Multiple Sclerosis at AAN 2010: Safety, Switching, and Emerging Therapies

Transcription

1 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Mrk S. Freedmn, MSc, MD Professor of Neurology, University of Ottw, Ottw, Ontrio, Cnd; Director, Multiple Sclerosis Reserch Unit, The Ottw Hospitl Generl Cmpus, Ottw, Ontrio, Cnd Amy Perrin Ross, APN, MSN, CNRN, MSCN Neuroscience Progrm Coordintor, Loyol University Helth Sciences, Mywood, Illinois Bruce Cree, MD, PhD Assistnt Professor of Clinicl Neurology, University of Cliforni, Sn Frncisco, Cliforni

2 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies CME/CE Relesed: 05/28/2010 Vlid for credit through 05/28/2011 Trget Audience This ctivity is intended for neurologists, multiple sclerosis (MS) specilists, primry cre prctitioners, MS nurse specilists, dvnced prctice clinicins, mnged cre personnel, nd ll clinicins who cre for ptients with MS. Gol The gol of this ctivity is to discuss key findings from bstrcts, posters, nd presenttions t AAN 2010 relted to MS mngement. Lerning Objectives Upon completion of this ctivity, prticipnts will be ble to: 1. Identify nd evlute therpeutic implictions of novel conference dt relted to MS therpies Credits Avilble Physicins - mximum of 0.50 AMA PRA Ctegory 1 Credit(s) Nurses ANCC Contct Hour(s) (0.5 contct hours re in the re of phrmcology) All other helthcre professionls completing continuing eduction credit for this ctivity will be issued certificte of prticiption. Physicins should only clim credit commensurte with the extent of their prticiption in the ctivity. Accredittion Sttements For Physicins Medscpe, LLC is ccredited by the Accredittion Council for Continuing Medicl Eduction (ACCME) to provide continuing medicl eduction for physicins. Medscpe, LLC designtes this eductionl ctivity for mximum of 0.5 AMA PRA Ctegory 1 Credit(s). Physicins should only clim credit commensurte with the extent of their prticiption in the ctivity. Medscpe, LLC stff hve disclosed tht they hve no relevnt finncil reltionships. Contct this provider: cme@medscpe.net For Nurses Medscpe, LLC is ccredited s provider of continuing nursing eduction by the Americn Nurses Credentiling Center s Commission on Accredittion. Awrded 0.5 contct hour(s) of continuing nursing eduction for RNs nd APNs; 0.5 contct hours re in the re of phrmcology. Accredittion of this progrm does not imply endorsement by either Medscpe, LLC or ANCC. Contct this provider: cme@medscpe.net Pg. 2

3 medscpe.com/spotlight/ms Instructions for Prticiption nd Credit There re no fees for prticipting in or receiving credit for this online eductionl ctivity. For informtion on pplicbility nd cceptnce of continuing eduction credit for this ctivity, plese consult your professionl licensing bord. This ctivity is designed to be completed within the time designted on the title pge; physicins should clim only those credits tht reflect the time ctully spent in the ctivity. To successfully ern credit, prticipnts must complete the ctivity online during the vlid credit period tht is noted on the title pge. Follow these steps to ern CME/CE credit*: 1. Red the trget udience, lerning objectives, nd uthor disclosures. 2. Study the eductionl content online or printed out. 3. Online, choose the best nswer to ech test question. To receive certificte, you must receive pssing score s designted t the top of the test. MedscpeCME encourges you to complete the Activity Evlution to provide feedbck for future progrmming. You my now view or print the certificte from your CME/CE Trcker. You my print the certificte but you cnnot lter it. Credits will be tllied in your CME/CE Trcker nd rchived for 6 yers; t ny point within this time period you cn print out the tlly s well s the certifictes by ccessing Edit Your Profile t the top of your Medscpe homepge. *The credit tht you receive is bsed on your user profile. medscpe.com/spotlight/ms Hrdwre/Softwre Requirements MedscpeCME is ccessible using the following browsers: Internet Explorer 6.x or higher, Firefox 2.x or higher, Sfri 2.x or higher. Certin eductionl ctivities my require dditionl softwre to view multimedi, presenttion or printble versions of their content. These ctivities will be mrked s such nd will provide links to the required softwre. Tht softwre my be: Mcromedi Flsh, Adobe Acrobt, or Microsoft PowerPoint. Supported by n independent eductionl grnt from: Pg. 3

4 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Authors nd Disclosures As n orgniztion ccredited by the ACCME, Medscpe, LLC, requires everyone who is in position to control the content of n eduction ctivity to disclose ll relevnt finncil reltionships with ny commercil interest. The ACCME defines relevnt finncil reltionships s finncil reltionships in ny mount, occurring within the pst 12 months, including finncil reltionships of spouse or life prtner, tht could crete conflict of interest. Medscpe, LLC, encourges Authors to identify investigtionl products or off-lbel uses of products regulted by the US Food nd Drug Administrtion, t first mention nd where pproprite in the content. Modertor(s) Mrk S. Freedmn, MSc, MD Professor of Neurology, University of Ottw, Ottw, Ontrio, Cnd; Director, Multiple Sclerosis Reserch Unit, The Ottw Hospitl Generl Cmpus, Ottw, Ontrio, Cnd Disclosure: Mrk S. Freedmn, MSc, MD, hs disclosed the following relevnt finncil reltionships: Received grnts for clinicl reserch from: Genzyme Corportion Served s n dvisor or consultnt for: Byer HelthCre Phrmceuticls; Biogen Idec Inc.; BioMS; Eli Lilly nd Compny; EMD Serono, Inc.; Novrtis Phrmceuticls Corportion; snofi-ventis Served s speker or member of spekers bureu for: Byer HelthCre Phrmceuticls; Merck Serono Dr. Freedmn does not intend to discuss off-lbel uses of drugs, mechnicl devices, biologics, or dignostics pproved by the US Food nd Drug Administrtion (FDA) for use in the United Sttes. Dr. Freedmn does intend to discuss investigtionl drugs, mechnicl devices, biologics, or dignostics not pproved by the FDA for use in the United Sttes. Presenter(s) Amy Perrin Ross, APN, MSN, CNRN, MSCN Neuroscience Progrm Coordintor, Loyol University Helth Sciences, Mywood, Illinois Disclosure: Amy Perrin Ross, APN, hs disclosed the following relevnt finncil reltionships: Served s n dvisor or consultnt for: Acord Therpeutics, Inc.; Byer HelthCre Phrmceuticls; EMD Serono, Inc.; Genzyme Corportion; Novrtis Phrmceuticls Corportion; Pfizer Inc.; Tev Neuroscience, Inc. Served s speker or member of spekers bureu for: Acord Therpeutics, Inc.; Byer HelthCre Phrmceuticls; EMD Serono, Inc.; Genzyme Corportion; Novrtis Phrmceuticls Corportion; Pfizer Inc.; Tev Neuroscience, Inc. Ms. Ross does not intend to discuss off-lbel uses of drugs, mechnicl devices, biologics, or dignostics pproved by the FDA for use in the United Sttes. Ms. Ross does intend to discuss investigtionl drugs, mechnicl devices, biologics, or dignostics not pproved by the FDA for use in the United Sttes. Pg. 4

5 medscpe.com/spotlight/ms Bruce Cree, MD, PhD Assistnt Professor of Clinicl Neurology, UCSF, Sn Frncisco, Cliforni; Attending Physicin, UCSF, Sn Frncisco, Cliforni Disclosure: Bruce Cree, MD, PhD, hs disclosed the following relevnt finncil reltionships: Received grnts for clinicl reserch from: BioMS; EMD Serono, Inc.; Genentech, Inc. Served s n dvisor or consultnt for: Biogen Idec Inc.; Tev Neuroscience, Inc. Served s speker or member of spekers bureu for: Biogen Idec Inc.; Tev Neuroscience, Inc. Dr. Cree does intend to discuss off-lbel uses of drugs, mechnicl devices, biologics, or dignostics pproved by the FDA for use in the United Sttes. Dr. Cree does intend to discuss investigtionl drugs, mechnicl devices, biologics, or dignostics not pproved by the FDA for use in the United Sttes. Editor Anne Roc, PhD Scientific Director, Medscpe, LLC Disclosure: Anne Roc, PhD, hs disclosed no relevnt finncil reltionships. CME Reviewer/Nurse Plnner Lurie E. Scudder, DNP, NP Accredittion Coordintor, Continuing Professionl Eduction Deprtment, Medscpe, LLC; Clinicl Assistnt Professor, School of Nursing nd Allied Helth, George Wshington University, Wshington, DC; Nurse Prctitioner, School-Bsed Helth Centers, Bltimore City Public Schools, Bltimore, Mrylnd Disclosure: Lurie E. Scudder, DNP, NP, hs disclosed no relevnt finncil reltionships. Pg. 5

6 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Modertor Mrk S. Freedmn, MSc, MD Professor of Neurology, University of Ottw Director, Multiple Sclerosis Reserch Clinic, The Ottw Hospitl-Generl Cmpus Ottw, Ontrio, Cnd Fculty Amy Perrin Ross, APN, MSN, CNRN, MSCN Certified Neuroscience Advnced Prctice Nurse Neuroscience Progrm Coordintor Loyol University Helth System Mywood, Illinois Bruce Cree, MD, PhD Assistnt Professor of Clinicl Neurology University of Cliforni Sn Frncisco Sn Frncisco, Cliforni Slide 1. Mrk Freedmn, MSc, MD: Hello I m Dr. Mrk Freedmn, Professor of Neurology t the University Ottw in Ottw, Ontrio, Cnd, nd the Director of the Multiple Sclerosis (MS) Reserch Clinic t the Ottw Hospitl Generl Cmpus. I d like to welcome you ll to this Spotlight presenttion on updtes in MS mngement t AAN 2010, with considertions in sfety, switching, nd emerging therpies. Our pnel will cover the clinicl relevnce of mny of the key findings from the bstrcts, posters, nd presenttions presented here in Toronto t the AAN 2010 s they re relted to the tretment of MS. Lerning Objective I m joined tody by 2 of my collegues: Miss Amy Perrin Ross, Certified Neuroscience Advnced Prctice Nurse nd Neuroscience Progrm Coordintor t Loyol University Helth System in Mywood, Illinois, nd Dr. Bruce Cree, n Assistnt Professor of Clinicl Neurology t the University of Cliforni in Sn Frncisco. Welcome nd thnk you for joining us. Identify nd evlute therpeutic implictions of novel conference dt relted to therpies for multiple sclerosis (MS) Amy Perrin Ross, APN, MSN, CNRN, MSCN: Thnk you. Bruce Cree, MD, PhD: Thnks, Mrk. Pg. 6 Immunomodultory Therpies: Interferons nd Mitoxntrone Interferon bet (IFNb)

7 Assistnt Professor of Clinicl Neurology University of Cliforni Sn Frncisco Sn Frncisco, Cliforni medscpe.com/spotlight/ms Lerning Objective Identify nd evlute therpeutic implictions of novel conference dt relted to therpies for multiple sclerosis (MS) Slide 2. Immunomodultory Therpies: Interferons nd Mitoxntrone Dr. Freedmn: Tody our lerning objective throughout this Spotlight will be to identify nd evlute some of the therpeutic implictions of novel conference dt relted to the therpies of MS. We re going to tlk in prticulr bout sfety issues, tolerbility of current therpies, nd emerging therpies. We re not sure wht the FDA [US Food nd Drug Administrtion] or other regultory gencies re going to do [with emerging therpies], but we re going to hypothesize little bit bout how to use these medictions in our prctice. Interferon bet (IFNb) - No risk for mlignncy with SC IFNb-1 - Use nd sfety of IM IFNb-1 b-d Mitoxntrone - Acute leukemi e - Crdiovsculr dverse events f SC = subcutneous; IM = intrmusculr Sndberg-Wollheim M, et l. AAN Abstrct P b Foulds P, et l. AAN Abstrct P c Lmpl C, et l. AAN Abstrct P d Herbert J, et l. AAN Abstrct P e Al-Sbbgh A, et l. AAN Abstrct P f Dngond F, et l. AAN Abstrct P Immunomodultory Therpies: Gltirmer Acette Pg. 7

8 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Immunomodultory Therpies: Interferons nd Mitoxntrone Interferon bet (IFNb) - No risk for mlignncy with SC IFNb-1 - Use nd sfety of IM IFNb-1 b-d Mitoxntrone - Acute leukemi e - Crdiovsculr dverse events f SC = subcutneous; IM = intrmusculr Sndberg-Wollheim M, et l. AAN Abstrct P b Foulds P, et l. AAN Abstrct P c Lmpl C, et l. AAN Abstrct P d Herbert J, et l. AAN Abstrct P e Al-Sbbgh A, et l. AAN Abstrct P f Dngond F, et l. AAN Abstrct P Slide 3. Immunomodultory Therpies: Gltirmer Acette Before we tlk bout new therpies, we should look t wht we currently hve for our ptients in terms of first-line therpies nd wht new issues hve come up, if ny. There hsn t been nything in terms of worrisome side effects especilly with regrd to interferons. In fct, we re looking t good 20 yers of sfety dt with regrd to the use of interferons. Nothing new hs come up with mitoxntrone, second-line therpy. We know tht leukemis continue to rise. We know there s dose-dependence effect on the hert nd we need to monitor closely for tht. Is it sfe for ptients to tke gltirmer cette less frequently? Is less frequent dosing more tolerble? There s been some interesting evolution with regrd to gltirmer cette. Bruce, do you wnt to tell us little bit of wht s come up on tht? Twice weekly vs dily gltirmer cette - Sme efficcy between dosing schedules - Twice-weekly injection: reduction in number of injection site problems Con C, et l. AAN Abstrct S Pg. 8 Immunomodultory Therpies: Ntlizumb Dosge-dependent risk for PML - PCR ssy for JC virus in blood or urine

9 Abstrct P e Al-Sbbgh A, et l. AAN Abstrct P f Dngond F, et l. AAN Abstrct P medscpe.com/spotlight/ms Immunomodultory Therpies: Gltirmer Acette Is it sfe for ptients to tke gltirmer cette less frequently? Is less frequent dosing more tolerble? Twice weekly vs dily gltirmer cette - Sme efficcy between dosing schedules - Twice-weekly injection: reduction in number of injection site problems Con C, et l. AAN Abstrct S Slide 4. Immunomodultory Therpies: Dr. Cree: Omr Khn gve very nice presenttion on rndomized tril where he compred ptients who were lredy on gltirmer cette. They were rndomly ssigned to continue on dily gltirmer cette or to go onto twice-weekly gltirmer cette. These ptients were Ntlizumb followed nd their relpse rte ws compred s well s MRI [mgnetic resonnce imging] metrics. There were bout 24 ptients in ech group. The interesting upshot of this study is tht there ws relly no difference in relpses or MRI metrics in terms of the disese Dosge-dependent ctivity between the 2 groups. I risk thought for this PML ws very interesting nd there were some interesting sfety observtions tht cme out of tht study s well. - PCR ssy for JC virus in blood or urine - ELISA ssy for nti-jc virus ntibodies b Discontinution, resurgence of disese ctivity Dr. Freedmn: For the longest time we ve never relly known wht dosge cn be used with gltirmer cette. The 20-mg [dose] cme out of study by Bornstein in the 80s. [1] Dr. Cree: Tht s right. Here the question ws: do you relly need to tke subcutneous injection every dy fter ptient hs been lredy on gltirmer for lest yer? The ide here is tht once you re on gltirmer cette, perhps you cn reduce the frequency of injections nd - tht Post-ntlizumb my reduce the frequency rebound: of side effects. IRIS c - Immunotherpy fter stopping ntlizumb in RRMS d The one thing tht relly cught my eye ws the drmtic reduction in the immedite postinjection rection. Tht continued to occur s you d expect in the once-dily treted group, but there were simply no postinjection systemic rections in the twice-weekly treted group. ELISA = enzyme-linked immunosorbent ssy; IRIS = immune reconstitution inflmmtory syndrome; PCR = polymerse chin rection; PML = progressive multifocl leukoencephlopthy; RRMS = relpsing-remitting MS Rudick R, et l. AAN Abstrct S b Gorelik L, et l. AAN Abstrct S c Peruml J, et l. AAN Abstrct P d Grg N, Kne K. AAN Abstrct P Updte on Emerging Therpies Teriflunomide in combintion with gltirmer cette or IFNb b more beneficil thn either lone s mesured by MRI Pg. 9

10 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Ms. Perrin Ross: Tht certinly bodes well for dherence for our ptients. As we know, if we cn t keep them dherent to therpies, we cn t relly expect much in terms of efficcy for them. If we did hve different dosing schedule, then dherence could be improved in these ptients. Dr. Freedmn: I know postinjection rections re rre, but they re pretty scry to ptients when they get tht. No mtter wht we sy to them, they still end up in the emergency room fering the worst. Dr. Cree: I hve to emphsize tht this ws smll tril nd essentilly pilot study, but now I think the question relly hs been posed s to whether there my be better, somewht sfer, nd slightly more tolerble wy of dministering gltirmer cette. Dr. Freedmn: Here we hve drug tht s been probbly in humn consumption for 25 yers. In generl, we ve seen tht these drugs re producing even lower relpse rtes in contemporry yers nd contemporry trils. Now there might be wy of using gltirmer cette where it s even sfer. Wht do you think? Are these drugs going to be round for while? Ms. Perrin Ross: I definitely think they re. I think with the proven sfety nd long-term efficcy tht we hve -- despite the fct tht there re orls nd there s lot of nticiption for the orls, which we ll be tlking bout in few minutes -- there s still some very significnt wys of pproching discussions with ptients bout long-term sfety nd efficcy for the pltform therpies tht re currently vilble. Dr. Freedmn: I gree, nd I think others do s well, nd we ll come bck to this lter fter we ve discussed the orls, becuse mybe the old ones don t look so bd. The other new kid on the block in recent yers hs been ntlizumb, nd there s been n ongoing fer of this terrible side effect, PML [progressive multifocl leukoencephlopthy]. The number [of PML cses] keeps going up. We re up to 46 s of just erly April; 46 cses in some 60,000 tretments. The worry is lwys who s going to get PML. There s been some interesting dt presented t this meeting tht might give us clue s to who my be t risk. Bruce, cn you discuss tht? Pg. 10

11 Con C, et l. AAN Abstrct S medscpe.com/spotlight/ms Immunomodultory Therpies: Ntlizumb Dosge-dependent risk for PML - PCR ssy for JC virus in blood or urine - ELISA ssy for nti-jc virus ntibodies b Discontinution, resurgence of disese ctivity - Post-ntlizumb rebound: IRIS c - Immunotherpy fter stopping ntlizumb in RRMS d ELISA = enzyme-linked immunosorbent ssy; IRIS = immune reconstitution inflmmtory syndrome; PCR = polymerse chin rection; PML = progressive multifocl leukoencephlopthy; RRMS = relpsing-remitting MS Rudick R, et l. AAN Abstrct S b Gorelik L, et l. AAN Abstrct S c Peruml J, et l. AAN Abstrct P d Grg N, Kne K. AAN Abstrct P Slide 5. Updte on Emerging Therpies Dr. Cree: I think the thing bout ntlizumb is tht there is dosge-dependent risk of developing PML. In the first yer, the risk is very low. In the second yer, tht risk goes up little bit. It s relly fter 2 yers tht the risk seems to be higher nd it even seems to cross the 1 in 1000 threshold tht we ve been telling our ptients. The question is: is there ny wy to predict who s going to develop PML? A couple of very nice studies were presented. Teriflunomide in combintion with gltirmer cette or IFNb b more beneficil thn either lone s mesured by MRI One study looked t JC virus PCR [polymerse chin rection] ssys from both blood nd urine. Essentilly, these ssys hd no predictive vlue in terms of development of PML. The other study looked t reltively new ssy for JC virus serology. Insted of trying to detect the virus itself directly by PCR, wht [the study investigtors] looked for re ntibodies ginst the virus. The immune system rises ntibodies with chronic virl infections, nd so wht Fingolimod you re looking for liner re ntibodies decrese ginst in JC brin virus; pretty volume much the loss sme over type of test s you would do to look for HIV infection, herpes 24 infections, monthsnd c so on. [This is ] very simple, stndrd ELISA [enzyme-linked immunosorbent ssy] nd it turns out tht this ssy probbly does hve some predictive vlue. Of 13 ptients who developed PML for whom serum smples were vilble pretretment with ntlizumb, ll 13 ptients tested seropositive. Then the question is: for the ptient popultion s whole, who s testing seropositive? The numbers come to bout 50%. When you go hed nd strt fctoring in the likelihood of testing seropositive or Tretment seronegtive, you considertions wind up ctully with some orl very therpies interesting positive nd negtive predictive vlues. If you model it out nd mke the ssumption tht 1 out of 20 ptients will be seronegtive nd will ultimtely go on to develop PML, then the positive predictive vlue - is It bout is importnt 0.2% for this ssy. to discuss So it cn t risks relly tell nd you benefits who s going of to use get PML, but the negtive predictive vlue is fntstic: it s bout % Orl negtive medictions, predictive in vlue. reltion We won t to be current ble to tell therpies, who is going lck to get PML, but I think we ll be ble to tell with gret degree of certinty who won t. long-term dt Freedmn M, et l. AAN Abstrct S b Freedmn M, et l. ECTRIMS Abstrct P878. C Rdue EW, et l. AAN Abstrct S Switching Immunomodultory Therpies Presenttions t AAN - Ntlizumb is effective in ptients with RRMS who re nonresponsive to IFNb nd gltirmer cette Pg. 11

12 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Dr. Freedmn: Does 50% rte of testing positive for JC virus men you re only going to give ntlizumb to 50% of the ptients? Dr. Cree: I think tht is something tht we re going to hve to consider. There re risks nd benefits for ntlizumb. There my be ptients who re seropositive who hve not responded to interferons or gltirmer cette who my still be resonble cndidtes for tretment with ntlizumb. Then the question is: wht do you do with these ptients when their risk increses? Perhps one of the things tht we could consider is dosge suspension. We don t know whether tht works or not, but it s certinly something to consider. Tht brings in the question bout some of the other therpies, once those become vilble, but for right now ntlizumb still remins the leding option for second-line therpy in MS. Dr. Freedmn: Certinly [ntlizumb is tretment option] over mitoxntrone, which hs its own pckge of side effects. Wht if you re negtive? Isn t there still risk of getting PML if you cquire it de novo? Dr. Cree: I suppose you re right. There could be risk, but with n ELISA ssy, one cn imgine monitoring ptients periodiclly. Exctly how tht s going to be done needs to be worked out, but you cn imgine going in nd getting your blood tested every 6 months or so [to screen] for de novo infection. Dr. Freedmn: Amy, you ve hd ptients who ve ctully expressed concern bout stying on ntlizumb, right? Ms. Perrin Ross: Right. Our ptient popultion, prticulrly the popultion on ntlizumb, tends to be very well educted nd very interested in the therpy. We do our best to tlk to them not only bout efficcy but lso bout sfety when we re going forwrd with tht kind of therpy. We ve ctully hd people come to us nd sk us for dose suspension. For the most prt, we ve greed if tht s wht they wnt to do. But we re still grppling with how long should we suspend ntlizumb. When cn ptients resume tretment, nd wht should we look for? If we hd this test vilble to us, then it might ssist us in terms of when to restrt nd wht to do with those people t tht point. Dr. Cree: Amy, in your experience, when ptients hve voluntrily stopped tking ntlizumb, hve you seen resurgence in disese ctivity? Certinly tht is one of the concerns in ptient with very ctive disese who s going on ntlizumb therpy, tht if you discontinue it, mybe [disese ctivity] is going to jump bck up. Ms. Perrin Ross: We ve not seen ny resurgence in clinicl ctivity. We ve ctully looked t people s MRIs t 3 months nd 6 months just for our own comfort, not becuse we hd ny specific guidelines. We lso didn t see ny resurgence in MRI ctivity. Tht s smll number of people, but it s reltively comforting for us to know tht, t lest s fr s wht we re doing with our own ptients, in light of ny lck of consistent guidelines. Dr. Freedmn: We hve seen some evidence t this meeting tht stopping ntlizumb cn led to resurgence of lesions. At lest very spectculr picture cn be seen on MRI, not necessrily symptomtic, which ws described by the Detroit group. Dr. Cree: Right. Agin, we re looking t smll cse series, nd smll cse series don t tell you the whole story. I think wht we relly need is systemticlly run tril or observtionl cohort study. Follow these ptients nd do MRI mesures s well s clinicl mesures in rigorous wy. I lso think we need to look t the immunologic consequences. The bsic ide is tht you might be ble to reconstitute the immune system. Then the question is: fter immune reconstitution, should you restrt ntlizumb therpy or should you be on n lterntive therpy such s corticosteroids, gltirmer cette, or bck to interferon? We don t know. We relly need to hve these questions nswered. Dr. Freedmn: We need to move on little bit, but I think it s intriguing tht there might be test. For you, Amy, if this test is negtive, Bruce is telling us tht you cn tell your ptients probbly to sit tight, tht the chnces of them getting PML re virtully zero from tht negtive predictive vlue. Now we cn move into the new er [of treting MS]. Everyone s nticipting the orls nd we ve herd little bit of dt t this meeting bout drugs tht we knew were coming nd some tht re certinly on the wy. Wht hs relly hit you Bruce in terms of new informtion? Pg. 12

13 Rudick R, et l. AAN Abstrct S b Gorelik L, et l. AAN Abstrct S c Peruml J, et l. AAN Abstrct P d Grg N, Kne K. AAN Abstrct P medscpe.com/spotlight/ms Updte on Emerging Therpies Teriflunomide in combintion with gltirmer cette or IFNb b more beneficil thn either lone s mesured by MRI Fingolimod liner decrese in brin volume loss over 24 months c Tretment considertions with orl therpies - It is importnt to discuss risks nd benefits of use - Orl medictions, in reltion to current therpies, lck long-term dt Freedmn M, et l. AAN Abstrct S b Freedmn M, et l. ECTRIMS Abstrct P878. C Rdue EW, et l. AAN Abstrct S Slide 6. Dr. Cree: We did see very nice re-presenttion on both fingolimod s well s cldribine. Also presented t this meeting were some very nice dt on combintion therpy with teriflunomide with gltirmer cette, nd teriflunomide with interferon. These were dd-on studies. In both studies, s you presented, there ws benefit to the ddition of teriflunomide to gltirmer cette- or interferon-treted ptients. Presenttions These were reltively short-term t AANstudies bsiclly intended to show sfety ffect, but in ddition to sfety there ws definitely signl with respect to MRI metrics. I think tht ws quite impressive. Mybe you cn tell us wht you found. Dr. Freedmn: I think tht ws unexpected, of course. When you find things tht re unexpected, they re even more intriguing. When we sw it with the interferon, we fully expected to see it with gltirmer cette nd we did. Of course, we cn t distinguish the teriflunomide signl from - Gltirmer the combintion cette signl. We d is effective love to think in it s ptients synergistic, but with we re RRMS going to hve to wit for the phse 3 dt to know wht the signl is for teriflunomide by itself. Dr. Cree: Tht s right. Anytime you re doing combintion therpy, to relly be sure, you need 3-rm study: you need [to study the effects of] ech gent Wht on its own is nd the the threshold [combined effects for of the chnge? 2 gents] together. Dr. Freedmn: I need you to help me push for tht becuse they ve been relly resistnt to doing tht kind of tril. Dr. Cree: It s n extr rm. Switching Immunomodultory Therpies - Ntlizumb is effective in ptients with RRMS who re nonresponsive to IFNb nd gltirmer cette who re nonresponsive to IFNb b - Consider clinicl evidence nd chnges in MRI - Determine whether symptom is chronic or evidence of relpse/inflmmtory ctivity Dr. Freedmn: It sure is. Wht bout new informtion on fingolimod? The publiction is out now. Everyone s seen the dt, but there re some new things. - If pst inflmmtory stge, mnge symptoms Dr. Cree: Right. I think Memon the thing A, et l. tht AAN cught my Abstrct eye ws P the rdiogrphic metric looking t brin volume loss over time. In this tril, the FREEDOMS [FTY720 Reserch Evluting Effects of Dily Orl b Orej-Guevr C, et l. AAN Therpy in MS] tril, we sw tht brin volume loss ws decresed with tretment with Abstrct fingolimod P both t 1 yer nd t 2 yers in rther liner mnner. This is something we hven t seen in other MS clinicl trils. I think this is probbly the first gent tht hs pretty incontrovertible evidence tht there is n impct on brin volume consistently over the 2 yers of the study. Insted of frctionting out wht hppens in yer 1 nd yer 2, we see very consistent effect over 2 yers. Why is it different from ntlizumb? Why is it different from interferon? Why is it different from gltirmer cette? I don t know, but perhps there is something bout fingolimod hving to do with its bility to cross the blood/brin brrier; perhps there is direct neurologic effect of the drug tht is simply not due to its immunologic effect. It certinly deserves further investigtion. Symptom Mngement: Dlfmpridine Interim nlysis of extension study (to 2.5 yers): Pg. 13

14 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Dr. Freedmn: Not everybody believes the brin volume s being be-ll nd end-ll of gry mtter preservtion. It would be wonderful to be ble to see n effect on cognition, nd I think the compnies re certinly working towrd this. Amy, with ll these orl therpies, ptients must be beting the doors down, sking, When re they coming? nd looking forwrd to [relief from] injection ftigue nd such. Cn you put these in perspective? Wht do you think is going to hppen when the FDA finlly puts the stmp of pprovl [on these orl gents]? Ms. Perrin Ross: People hve been beting the doors down for 2 yers nd every time they come in I sy, Hold on! Mybe in the next 6 months. Some of them re tired of sking me these questions. I think one of the importnt things we need to do is frme the risk-benefit rtio with these people. We hve long-term dt with the current pltform therpies either IV [intrvenous] or injectble. There still re lot of unknowns in the long-term rnge with respect to the orls. The other thing tht people re quite confused bout is the thought tht orl therpy mens there re no side effects. I do not men to be nysyer, but we need to set some very relistic expecttions for wht ptients cn expect not only in terms of disese ctivity but lso in terms of dily life; [we my be] mnging the side effects of the orls s well. Dr. Freedmn: Convenience is one thing, but if ptient perception is tht orl gents re more efficcious, then there must be clue bout how to follow ptients to know when it s pproprite to mke switch to n orl. Would you like to comment on tht? Pg. 14

15 Freedmn M, et l. AAN Abstrct S b Freedmn M, et l. ECTRIMS Abstrct P878. C Rdue EW, et l. AAN Abstrct S medscpe.com/spotlight/ms Switching Immunomodultory Therpies Presenttions t AAN - Ntlizumb is effective in ptients with RRMS who re nonresponsive to IFNb nd gltirmer cette - Gltirmer cette is effective in ptients with RRMS who re nonresponsive to IFNb b Wht is the threshold for chnge? - Consider clinicl evidence nd chnges in MRI - Determine whether symptom is chronic or evidence of relpse/inflmmtory ctivity - If pst inflmmtory stge, mnge symptoms Memon A, et l. AAN Abstrct P b Orej-Guevr C, et l. AAN Abstrct P Slide 7. Symptom Mngement: Dlfmpridine Dr. Cree: I think this is big question in generl for us. We currently hve 4 clsses of therpies right now. We ve got the interferons, gltirmer cette, mitoxntrone, nd ntlizumb. One of the questions tht s sked right wy is: how do you decide if nd when to switch? When you re done with interferon, do you go on to gltirmer cette? Do you go on to mitoxntrone? Do you go on to ntlizumb? How do you mke tht decision? Wht s the evidence for bsing tht decision? Interim nlysis of extension study (to 2.5 yers): I think lot of us in clinicl prctice decide tht once ptient hs mnifested ongoing disese ctivity despite first-line therpy, gltirmer cette nd interferons, we will go on to second-line therpy. But wht s relly the evidence for tht? The MIMS [mitoxntrone in MS] study sustined [2] nd the ntlizumb improvement trils relly in didn t wlking nswer speed tht question compred for us. I think we do lot of things in clinicl prctice tht re not perfectly bsed on evidence from clinicl trils. Switching tretment is perfect exmple of prt of the rt in medicine nd prt of with mking bseline, decisions when no new you don t sfety hve every signls possible piece of evidence to bck up your choices. Efficcy bsed on timed wlk responder sttus: didn t vry with MS disese chrcteristics, gender, ge, BMI, or Amy, how do you go bout this with our current therpies? Wht is your strtegy in terms of switching tretment? Ms. Perrin Ross: Our strtegy in terms of switching is to look efficcy nd tolerbility. Sometimes we hve to be cretive to find out bout tolerbility. concomitnt If you sk ptients tretment if they re tking with their immunomodultor therpy nd the nswer is, Oh, drugs yes, b but when you drill down little bit nd sk how they Consider re tking their ptient therpy, selection they sy, Oh, nd I tke sfety it once issues week. If they re (do not on dily injection nd they only tke it once week, obviously tht s going to impct the efficcy. Before we strt switching therpies, we wnt to mke sure tht they re ctully tking [their medictions] s prescribed. exceed prescribed dose) If ptients hve been truly dherent to their therpy nd it s cler tht efficcy hs been decresed, sometimes it s chllenge when we hven t seen BMI lot of = body chnges mss in index clinicl signs nd symptoms, but we clerly see chnges on n MRI. We sit down with our ptients nd try to show Goodmn them the AD, chnges et l. AAN tht we cn Abstrct see nd S mke b Brown cse for T, the et l. chnge. AAN When Abstrct the orls P become vilble, tht will muddy the wters of our cse for mking chnges, but in some respects, [ptients] my be little more encourged bout ctully mking some of those chnges. Dr. Cree: We ll definitely hve more options. Symptom Mngement (cont) Efficcy of donepezil on memory impirment in MS Pg. 15

16 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Dr. Freedmn: With wht we hve right now, nd we don t hve the new orls yet, surely you re not expecting ptients to hve zero ctivity. It s like dibetic hving 1 glucose mesure tht s elevted; you re not going to chnge everything on the bsis of tht. If the relity is [disese] control, wht s your threshold [for switching therpies]? Is it 1 new lesion, sensory ttck? You must hve some ide of wht your thresholds for chnge re going to be. Dr. Cree: In my personl prctice, if I hve ptient who s strted on therpy nd hs hd resonble time to be on tretment nd they hve evidence of new disese ctivity such s contrst enhncement on MRI, prticulrly if you see multiple lesions or lrge lesions despite being dherent with tretment, then I hve pretty low threshold for moving on in such ptient. I lso look t clinicl ctivity: chnge in EDSS [Expnded Disbility Sttus Scle] score, cognitive function, nd new relpses. When ptient strts to show evidence tht the mount of disese ctivity hs incresed, you hve to strt hving tht discussion with your ptient, but the decisions re never up to us in its entirety. All we do is provide resource of informtion for our ptients nd give them options. Ms. Perrin Ross: Tht relly points to the wy things go in my prctice. It points to the importnce of setting up relistic expecttions with ptients from the beginning. Neither of the therpies tht we hve nor ny of the therpies tht I cn see in the future is going to totlly stop this disese. People will still hve symptoms, nd becuse they re hving symptoms doesn t necessrily men tht their therpy is ineffective. We hve to tke the whole picture: look t MRI s well s clinicl ctivity nd try to differentite chronic symptom or disbling symptom vs new evidence of relpse or inflmmtory ctivity. Dr. Freedmn: Symptoms by themselves do not necessrily indicte disese ctivity per se. It s hrd sometimes to get ptients to understnd tht. Dr. Cree: Wht do you do for ptient who s insidiously progressing nd getting worse, but you hve no relpses nd you hve no evidence of new lesions on brin MRI or spinl cord imging? Do you go on to use ntlizumb? Do you use mitoxntrone? Dr. Freedmn: It s chllenge, becuse if you clerly believe tht they re out of the inflmmtory phse, these drugs hve relly been centered on the bility to counter nd reduce inflmmtion, which we feel is contributing to the progression. If they re well into this progressive phse without stitch of evidence of inflmmtion, we don t offer them these medictions. I tell them the truth, Unfortuntely, this is prt of the disese tht we cnnot tret. Tht doesn t men we cn t offer things to improve qulity of life, which mens ddressing symptoms. I think this leds us into discussion of some of the things tht we ve herd bout on symptom mngement. There hve been some new medictions nd some reveltions. Do you wnt to tke us through those, Amy? Pg. 16

17 Memon A, et l. AAN Abstrct P Orej-Guevr C, et l. AAN Abstrct P medscpe.com/spotlight/ms Symptom Mngement: Dlfmpridine Interim nlysis of extension study (to 2.5 yers): sustined improvement in wlking speed compred with bseline, no new sfety signls Efficcy bsed on timed wlk responder sttus: didn t vry with MS disese chrcteristics, gender, ge, BMI, or concomitnt tretment with immunomodultor drugs b Consider ptient selection nd sfety issues (do not exceed prescribed dose) BMI = body mss index Goodmn AD, et l. AAN Abstrct S b Brown T, et l. AAN Abstrct P Slide 8. Symptom Mngement (cont) Ms. Perrin Ross: From the symptom mngement perspective, some of the informtion tht ws presented here reltes to dlfmpridine. One of the studies looked t n interim nlysis of the extension study, which ws up to 2.5 yers. One of the good pieces of news is tht there were no new sfety signls with the use of this therpy. Efficcy lso didn t vry with ny of the disese chrcteristics, gender, Efficcy ge, body mss of donepezil index, or concomitnt on tretment memory with the impirment immunomodultor in drugs. MSTht ws very positive nd reffirming pproch to the informtion tht s been originlly presented on dlfmpridine. Bruce, who do you think should be considered to receive therpy like this? Dextromethorphn 30 mg or 20 mg nd quinidine Dr. Cree: I use nd hve used for yers 4-minopyridine (dlfmpridine) in compounded formultion nd I hve done tht for ptients who hve mbultory impirment nd wnt some help with it. I hven t relly used it for cognitive dysfunction or ftigue. I ve used it primrily s 10 drug mg to for ssist pseudobulbr ptients with mbultion. ffect I m very encourged (STAR) by the studies with dlfmpridine; 2 well-conducted controlled trils both - Extension showed in the study subgroup showed of ptients 47.2% tht there s reduction tretment in response. episode I think this is very importnt point tht it s subgroup of ptients who benefit. I think the drug my be worth try in ptients who ve got mbultory impirment. After period of time, rtes if the ptients vs plcebo re benefiting, b then gret: if they re not benefiting, then the drug cn be discontinued just like ny symptomtic mediction. - Sfe nd tolerble up to 24 weeks without new Dr. Freedmn: There s the physicl ftigue component of MS, but there re mny people who tell you tht they hve cognitive ftigue. There re lot of people tretment-relted who cn wlk well who side probbly effects hven t b entered these studies with dlfmpridine, but yet their endurnce is ffected. Do you think they might benefit from this drug? - No serious crdic side effects, low doses of quinidine = smll chnges in QT intervl c Krupp LB, et l. AAN Abstrct S b Pioro E, et l. AAN Abstrct P c Kye R, Prtt C. AAN Abstrct P Adherence nd Cost Clinicl nd economic impct of dherence to Pg. 17

18 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Dr. Cree: It s possible. Agin in the bsence of evidence it s hrd to know for sure. I suspect there s going to be widespred off-lbel usge of dlfmpridine. I suspect there s going to be usge in ptients who cn no longer mbulte, becuse if it cn help you mbulte nd cn improve leg strength, perhps it cn help you trnsfer little bit. Perhps if you re developing triplegi, mybe it s going to help you with tht lst rm in keeping some strength. I think there s probbly going to be lot of trils with this mediction. In my mind, the big question is the cost nd whether thirdprty pyers in the United Sttes re going to cover it. I don t know whether it s being looked t in Cnd. All of these things ultimtely hve to be blnced, but I m very encourged by the sfety dt, which re very consistent. Ms. Perrin Ross: I m lso encourged by the sfety dt, becuse in the Chicgo re I hve mny, mny ptients who hve been using 4-minopyridine in the compounded form for mny yers. The fct tht the dlfmpridine study showed in the interim nlysis no new sfety signls is very encourging to me. I find tht when our ptients re using the compounded formul, prticulrly 5 mg, sometimes they sy I m up lte tonight I m going to tke n extr one or I m going to get up in the middle of the night to go to the restroom, so I m going to tke n extr one. I think tht s relly when we ve seen problems; it is when ptients supersede their dose. The sustined-relese formultion of dlfmpridine speks well to the whole sfety signl issue. Dr. Freedmn: If it s $50.00 pill, you might think twice bout tking the extr one. Wht bout other symptoms? Hve there been other medictions? I know tht there hve been some studies in cognition nd some of the other difficult to tret symptoms like pseudobulbr ffect? Pg. 18

19 medscpe.com/spotlight/ms Symptom Mngement (cont) Efficcy of donepezil on memory impirment in MS Dextromethorphn 30 mg or 20 mg nd quinidine 10 mg for pseudobulbr ffect (STAR) - Extension study showed 47.2% reduction in episode rtes vs plcebo b - Sfe nd tolerble up to 24 weeks without new tretment-relted side effects b - No serious crdic side effects, low doses of quinidine = smll chnges in QT intervl c Krupp LB, et l. AAN Abstrct S b Pioro E, et l. AAN Abstrct P c Kye R, Prtt C. AAN Abstrct P Slide 9. Adherence nd Cost Ms. Perrin Ross: One of the studies tht mny of us were extremely hopeful bout ws second study tht Dr. Luren Krupp nd her group did on donepezil for memory impirment in MS. It ws n efficcy study. Unfortuntely, they did not find ny difference with the donepezil study, which is different from the originl study [3] tht she presented severl yers go. Tht ws bit defeting for those of us tht hve used it nd in some situtions ctully hve seen some improvement. Clinicl nd economic impct of dherence to There ws nother presenttion on the use of dextromethorphn either 30 mg or 20 mg in combintion with quinidine 10 mg for pseudobulbr ffect. It bsiclly ws sfety nd tolerbility study, not efficcy. This ws n open-lbel extension study nd they bsiclly didn t identify immunomodultory ny new crdic problems. I think therpies crdic problems were seen in ptients who hd used much higher doses, so with this the sfety reported ws quite good. - Adherence = fewer relpses, lower totl medicl costs Dr. Cree: And just for people who ren t fmilir with this, dextromethorphn plus quinidine hs been shown to ffect pseudobulbr ffect in ALS [myotrophic lterl sclerosis] nd MS ptients. Helth resource utiliztion with cldribine (CLARITY) - Cldribine-treted ptients hd fewer clinic nd emergency deprtment visits, dys in hospitl, nd dys lost to work compred with plcebo-treted ptients b CLARITY = Cldribine Tblets Treting Multiple Sclerosis Orlly Phillips AL, et l. AAN Abstrct P b Ali S, et l. AAN Abstrct P Clinicl Perls from AAN 2010 Pg. 19

20 Krupp LB, et l. AAN Abstrct S b Pioro E, et l. AAN Abstrct P c Kye R, Prtt C. AAN Abstrct P Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Adherence nd Cost Clinicl nd economic impct of dherence to immunomodultory therpies - Adherence = fewer relpses, lower totl medicl costs Helth resource utiliztion with cldribine (CLARITY) - Cldribine-treted ptients hd fewer clinic nd emergency deprtment visits, dys in hospitl, nd dys lost to work compred with plcebo-treted ptients b CLARITY = Cldribine Tblets Treting Multiple Sclerosis Orlly Phillips AL, et l. AAN Abstrct P b Ali S, et l. AAN Abstrct P Slide 10. Dr. Freedmn: There s been some new stuff hppening, new medictions on the horizon. This is going to chnge how we del with ptients. The cost of these re going to enter into discussion, dherence my improve in some cses. Wht do you expect Amy? Wht do you think is going to hppen? Clinicl Perls from AAN 2010 Ms. Perrin Ross: There were number of presenttions on dherence nd cost nd qulity-of-life issues. One of the studies looked t the clinicl nd economic impct of dherence to disese-modifying therpies. I think it s probbly no surprise to us tht people who were truly dherent Serologic to their therpies ssy for sw JC fewer virus relpses my nd determine the fewer relpses ptient contributed risk to for lower PML totl medicl costs. There ws lso presenttion with ntlizumb on helth resource utiliztion with respect to the CLARITY [Cldribine Tblets Treting Multiple Sclerosis Orlly] tril. Wht they sw ws reduction in the number of clinic visits, emergency room visits, dys in the hospitl, s well s dys lost to work. In Fingolimod looking for the potentil reduction economic of brin impct of volume some of the loss newer indictes therpies, potentil certinly tht ws shown with tht helth resource utiliztion study. nti-inflmmtory nd perhps neuroprotective effects We need to think bout other chllenges. As you sid, Mrk, dherence n issue. Agin, becuse therpy is orl doesn t necessrily men there s going Emerging to be mrked orl improvement therpies, in dherence; while promising, possible yes, but lck not the necessrily long-term so. sfety nd efficcy dt of current therpies. Set relistic expecttions with ptients nd discuss the risk-benefit rtio of ll gents Dr. Freedmn: There s no free lunch, is there? There my be sfety issues. We ll need to hve lengthy discussions with ptients. Some people my not be ble to fford them. We ll hve to wit nd see how the regultory gencies put these drugs on the mrket. Dr. Cree: With the CLARITY tril with regrd to [poor dherence due to] tolerbility issues, wht impressed me is you tke the drug for 4 or 5 dys in row, 1 or 2 pills dy, you do tht for 2 weeks nd you re good for the yer. From tolerbility perspective, it s very, very ttrctive nd tht dherence question is relly pretty well resolved. Once you re on the drug, you re on the drug for better or worse. Pg. 20 Thnk you for prticipting

21 CLARITY = Cldribine Tblets Treting Multiple Sclerosis Orlly Phillips AL, et l. AAN Abstrct P b Ali S, et l. AAN Abstrct P medscpe.com/spotlight/ms Clinicl Perls from AAN 2010 Serologic ssy for JC virus my determine ptient risk for PML with ntlizumb Fingolimod reduction of brin volume loss indictes potentil nti-inflmmtory nd perhps neuroprotective effects Emerging orl therpies, while promising, lck the long-term sfety nd efficcy dt of current therpies. Set relistic expecttions with ptients nd discuss the risk-benefit rtio of ll gents Slide 11. Dr. Freedmn: We need to lmost wrp up here, so I d like to sk you wht re the 2 things you don t wnt to miss from this meeting in Toronto, AAN 2010? Wht re your 2 rel tke-home points? Dr. Cree: I think the first thing is the serologic ssy for the JC virus. I think this is going to be n extremely importnt ssy for us in terms of use of ntlizumb. It s relly something which is going to help strtify ptients nd I believe will ultimtely inform us bout the rel risks for development of PML. Thnk you for prticipting in this ctivity. I lso think tht the dt on fingolimod with respect to brin volume loss ws very encourging nd relly emphsizes the potentil impct of this drug s not only n nti-inflmmtory mediction but lso possibly s neuroprotective gent. Further study, of course, is needed. Ms. Perrin Ross: I d just like to reiterte the importnce of working with ptients in terms of relistic expecttions with the orl therpies on the horizon. We hve long-term history of sfety nd efficcy with our pltform therpies. While we hve lots to be optimistic bout with To respect proceed to the to orls, the we online need to CME blnce test, the good click with on the the bd, Ern nd [discuss] CME the Credit risk-benefit profiles for our ptients nd set expecttions. link on this pge. Dr. Freedmn: We keep hering bout benefit to risk nd I think we re going to keep hering bout it s we go to emerging therpies. Dr. Freedmn: Here we hve whole wrp up of AAN 2010 in the spring, but we ve got this big meeting coming in the fll. Is there ny insight s to wht we might her bout t ECTRIMS? Dr. Cree: I think the big one is going to be teriflunomide: TEMSO [Study of Teriflunomide in Reducing the Frequency of Relpses nd Accumultion of Disbility in Ptients With Multiple Sclerosis] 1, TEMSO 2 studies, I believe, re probbly going to be highlighted t the ECTRIMS meeting, nd I think we re lso going to see dt on ocrelizumb. Dr. Freedmn: Finlly some more phse 3 dt. Tht will be exciting. Dr. Cree: Ocrelizumb is phse 2. The phse 3 dt for teriflunomide will be there. Pg. 21

22 Multiple Sclerosis t AAN 2010: Sfety, Switching, nd Emerging Therpies Thnk you for prticipting in this ctivity. To proceed to the online CME test, click on the Ern CME Credit link on this pge. Slide 12. Dr. Freedmn: I wnt to thnk my collegues here for joining me in this very importnt discussion tht we ve hd bout some of the highlights t AAN For ll of you, you my now complete the CME CE post-test. Thnk you for joining us. Supported by n independent eductionl grnt from Tev Neuroscience. This rticle is CME/CE certified ctivity. To ern credit for this ctivity visit: References 1. Bornstein MB, Miller A, Slgle S, et l. A pilot tril of Cop 1 in excerbting-remitting multiple sclerosis. N Engl J Med. 1987;317: Krpf H, Morrissey SP, Zenker O, et l. Effect of mitoxntrone on MRI in progressive MS: results of the MIMS tril. Neurology. 2005;65: Krupp LB, Christodoulou C, Melville P, Scherl WF, McAllister WS, Elkins LE. Donepezil improved memory in multiple sclerosis in rndomized clinicl tril. Neurology. 2004;63: Disclimer The mteril presented here does not necessrily reflect the views of Medscpe, LLC, or compnies tht support eductionl progrmming on These mterils my discuss therpeutic products tht hve not been pproved by the US Food nd Drug Administrtion nd off-lbel uses of pproved products. A qulified helthcre professionl should be consulted before using ny therpeutic product discussed. Reders should verify ll informtion nd dt before treting ptients or employing ny therpies described in this eductionl ctivity. MedscpeCME Pg. 22