetil
Cyclosporine
3rd Line: IVIg
Plasmapheresis
My Rx Recommendations – 2016
1st Line: Enlon
Pyridostigmine
Prednisone
Thymectomy !
2nd Line: Azathioprine
Cyclosporine
IVIg
3rd Line: Plasmapheresis
Mycophenolate Mofetil
Methotrexate
4th Line: Rituximab
? 5th Line: ? Cyclophosphamide
? Tacrolimus

13. Poor Internal Validity?
Study Risk of Bias Meriggioli 2003 MMF Class II MSG 2008 MMF Class I Sanders 2008 MMF Class I Pasnoor 2016 MTX Class I

14. Difference in Change in QMG
Imprecision?
Meta-analysis MMF
Pasnoor 2016 MTX
Difference in Change in QMG
Favors MMF or MTX
Favors Placebo
Difference in Daily Prednisone Use
Sanders 2008 MMF
Pasnoor 2016 MTX
Favors MMF or MTX
Favors Placebo

15. Poor External Validity?