The following is a transcript from a web-based CME-certified multimedia activity. Interactivity applies only when viewing the activity online. This activity is supported by an educational grant from Teva Pharmaceuticals, Ltd. Slide 1 Dr. Boster: Hello, this is Dr. Aaron Boster from the Ohio State University Multiple Sclerosis Center. Welcome to this educational activity on the management of multiple sclerosis. This activity comprises two separate presentations. complete the post-test and evaluation for CME credit: 1
Slide 2 Dr. Boster: The slides, transcript, audio, Practice Aids, and other activity features are available for download for easy access anytime, anywhere. complete the post-test and evaluation for CME credit: 2
Slide 3 Dr. Perumal: Currently we have nine FDA-approved treatments for MS. This is very different from what it was like ten years ago. With the nine therapies we cannot just give patients the handouts and say, "Pick one." I think it falls on us to keep updated on the therapies, and also to best fit the right treatment with the patient. We have not perfected this personalized medicine yet based on biomarkers or treatment responses. But I think we are getting there. And we ought to use what we have currently available in terms of clinical features or MRI factors in deciding what treatment to choose for what patient. And once we have brought it down to a couple of options, discuss that in detail with the patient and start them on it rather than telling them, "Hey, these are all the therapies that are all there," and go ahead and take one. complete the post-test and evaluation for CME credit: 3
Slide 4 complete the post-test and evaluation for CME credit: 4
Slide 5 DMT: disease-modifying therapy; FLAIR: fluid-attenuated inversion-recovery; GdE: gadolinium-enhancing. Dr. Perumal: J.K. is a 28-year-old woman. She has had an episode of optic neuritis. And based on her exam and the MRI findings, she has MS. And once you confirm the diagnosis, you don't wait for patients to have a second episode before we start treatment. complete the post-test and evaluation for CME credit: 5
Slide 6 complete the post-test and evaluation for CME credit: 6
Slide 7 AV: atrioventricular; DLCO: diffusing capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 second; IFN: interferon; IM: intramuscular; IV: intravenous; PML: progressive multifocal leukoencephalopathy; PO: orally; QD: daily; QOD: every other day; Q3M: every 3 months; Q4W: every 4 weeks; QW: weekly; SC: subcutaneous; TIW: three times weekly. 1. Martinelli V et al. 61st American Academy of Neurology Annual Meeting (AAN 2009). Abstract LB3.001. Dr. Perumal: The interferons side-effect profile is similar. They're just different in terms of how much you use, how frequently you use it, and how often one injects. Glatiramer acetate currently is a daily injection. It doesn't have flu-like symptoms associated with interferons, and one does not need to monitor liver enzymes or blood count on a regular basis. Fingolimod is an oral agent. The first time somebody takes this drug, it has to be done in a monitored environment, because it can cause bradycardia. The newest medication to get approved for MS is teriflunomide. You do need to monitor liver enzyme. Potential side effects are hair thinning, nausea, and diarrhea. complete the post-test and evaluation for CME credit: 7
Teriflunomide is a pregnancy category X, so one needs to be cautious when using it in young women of potential childbearing age. Natalizumab is a monthly infusion. The JC virus antibody can determine one's risk of getting PML on natalizumab. Mitoxantrone is a chemotherapy agent that's available for MS, but it probably is being used less because there is a cumulative dose toxicity associated with it. You have to find the best fit for the patient irrespective of clinical trial data. complete the post-test and evaluation for CME credit: 8
Slide 8 Dr. Perumal: Our goal is that we control the disease very effectively in the beginning, and make sure they don't have relapses, any increase in their baseline disability, and any MRI activity. A first-line therapy has to have demonstrated efficacy, be well tolerated, and have a very good safety profile. If you're looking at somebody who has highly active disease or who had started treatment with a first-line agent but their disease is not being controlled on a first-line agent, then you go on to one of the more aggressive therapies. complete the post-test and evaluation for CME credit: 9
Slide 9 ARR: annualized relapse rate; EDSS: Expanded Disability Status Scale; GA: glatiramer acetate; RRMS: relapsing-remitting MS. 1. Lublin F et al. 64th American Academy of Neurology Annual Meeting (AAN 2012). Abstract PL02.003. 2. Wolinsky J et al. AAN 2012. Abstract S11.002. Dr. Perumal: CombiRX was a trial of more than 1,000 patients comparing interferon β- 1a alone to glatiramer alone to a combination of both interferon β and glatiramer acetate. The primary endpoint was annualized relapse rate. So the interferons and glatiramer continue to demonstrate efficacy in reducing the relapse rate. complete the post-test and evaluation for CME credit: 10
Slide 10 1. Kahn O et al. 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2012). Abstract 166. Dr. Perumal: GALA was comparing glatiramer acetate 40 mg three times a week versus placebo. Currently, glatiramer is a 20-mg subcu[taneous] injection every day. The primary endpoint was the annualized relapse rate. And glatiramer demonstrated efficacy compared to placebo in controlling the relapse rate, and also on the MRI outcomes. So I think three times a week will definitely make it more convenient and should decrease the rate of lipoatrophy that comes from prolonged subcutaneous injections. complete the post-test and evaluation for CME credit: 11
Slide 11 complete the post-test and evaluation for CME credit: 12
Slide 12 CDP: confirmed disability progression. 1. Kappos L et al. ECTRIMS 2012. Abstract 153. 2. O Connor P et al. N Engl J Med. 2011;365:1293-1303. Dr. Perumal: TOWER is a phase 3 study of teriflunomide in patients with MS. This follows TEMSO, where two doses of teriflunomide, 7 mg and 14 mg daily, demonstrated superiority to placebo on both the clinical outcomes and the MRI. TOWER, again, looks at 7 mg and 14 mg of teriflunomide versus placebo. In the annualized relapse rate, both the doses were superior to placebo. When you looked at disability, the 14-mg/day dose was statistically significant, but the 7-mg/day [dose] was not significant compared to placebo. One needs to be cautious about infections, potential hair loss, nausea, and GI symptoms. And pregnancy category remains the biggest issue with teriflunomide, especially if you are looking to start newly diagnosed patients, who are often young and who are mostly women, because the drug has been demonstrated to have potential adverse effects on the fetus. complete the post-test and evaluation for CME credit: 13
Slide 13 1. Chin PS et al. ECTRIMS 2012. Abstract P459. Dr. Perumal: So next we are looking at a subanalysis of the clinical trials for fingolimod. Here, fingolimod did demonstrate efficacy on both the clinical outcomes and MRI outcomes in its phase 3 trials. So they looked at relapse rate in 3 months after initiation of treatment, and then 6 months after initiation of treatment. Compared to placebo, the onset of action seemed to be faster, and it was effective, as well, on the MRI atrophy data, looking at MRI volumes. So apart from being perceived to be more effective, it also shows the onset of action as quicker, and one doesn't have to wait for 6 months or 1 year to see the therapeutic benefit. complete the post-test and evaluation for CME credit: 14
Slide 14 1. Kappos L et al. J Neurol. 2013 Jan 5. [Epub ahead of print]. Dr. Perumal: The next slide is a similar analysis on patients who started natalizumab. It's given as a monthly infusion. Patients' quality of life on this drug is very good. Again, this analysis looked at the benefit within 3 months of starting treatment, and it shows that even in patients with active disease, the onset of action for natalizumab was pretty [quick], and within 3 months you could see a benefit in the annualized relapse rate. complete the post-test and evaluation for CME credit: 15
Slide 15 JC: John Cunningham. Dr. Perumal: Patient-specific factors to consider in selecting treatment for MS is, of course, the patient's inherent disease. So if patients have back-to-back relapses, many relapses within the first 5 years of diagnosis or the inter-relapse interval is very short. If they do not recover well from their initial relapse and are left with significant deficits. Generally, African Americans tend to have a worse disease course compared to Caucasians. Patients who start with a large burden of disease on MRI and who on treatment continue to have MRI changes or accumulate lesions tend to do poorly long term. Several studies have demonstrated that [for] patients who develop neutralizing antibodies to interferons, the drug is not as effective anymore. I think it is important to get the neutralizing antibody test done, and if it is present and if the titers are high, then they probably should come off the drug. Pregnancy status is relevant because most patients with relapsing MS are diagnosed in their 20s or 30s. Among the known therapies, glatiramer has the best pregnancy category. Teriflunomide recently got approved as a pregnancy category X with known adverse effects during pregnancy. complete the post-test and evaluation for CME credit: 16
On the other hand, you know, this has to be a decision the patient and the physician make together, and this is not a unilateral decision either one makes as to what they need to do about their disease. complete the post-test and evaluation for CME credit: 17
Slide 16 IS: immunosuppression. 1. Bloomgren G et al. New Engl J Med. 2012;366:1870-1880. Dr. Perumal: The risk factors for developing PML [in] patients who are on natalizumab for MS are, one, their prior JC virus antibody status. The second risk factor is the duration of natalizumab treatment. Around 12 months is when you start seeing patients have PML. The highest risk is after they've been on natalizumab for 2 years and beyond. The third risk factor is prior chemotherapy [immunosuppressive therapy]. So the lowest risk would be somebody who's JC virus negative. The highest-risk group would be somebody who's JC virus positive, has received prior immunosuppression, and has been on natalizumab for longer than 2 years. complete the post-test and evaluation for CME credit: 18
Slide 17 Dr. Perumal: This is a newly diagnosed patient. She has just had her initial event. She has a history and an MRI that is consistent with MS. She is not starting with a very aggressive or very highly active disease. JC virus antibody was tested on her, and she's seronegative. She's 28, but she does not plan to have children now, but does not want to take contraception either. I would discuss whether she wants to go on glatiramer or one of the interferons. And given the side-effect profile, my first choice would be glatiramer acetate. complete the post-test and evaluation for CME credit: 19
Slide 18 Dr. Perumal: There are several treatment options available for MS. No drug is a onedrug-fit-all. It has to be based on the patient's individual characteristics. Even if we don't have those perfect biomarkers yet, biomarkers should be adequately used, which includes the patient's clinical features and MRI characteristics, which can help us decide what is the best treatment to start folks on once they're diagnosed with MS. complete the post-test and evaluation for CME credit: 20
Presentation 2 Slide 1 Dr. Boster: Today we're going to be discussing emerging biomarkers and how they might improve management of MS patients moving into the future. complete the post-test and evaluation for CME credit: 21
Presentation 2 Slide 2 complete the post-test and evaluation for CME credit: 22
Presentation 2 Slide 3 ARR: annualized relapse rate; GA: glatiramer acetate; NPV: negative predictive value; PPV: positive predictive value. 1. Macciardi F et al. 2012 American Academy of Neurology Annual Meeting (AAN 2012). Abstract P05.129. 2. Macciardi F et al. AAN 2012. Abstract IN3-2.003. Dr. Boster: First, we will look at genetic models for predicting response to glatiramer acetate. Patients were defined based on clinical and MRI metrics as being responders, super-responders, and nonresponders. In the FORTE trial, patients identified as responders had a 62% reduction in their annualized relapse rate compared to nonresponders. The responders had a 35% reduction in annualized relapse rate compared to the overall population. Super-responders were found to have a 79% reduction in annualized relapse rate compared to nonresponders, and a 64% reduction compared to the total population. Similar results were seen in the European/Canadian study. In summary, this genetic model was able to predict the clinical response to therapy only in actively treated glatiramer acetate patients, but not in patients with ineffective therapy. The potential implications of such a study are profound, and the possibility that one day we could draw GWA data on an individual patient a priori before starting them on therapy with a better sense of the likelihood that they'll be a responder to the therapy this would definitely be a game-changer and something to look forward to in the future of applying MS therapeutics. complete the post-test and evaluation for CME credit: 23
Presentation 2 Slide 4 EDSS: Expanded Disability Status Scale; IFN: interferon. 1. Bustamante M et al. 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2012). Abstract P 1083. Dr. Boster: In reviewing the study design, SNP selection involved three biologic pathways. Patients were categorized as being responders if they had no increase in their EDSS and no relapses for the time on trial. Nonresponders manifested a one-point increase in EDSS or one or more relapses during the same time period. The combined analysis results, which reviewed 525 responder samples and 524 nonresponder samples, showed four polymorphisms that were associated with response to treatment and may be potential response biomarkers. Further studies are needed to validate this in a larger cohort and confirm the results. Again, the future holds promise that we can a priori identify patients based on pharmacogenomics who are more or less likely to respond to interferon, keeping in mind that presently it takes an astute clinician upwards of a year or two of watching a patient prospectively to determine if they're responding. This would definitely aid in our ability to apply therapeutics effectively. complete the post-test and evaluation for CME credit: 24
Presentation 2 Slide 5 complete the post-test and evaluation for CME credit: 25
Presentation 2 Slide 6 RRMS: relapsing-remitting MS. 1. Mowry E et al. 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS 2011). Oral 29. 2. Soilu-Hänninem M et al. ECTRIMS/ACTRIMS 2011. Poster 454. Dr. Boster: We now shift our attention to assessing the effects of vitamin D in MS patients. The first study reviewed looked at endogenous levels of D 3 in a 5-year longitudinal study including 469 patients. The results revealed that for every 10-ng/ml increase in the D 3 blood levels, there was an associated 32% reduction for developing new gad lesions and an associated 15% reduction for developing new T2 lesions. Both of those associations were highly statistically significant. Separately, an investigation reviewed the effects of supplemental D 3 in a 12-month study involving 66 relapsing MS patients who were all receiving interferon β-1a diseasemodifying therapy for at least 1 month in duration. They were randomly assigned to receive either placebo or 500 ng of vitamin D per week. The results revealed no between-group differences in adverse events, relapse rates, EDSS, or timed 25-foot walk. However, significantly fewer gad lesions were seen in the vitamin D group at 12 months as compared to the placebo group. complete the post-test and evaluation for CME credit: 26
Presentation 2 A 12-month study with only 66 patients may not be powered adequately to determine the clinical effects, and it is encouraging that both studies identify a radiographic benefit to supplemental D 3. There is emerging data that vitamin D does probably play a role in the inflammatory activity of relapsing-remitting MS. Larger confirmatory and prospective studies are needed to confirm these interesting early results. complete the post-test and evaluation for CME credit: 27
Presentation 2 Slide 7 JCV: John Cunningham virus; Q6M: every 6 months. 1. Lee P et al. 22nd Meeting of the European Neurological Society (ENS 2012). Poster P467. Dr. Boster: The JC virus antibody status is used to help assess the risk of PML in the setting of natalizumab therapy for relapsing MS patients. The first-generation JC virus antibody test, which used a double-elisa assay, was qualitative in nature, giving the clinician a positive result, a negative result, or an intermediate. The second-generation assay provides quantitative data by providing an actual value of the optic density. This allows us to be more precise about the JC virus status. Specifically, [for] the positive and negative patients, percentages look about the same. Interesting data is emerging, suggesting that a low-positive intermediate patient may not have the same ultimate risk to develop PML as compared to a patient that is highly positive. In summary, the second-generation assay is more able to delineate low levels of JC virus antibody response, hopefully reducing the rate of samples that had intermediate-positive results over time with the first assay. complete the post-test and evaluation for CME credit: 28
Presentation 2 Slide 8 GM: grey matter; GMF: grey matter fraction; MSSS: Multiple Sclerosis Severity Score; MTR: magnetization transfer ratio. 1. Fillipi M et al. ECTRIMS 2012. Abstract 120. Dr. Boster: Dr. Filippi and colleagues reviewed the effects of grey matter damage as a predictor for disability accumulation and importantly cognitive impairment in MS patients. Damage to brain grey matter in terms of atrophy and accumulation of diffuse damage during the first year in the study predicted with reasonable accuracy disability accumulation over time in these MS patients as measured both by EDSS worsening and an increase in the Multiple Sclerosis Severity Scale. Specifically, the grey matter fraction was the strongest predictor of long-term clinical evolution amongst all the MRI predictors studied, both to predict favorable and unfavorable disease course. Baseline grey matter magnetization transfer ratio was the only predictor for global cognitive impairment assessed 13 years later. This provides early information of a potential biomarker that would have profound clinical implications in prognosticating, and also in assessing possible treatment response. complete the post-test and evaluation for CME credit: 29
Presentation 2 Slide 9 EOD: every other day; LVV: lateral ventricle volume; SDGM: subcortical deep grey matter. 1. Zivadinov R et al. AAN 2012. Abstract P03.063. Dr. Boster: In a separate study done by Dr. Zivadinov and colleagues, subcortical and cortical atrophy were measured as predictors for possible progression over a period of 5 years in a cohort of patients with very early relapsing MS. Patients were more likely to experience disability progression if the initial MRI showed that they had a higher T2 lesion volume or a smaller whole brain cortical or deep brain tissue volume. Significant interactions were determined between time and disability progression when considering subcortical deep grey matter volume and lateral ventricle volume after adjustments were made. A greater extent of subcortical deep grey matter atrophy was seen in patients with sustained disability progression as compared to patients that remained stable clinically. By contrast, cortical volume changes seen at 5 years were not significantly correlated with disability progression. Measurements of subcortical deep grey matter even in very early patients may therefore have a future potential for predicting disease course. complete the post-test and evaluation for CME credit: 30
Presentation 2 Slide 10 FLAIR: fluid-attenuated inversion-recovery; NAWM: normal-appearing white matter; OCT: ocular coherence tomography. 1. Saidha S et al. JAMA Neurology. 2013;70:34-43. Dr. Boster: We now turn our attention to the relationship between ocular coherence tomography and MRI measures of global CNS pathology in a study done by Dr. Saidha and colleagues. They studied 84 patients with MS as compared to 24 controls. What they found was that individual nerve fiber layers, as determined by OCT, correlated with grey matter and caudate volumes in patients with and without previous optic neuritis. Interestingly, the internuclear layer, for example, in patients with MS who had not suffered optic neuritis had a positive association with the volume of FLAIR lesions and were inversely associated with normal-appearing white matter. This early study suggests that metrics determined by OCT do, in fact, reflect global CNS pathology, and that the thickness of the discrete layers identified by OCT may be associated with distinct CNS processes. OCT measures appear to be correlated with intracranial volume in patients with MS and healthy controls. Whereas this study needs to be replicated and validated in larger prospective cohorts, the implications for the use in diagnostics and prognostication in MS are exciting. complete the post-test and evaluation for CME credit: 31
Presentation 2 Slide 11 Dr. Boster: In conclusion, several recently presented data have potential genetic markers for predicting therapeutic response to both glatiramer acetate and interferon β products in relapsing patients with MS. However, additional studies, of course, are necessary to validate their clinical utility. Other data reviewed highlights the potential predictive and prognostic values of endogenous vitamin D levels in MS patients and potential benefit to vitamin D supplementation. We reviewed a second-generation ELISA assay to help practitioners [stratify] the exact risk of PML in natalizumab-treated MS patients. And lastly, grey matter atrophy and damage, as well as OCT, have the potential to help us predict progression and prognosticate in our MS population. complete the post-test and evaluation for CME credit: 32
Presentation 2 Slide 12 Narrator: This activity has been jointly sponsored by Penn State College of Medicine and PVI, PeerView Institute for Medical Education. complete the post-test and evaluation for CME credit: 33