Therapeutic Advances in Neurological Disorders Original Research

Ther Adv Neurol Disord A randomized, blinded, parallel-group, (2010) 3(1) 15—28 DOI: 10.1177/ pilot trial of mycophenolate mofetil (CellCept) 1756285609353354 ! The Author(s), 2010. Reprints and permissions: compared with interferon beta-1a (Avonex) http://www.sagepub.co.uk/ journalsPermissions.nav in patients with relapsing—remitting multiple sclerosis

Elliot M. Frohman, Gary Cutter, Gina Remington, Hongjiang Gao, Howard Rossman, Bianca Weinstock-Guttman, Jacqueline E. Durfee, Amy Conger, Ellen Carl, Katherine Treadaway, Eric Lindzen, Amber Salter, Teresa C. Frohman, Anjali Shah, Angela Bates, Jennifer L. Cox, Michael G. Dwyer, Olaf Stu¨ve, Benjamin M. Greenberg, Michael K. Racke and Robert Zivadinov

Abstract: Background: Mycophenolate mofetil (MMF, CellCeptÕ) has been utilized as an antirejection agent in transplant recipients and in patients with myriad autoimmune disorders including multiple sclerosis (MS). Correspondence to: Elliot M. Frohman, Objective: To investigate radiographic and clinical safety involving monotherapy use of daily MD, PhD Õ Departments of Neurology oral MMF (1 g b.i.d.) versus weekly intramuscular interferon beta 1a (Avonex at 30 mcg) and Ophthalmology, in relapsing—remitting MS (RRMS). University of Texas Southwestern Medical Methods: We organized a randomized, serial, 6-monthly, MRI-blinded, parallel-group Center, Dallas, TX, USA multicenter pilot study to determine the safety of MMF versus interferon beta monotherapy elliot.frohman@ utsouthwestern.edu in 35 untreated patients with RRMS, all of whom exhibited evidence of gadolinium (Gd) Gary Cutter, PhD enhancement on a screening MRI of the brain. The primary outcome was the reduction in the Amber Salter Department of cumulative mean number of combined active lesions (CAL), new Gd-enhancing lesions, and Biostatistics, University of new T2 lesions on MRI analyses. Albama, Birmingham, AL, USA Results: Both interferon beta and MMF appeared safe and well tolerated in the majority of [email protected] patients. There was no difference between MMF therapy and the standard regimen of Robert Zivadinov, MD, PhD interferon beta therapy on the primary safety MRI endpoints of the study. However, the MMF The Jacobs Neurological group showed a trend toward a lower accumulation of combined active lesions, CAL, Gd and T2 Institute and the Buffalo Neuroimaging Analysis lesions when compared with interferon beta treated patients. Center, State University of New York, Buffalo, NY, Conclusions: The results from this pilot study suggest that the application of MMF USA monotherapy in MS deserves further exploration. [email protected] Hongjiang Gao Department of Biostatistics, Keywords: mycophenolate mofetil, CellCept, interferon beta 1a, MRI activity, immunosuppres- University of Albama, Birmingham, AL, USA — sion, relapsing remitting multiple sclerosis Gina Remington Amy Conger Katherine Treadaway Teresa C. Frohman Angela Bates Olaf Stu¨ve First-line disease modifying therapy (DMT) for be well tolerated and exquisitely safe in the Benjamin M. Greenberg multiple sclerosis (MS) has included the admin- majority of treated patients. Despite these impor- Department of Neurology, University of Texas istration of parenteral agents such as interferon tant safety merits, the efficacy of these drugs, Southwestern Medical beta or glatiramer acetate [Corboy et al. 2003; while more than adequate for some patients, Center, Dallas, TX, USA Goodin et al. 2002]. Over a long period of utili- has been insufficient for others, particularly Howard Rossman Michigan Institute for zation, from clinical trials to post-marketing sur- over time. Furthermore, adherence to parenteral Neurological Disorders, veillance, these agents have been demonstrated to forms of MS DMTs has been a challenge for Farmington Hills, MI, USA

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Bianca Weinstock- many patients, which is a consideration that has expression of T-cell surface antigens in whole Guttman clear implications for the effectiveness of treat- blood lymphocyte analysis derived from treated Eric Lindzen The Jacobs Neurological ment [Treadway et al. 2009]. allograft recipients [Barten et al. 2002a, 2002b]. Institute, State University MPA has been shown to inhibit interferon of New York, Buffalo, NY, USA Modest efficacy, adherence problems and injec- gamma (IFN-g) and lipopolysaccharide (LPS)- Jacqueline E. Durfee tion-related adverse events have catalyzed a series induced interleukin-6 (IL-6) and nitric oxide Ellen Carl of investigations aimed at the identification of Jennifer L. Cox [Miljkovic et al. 2002]. This latter activity may Michael G. Dwyer an effective oral therapy for MS. There are correspondingly confer therapeutic benefits for Buffalo Neuroimaging now five agents in phase III clinical trials that patients with MS, given that the disease mecha- Analysis Center, State University of New York, appear promising in providing superior efficacy, nism appears to involve a skewing or bias toward Buffalo, NY, USA greater convenience of oral administration, and pro-inflammatory immune responses, in part Anjali Shah improved adherence for our MS patients. These characterized by the inappropriate elaboration Department of Physical Medicine and include cladribine, FTY-720, dimethylfumarate of IL-6 and nitric oxide [Noseworthy et al. Rehabilitation, University (BG-12), laquinimod and teriflunomide 2000]. Further, mononuclear cell trafficking from of Texas Southwestern Medical Center, Dallas, [Cohen, 2009; Menge et al. 2008]. The latter blood into the brain can be modified by MMF TX, USA agent is related to the approved drug lefluno- by reducing the expression of vascular cell adhe- Michael K. Racke mide, which has long been utilized for the treat- Department of Neurology, sion molecule 1 [Blaheta et al. 1999]. Humorally Ohio State University, ment of rheumatoid arthritis. Teriflunomide is MMF effectively suppresses anti-blood type IgG Columbus, OH, USA an inhibitor of dihydro-orate dehydrogenase, antibodies in patients receiving ABO mis- a key enzyme in the synthesis of pyrimidines matched renal transplants [Ishida et al. 2002]. [O’Connor et al. 2006]. Preliminary studies have shown good tolerability Compared with the proprietary oral agents under and safety when MMF is utilized as monotherapy development, mycophenolate mofetil (MMF) is a or in combination with interferons or glatiramer readily available and cost effective therapy. MMF acetate [Vermersch et al. 2007; Frohman et al. would be of potentially great interest in MS ther- 2004]. We now report the results of a rando- apeutics given that this agent exerts pleiotropic mized, blinded, parallel-group, head-to-head effects on T and B cells and macrophages, all pilot study of MMF compared with weekly intra- key cellular participants involved in the orches- muscular interferon beta 1a, in untreated RRMS tration of CNS tissue injury [Frohman et al. patients who presented with evidence of gadoli- 2006, 2004]. Similar to teriflunomide, MMF is nium (Gd)-enhancing MRI brain lesions. The a DNA base synthesizing enzyme system inhibi- principal aim of our pilot study was to assess 6- tor. Specifically, MMF is a selective inhibitor month safety and potential efficacy of MMF of inosine 50-monophosphate dehydrogenase (CellCept) versus interferon beta-1a (Avonex) (IMD) type II, which is a potent immunosup- (6.0 Million international units (MIU) adminis- pressant, principally used in transplant medicine tered i.m. each week) therapy, by comparing as an antirejection agent [Jonsson and Carlsten, month-to-month changes of two inflammatory 2002]. IMD is responsible for the de novo synthe- MRI measures — Gd-enhancing and T2 lesion sis of the purine nucleotide guanine within acti- metrics. vated lymphocytes, and macrophages, without affecting purine salvage pathways. MMF is the Methods prodrug of mycophenolic acid (MPA), which has been shown to be on the order of five times Patient selection more potent than MMF as an inhibitor of the Patients were enrolled and randomized from type II isoform of IMD. This observation is rele- three centers: University of Texas Southwestern vant in that the type II isoform is predominant in Medical Center at Dallas, the Michigan Institute lymphocytes, whereas the type I variety is the for Neurological Disorders and the Jacobs principal form in all other cell types [Allison Neurological Institute, State University of New and Eugi, 1993; Allison et al. 1993]. York, Buffalo, NY. All subjects signed informed consent prior to any study-related assessments MMF has been shown to exert a number of and the study was approved by each center’s immunomodulatory activities that may be useful local Institutional Review Board. in the treatment of immune-mediated diseases. For instance, MMF exhibits the capability to Inclusion criteria. Patients were eligible for suppress lymphocyte proliferation and the this study if they were diagnosed with clinically

16 http://tan.sagepub.com EM Frohman, G Cutter et al. definite MS according to McDonald criteria previous year. All subjects had to have one [Polman et al. 2005], were aged 18—55 inclusive, Gd-enhancing brain lesion on a screening MRI, had a relapsing—remitting (RR) disease course, along with 2 T2 brain lesions consistent with and Expanded Disability Status Score (EDSS) MS on the baseline scan. less than or equal to 5.0 (Table 1). Candidate patients were required to have at least one med- Exclusion criteria. Patients were excluded from ically documented clinical relapse within 12 participation if they did not fulfill all of the inclu- months prior to randomization (for eligibility, a sion criteria and if they received treatment 3 prestudy relapse was defined as neurologic signs months prior to study entry with any standard and symptoms documented by review of the his- DMT (interferon-beta and glatiramer acetate, tory with the subject or clearly documented in the intravenous immune globulin (IVIG) or plasma- medical record, of sufficient severity and duration pheresis). Further, patients were excluded if they to be determined by the investigator as consistent previously received treatment 12 months prior to with an acute MS relapse; the relapse did not study entry with immunosuppressant agents such need to have been treated to qualify) and/or as mitoxantrone, cyclophosphamide, cladribine, have progression of 1.0 points in EDSS in the fludarabine, cyclosporine, total body irradiation

Table 1. Baseline characteristics of enrolled patients. Characteristic Interferon beta MMF p value* (n ¼ 19) (n ¼ 16) Age — years, mean±SD 38.6±9.4 37.4±8.3 0.72 Female — no (%) 14 (73.7) 11 (68.8) 0.75 Weight — kg, mean±SD 90.8±21.3 82.9±20.7 0.28 Height — m, mean±SD 1.66±0.10 1.71±0.11 0.18 Blood pressure — mmHg Systolic blood pressure, mean±SD 124.4±14.9 120.7±13.9 0.46 Diastolic blood pressure, mean±SD 79.7±7.9 77.8±12.5 0.60 Race — no (%) 0.24 Caucasian 11 (57.8) 14 (87.5) African-American 4 (21.1) 1 (6.3) Other 4 (21.1) 1 (6.3) Disease duration in months, mean±SD 33.3±46.4 30.9±38.5 0.87 Relapses within last 12 month prior 0.88 to the study, no. (%) 0 0 (0.0) 1 (6.3) 1 16 (84.2) 13 (81.3) 2 2 (10.5) 2(12.5) 3 1 (5.3) 0 (0.0) EDSS, mean±SD, median (min — max) 2.5±1.3, 2.3 (0.0—6.0) 2.6±1.2, 2.3 (0.8—5.3) 0.85 MSFC 0.12±0.58 0.13±0.94 0.37 Arm, mean±SD 0.47±1.35 0.24±1.21 0.11 Leg, mean±SD 0.04±0.56 0.05±1.36 0.81 PASAT, mean±SD 0.36±1.27 0.20±0.98 0.16 Quality of life (QOL-54) Physical, mean±SD 58.2±20.0 66.0±16.6 0.22 Emotional, mean±SD 58.3±21.9 70.2±19.6 0.10 Beck’s Depression Index, mean±SD 13.2±10.1 12.9±9.9 0.93 # No Gd lesions, mean±SD, median (min — max) 5.7±7.1, 2 (1—24) 4.3±6.5, 2 (1—27) 0.56 # No T2 lesions, mean±SD, median (min — max) 34.8±24.9, 28 (2—82) 31.6±18.3, 30 (4—65) 0.82 # Combined active lesions, mean±SD, 40.5±27.9, 32(3—96) 35.9±19.6, 39.5(5—69) 0.79 median (min — max) T2-LV (ml), mean±SD, median (min — max) 11.6±13.7, 7.2 (0.2—46.3) 11.9±7.1, 2.6 (1.3—57.2) 0.94 T1-LV (ml), mean±SD, median (min — max) 1.8±4.7, 0.5 (0—20.8) 1.2±2, 0.3 (0—6.8) 0.69 Gd-LV (ml), mean±SD, median (min — max) 0.5±1, 0.1 (1—4) 0.6±1, 0.2 (0.02—3.5) 0.93

SD, standard deviation; number (no.); EDSS, Expanded Disability Status Scale; MSFC, Multiple Sclerosis Functional Composite; PASAT, Paced Auditory Serial Addition Tests; QOL, Quality of Life; LV, lesion volume. Baseline characteristics were compared by either parametric or nonparametric methods where appropriate.

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or any other immunomodulatory therapies (e.g., Scale (MFIS)-21 and the Beck’s Depression azathioprine, methotrexate, MMF, natalizumab, Index (BDI)-21. or other immunomodulators/monoclonal agents). Patients could not be enrolled if they received Randomization and administration of study steroid treatment 30 days prior to the baseline medications MRI scan date. Also excluded were women Patients were randomized by the study pharma- who were pregnant, lactating or of childbearing cist to receive either Avonex or CellCept, and age, who did not consent to utilize approved began treatment at day 0. Initiation of study contraceptive use during the study. medication did not exceed 60 days from the date of the qualifying MRI scan. Avonex was Conduct of the study, randomization, and study initiated at ¼ of the target dose for the first discontinuation week, and then increased by ¼ dose weekly This investigation maintained an MRI-blinded until the full dose was achieved (i.e. ¼ dose at treatment assignment throughout the duration week 1, ½ dose at week 2, g dose at week 3, and of the study. Further, blinded clinical study full dose at week 4). CellCept was initiated at personnel included the certified EDSS examiner, 500 mg twice daily taken on an empty stomach Multiple Sclerosis Functional Composite (defined by 1 h before or 2 h after a meal). This (MSFC) technician, and ophthalmology techni- dose was continued for the first 2 weeks and then cian (who completed all visual assessments). The increased to 1000 mg twice daily thereafter. patients and treating physicians were not blinded As such, treatment titration took place over 1 to treatment assignment. The reason for this was month as above, and then maintenance treatment that we were unable to purchase identically was continued for five consecutive months. We appearing placebo Avonex injection kits, and as recognized that a ‘standard’ target dose regimen such were thereby precluded from conducting for CellCept does not take into account poten- a ‘double-dummy’ controlled trial. An inves- tially important pharmacologic factors such as tigational drug services pharmacist created the body weight, plasma peak and trough drug randomization scheme and dispensed study levels, and IMD enzyme inhibition effects (per- medications to the nurse coordinator. haps signifying pharmacogenomic differences among patients, possibly related to IMD gene Following completion of the consent process, polymorphisms). At the time when our study each patient underwent baseline assessments was planned, we had no evidence-based litera- (physical exam by the treating neurologist, ture, nor available assay systems from which to EKG, chest X-ray, and laboratory assessments determine ‘appropriate’ and validated dosing for human immunodeficiency virus (HIV), schemes in individual patients. Similar limita- rapid plasma reagin (RPR), and hepatitis B) for tions may also apply to interferon beta and safety prior to initiation of study medication. other MS therapies. Following run-in and qualifying MRI brain Reasons for discontinuation scans, patients had six additional monthly MRIs Conditions in which a patient could have been with Gd contrast performed at day 0, 60, 90, discontinued from the study included worsening 120, 150 and 180, in this head-to-head compar- of the patient’s condition (requiring more aggres- ison study. Neurological assessments included sive therapy outside of the trial), study medica- the Kurtzke EDSS and the MSFC (comprised tion complications and/or intolerable side effects, of the 9-Hole Peg Test, Paced Auditory Serial a patient’s voluntary withdrawal, the investiga- Addition Test, 25-Foot Timed Walk and the tor’s decision (based on risk/benefit ratio for Sloan Low-Contrast Letter Acuity Chart — each individual patient), a patient’s repeated fail- 1.25%). These assessments were performed ure to comply with study procedures, inability to every 3 months following the baseline assessment complete all research assessments, and/or closure for 180 days. Laboratory investigations (com- of the study by either the sponsor or the FDA. plete blood count, comprehensive metabolic panel and pregnancy test) were done at the initi- Safety evaluation ation of study medication (day 0) and again at The objective of our safety surveillance plan was day 30, 60, 90 and 180. Questionnaires were to compare MMF with interferon beta mono- administered by the nurse coordinator at baseline therapy groups with respect to patient-reported and day 180 and included the MS Quality of adverse events, and to assess for any laboratory Life-54 (MSQOL-54), Modified Fatigue Impact derangements during the course of treatment.

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Treatment of exacerbations The MRI was performed at the Dallas site on a During each of the study visits, all patients were Philips 1.5T scanner, at the Buffalo site on a reminded to report any new symptoms and/or General Electric 1.5T scanner and at the new concomitant medications (including over- Michigan site on a Siemens 1.5T scanner. The the-counter supplements), to the nurse coordina- protocol was standardized by the central MRI tor. Patients with suspected exacerbations were reading center (Buffalo) and then implemented instructed to return to the clinic to be evaluated. at all sites. We performed a dual spin echo (SE) If the treating neurologist decided that worsening sequence (PD/T2), 3D-spoiled gradient-recalled of the clinical course was due to an MS exacer- (SPGR) T1-weighed image (T1-WI), pre- and bation, the patient was then evaluated by the postcontrast SE T1-WI (the postcontrast blinded EDSS examiner and MSFC technician. sequence was obtained 5 min after administration Patients were then offered treatment with either of contrast agent as a single-dose, intravenous 1 g of methylprednisolone administered intrave- bolus [0.1 mMol/kg Gd-DTPA]), fast fluid atte- nously (or orally) daily for 3 days (or dexametha- nuated inversion recovery (FLAIR), MTI and sone at 100 mg given i.v. or orally b.i.d. for 3 DTI sequences. The acquisition parameters are days) without a taper. If the acute exacerbation summarized in the supplemental data. occurred within 30 days prior to the anticipated commencement of the therapeutic phase of the Supplemental data. The axial dual SE sequence study, treatment with either interferon beta or was acquired with TE 12/95, TR 3000, NEX 1, MMF was delayed such that there was at least ETL 14, FOV 25.6, matrix 256 192, 3-mm 30 days between receiving the last dose of steroid slice thickness with a total of 48 slices, no gap, medication and the beginning of drug therapy, and scan time 3 : 37 min. The axial 3D-SPGR and also 60 days from the onset of the exacerba- T1-WI scan was acquired with FOV 24, matrix tion. MRI assessments at different time points 256 192, 1.5-mm thickness, 110 slices, no gap, TE 6, TR 25, NEX 1, FLIP 30, scan time during the study were not delayed because of 9 : 11 min; axial SE T1-WI pre- and postcontrast exacerbations or treatment with steroids. with FOV 25.6, matrix 256 256, 48 slices, Baseline MRI was obtained prior to any steroid 3-mm thickness, no gap, TE 9, TR 600, NEX treatment. 1, scan time 4 : 07 min (the postcontrast sequence was obtained 5 min after administration of con- Outcome measures trast agent as a single-dose intravenous bolus Measurement of inflammatory brain MRI indices [0.1 mMol/kg Gd-DTPA]) and axial FLAIR represented the primary safety and exploratory with FOV 24 cm, matrix 256 192, 48 slices, efficacy outcome measures, and included a 3-mm thickness, no gap, TE 120, TI 2100, TR change in the cumulative mean number of new 8500, ETL 22, NEX 1, with scan time of Gd-enhancing lesions, new T2 lesions, and 3 : 25 min. The MTI was acquired with 3D-GE combined active lesions (CAL). The secondary sequence (TR, 50 ms; NEX, 2; flip angle, 10; outcomes included clinical relapse and disability- matrix size, 256 160; FOV, 24 cm; 3-mm thick- based measures. Tertiary measures included two ness; scan time: 4 : 36 min both with [MS] and nonconventional MRI measures (magnetization- without [M0] a pre-pulse [1500 Hz off-water res- transfer imaging [MTI] and diffusion-tensor onance pulse]). DTI consisted of axial; TR, 9000 imaging [DTI]; the subject of a subsequent gated; matrix size, 64 64, FOV, 24 cm; 3 b 0 publication), MSFC, MSQOL-54, FIS and BDI. smm-2 images; 60 DW images with d ¼ 32 ms, Á ¼ 40 ms, and max b ¼ 1000 smm-2; slices, 42; 3-mm thickness, directions, 11; scan time: MRI methods 2 : 06 min.

MRI study protocol. All patients underwent MRI analysis serial MRI scans of the brain at screening The central screening and on-site image analysis (unless the patient had a qualifying MRI done validation was performed at the Buffalo at an outside facility within 30 days with at least Neuroimaging Analysis Center, Department of one Gd-lesion), and at the following time points: Neurology, University at Buffalo, Buffalo, NY. days 0, 60, 90, 120, 150 and 180 (the noncon- The operators and neuroradiologists were ventional MRI measures were performed only at blinded to the patients’ clinical characteristics, days 0, 90 and 180). clinical status, and treatment assignment.

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Lesion activity analysis. A new Gd-enhancing the average in each treatment group from day 0 lesion was defined as a typical area of to day 180. Type I error for significance was set at hyperintense signal on postcontrast T1-WI. the 0.05 level for all analyses. We calculated the mean cumulative number of Gd-enhancing lesions per patient over the Results 180-day treatment period, defined as the period following the first month to the last month of this Patient demographic, clinical and MRI head-to-head comparison study (day 180). Other characteristics at baseline Gd-based MRI lesion activity outcomes included Of the 47 patients screened for the study, 35 the number of total new Gd-enhancing lesions patients were enrolled and randomized from per patient and the number of persistent three centers (Dallas, n ¼ 23; Michigan, n ¼ 9, Gd-enhancing lesions (enhancing lesions that and Buffalo, n ¼ 3). The reasons for screening had also been present on the previous monthly failures are outlined in Figure 1. The patient scan). characteristics were well matched at baseline (Table 1) and not significantly different between A new or newly enlarging lesion on T2-weighted the two parallel treatment groups. The mean age images was defined as a rounded or oval lesion was 38.6 years in the interferon beta group and arising from an area previously considered as 37.4 years in the MMF arm, whereas the mean normal appearing brain tissue (NABT) and/or disease duration was 33.3 and 30.9 months showing an identifiable increase in size from a respectively. The median EDSS in the interferon previously stable-appearing lesion. We measured beta and MMF groups were 2.5 and 2.6. There the mean number of new T2 lesions per patient were a higher proportion of African-Americans over the 180-day treatment period, defined as the and patients with ‘other race’ (other than period following the first month to the last month Caucasian) designation in the interferon beta of the comparison study (day 180). We also compared with the MMF treatment arm, but determined the mean number of new CALs, as this was not statistically significant. Both groups the number of new enhancing lesions plus the showed a high number of T2 lesions on the base- number of new or newly enlarging, nonenhan- line scan (mean of 34.8 in the interferon beta cing lesions on T2-WI. An active scan was group and 31.6 in the MMF arm), and showed defined as showing any new, enlarging or recur- high acute MRI activity at baseline (mean no. of rent lesion(s) on postcontrast T1- and T2-WI. Gd lesions of 5.7 in the interferon beta arm and The calculations of new Gd-enhancing, T2 4.3 in the MMF arm). lesions, CAL, and the proportion of active scans were based on semi-automated tracing Disposition and dropouts methods applied to computer-displayed images Of the 35 patients enrolled in the study, 19 were at days 0, 60, 90, 120, 150 and 180. randomized to interferon beta and 16 to MMF treatment (Figure 1). Four patients did not com- Quantitative lesion analysis. The number plete the study, but were entered into the inten- and volume of Gd, T2 and T1 lesions were mea- tion-to-treat (ITT) analysis. Of the three dropout sured using a semi-automated edge detection patients in the MMF arm, one patient voluntarily contouring-thresholding technique, as previously withdrew due to intolerable side effects (severe described [Zivadinov et al. 2004, 2001]. change in mood) at day 2 after receiving only two doses of MMF. The primary investigator Statistical analysis classified the adverse event as ‘not likely’ related Analyses were performed using SAS 9.2 (SAS to the study medication. The other two early ter- Institute, Cary, North Carolina). MRI endpoints mination patients in the MMF treatment arm were fitted with a negative binomial model were lost to follow-up at day 120. One patient accounting for overdispersion. Baseline and in the Avonex arm was lost to follow-up at day repeated measurements over time were also 120. adjusted for the above-characterized end points, with the use of generalized estimating equations MRI outcomes (GEE) in Genmod procedure. Mixed-effect Least square means of active Gd, T2 and CAL models were applied for clinical end points lesions over time, were adjusted by each corre- adjusted by baseline as well. In the calculation sponding baseline measure at day 0, and is shown of adverse event incidence rate, duration was in Figure 2. There was no significant treatment

20 http://tan.sagepub.com EM Frohman, G Cutter et al.

47 Patients screened

11 Ineligible (no Gad)

36 Eligible 1 Patient withdrawn - neuromyelitis optica antibody positive 35 Randomized

19 Interferon 16 MMF

1 Early termination 3 Early terminations

1 Lost to 1 Lost to 1 Lost to follow-up 1 follow-up follow-up at day 90 Withdrawal at day 90 at day 120 at day 2

18 Completed study 13 Completed study

Figure 1. Enrollment of study patients, discontinuation and study completion.

effect observed for new T2 active lesions (p ¼ mean cumulative number of new T2 lesions 0.1), new active Gd lesions (p ¼ 0.29) or for over 180 days was 9.7±25 for the interferon CAL (p ¼ 0.15) between the two treatment arms. beta arm and 2.6±1.4 for the MMF arm (p ¼ NS). The mean cumulative number of Gd active lesions over the entire 180 days of the trial was Clinical outcomes 7.2±17.4 for Interferon beta and 1.1±1.8 for Five confirmed relapses occurred during the the MMF arm. During the 180 days of the study, three in the interferon beta group (at 60 study, 52.6% of the T1-postcontrast scans were and 120 days) and two in the MMF group (at 60 active in the interferon beta arm versus only 40% and 90 days). All five attacks were categorically of the scans in the MMF arm (p ¼ NS). In total, designated as mild by the evaluating neurologists. ten patients in the Interferon beta arm developed Of 19 patients in the interferon beta arm, a total of 137 new Gd-enhancing lesions over 180 17 (89.5%) were relapse-free (one patient pre- days, while 7 patients in the MMF arm devel- sented with two relapses) and of 16 patients in oped a total of only 17 new Gd-enhancing lesions the MMF arm, 14 (87.5%) were relapse free (p ¼ NS). The following represents the distribu- (p ¼ NS). No differences in other functional out- tion of the Gd-enhancing lesions in the interferon comes were observed between the two treatments beta arm: five patients had one lesion, one patient arms at 90 and 180 days of the study (Table 2). had six, one had 13, one had 19, one had 20, and one had 74 lesions. In the MMF arm: two Safety/tolerability patients had one lesion, one patient had two, Both interferon beta and MMF appeared safe one had three, one had four and one had six. and well tolerated. The total number of AEs in The two treatment groups had one patient the interferon beta group was not significantly each, with a single persistent Gd-enhancing different to those documented in the MMF lesion. Similar trends in favor of MMF were group over the 180 days of the study (93 versus identified on analyses of CAL and new T2 71, p ¼ NS) (Table 3). Overall, 13 (68.4%) lesions, as shown in Figure 2. The mean cumu- patients in the interferon beta arm and eight lative number of new CAL over 180 days was (50%) in the MMF arm reported at least one 11.4±24.9 for the interferon beta arm and AE over the study period (p ¼ NS). There was a 3±2 for the MMF arm (p ¼ NS), whereas the higher proportion of patients describing pain,

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Avonex CellCept 1.0 1.5 2.5 Combined active lesions Combined active 0.5 Gd lesions 1.0 1.5 2.5 0.5 T2 lesions 0.4 0.6 0.8 1.0 1.2 0.2

60 90 120 150 180 Days in trial

Figure 2. Least square means of combined active lesions, gadolinium (Gd)-enhancing lesions, and T2 lesions over time adjusted by respective baseline at day 0. There was no significant treatment effect observed for new T2 active lesions (p ¼ 0.1), new active Gd lesions (p ¼ 0.29), or for combined active lesions (CAL) (p ¼ 0.15).

weakness, dizziness, fatigue, numbness, flu-like tuberculosis), except for the occurrence of a symptoms, depression, nausea, sinusitis, anxiety, right thigh abscess in one patient in the interferon trauma, speech problems, hemorrhoids, site reac- beta arm. Of all the AEs in the interferon beta tions, suicidal thoughts and trigeminal symptoms group, 74.4% were deemed unlikely related to in the interferon beta arm, whereas headache, treatment, whereas of all AEs in the MMF arm, diarrhea, itching/pruritus, upper respiratory 65% were considered to be unlikely related to the tract infection, tooth infection, eye infection, treatment (p ¼ NS). While not significant, we did metal taste, influenza, ear infection, and bleeding identify a higher proportion of infections in the of the nose occurred more frequently in the MMF treated patients. No differences were MMF arm (Table 3). Overall pain, urinary tract detected in the frequency of laboratory derange- infections, headache, weakness, dizziness and ments between the two treatment arms (three in diarrhea were the most common AEs reported. the interferon beta group and three in the MMF group) (Table 3). No differences in the severity of AEs occurred between the two treatment arms. There were Racial effects on study outcomes no serious AEs in either treatment group Given the higher proportion of African- (no malignancies, opportunistic infections or Americans and patients with ‘other race’

22 http://tan.sagepub.com EM Frohman, G Cutter et al. designations (other than Caucasian) in the inter- Table 2. Functional outcomes by treatment assignment. feron beta arm, we investigated the ‘race effect’ Variable Interferon MMF p on study outcomes between the two different beta (mean) value arms. No significant differences were found for (mean) any of the clinical, laboratory or radiographic EDSS analyses. Day 90 2.05 1.74 0.45 Day 180 2.03 1.76 0.51 Discussion MSFC From the patient’s quality-of-life perspective, the Day 90 0.24 0.19 0.13 availability of effective, convenient and safe oral Day 180 0.002 0.34 0.23 MSFC — leg disease modification for MS would constitute a Day 90 0.40 0.23 0.66 monumental advance. Since the FDA approval of Day 180 0.07 0.05 0.97 the first DMT for MS in 1993 (Betaseron), the MSFC — arm subsequent treatment options have all been par- Day 90 0.008 0.19 0.37 enterally administered agents (interferon beta1a, Day 180 0.20 0.35 0.46 MSFC — PASAT glatiramer acetate, mitoxantrone, and most Day 90 0.01 0.22 0.26 recently natalizumab) [Frohman et al. 2006; Day 180 0.17 0.41 0.26 Corboy et al. 2003; Goodin et al. 2002]. Both Ambulation Index physicians and patients now expectantly look for- Day 90 0.68 0.87 0.51 ward to the approval of oral formulations that Day 180 0.84 0.94 0.86 Sloan visual acuity appear to exert impressive efficacy on clinical Day 90 25.40 32.29 0.12 and radiographic aspects of disease activity, in Day 180 27.91 24.90 0.50 addition to potential neuroprotective effects, Quality of life (QOL-54) 63.07 67.59 0.32 and superb tolerability and convenience. — physical, day 180 Quality of life (QOL-54) 61.31 66.26 0.37 — emotional, day 180 An advantage of conventional MS DMT is that Fatigue Impact Scale 38 33.2 0.51 there have been no data linking interferon or gla- - day 180 tiramer acetate treatment to the serious and Beck’s depression index 14.54 8.64 0.10 potentially life-threatening opportunistic infec- - day 180 tions (OIs) that have been associated with the EDSS, Expanded Disability Status Scale, MSFC; Multiple Sclerosis Functional potent immunosuppressive agents (e.g. natalizu- Composite; PASAT, Paced Auditory Serial Addition Tests; QOL, quality of life. mab, rituximab, azathioprine, MMF, cladribine, The differences were compared by either parametric or non-parametric method and fingolimod) [Berger and Houff, 2009; where appropriate. Cohen, 2009; Hemmer et al. 2006]. All of the newer agents have limited short-term safety data when compared with the interferons and glatiramer acetate. Further, mitoxantrone has [Chaudry et al. 2001; Ciafaloni et al. 2001; been associated with the risk of potentially Mowzoon et al. 2001; Hauser et al. 1998; serious cardiotoxicity and the development Schneizer et al. 2001], chronic inflammatory of leukemias [Ellis and Boggild, 2009; Moses demyelinating polyneuropathy [Chaudry et al. and Brandes, 2008; Goodin et al. 2003]. 2001; Mowzoon et al. 2001;], polymyositis Nevertheless, the greater efficacy, improved con- [Schneider et al. 2002; Chaudry et al. 2001; venience and adherence of the newer oral thera- Mowzoon et al. 2001], treatment of refractory pies will likely provide compelling justification for skin manifestations of dermatomyositis [Gelber the application of these more expensive and et al. 2000], inclusion body myositis [Mowzoon higher risk approaches, in carefully selected et al. 2001], psoriasis [Schrader et al. 2002; patients. Ameen et al. 2001], neuromyelitis optica (NMO) [Schrader et al. 2002; Ameen et al. There is an expanding literature suggesting 2001], and Susac’s disease [Pawate et al. 2009]. that MMF has the ability to effectively treat a A small open-label surveillance study involving broad diversity of inflammatory disorders. seven MS patients treated with MMF was These have included lupus [Karim et al. 2002; reported in 2001 and suggested evidence of tol- Lui et al. 2002; Schanz et al. 2002], cANCA erability and potential efficacy in this small vasculitis [Waiser et al. 1999], Takayasu’s cohort [Ahrens et al. 2001]. We extended this arteritis [Daini et al. 1999], myasthenia gravis observation with our open-label surveillance

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Table 3. Adverse events (AE) by treatment assignment. With the recent approval of generic status for Adverse events, n (%) Interferon beta MMF MMF, we believe that the results presented in (n ¼ 19) (n ¼ 16) this study are potentially important to our MS patients, and for those of us who struggle to ade- All/any AE 93 71 quately and economically manage this complex Pain Extremities 13 (68.4%) 8 (50%) and highly heterogeneous inflammatory disorder. Back pain 6 (31.6%) 2 (12.5%) If MMF can be confirmed as an effective DMT Abdominal pain 1 (5.3%) 3 (18.6%) for MS in adequately powered controlled efficacy Facial 3 (15.8%) 4 (25%) trials, both cost and our extensive experience Urinary tract infection 6 (31.6%) 6 (37.5%) with this agent in transplant medicine would Headache 3 (15.8%) 6 (37.5%) Weakness 6 (31.6%) 2 (12.5%) make it an attractive oral option that could rival Dizziness 5 (26.3%) 0 agents under development that will no doubt be Diarrhea 1 (5.3%) 5 (31.3%) financially exorbitant. Fatigue 4 (21.1%) 2 (12.5%) Numbness 4 (21.1%) 2 (12.5%) Our trial patients were representative of RRMS Itching/pruritis 2 (10.5%) 4 (25%) Flu-like symptoms 4 (21.1%) 0 patients studied in previous clinical trials. Depression 4 (21.1%) 0 Further, we specifically directed our treatment Upper respiratory infection 0 4 (25%) to those individuals with evidence of new inflam- MS relapse 3 (15.8%) 2 (12.5%) matory MRI activity, in order to assess safety of Laboratory abnormalities 3 (15.8%) 3 (18.6%) MMF when compared with a standard, effective, Nausea 3 (15.8%) 1 (6.3%) Sinusitis 3 (15.8%) 0 generally well-tolerated, and commonly utilized Tooth infection 1 (5.3%) 3 (18.6%) MS DMT, interferon beta. Over the course of Eye infection 0 3 (18.6%) the current 6 month pilot trial both agents were Metal taste 1 3 (18.6%) well tolerated in the majority of patients, validat- Influenza 2 (10.5%) 3 (18.6%) ing the outcomes of our previous safety surveil- Anxiety 2 (10.5%) 1 (6.3%) Trauma 2 (10.5%) 0 lance study in 79 MMF-treated patients Speech problems 2 (10.5%) 0 [Frohman et al. 2004]. Hemorrhoids 2 (10.5%) 0 Site reaction 2 (10.5%) 0 MRI metrics of MS disease activity represented Insomnia 1 (5.3%) 1 (6.3%) the primary safety and efficacy outcome of our Abscess 1 (5.3%) 0 Suicidal thoughts 1 (5.3%) 0 study. It should be emphasized that a potential Trigeminal symptoms 1 (5.3%) 0 confounding variable that could have influenced Incontinence 1 (5.3%) 1 (6.3%) the outcomes we have characterized is the differ- Bleeding of the nose 0 1 (6.3%) ential delay in drug action between MMF and Ear infection 0 1 (6.3%) interferon beta. We titrated to the target dose The adverse events are listed in descending order of frequency. The differences in over 4 weeks with both agents. However, the total number and frequency of adverse events between the two treatment arms onset effects may be quite different. As such, are shown. longer controlled trials along with measures of bioavailability (e.g. MxA levels after interferon injection), serum drug peak and trough concen- study of MMF (CellCept) in 79 patients with MS tration, and enzyme inhibition effects (for MMF) [Frohman et al. 2004]. Vermersch and colleagues will be important features to consider in any class conducted an open-label pilot safety study in 30 I randomized controlled comparison trials for MS patients treated with weekly intramuscular efficacy and safety. While we did not identify interferon beta 1a for at least 6 months, and any differences between our two study groups who had at least one exacerbation within the in terms of prestudy characteristics, in a small last 6 months from the time when MMF was pilot study we cannot preclude the possibility added [Vermersch et al. 2007]. Over 6 months that the retrospective assessment of relapses and of systematic assessment, there appeared to be corresponding treatment with steroids may rep- both clinical and radiographic benefits demon- resent a potential confounder. strated with acceptable safety. In a retrospective study involving 42 MS patients who were treated We confirmed our principal hypothesis that with either mitoxantrone or MMF, all appeared MMF appeared safe compared with interferon to either stabilize or exhibit improvement beta, when considering any radiographic, clinical [Vukusic et al. 2004]. or laboratory measure. While not statistically

24 http://tan.sagepub.com EM Frohman, G Cutter et al. significant, we observed that the mean cumula- quantifiable linkage between new lesions, their tive number of CAL, Gd- and T2-active lesions accumulation, and microstructural alterations over the entire 180 days of the trial was less in (demyelination, axonal transection, gliosis, etc.) those treated with MMF versus interferon beta. to relevant clinical measures remains elusive. During the 6 months of the study, 52.6% of the T1-postcontrast scans were active in the inter- With the advent of more sensitive and noncon- feron beta arm, whereas only 40% of the scans ventional imaging technology, we can begin to were active in the MMF arm. Those patients in better characterize MS brain and spinal cord the interferon beta arm exhibited 137 new Gd- lesions, than has been feasible with traditional enhancing lesions, while 17 new Gd lesions were T2- and T1-weighted measures. Such capabil- documented in seven patients treated with MMF ities will be germane to understanding the basis (p ¼ NS). Another observed trend (not signifi- of the clinical—radiological paradox, which sig- cant) from our analyses was the distribution of nifies the discrepancy between these older and new lesions per patient, which was higher in nonspecific imaging markers and corresponding interferon beta compared to MMF-treated measures of clinical disability [Barkhof et al. patients. Assessment of the number of CAL and 2009; Filippi and Rocca, 2009; Bar-Zohar et al. new T2 lesions demonstrated similar trends. 2008]. Clinical exacerbations were similar between the two groups, as was the categorical designation of While the primary outcome of our study utilized attack severity (all were scored as mild). MRI metric-based analyses and involved blinded technicians and neuroradiologists, another limi- Our study has a number of important limitations tation of our study is that the study patients and that must be characterized in order to put our the treating physicians were informed of the ran- observations into appropriate perspective. domized treatment assignment. We originally Within the scope of a pilot trial, we studied a intended to perform a ‘double-dummy’ trial, population of relapsing MS patients who had but were unable to acquire identically appearing brain MRI evidence of Gd-enhancing lesions in Avonex injection kits. order to reduce the necessary sample size to ade- quately assess radiologic safety of MMF when The expectation of type and intensity of treat- compared with interferon beta, an established ment regimen can bias and confound any clinical safe and effective therapy. Without doubt, the investigation. However, unlike unblinded studies small number of enrolled patients thereby pre- which seek to evaluate the differential efficacy of cludes us from generating any valid generaliza- higher versus lower dose frequency of a particular tions with respect to efficacy. Notwithstanding therapy (which can influence those who believe this limitation, some favorable trends were that ‘more is better’; the ‘supersize effect’), when observed for MMF when compared with inter- consenting study participants in our pilot inves- feron beta. As with many early-stage exploratory tigation, we were clear to underscore the princi- and safety trials, any and all of the effects exerted ple that both interferon beta and MMF both on MRI indices of CNS inflammation and gliosis, exert potent immunological effects on immune must be corroborated in larger controlled trials. function that would appear to be fundamental Similarly, there is still to date no evidence-based to controlling our primary outcome measures, controlled studies demonstrating disease-modify- the development of new MRI lesions. Further, ing efficacy of MMF in MS. we informed patients of the long-term efficacy and safety data associated with interferon beta Objective imaging metrics were utilized as the therapy, but likewise discussed the long-standing primary outcomes in our study. These measures utilization of MMF in transplant recipients, and are important as they provide structural and in patients with a variety of immune-mediated pathophysiological information regarding a treat- disorders. We informed patients that MMF’s ment’s possible efficacy in controlling aspects of action to inhibit immune rejection in those with inflammation in MS that are detectable on scans, organ transplants, is analogous to its potential and that are estimated to occur at a rate that far action in reducing inflammation and tissue exceeds the occurrence of clinical events. damage in autoimmune diseases (a variation of However, while there is an abundance of evi- rejection), including MS. Despite this education, dence that MRI is an effective biomarker for dis- interferon beta is an FDA approved and estab- ease activity in MS, demonstration of a rigorously lished DMT for MS, while MMF is not.

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As such, this might have biased the study in favor no role in the drafting or editing of the manu- of interferon beta based on the possible expecta- script. We (EMF, RZ, GC) had full access to all tion of either (1) receiving established therapy of the data in the study and take responsibility with interferon beta or (2) receiving unproven for the integrity of the data and the accuracy of experimental treatment in the case of MMF. the data analysis. Alternately, we could have anticipated that par- enteral therapy with interferon beta might have been associated with a lower rate of adherence when compared with oral MMF, potentially References impacting upon efficacy. The reciprocal consid- Ahrens, N., Salama, A. and Haas, J. (2001) eration might also be true, that weekly intramus- Mycophenolate-mofetil in the treatment of refractory multiple sclerosis. J Neurol 248: 713—714. cular interferon beta adherence might have been anticipated to be superior to twice-daily MMF, Allison, A.C. and Eugui, E.M. (1993) The design and which requires administration on an empty sto- development of an immunosuppressive drug, myco- mach. Notwithstanding such potential confoun- phenolate mofetil. Springer Semin Immunopathol 14: 353—380. ders of a non-double-dummy trial, and the potential bias that could result from the knowl- Allison, A.C., Kowalski, W.J., Muller, C.D. and Eugui, edge of treatment assignment, adherence rates E.M. (1993) Mechanisms of action of mycophenolic — were indistinguishable between the two groups. acid. Ann N Y Acad Sci 696: 63 87. Ameen, M., Smith, H.R. and Barker, J.N. (2001) Given the similar risk of producing serious OIs Combined mycophenolate mofetil and cyclosporin that has been documented with other immuno- therapy for severe recalcitrant psoriasis. Clin Exp Dermatol 26: 480—483. suppressive agents, we anticipate that MMF, if successful in demonstrating safety and efficacy Bar-Zohar, D., Agosta, F., Goldstaub, D. and Filippi, in larger studies, will likely be considered a M. (2008) Magnetic resonance imaging metrics and more intensive and higher risk treatment strategy their correlation with clinical outcomes in multiple sclerosis: a review of the literature and future per- when compared with the parenterally adminis- spectives. Mult Scler 14: 719—727. tered interferons and glatiramer acetate. For instance, a number of safety concerns have been Barkhof, F. and Filippi, M. (2009) MRI — the perfect associated with the use of MMF, the most omi- surrogate marker for multiple sclerosis? Nat Rev Neurol 5: 182—183. nous of which has been the confirmation of pro- gressive multifocal leukoencephalopathy (PML) Barten, M.J., van Gelder, T., Gummert, J.F., Boeke, [Food and Drug Administration 2009]. Most of K., Shorthouse, R., Billingham, M.E. et al. (2002a) Pharmacodynamics of mycophenolate mofetil after the MMF-associated PML cases have occurred heart transplantation: new mechanisms of action and in organ transplant recipients, and those with correlations with histologic severity of graft rejection. complicated systemic lupus erythematosis. Am J Transplant 2: 719—732. Barten, M.J., van Gelder, T., Gummert, J.F., Despite the limitations of our small pilot study, Shorthouse, R. and Morris, R.E. (2002b) Novel assays we believe that our data provide preliminary evi- of multiple lymphocyte functions in whole blood dence for the safety and tolerability of MMF in measure: new mechanisms of action of mycophenolate comparison with an established, effective, safe, mofetil in vivo. Transpl Immunol 10: 1—14. and generally well-tolerated parenteral MS ther- Berger, J.R. and Houff, S. (2009) Opportunistic apy. Ultimately these results must be corrobo- infections and other risks with newer multiple sclerosis rated in larger controlled trials to determine if therapies. Ann Neurol 65: 367—377. this convenient, oral, and now cost-effective Blaheta, R.A., Leckel, K., Wittig, B., Zenker, D., immunosuppressant agent is to be confirmed as Oppermann, E., Harder, S. et al. (1999) a safe and effective candidate agent for inclusion Mycophenolate mofetil impairs transendothelial into the MS treatment armamentarium. migration of allogeneic CD4 and CD8 T-cells. Transplant Proc 31: 1250—1252. Conflict of interest statement Chaudhry, V., Cornblath, D.R., Griffin, J.W., O’Brien, This investigator-initiated study (EMF, RZ, and R. and Drachman, D.B. (2001) Mycophenolate GC) was funded by an unrestricted grant from mofetil: a safe and promising immunosuppressant in Aspreva Pharmaceuticals. This entity played no neuromuscular diseases. Neurology 56: 94—96. role whatsoever in the design, execution or ana- Ciafaloni, E., Massey, J.M., Tucker-Lipscomb, B. and lysis of this trial. Furthermore, the sponsor had Sanders, D.B. (2001) Mycophenolate mofetil for

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