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ABSTRACTS in PERSPECTIVE - Based on presentations from the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

Copenhagen, Denmark / October 2-5, 2013

EDITORIAL OVERVIEW:

Paul Giacomini, MD, FRCPC
Associate Director, Montreal Neurological Institute Multiple Sclerosis Clinic,
Montreal Neurological Institute, McGill University
Assistant Professor, Department of Neurology and Neurosurgery, McGill University
Montreal, Quebec

Marcelo Kremenchutzky, MD, FRCPC
Director of the Multiple Sclerosis Clinic
London Health Sciences Centre
University Hospital
London, Ontario

The era of disease-modifying therapies (DMTs) for multiple sclerosis (MS) started with the introduction of injectable human interferon (IFNb-1b) in the early to mid-nineties. Since then, glatiramer acetate (GA) and IFNb-1a—both administered by injection—have rounded out what is still standard-of-care for relapsing-remitting MS (RRMS). Fingolimod was the first oral agent to be approved for use in RRMS in North America and Europe.  Although more effective than IFNb-1a in the TRANSFORMS study (N Engl J Med 2010; 362:402-415), the first dose of fingolimod needs to be given under observation for 6 hours to rule out bradycardia and the drug should be used with caution in certain patients with cardiovascular conditions.

Other agents, including the monoclonal antibodies natalizumab and alemtuzumab—the latter an older drug with established indications for certain malignancies—have been tested and used (and in the case of natalizumab, approved here in Canada; alemtuzumab has been approved in Europe) in RRMS. Because both are monoclonal antibodies, these drugs must be given through IV infusion. Meanwhile, it’s now known that longer-term exposure to natalizumab (>24 months), antibody positivity to the John Cunningham (JC) virus and prior immunosuppressant therapy all significantly increase the risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal viral infection, for patients receiving natalizumab. Research into the use of alemtuzumab in RRMS continues, as preliminary findings suggest it can be highly effective.

However, caution is called for when considering alemtuzumab in RRMS as immune-mediated thyroid diseases have been reported in a significant proportion of patients. Alemtuzumab-induced thrombocytopenic purpura (TP) occurs in a few per cent of recipients and frequent thrombocyte counts are required to monitor patients for thrombocytopenia.

Thus, the search for equally effective but safer and more convenient medications for RRMS was deemed of paramount importance to the field.  To date, efforts to satisfy the “Holy Trinity” of safety, efficacy and convenience have met with considerable success.

Pegylated Interferon b-1a

Though it still needs to be injected, pegylation extends the half-life of IFNb-1a, allowing for dosing every 2 to 4 weeks instead of weekly injections. In the ADVANCE phase 3 study (P 514), both biweekly and monthly pegIFN b-1a,125 μg SC, reduced the annualized relapse rate (ARR) compared with placebo, with a 36% reduction in relapse risk for the biweekly schedule and 28% reduction in relapse risk for the monthly schedule at one year relative to placebo (P=0.0007 and P=0.011, respectively) according to principal investigator Dr. Peter Calabresi, Professor of Neurology, Johns Hopkins University, Baltimore, Maryland.

PegIFNb-1a also reduced the risk of 12-week confirmed disability progression as measured by EDSS by 38% in both dosing arms (P<0.04) vs placebo. The biweekly—though not monthly—schedule also led to a statistically significant 86% reduction in the mean number of Gd+ lesions at one year compared with placebo (P<0.0001) and a 67% reduction in new and newly enlarging T2 lesions. Importantly, the proportion of disease activity-free patients over 1 year was significantly higher in the every-2-week arm at 34% (P<0.0001) and the every-4-week arm at 22% (P=0.01) compared with 15% for placebo controls.

Fumaric Acid Esters

In Germany, fumaric acid esters have a longstanding history for the treatment of psoriasis. Dimethyl fumarate (DMF), a second-generation fumaric acid derivative, is believed to have anti-inflammatory properties and is felt to improve cellular response to oxidative stress, both of which are implicated in the pathophysiology of MS. Developed as an oral agent for RRMS, DMF is now approved for the treatment of RRMS in Canada and many of those involved in its development feel DMF is an ideal first-line agent because of its safety, efficacy and convenience profile. In the two phase 3 DEFINE and CONFIRM studies (N Engl J Med 2012;376:1098-107 and 1087-97), DMF demonstrated significant efficacy on both clinical and MRI measures over 2 years compared with placebo.

As reported here (P 538), in ENDORSE—the 5-year extension study of DEFINE and CONFIRM—approximately 15% of patients who continued treatment on the 240 mg dose of DMF given twice or 3 times a day through to the extension trial had low rates of disease progression (~15%) over 4 years as measured by the 24-week Expanded Disability Status Scale (EDSS). For those initially randomized to placebo in both phase 3 studies, approximately 20% of patients had disease progression after 4 years of DMF treatment in ENDORSE.

In CONFIRM, one arm was initially randomized to GA as an active comparator. For these patients, the proportion with disease progression after 4 years ranged from 16% to 23%, depending on the DMF dosing schedule used in ENDORSE. “The 4-year follow-up shows that there is no development of tolerance, that the beneficial effects of the drug on relapse rates were maintained and that there were no unexpected side effects after 4 years either,” said principal investigator, Dr. Ralf Gold, Professor of Neurology, Ruhr-Universitat Bochum, Bochum, Germany.  “Overall, the 4-year follow-up in ENDORSE corroborates the strong therapeutic activity and safety of DMF in RRMS.”

Again, in patients who continued on DMF during 2 years of ENDORSE, DMF also had a significant effect on the development of MRI lesions over the total of 4 years of exposure to the agent (P 1004). Specifically, the adjusted mean numbers of new/enlarging T2-hyperintense lesions were 1.3 for the twice daily groups and 1.6 for the three-times-daily groups. Mean numbers of new, non-enhancing T1-hypointense lesions for the same groups of patients were 0.6 and 0.7 for the b.i.d., t.i.d. groups, respectively.

The mean numbers of Gd+ lesions were 0.3 among patients continuing to receive DMF twice a day, and 0.4 for those who continued to receive DMF 3 times a day. Patients initially assigned to GA who then received DMF in ENDORSE had similar MRI outcomes to those observed in DMF-treatment groups in the parent studies. In a post-hoc analysis of the clinical efficacy of DMF in patients stratified according to prior treatment with IFNb-1a or 1b or GA first-line therapies (P 563), investigators also found that both doses of DMF reduced the annualized relapse rate (ARR) at 2 years compared with placebo in both treatment-naïve and prior ABCR (Avonex, Betaseron, Copaxone and Rebif) subgroups: 40 to 53% with the twice-daily dose, and 52 to 59% for the 3-times-a-day dose.

Both b.i.d. and t.i.d. doses of DMF reduced the risk of relapse at 2 years by 28 to 47% and 50 to 61%, respectively compared with placebo regardless of prior therapy.

Other Oral Options

Another new oral option for RRMS is teriflunomide. As reported by Macdonell et al (P 1095), results from a post-hoc analysis of the pooled TEMSO and TOWER studies showed that teriflunomide at both 14 mg and 7 mg a day significantly reduced ARR including relapses with sequelae defined by the investigator, relapses leading to hospitalization, and relapses requiring IV corticosteroids. The higher dose of the drug also reduced severe relapses including relapses requiring healthcare resources, suggesting treatment with teriflunomide may attenuate relapse-related healthcare costs.

Importantly, there is little difference in the adverse event (AE) profile between the higher and the lower dose of teriflunomide, although there is a dose-dependent effect on hepatic enzymes. (Indeed, the FDA has “black-boxed” the drug in the US because cases of liver failure have been reported in association with its parent drug, even though there is little indication that teriflunomide is associated with the same risk). “Studies have shown that because of the mechanics of continually having to take an injectable preparation and the AEs, most patients only remain on [injectable] treatment for 18 to 24 months,” confirmed Dr. Richard Macdonell, Director of Neurology, Austin Health, Heidelberg, Australia. “So having an oral option should make it easier for patients to comply and achieve the best possible outcomes.”

In a separate study (P 543), Dr. Mark Freedman, Professor of Neurology, University of Ottawa, Ontario and colleagues analyzed the long-term safety and efficacy of teriflunomide in RRMS patients in the TEMSO extension trial.  As of June 2012, the cumulative duration of exposure to the drug was over 1100 patient-years for both doses. Relapse rates remained low from the core study throughout the extension phase. ARR rates were 0.19 and 0.22 for patients who had continuously received teriflunomide 14 or 7 mg and 0.21 and 0.24 for patients who had switched from placebo to either dose of teriflunomide in the extension trial.

Safety observations in the extension study were also consistent with the 2-year core trial with no new unexpected AEs with long-term exposure, as investigators point out. As Dr. Freedman noted, they soon will be reporting 9-year data and “there are no surprises there either.”

Also promising for RRMS patients is laquinimod. The phase 3 BRAVO study assessed the safety, efficacy and tolerability of once-a-day oral laquinimod, 0.6 mg vs placebo across 24 months. In BRAVO, IFNb-1a served as an active treatment arm as well. 

The open-label continuation of the phase 3 BRAVO study (P 1055) showed that the ARR declined during the 4-year follow-up from 0.3 at year 1 to 0.25 at year 4. Mean EDSS also remained stable at 2.8 throughout the 4-year follow-up. At the end of the third year, confirmed rates of disease progression were roughly similar at about 13% depending on the group involved. A post-hoc subgroup analysis of both the ALLEGRO and BRAVO studies (P 1036) showed that approximately one-third of patients in both studies who had disease progression did not experience a relapse.

“The ARR is still a relatively modest decrease, in the range of 20 to 25% so the drug does not have a dramatic effect on relapse rates,” Dr. Timothy Vollmer, Professor of Neurology, University of Colorado, Denver, said. “But the fact that laquinimod has a relatively disproportionate effect on disability progression as well as on brain atrophy is far more important for long-term disability than relapse rates.”

Putting Therapeutic Choices into Perspective

As the number of therapeutic choices for RRMS expands, consideration needs to be given to the comparative efficacy of older and emerging treatments to inform clinical care and health policy. By allowing indirect comparisons between drugs, a network meta-analysis (NMA) facilitates this comparison. As presented by Emer Fogarty, pharmacist, National Centre for Pharmacoeconomics, Dublin, Ireland (P 628), investigators first identified 20 randomized, placebo-controlled and direct comparative trials of DMTs in RRMS. The comparison included older drugs such as IFNb, GA, natalizumab, alemtuzumab and fingolimod as well as emerging drugs—notably DMF, teriflunomide and laquinimod.

Results from the group’s network meta-analysis demonstrated that alemtuzumab, natalizumab, fingolimod and DMF were all significantly more efficacious than other DMTs in reducing the ARR, with alemtuzumab having the highest probability of being ranked as the most efficacious treatment at 60% followed by natalizumab at 40%. IFNb-1a IM 30 mcg was ranked as being the least efficacious in reducing ARR. Short-term disability progression was also significantly lower with alemtuzumab, natalizumab, fingolimod, laquinimod, DMF and teriflunomide 14 mg vs placebo.

“I’m not sure how useful clinicians will find this because they are not going to have to choose between a range of therapies all the time,” Fogarty said. “But from a policy perspective, if payers want to look at what the relative efficacy of one drug is vs another and how it relates to additional cost, I think that’s the main value of having a network meta-analysis like this.”   

ABSTRACT 176

Is risk stratification possible with the new treatments?  
P.S. Sørensen

Several new treatments for multiple sclerosis (MS) have been launched during recent years and other therapies are pending and will be available within the next year. Some of these therapies carry the risk of severe or even life-threatening adverse effects, and the possibility to identify patients at risk of adverse events is of paramount importance for the utility of these therapies.

Treatment with natalizumab can be associated with development of anti-natalizumab antibodies that abrogate the therapeutic effect. Occurrence of these antibodies is related to both so-called acute infusion-related reactions, and, in particular, hypersensitivity reactions. Persistency of antibodies can be predicted from antibody titres.

The most severe adverse event associated with natalizumab treatment is the occurrence of PML, for which latent infection with JC virus, duration of natalizumab therapy, and prior use of immunosuppressive therapies are established risk factors for development of PML. With the development of reliable and validated assays for detection of antibodies directed against JC virus, it is now possible to identify persons who are carriers of JC virus. The availability of this assay, and, recently, measurements of antibody concentrations, provides an additional option for risk stratification of PML in patients using or considering natalizumab therapy.

Fingolimod therapy can be associated with herpes virus infections, in particular primary infection or reactivation of varicella-zoster virus. Hence, a varicella-zoster virus antibody titre should be measured, and if it is low or absent the patient should be vaccinated. After the first administration of fingolimod, some patients develop severe bradycardia or heart block. To avoid this complication, treatment with drugs that lower hearth rate or which could influence conduction e.g. antiarrhythmic drugs (quinidine, disopyramide, amiodarone, sotalol), Ca++-channel blockers (eg, verapamil, digoxin); beta-blockers (eg, atenolol); anticholinesteratic agents; or pilocarpine, should be avoided.

Alemtuzumab causes immune-mediated thyroid diseases in close to 30% of patients; family history and smoking are predictive factors. Idiopathic thrombocytopenic purpura (ITP) occurs in a few per cent, which in one clinical trial, resulted in a fatal intracranial haemorrhage.Only frequent complete blood counts can be used to guard against the deleterious complications of severe thrombocytopenia.

Commentary on abstract 176

Perhaps because some of the newer therapies for RRMS are so effective, the risk of using these drugs is greater than the less effective but safer first-line agents. Patients who are antibody-positive to the John Cunningham (JC) virus, for example, are at risk to develop progressive multifocal leukoencephalopathy (PML) on being exposed to natalizumab. The longer the exposure (>24 months), the greater the risk; if patients have received prior immunosuppressant (IS) therapy, the PML risk appears to be as high as 11.2/1000 if all 3 risk factors are present.  Thus, prior to initiation of natalizumab, patients’ JC antibody status and prior IS use should be determined to better estimate PML risk. With fingolimod, the first dose response is an issue and it should be given under observation for 6 hours to rule out the risk of bradycardia. Patients taking an antiarrhythmic, antineoplastic, immunosuppressive or immune-modulating therapy should not receive fingolimod nor should they receive attenuated live vaccines. At least 30% of patients receiving alemtuzumab develop thyroid disorders between 12 and 48 months of treatment initiation. Drug-induced thrombocytopenic purpura (TP) occurs as well, although rarely, and a few cases of nephropathies have been seen in alemtuzumab trials. When initiating alemtuzumab, corticosteroids should be used for the first 3 days, oral anti-herpes medication for at least 1 month and live attenuated vaccines should again be avoided.

Questions and answers with Dr. Per Sorensen, Head, MS Research Unit, Copenhagen MS Clinic, Copenhagen University Hospital, Rigshospital, Copenhagen, Denmark

Q: What is your strategy when you see patients developing very low lymphocyte counts?

A: We simply stop treatment temporarily and wait until the lymphocytes recover. If treatment is discontinued for more than 2 weeks, we have to go through the first-dose regimen again with them. You could also reduce the frequency of the drug but if patients develop very low lymphocyte counts, you have to reduce the dose or stop the drug.

Q: Could you ever develop a general algorithm of risk assessment for these agents?

A: The risks are very different between the different drugs as are the side effects that occur at different times during the course of treatment so it would be very difficult to arrive at a common strategy for all drugs. You need to take each drug by itself and do the risk stratification for each drug on its own based on an individual patient’s own risk profile.

ABSTRACT P 990

Effect of BG-12 (Dimethyl Fumarate) in Newly Diagnosed RRMS Patients from the DEFINE and CONFIRM Studies
Ralf Gold

Background: BG-12 (dimethyl fumarate) demonstrated consistent clinical and radiological efficacy across a broad range of patients with relapsing-remitting multiple sclerosis (RRMS) in clinical trials.

Objectives: To evaluate the impact of BG-12 on the clinical efficacy in the newly diagnosed RRMS patient population from the DEFINE and CONFIRM trials.

Methods: Patients included in these post-hoc analyses were diagnosed with RRMS within one year of entry into DEFINE or CONFIRM and were naive to treatment with a disease-modifying therapy. Treatment efficacy was assessed by annualized relapse rate (ARR) and time to first relapse over 2 years. ARR was analyzed using a negative binomial model. Time to relapse was analyzed using a Cox proportional hazards model adjusted for the number of relapse(s) one year prior to study entry, baseline age (<40, >=40 years), EDSS score (<=2.0, >2.0), and region.

Results: A total of 678 patients were assigned to placebo (N=223), BG-12 240 mg twice daily (BID) (N=221), or BG-12 240 mg three times daily (TID) (N=234). Baseline demographic and clinical characteristics were similar across treatment groups. A median (range) of 2.0 (0-31.0), 2.0 (0-42.0), and 2.0 (0-23.0) years had elapsed since first MS symptoms, and 1.0 (0-1.0) year had elapsed since diagnosis in each of the placebo, BG-12 BID, and BG-12 TID groups. ARR in the newly diagnosed population over 2 years was 0.38 (95% CI 0.30-0.50) in the placebo group compared with 0.17 (0.12-0.23) in the BG-12 BID group and 0.15 (0.11-0.21) in the BG-12 TID group. At 2 years, BG-12 BID and BG-12 TID reduced ARR versus placebo by 56% (rate ratio 0.44 [95% CI 0.30.-0.65]) and by 60% (0.40 [0.27-0.58]), respectively. The proportion of subjects relapsed over 2 years was 42.2% with placebo, 21.3% with BG-12 BID, and 20.5% with BG-12 TID using the Kaplan-Meier method. The risk of relapse at 2 years was reduced by 54% (hazard ratio 0.46 [0.32-0.67]) and 57% (0.43 [0.30- 0.62]) in the BG-12 BID and BG-12 TID groups vs placebo, respectively.

Conclusion: BG-12 demonstrated strong treatment effect on ARR and time to first relapse in the newly diagnosed MS population. Together with an acceptable safety profile in the overall population, this analysis further supports the potential for BG-12 to become a valuable oral treatment option for patients newly diagnosed with MS.

Commentary on abstract P 990

Both DEFINE and CONFIRM demonstrated that DMF had a significant therapeutic effect on both clinical and MRI measures in RRMS patients at 2 years. In a post-hoc analysis, investigators defined the newly-diagnosed subgroup as patients who had been diagnosed with RRMS within a year from study entry and who had received no prior MS therapy or who had only been treated with steroids. In this newly-diagnosed subgroup, DMF given both twice and 3 times a day reduced the ARR by 56% and 60%, respectively, relative to placebo at 2 years. The same 2 dosing regimens also reduced the risk of relapse at 2 years by approximately 55% compared with placebo. The twice-daily dose reduced the risk of confirmed disability progression at 12 weeks by 71% while thrice-daily DMF reduced the same endpoint by 47% relative to placebo. Both new and enlarging T2-hyperintense lesions as well as Gd+ activity was reduced by between 80 and 92% with both doses again relative to placebo. This post-hoc analysis confirms that patients with newly-diagnosed RRMS derive comparable clinical and neuroradiologic benefit from DMF as do other subpopulations in DEFINE and CONFIRM. With an acceptable safety profile, the analysis also supports the use of DMF as a valuable oral option for newly-diagnosed RRMS patients.

Questions and answers with Dr. Robert Fox, Medical Director, Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio

Q: Would you like to see DMF introduced early in treatment-naïve patients or do you think physicians should be waiting to use DMF later on in the course of the disease?

A:  We are using DMF in 3 main patient populations. One is in the newly-diagnosed patient as an initial treatment option. I believe there is good evidence to support the risk-benefit ratio of this drug being used as first-line therapy. But we are also using it in patients who have breakthrough disease activity on other therapies or who are intolerant of other therapies—so DMF is a very good go-to therapy. Again, the risk-benefit ratio in this patient group is strong. Lastly, we are using DMF as a treatment option for patients in whom the risk-benefit ratio of their current treatment is no longer favourable—most notably natalizumab-treated patients who test positive for the JC virus. For these patients, the estimated risk of PML is starting to be of concern, and if they’ve been on natalizumab for longer than 24 months, PML risk is higher still and if they’ve had previous chemotherapy, it’s even higher. So for patients with some mixture of those 3 risk factors, we are shifting to something different and I think DMF is a very good treatment option for these patients as well.

ABSTRACT P 563

Clinical efficacy of BG-12 (dimethyl fumarate) for relapsing remitting multiple sclerosis according to prior therapy: an integrated analysis of the phase 3 DEFINE and CONFIRM studies 
M. Hutchinson

Background: Oral BG-12 (dimethyl fumarate) demonstrated strong positive efficacy and an acceptable safety profile in people with relapsing-remitting multiple sclerosis (RRMS) in the phase 3 DEFINE and CONFIRM studies. A post-hoc, integrated analysis of DEFINE and CONFIRM, contingent upon homogeneous baseline characteristics and treatment effects across studies, was conducted to evaluate the clinical efficacy of BG-12 according to prior treatment with one or any number of approved interferon beta-1a/b (IFN) or glatiramer acetate (GA) treatments (ABCR).

Methods: Eligible patients were aged 18-55 years and had a diagnosis of RRMS per McDonald criteria and an Expanded Disability Status Scale (EDSS) score of 0-5.0, inclusive. Patients were randomized to receive placebo, BG-12 240 mg twice (BID) or three times daily (TID), or subcutaneous GA (a reference comparator; CONFIRM only). Primary endpoints at 2 years were the proportion of patients relapsed (DEFINE) and annualized relapse rate (CONFIRM).

Results: The integrated intent-to-treat (ITT) population comprised 771, 769, and 761 patients assigned to placebo, BG-12 BID, and BG-12 TID, respectively, of whom 221, 202, and 193 had received treatment with any number of approved ABCR therapy(s) and 164, 155, and 145 had received one prior ABCR. BG-12 BID and TID showed a consistent positive effect on clinical outcomes over 2 years versus placebo. Rate ratios (95% confidence intervals) for reductions in annualized relapse rate with BG-12 BID and TID, respectively, versus placebo at 2 years were as follows: any prior ABCR, 0.60 (0.43-0.82) and 0.48 (0.34-0.68); one prior ABCR, 0.60 (0.42-0.85) and 0.41 (0.28-0.61).

Conclusions: The integrated analysis indicates consistent clinical efficacy of both BG-12 dosing regimens in RRMS patients previously treated with one or any number of ABCR therapies. The findings mirror the results reported for the overall DEFINE and CONFIRM study populations evaluated in the integrated analysis.

Commentary on abstract P 563

In another post-hoc analysis of the clinical efficacy of DMF in subgroups of patients in DEFINE and CONFIRM—this time stratified according to prior treatment with IFNb-1a or 1b or GA first-line therapies—investigators evaluated clinical efficacy endpoints in patients who received only ABCR therapies. Each ABCR therapy was counted as an individual treatment so the number of prior treatments was between 1 and 4. Both doses of DMF reduced the ARR at 2 years compared with placebo in treatment-naive and prior ABCR subgroups: 40 to 53% with the twice-daily dose, and 52 to 59% for the 3-times-a-day dose. Both b.i.d. and t.i.d. doses of DMF reduced the risk of relapse at 2 years by 28 to 47% and 50 to 61%, respectively, regardless of prior therapy. The disability progression analysis had to be interpreted with caution due to the low numbers of events in subgroups with smaller sample sizes. Results indicate that treatment response to DMF is generally consistent across subgroups of patients with RRMS, regardless of prior lines of MS therapies. DMF thus remains an effective option for the treatment of RRMS patients regardless of prior ABCR use.

Questions and answers with Dr. Michael Hutchinson, Consultant Neurologist, St Vincent’s University Hospital, Clinical Research Professor, University College Dublin, Dublin, Ireland

Q: What key observations have you made in this poster?

A: Basically, we were just examining patient response to DMF in relation to any prior first-line treatment they had received.  And no matter what other treatments patients had been on, changing or what I call escalation to DMF therapy was effective no matter what the previous ABCR line of treatment was.

Q: Would that be unusual relative to some of the newer RRMS therapies now under investigation?

A: No, I think this is what we might expect. Basically, one would anticipate that patients who are not doing well for various reasons with first-line DMTs might choose to go on DMF as a first-line option because of the relatively low toxicity of this drug. It does have side effects but they occur early on and they can be managed with adjustment of dosing and things like aspirin for the flushing.

Q: Do MS patients ever develop psoriasis? In Germany, the fumarates have been used for psoriasis for a long time and if a patient has both MS and psoriasis, DMF would be a natural for them, would it not?

A: Yes, the drug they’ve been using in Germany to treat psoriasis is a mixture of fumarates and it is very effective in that disease. In fact, I have a few patients who have both MS and psoriasis and they have been on the fumarates for some years now—they get it from Germany—and they talk very happily about it. They are hoping to get onto the new DMF when it becomes available in Europe. I’m sure it’ll be approved as there are no problems in relation to safety or toxicity with this drug and we are hoping that early in 2014, we’ll be able to get it and use it.

ABSTRACT P 538

Four-year follow-up of oral BG-12 (dimethyl fumarate) treatment in relapsing-remitting multiple sclerosis (RRMS): integrated clinical efficacy data from the DEFINE, CONFIRM, and ENDORSE studies
R. Gold

Background: BG-12 (dimethyl fumarate) demonstrated efficacy and safety in RRMS in the 2-year, phase 3 DEFINE and CONFIRM studies. Here we report interim clinical efficacy outcomes from ENDORSE, an ongoing, 5-year, dose-blind extension of DEFINE and CONFIRM.

Methods: Patients previously randomized to BG-12 240 mg twice (BID) or three times daily (TID) in DEFINE/CONFIRM continued on the same dose in ENDORSE. Patients treated with placebo (PBO) (DEFINE/CONFIRM) or glatiramer acetate (GA) (CONFIRM) were randomized 1:1 to BG-12 240 mg BID or TID. Efficacy was analyzed (cutoff date 01 May 2012) according to treatment received in parent/extension study (eg, BID/BID, TID/TID).

Results: Of 2,651 patients initially randomized and dosed, 2,079 completed DEFINE/CONFIRM and 1,736 were dosed in ENDORSE (n=501 [BID/BID], 502 [TID/TID], 249 [PBO/BID], 248 [PBO/TID], 118 [GA/BID], and 118 [GA/TID]). Among them, 436 (BID/BID), 439 (TID/TID), 188 (PBO/BID), 192 (PBO/TID), 87 (GA/BID), and 74 (GA/TID) completed 1 year at cutoff. BID/BID and TID/TID groups showed consistent efficacy over 3 years (2 years in DEFINE/CONFIRM; 1 year in ENDORSE): adjusted annualized relapse rate (ARR) (and 95% confidence interval [CI]) in Years 1, 2 and 3: 0.202 (0.162–0.252), 0.163 (0.128–0.208) and 0.134 (0.101–0.178) for BID/BID, and 0.239 (0.195–0.294), 0.123 (0.094–0.162) and 0.162 (0.124–0.212) for TID/TID, respectively; Kaplan–Meier estimate of proportion relapsed at 3 years was 31.4% (27.5–35.6%) and 31.0% (27.1–35.2%), respectively. For patients switching treatment in ENDORSE from PBO, ARR (95% CI) in Year 3 (first year of BG-12 treatment) was 0.167 (0.115–0.245) for PBO/BID, and 0.116 (0.076–0.177) for PBO/TID. Disability progression results will be presented.

Conclusion: BG-12 demonstrated consistent efficacy over 3 years of treatment. Together with an acceptable safety profile, these results support the potential for BG-12 to be a long-term treatment option for MS.

Commentary on abstract P 538

ENDORSE is a 5-year extension study of DEFINE and CONFIRM currently being carried out to evaluate the long-term safety and efficacy of DMF in RRMS patients. In this analysis, investigators reported 2-year interim outcomes in ENDORSE, with up to 4 years of efficacy data in some patients. For patients continuing treatment with DMF throughout the parent studies and on into ENDORSE, approximately 36% had relapsed at 4 years (2 years DEFINE/CONFIRM; 2 years ENDORSE). This compared to approximately half of patients who had switched from placebo to DMF at either dose in the ENDORSE trial at the same 4-year follow-up. Relapse rates were slightly lower in patients who had switched from GA in CONFIRM to DMF in ENDORSE. Approximately 15% of patients who continued treatment on either dose of DMF had disease progression over 4 years as measured by 24-week EDSS. This compares to approximately 20% of patients initially randomized to placebo then switched to one of 2 doses of DMF in ENDORSE and between 16% to 23% of patients who were switched from GA to DMF on enrollment in ENDORSE. Investigators concluded that the efficacy of DMF after 4 years of continued treatment is sustained and that results support the potential for DMF to be used long-term in RRMS.

 
Questions and answers with Dr. Ralf Gold, Professor of Neurology, Ruhr-Universitat Bochum, Bochum, Germany

Q: Was there anything significant that fell out at 4 years in your analysis of the 2 parent studies and the open-label extension trial?

A: The 4-year follow-up shows that there is no development of tolerance, that the beneficial effects of the drug on relapse rates were maintained and that there were no unexpected side effects after 4 years either. The drug was well tolerated, flushing and GI effects happen in the beginning and then disappear after that. So overall, the 4-year follow-up in ENDORSE corroborates the strong therapeutic activity and safety of DMF in RRMS. Patients who were switched from PBO to DMF later on also responded quite well, as did those who were placed on the drug, either b.i.d. or t.i.d., early on, they also responded quite well. So it’s a very positive signal for the use of fumarate in MS.

Q: How would DMF compare to the other newer agents? Are they all on the same footing in terms of safety?

A: The safety signals for DMF are actually very good and this is in contrast to some of the other new therapies. With the exception of the first 6 to 8 weeks, during which time you will see whether patients develop side effects or not, tolerance is excellent in the long run. There may be a small proportion of patients—perhaps 3 to 5%—who are not able to tolerate the drug during the initial weeks and for whom you may need to discontinue treatment. But safety in the long run is very good and that is extremely important for MS patients.

ABSTRACT P 1004

4-Year Follow-up of oral BG-12 (Dimethyl Fumarate) Treatment in Relapsing-Remitting Multiple Sclerosis (RRMS): Integrated Magnetic Resonance Imaging (MRI) Outcomes from DEFINE, CONFIRM and ENDORSE
David H. Miller

Background: Oral BG-12 (dimethyl fumarate) demonstrated efficacy and safety in RRMS in the 2-year, phase 3 DEFINE and CONFIRM studies. Here we report interim MRI outcomes from ENDORSE, an ongoing, 5-year, dose-blind extension of DEFINE and CONFIRM.  

Methods: Patients randomized to BG-12 240 mg twice (BID) or three times daily (TID) in DEFINE/CONFIRM continued on the same dose in ENDORSE. Patients treated with placebo (PBO) (DEFINE/CONFIRM) or glatiramer acetate (GA) (CONFIRM) were randomized 1:1 to BG-12 240 mg BID or TID in ENDORSE. Brain MRI scans were obtained yearly in a subset of patients (MRI cohort). Efficacy was analyzed (cutoff 01 May 2012) by parent/extension study treatment: BID/BID, TID/TID, PBO/BID, PBO/TID, GA/BID, and GA/TID.

Results: Of 1,221 patients in the MRI cohort of DEFINE/CONFIRM, 982 completed those parent studies, and 725 were dosed in the ENDORSE extension study (n=210 [BID/BID], 216 [TID/TID], 96 [PBO/BID], 94 [PBO/TID], 49 [GA/BID], and 60 [GA/TID]). MRI data were available for Year 1 of ENDORSE for 187 (BID/BID), 193 (TID/TID), 67 (PBO/BID), 75 (PBO/TID), 39 (GA/BID), and 41 (GA/TID) patients. Among patients continuing BG-12 treatment in ENDORSE, 64% (BID/BID) and 60% (TID/TID) were free of new/enlarging T2 lesions during Year 3, 73% (BID/BID) and 67% (TID/TID) were free of new T1 hypointense lesions during Year 1 of ENDORSE, and 89% (BID/BID) and 84% (TID/TID) were free of gadolinium-enhancing (Gd+) lesions at Year 1 of ENDORSE. For patients switching from PBO to BG-12 in ENDORSE, the proportion with no new/enlarging T2 lesions was 31% (PBO/BID) and 19% (PBO/TID) during Year 1 of DEFINE/CONFIRM and 43% (PBO/BID) and 49% (PBO/TID) during Year 1 of ENDORSE (first year receiving BG-12).

Conclusions: Reductions in T2, T1, and Gd+ lesions were sustained over 3 years of BG-12 treatment, and similar outcomes were attained by patients switching from PBO to BG-12 in ENDORSE. Together with clinical efficacy and an acceptable safety profile, these results support the potential for BG-12 as a long-term treatment option for MS.

Commentary on abstract P 1004

Eligible patients from the 2-year parent studies—DEFINE and CONFIRM—in which DMF was evaluated in patients with RRMS, were enrolled into ENDORSE, an extension trial with up to 4 years follow-up. In patients who continued on DMF throughout the parent study and during 2 years of ENDORSE, the adjusted mean numbers of new/enlarging T2-hyperintense lesions were 1.3 for the twice-daily groups and 1.6 for the three-times-daily groups. Mean numbers of new, non-enhancing T1-hypointense lesions for the same groups of patients were 0.6 and 0.7 for the b.i.d., t.i.d. groups, respectively. The mean numbers of Gd+ lesions were 0.3 among patients continuing to receive DMF twice a day, and 0.4 for those who continued to receive DMF 3 times a day.  Patients initially assigned to GA who then received DMF in ENDORSE had similar MRI outcomes to those observed in DMF-treatment groups in the parent studies. Investigators concluded that continued treatment with 240 mg DMF b.i.d. and t.i.d. resulted in a low frequency of any type of MRI lesion over a total of 4 years (2 years in DEFINE and CONFIRM and 2 years in ENDORSE) and that the efficacy of DMF in reducing the frequency of new MRI lesions is maintained over 4 years.

Questions and answers with Dr. Robert Fox, Medical Director, Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio

Q: Could you comment on the continued efficacy of DMF as imaged on MRI in this integrated analysis?

A: As patients rolled over into the open-label ENDORSE extension, we found that the efficacy of DMF has continued. So there does not appear to be a diminution of the efficacy of the drug as patients stay on it longer.

Q: Are findings on MRI the most significant reflection of a drug’s efficacy in general as opposed to any change in clinical signs and symptoms?

A: I’m an imaging person so yes, I think they are. But I wouldn’t say ‘significant’, I would use the word ‘sensitive’. The numbers of MRI lesions that develop over time are much greater than clinical relapse rates. So MRI lesions are a more sensitive metric because you are getting more outcomes and if you get more outcomes, you can measure the impact of a therapeutic intervention with better precision. So MRI findings I think give us greater confidence in terms of our point estimate of the efficacy of a therapy. And we saw that DMF does appear to have quite a robust effect on MRI lesions.

Q: If you have a more robust effect on MRI lesions, does that translate into less clinical disease?

A: Absolutely. What we don’t see—and it’s been one of the puzzles in the field—is the same efficacy level on MRI. For example, natalizumab, arguably our most effective therapy, reduces new lesions on MRI by 94%, yet its relapse reduction rate is only 66%. This is in part because there is less ‘noise’ on MRI. Sometimes, it’s hard to figure out whether a patient is having a relapse or not. But if there’s a new scar on the MRI, you can bet your boots it’s from MS and not from anything else. So you can be much more confident about MRI findings than you can be with relapses.

ABSTRACT P 549

Management strategies for flushing and gastrointestinal events associated with BG-12 (dimethyl fumarate): expert panel recommendations
J. T. Phillips

Background: In the phase 3 DEFINE and CONFIRM trials, common adverse events (AEs) associated with oral BG-12 included flushing and gastrointestinal (GI) events. The incidence of these events was highest in the first month of treatment and the severity was mild or moderate for most patients with events. The rate of BG-12 discontinuation due to these AEs was relatively low, indicating that AEs were effectively managed in a clinical trial setting. The aim of this survey was to further understand management strategies for flushing and GI events in the phase 3 clinical trials and identify potential strategies for use in clinical practice.

Methods: Using the Delphi process, a questionnaire was developed to characterize and identify effective approaches for managing patients experiencing flushing or GI events in the clinical setting. Eligible investigators had at least 10 patients in DEFINE or CONFIRM.

Results: Of 84 eligible investigators, 50 agreed to participate and 30 completed the questionnaire. Participating investigators enrolled a mean of 12.7 patients across all treatment groups. Patients of these participating investigators represented approximately 20% of the total BG-12 study population in DEFINE and CONFIRM, and 377 patient-years of BG-12 exposure. The patient population represented by investigators who completed the survey was similar to the patient populations of DEFINE and CONFIRM. The percentage of investigators indicating they had at least one patient with an event was 93.3% (flushing), 70% (nausea/vomiting), 40% (abdominal pain), and 36.7% (diarrhea). Most investigators considered it at least somewhat important to manage these events. Various flushing and GI AE management strategies used in the studies will be reviewed. Less than half of the investigators indicated they had used dose reduction or interruption. Recommended management strategies for clinical practice included setting patient expectations prior to initiating treatment and taking BG-12 with food (all events); aspirin and antihistamines (flushing); antiemetics (nausea/vomiting); proton pump inhibitors and H2 receptor antagonists (abdominal pain); and antidiarrheals (diarrhea).

Conclusion: This survey provides experience-based guidance on the management of flushing and GI events in BG-12-treated patients that may be helpful in real-world practice. Future studies prospectively evaluating the efficacy of these management strategies are warranted

Commentary on abstract P 549

Flushing and gastrointestinal (GI) AEs (nausea, vomiting, abdominal pain, diarrhea) have been reported by patients receiving DMF during the phase 3 trials. However, discontinuation rates as a result of these events were relatively low at 2% for flushing and 4% for GI AEs. Most AEs were mild to moderate in severity and decreased in incidence after the first month of treatment. A questionnaire was developed to characterize and identify effective approaches for managing patients experiencing flushing or GI events in an office-based setting. Eligible investigators had at least 10 patients in DEFINE or CONFIRM. Over 90% of investigators indicated they had at least one patient who had experienced an event, the majority of them flushing. Most investigators agreed it was at least somewhat important to manage these events. Recommendations from this survey include the following: prior to initiation of DMF, physicians should advise patients to take each dose with food. Following initiation of treatment, flushing may be prevented by taking aspirin, 325 mg, prior to each dose, as well as antihistamines, if needed. Nausea and vomiting may be managed by drugs such as metoclopramide, while proton pump inhibitors or H2 receptors may help with abdominal pain. Antidiarrheals may be recommended to control diarrhea.

Questions and answers with Dr. Ralf Gold, Professor of Neurology, Ruhr-Universitat Bochum, Bochum, Germany

Q: How do you personally manage GI effects when patients first start on DMF?

A:  In Germany, we’ve had fumarates for 20 years for the treatment of psoriasis, and dermatologists use them in a step-wise approach, so they increase the dose slowly. So if a patient develops GI side effects, don’t put them on a full dose, rather go down to perhaps 120 mg once a day until the gut gets acquainted with the drug and patients become more tolerant to its effects. If they have persistent cramping and diarrhea, you have to titrate the drug up more slowly, wait 6 to 8 weeks until you get to the full dose and by doing this, most patients tolerate the drug well. Importantly, not every patient needs the full 240 mg twice a day as it was used in the trials. There is a lot of genetic variability in terms of being able to digest the fumarates and we know from using these agents in psoriasis that sometimes a lower dose is sufficient to achieve a good therapeutic response. Patients also shouldn’t take DMF on an empty stomach, they need to take it together with a meal because food delays the peak of absorption of the drug and when the peak of absorption is delayed, you have fewer side effects.

Q: The drug was also used three times a day in the clinical trials. Which dose are you using it at now?

A: We give it twice a day, twice a day is sufficient. But again, some patients don’t need even this dose for genetic variations of metabolism. If they can only tolerate 120 mg once a day and if they respond well in clinical terms, you do not need to go to 240 mg, twice a day. (Editor’s note: Physicians need to remember however that the approved dose of DMF is still 240, twice a day).

Q: What about flushing? Have you found aspirin works for you?

A: I don’t think flushing is a major problem but yes, for the flushing you can use aspirin. In the US and Canada, you have regular aspirin at 325 mg, so patients can just take the aspirin 30 minutes before taking DMF.

ABSTRACT P 1018

Lymphocyte Count Reduction in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients Treated with Oral BG-12 (dimethyl fumarate): Integrated Analysis of the Placebo-Controlled Studies
R.J. Fox

Background: BG-12 demonstrated significant efficacy and an acceptable safety profile in placebo-controlled clinical trials, including a phase 2b trial and the phase 3 DEFINE and CONFIRM studies. The most common AEs with BG-12 were flushing and GI events, but BG-12 was also associated with a reduction in lymphocyte counts. An integrated analysis of the placebo-controlled studies was conducted to examine the severity, reversibility, and implications of lymphocyte count reductions in patients treated with BG-12 or placebo (PBO).

Methods: The population for this integrated analysis comprised 2,428 RRMS patients (aged 18-55 years; EDSS score 0-5.0) who were randomized and received treatment with placebo (n=836) or BG-12 240 mg BID (n=769) or TID (n=823) for up to 96 weeks. CONFIRM included a GA reference comparator arm (n=351). Hematological tests were performed at weeks 4, 8, and 12, and at 12-week intervals thereafter.  

Results: Results are shown here for placebo and the recommended dosing regimen of BG-12 (240 mg BID). Mean lymphocyte counts decreased by approximately 30% from baseline to Week 48 in BG-12 BID-treated patients, then plateaued, but remained within normal limits (lower limit of normal [LLN]: 0.91x109/L) throughout the 2-year observation period. The minimum post-baseline lymphocyte count was =0.8x109/L (CTC Grade 1) in 2% (PBO) and 10% (BG-12 BID) of patients; <0.8->=0.5x109/L (CTC Grade 2) in 2% (PBO) and 22% (BG-12 BID) of patients; and <0.5x109/L (CTC Grade 3) in <1% (PBO) and 6% (BG-12 BID) of patients. No patients discontinued BG-12 BID due to AEs associated with low lymphocyte counts. The incidence of infections (56% PBO, 60% BG-12 BID) and serious infections (1.4% PBO, 2.2% BG-12 BID) was similar across groups. There were no opportunistic infections in BG-12 BID-treated patients. There was no increased incidence of serious infections observed in BG-12 BID-treated patients with lymphocyte counts <0.8x109/L or <0.5x109/L. In a subgroup of subjects with data available 4 weeks after stopping BG-12 BID, lymphocyte counts increased slightly but did not return to baseline.

Conclusions: In PBO-controlled studies, lymphocyte count reductions associated with BG-12 BID were not associated with an increased risk of infections, serious infections, or opportunistic infections. Slight increases in lymphocytes counts were observed within 4 weeks following the last dose of BG-12 BID.

Commentary on abstract P 1018

In the phase 3 DEFINE and CONFIRM studies, the most common AEs associated with DMF were flushing and GI events. However, DMF was associated with a decrease in white blood cell and lymphocyte counts as well. In this analysis, investigators described the clinical relevance of lymphocyte count reduction in DMF-treated patients based on an integrated analysis of the 2 studies. For the majority of patients, lymphocyte counts were within normal limits at all time points investigated.  More patients receiving DMF had more than 1 grade 3 or 4 lymphocyte count or consecutive grade 3 or 4 lymphocyte counts than among placebo patients at between 1 to 3% for both end points in the DMF arms compared to 0% for placebo patients. However, lymphopenia in DMF patients was not clearly associated with an overall increased risk of infections, serious infections or opportunistic infections. Moreover, 4 weeks after stopping DMF, mean lymphocyte counts increased although they did not return to baseline levels. Similar to other MS therapies, including IFNb-1 agents, DMF was associated with a decrease in lymphocyte counts but across both studies, only 1 patient in the DMF three-times-daily group discontinued the drug due to an AE associated with leucopenia and no DMF patient discontinued study drug due to lymphopenia.

Questions and answers with Dr. Robert Fox, Medical Director, Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio

Q: Why do MS therapies in general seem to affect lymphocyte counts?

A:  Some physicians embrace the concept that MS is a lymphocyte ‘confused’ disease where the lymphocytes are over-activated; they go to the brain and to the spinal cord and attack them, so what we need to do is suppress lymphocytes. And indeed, many of our therapies do suppress lymphocyte counts including fingolimod. So similar to what we do with DMF-treated patients, we monitor patients and when the lymphocytes get too low, we do something about it.

Q: When they drop down, does the lymphocyte count stay down?

A:  What we usually see is a gradual decrease in lymphocytes over about 12 months and then they nadir at the lower level at the 12-month period.  As long as patients stay on the treatment, the counts do stay at that lower level. Probably patients whose lymphocyte counts dip transiently are not as much of a concern. But even in patients whose counts drop down to rather low levels, it doesn’t appear that there is any significantly increased risk of infections or other complications and it’s a very small proportion of patients who do have these low lymphocyte counts. So it’s reassuring but it doesn’t mean we should ignore the lymphocyte counts. The FDA recommends we monitor the counts once a year but I myself am doing them every 6 months as it’s a simple enough test and a worthwhile monitoring tool.

ABSTRACT P 514

Peginterferon beta-1a provides improvements in clinical and radiological disease activity in relapsing-remitting multiple sclerosis: year 1 findings from the phase 3 ADVANCE study
P. Calabresi

Background: Peginterferon beta-1a is a pharmacologically distinct molecule in which interferon (IFN) beta-1a is pegylated to extend its half-life; thus potentially enabling less frequent dosing schedules. Pegylation of other drugs and the use of IFN beta-1a as a disease-modifying therapy have been practiced successfully for >15 years. The pivotal phase 3 ADVANCE study evaluated the efficacy, safety, and tolerability of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS); here we present data from the first year (placebo-controlled period) of this 2-year study.

Methods: ADVANCE is a multicentre, double-blind, parallel-group study. Patients were randomised (1:1:1) to placebo or peginterferon beta-1a 125 µg self-administered subcutaneously every 2 (Q 2W) or 4 (Q 4W) weeks. The primary efficacy endpoint is annualised relapse rate (ARR) at Year 1. Secondary endpoints are total number of new/newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans, the proportion of patients relapsing, and risk of 12-week confirmed disability progression at Year 1. Additional endpoints included the total number of new T1 hypointense and gadolinium-enhancing (Gd+) lesions, along with safety and tolerability. A post-hoc analysis of disease activity-free patients was also carried out.

Results: 1512 patients were randomised and received study drug (placebo n=500; peginterferon beta-1a Q 4W n=500; peginterferon beta-1a Q 2W n=512); Year 1 completion rates were 91%, 88%, and 86%, respectively. Compared with placebo, peginterferon beta-1a demonstrated a significant reduction in ARR (Q 2W 36% [p=0.0007]; Q 4W 27% [p=0.011]), risk of relapse (Q 2W 39% [p=0.0003]; Q 4W 26% [p=0.02]), and risk of 12-week disability progression (38% for both Q 2W and Q 4W [p<0.04]). T2 hyperintense lesions were also reduced (Q 2W 67% and Q 4W 28%; both p<0.001), as were T1 hypointense (Q 2W 53% [p<0.0001]; Q 4W 18% [p=0.082]) and Gd+ (Q 2W 86% [p<0.0001]; Q 4W 36% [p=0.07]) lesions. The proportion of disease activity-free patients over 1 year was significantly higher in the Q 2W (34%; p<0.0001) and Q 4W (22%; p=0.01) groups versus placebo (15%). The safety profile of peginterferon beta-1a was similar across both dosing regimens.

Conclusion: Peginterferon beta-1a Q 2W provides significant improvements in all clinical and radiological outcomes versus placebo, with a safety profile reflecting that of established IFN beta-1a therapies for MS.

Commentary on abstract P 514

IFNb therapies have consistently been shown to reduce the ARR and disability progression in patients with RRMS. Their main disadvantage is the need for frequent injectable dosing. Pegylation extends the half-life of IFNb-1a, allowing for less frequent dosing. In the on-going ADVANCE phase 3 study, both biweekly and monthly pegIFNb-1a,125 μg SC, reduced the ARR compared with placebo, with a 36% reduction in relapse risk for the biweekly schedule and 28% reduction in relapse risk for the monthly schedule.  PegIFNb-1a also reduced the risk of 12-week confirmed disability progression as measured by EDSS by 38% in both dosing arms. The biweekly—though not monthly—schedule also led to a statistically significant 86% reduction in the mean number of Gd+ lesions at one year compared with placebo and a 67% reduction in new and newly enlarging T2 lesions. A post-hoc analysis also showed that 21.5% of patients in the every-4-week arm, and 33.9% of patients in the every-2-week arm were free of disease activity at one year compared with 15.1% of placebo patients. Approximately half of patients in the pegIFNb-1a arms developed an influenza-like illness but the risk of serious infections was minimal and equal across the 2 treatment arms. Discontinuation rates in both active treatment arms were 5%.

Questions and answers with Dr. Peter Calabresi, Director, Johns Hopkins Multiple Sclerosis Center and Professor of Neurology, Johns Hopkins University, Baltimore, Maryland

Q: How long does influenza-like illness last? Do patients feel as if they have influenza all the time?

A: That was the first question I asked after I saw the phase I data because if you are making people sick all the time, how is that an advantage? But it seems to be limited to about 24 hours although it can spill over until the next day. So basically patients have one day of influenza-like illness after the injection. Patients usually say that they can handle this, especially if they’ve been injecting IFN 3 times a week.  

Q: Do you think it’s premature to favour the every 2-week schedule vs every 4 weeks?

A:  I found the every-2-week data compelling because the MRI effect was significant for both Gd+ lesions and the T2 lesions with a large effect size, especially for the Gd+ lesions at 86% which is pretty good. I think this is going to translate into better effects on disability at year 2 and onwards down the road. So I think the every-2-week regimen is looking good.

ABSTRACT P 628

Which drugs are most effective for relapsing-remitting multiple sclerosis? A network meta-analysis of disease modifying therapies
E. Fogarty

Introduction: Management of relapsing-remitting multiple sclerosis has become increasingly complex with the introduction of newer disease-modifying therapies (DMTs). This network meta-analysis incorporates direct and indirect comparisons to determine the relative efficacy of DMTs in reducing relapses and slowing short-term progression of disability.

Methods: A systematic review identified twenty randomised, placebo-controlled and direct comparative trials of DMTs in RRMS, including interferon-beta, glatiramer-acetate, natalizumab, alemtuzumab, fingolimod, teriflunomide, laquinimod, and BG-12.  

Results: All DMTs significantly reduced annualised relapse-rate versus placebo, in the range 16%-69%; alemtuzumab, natalizumab, fingolimod, and BG-12 were significantly more efficacious than other DMTs.

The risk of short-term disability progression was significantly lower with alemtuzumab, natalizumab, fingolimod, laquinimod, BG-12, and teriflunomide (14mg) versus placebo (HR 0.27-0.54); alemtuzumab was significantly more efficacious than other DMTs (HR 0.32-0.49).  Alemtuzumab and interferon beta 1a 30mcg had the highest probability of being ranked most and least effective treatments respectively for both outcomes

Conclusions: Among patients with RRMS treated with DMTs, significant reductions in MS relapses are demonstrated by newer second-line agents compared with older first-line agents interferon-beta and glatiramer acetate. Relative advantages among DMTs in reducing short-term progression are equivocal with the exception of alemtuzumab which appears to significantly reduce the hazard of short-term progression compared with other DMTs. Longer-term studies are required to elucidate the clinical significance of these findings. Despite the potential advantages of second-line agents, their relative position on the RRMS treatment landscape remains to be defined, due to potentially serious side effects and limited long-term safety data.

Commentary on abstract P 628

As the number of therapeutic choices for RRMS expands, consideration needs to be given to the comparative efficacy of the new treatments to inform clinical care and health policy. A network meta-analysis (NMA) incorporates direct and indirect comparisons to determine the relative efficacy of DMTs in their ability to reduce relapses and slow short-term progression of disability. The authors included 20 RCTs which met their inclusion criteria in the NMA. Results showed that all DMTs significantly reduce the ARR compared with placebo, in the range of 16 to 33% for IFNb and GA and by between 24% and 69% for all other agents. Alemtuzumab, natalizumab, fingolimod and DMF were all significantly more efficacious than other DMTs in reducing ARR, with alemtuzumab having the highest probability of being ranked as the most efficacious treatment at 60% followed by natalizumab at 40%. IFNb-1a IM 30 mcg was the least efficacious in reducing ARR. The risk of short-term disability progression was also significantly lower with alemtuzumab, natalizumab, fingolimod, laquinimod, DMF and tenflunomide 14 mg vs placebo. In this regard, alemtuzumab was again significantly more efficacious than other DMTs, and IFNb-1a 30 mcg the least. The relative efficacy of teriflunomide, 7 mg, IFNb and GA vs placebo on disability progression did not achieve statistical significance.

Questions and answers with Emer Fogarty, Pharmacist, National Centre for Pharmacoeconomics, Dublin, Ireland

Q: What does a network meta-analysis allow you to do that a standard meta-analysis does not?

A: Traditionally, a meta-analysis takes all the trials that compared 2 treatments—for example IFNb with placebo— and arrives at a weighted average of the treatment efficacy of IFNb compared with placebo. But that’s not very helpful from an overall decision-making point of view because we are rarely deciding between just 1 or 2 treatments—we have 10 treatments now for RRMS—so when it comes to deciding on a treatment, we need to ask, What is the comparative effectiveness of all available treatments? A network meta-analysis allows researchers to combine evidence from clinical trials of drugs that have been compared both directly and indirectly and they can arrive at the relative efficacy of each of the treatments compared to all of the others.

Q: So what were your main findings?

A:  We included all of the drugs that are either approved for use in RRMS or which are seeking approval from regulatory agencies and some of the drugs are licensed for different indications so it’s up to individuals to look at what they think are relevant comparisons. But we do see that alemtuzumab is more effective than other treatments for relapse outcomes followed by natalizumab. And for the prevention of short-term disability progression, alemtuzumab again had the highest probability of being the most effective drug for that outcome as well.

Q: What’s your take-home message from this network meta-analysis?

A:  I’m not sure how useful clinicians will find this because they are not going to have to choose between a range of therapies all the time. But from a decision-makers’ point of view, a policy perspective, if they want to look at what the relative efficacy of one drug is vs another and how that relates to additional cost, I think that’s the main value of having a network meta-analysis like this.

ABSTRACT P 1055

Results of Switching to Laquinimod in the Open-Label Extension phase of the BRAVO Study
T. Vollmer

Background: The BRAVO study assessed laquinimod 0.6 mg vs placebo in a double- blind (DB) design, with a reference arm of interferon beta-1a (IFNB-1a IM) in a rater-blinded design. BRAVO, consistent with the ALLEGRO trial, showed lesser effects of laquinimod on clinical indices of focal inflammatory disease activity but more impactful and consistent effects in reducing disability progression and brain atrophy. BRAVO continues as open-label extension (OL-Ext) for up to 54 months.  

Objective: To report the effect of laquinimod treatment on disease course for the overall study population, as well as for the Laquinimod-Early-Start, Placebo-Delayed-Start and IFNB-1a IM Delayed-Start groups.  

Methods: All patients who completed the DB phase (N=1090) were given the opportunity to receive laquinimod in the OL-Ext phase. Scheduled visits occurred at month 0/DB phase termination visit and every 6 months thereafter. Annualized relapse rate (ARR) was assessed at the end of the 4th year of DB and OL-Ext phase. As only 17 patients completed year 4, mean EDSS and disability progression (increase from the baseline score of 1.0 or more points if EDSS 0-5.0, or 0.5 points if EDSS 5.5 or higher, sustained 6 months) were assessed at the end of the 3rd year of DB and OL-Ext phases.

Results: 1047 patients entered the OL-Ext and 929 are ongoing. At the end of year 4, cumulative ARR in total population remains low (0.29). Difference in cumulative ARR between laquinimod and placebo group in the DB phase was maintained at the end of year 4: cumulative ARR for Laquinimod-Early-Start and Placebo-Delayed-Start group is 0.28 and 0.33, respectively. ARR reduction achieved with IFNB-1a IM during the DB phase was maintained under treatment with laquinimod: at the end of year 4, cumulative ARR for the IFNB-1a IM Delayed-Start group was 0.27. During 3 years of the study, EDSS remained stable (mean [SD] EDSS at the end of year 3 is 2.8 [1.4]) and 87% of the overall population were free from 6-month EDSS confirmed progression. At end of year 3, 14.4% of patients in Placebo-Delayed-Start group had confirmed disease progression vs 12.7% in Laquinimod-Early-Start group and 13.2% in IFNB-1a IM Delayed-Start-group.

Conclusions: Long term analysis of ARR, mean EDSS score and confirmed 6-month disability progression support the favorable effects of laquinimod achieved during the DB phase.

Commentary on abstract P 1055

In this open-label continuation phase of the phase 3 BRAVO study, investigators assessed the effect of laquinimod on disease course for the overall study population as well as in the early-start, delayed-start-placebo and the delayed-start-IFNb-1a group. The ARR was assessed at the end of the 4th year of the combined double-blind and open-label extension phases of the trial. The ARR declined during the study from 0.3 at year 1 to 0.25 at year 4. During 3 years of the BRAVO study, the mean EDSS at 2.8 remained stable. The difference in cumulative ARR between the laquinimod and placebo groups in the double-blind phase was also maintained. Reduction in the ARR with the IFNb-1a arm during the double-blind phase was maintained during treatment with laquinimod. At the end of the 3rd year, 12.7% of the early start group, 13.2% of the delayed-start-IFNb-1a group and 14.4% of the delayed-start-placebo group had confirmed disease progression. Results indicate that outcomes in terms of ARR, EDSS score and confirmed disability progression support laquinimod as being just as beneficial over a longer-term follow-up as it was demonstrated to be during the double-blind phase of BRAVO.

Questions and answers with Dr. Timothy Vollmer, Professor of Neurology, University of Colorado, Denver, Colorado

Q: Were you impressed by the cumulative reduction in the ARR rate seen at year 4 in this open-label extension?

A: The ARR in this open-label extension phase very much mirrored what we saw in the randomized phase of the trial. It’s still a relatively modest decrease, in the range of 20 to 25%, so the drug does not have a dramatic effect on the relapse rate. However, if you ask patients what’s most important for them, it’s avoiding disability, not relapses. They don’t want to lose their ability to walk or their cognitive abilities or their vision. So the fact that laquinimod has a relatively disproportionate effect on disability progression as well as on brain atrophy is far more important for long-term disability than relapse rates.

Q: How do you think laquinimod is achieving this disproportionate effect on long-term disability?

A: I think these findings confirm that this drug is not simply suppressing the immune system. Rather, it’s probably working directly in the brain to affect the cascade of events that lead to neuronal injury. People think of MS as a disease of myelin, it’s actually not. It’s a disease of the entire CNS and the neurons are targeted as well. MRI parameters that correlate and predict with disability are not changes in the myelin, they are changes in the neurons and we can see that by brain atrophy or gray matter volumes in a variety of studies. So my particular perspective on this drug is that it’s more neuroprotective than other agents which in fact would be a major advance if laquinimod is finally approved.          

ABSTRACT P 1036

Disease Progression in Relapse-Free Patients Treated with Laquinimod
G. Comi

Background: The observed clinical benefits of laquinimod indicate a distinctive efficacy profile with a robust effect on relapse rate coupled with a larger effect on disability progression. The relationship between relapses and disability is complex and effects on relapse rate reduction and disability are difficult to separate. Regardless of whether the effect of laquinimod in reducing disability and relapse rate is mediated through a common pathway or through distinct pathways, the portion of the effect on reducing disability that may be related to a reduction in relapse rates is difficult to estimate.

Objective: To assess the relation between relapses and disability through analysis of disability progression in subgroups of patients who relapsed or were relapse-free during ALLEGRO and BRAVO trials.  

Methods: A subgroup analysis of patients that either experience a relapse or were relapse–free during the study was performed based on the pooled double blind phase 3 data, comprising 1006 placebo and 984 laquinimod patients. It should be noted that this analysis is limited by the potential bias of confounding by treatment effect because the subgroup analysis is based upon on-treatment outcome and not on baseline characteristics.  

Results: At the end of the study there were 640 relapse-free and 344 relapsing patients for the laquinimod treated patients and for placebo, 580 relapse-free and 426 relapsing patients. Most patients (88%) regardless of their relapse status experienced no disability progression. Approximately one third of the patients who progressed were relapse-free. Of patients treated with placebo, 22% of those who relapsed also progressed, and 7.6% of the relapse-free progressed. Of patients treated with laquinimod, 19% of those who relapsed also progressed and 4.8% of the relapse-free progressed. Overall, laquinimod reduced disability progression relative to placebo with a treatment effect of 26.7% in relapsing patients (P=0.058) and 38.9% effect in relapse-free patients (P=0.036).

Conclusions: There were patients in ALLEGRO and BRAVO who showed disease progression without experiencing a relapse during the study. In the placebo group, this suggests that disability progression and relapses are not solely mediated through a common pathway. These data support an effect of laquinimod on both inflammation and broader underlying mechanisms outside of inflammation.

Commentary on abstract P 1036

A post-hoc subgroup analysis of both the ALLEGRO and BRAVO phase 3 studies showed that approximately one-quarter of patients in both studies who had disease progression did not experience a relapse.  In relapse-free patients, 4.8% of those on laquinimod had disability progression compared with 7.6% of placebo controls. Among relapsed patients, 18.9% on active therapy had disability progression vs 22.1% of placebo patients. Overall, compared with placebo, laquinimod reduced disability progression by 38.9% in relapse-free patients and by 26.7% in relapsing patients. The overall frequencies of AEs, including infection rates, were comparable in both treatment arms. Investigators concluded results from this pooled analysis support a treatment effect on disability in patients who relapse while on laquinimod and those who remain relapse-free. Findings also suggest suggesting that laquinimod has an effect on both inflammation and on some other broader underlying disease pathology not associated with inflammation.

Questions and answers with Dr. Timothy Vollmer, Professor of Neurology, University of Colorado, Denver, Colorado

Q: The authors of this study note that most patients regardless of their relapse status experienced no disability progression during the study interval. What do you think is going on here?

A:  It appears that this drug affects inflammation that is causing relapse so that the inflammation doesn’t result in as much neurological injury as it might otherwise. In other words, the drug’s protecting the brain from inflammation. It’s important to keep in mind that the vast majority of inflammation as measured by Gd+ enhancing lesions in MS is clinically silent—between 90 to 95% of new lesion formation is not apparent to either the patient or the physician unless the physician does an MRI. And this drug is treating that clinically silent inflammation and is decreasing the amount of residual damage to the brain that normally occurs.

Q: Don’t patients have to relapse in order to experience disease progression? Or are relapse and disease progression 2 different entities?

A: Relapse means a patient has developed an acute lesion that leads to neurologic symptoms. Even if a patient is not having symptoms, if you did an MRI on MS patients each month, you would see a lot of Gd+ enhancing lesions that are coming and going and they are leaving scars and the brain is shrinking. So in MS patients, the brain is shrinking steadily even if patients look clinically stable. The reason they look stable is that young adults have brain reserve and they are using it. Once they’ve run out of brain reserve, patients are in the progressive phase of MS and that’s when their disability gets worse.

Q: Where do you think laquinimod should be used during the course of MS?

A:  We need to use all the drugs we’ve got to get as much of a treatment effect as we can early on in the course of the disease so patients can age normally. If we don’t preserve brain volume in early relapsing disease, patients aren’t going to have it when they’re 55 and 60 and don’t have the ability to mask aging so they become more and more disabled because of normal aging effects. This drug has a very good safety profile so it could be used as an add-on treatment to almost anything else, although I would favour it as an add-on to some of the newer therapies rather than to the older agents.

ABSTRACT P 1095

Teriflunomide reduces relapse-related sequelae, severe relapses, hospitalisations, and corticosteroid use: Pooled data from the phase 3 TEMSO and TOWER studies
Richard Macdonell

Introduction: Teriflunomide is a once-daily, oral immunomodulator approved in the USA, Australia and Argentina for relapsing multiple sclerosis (RMS). In the phase 3 TEMSO (NCT00134563) and TOWER (NCT00751881) studies, teriflunomide 14 mg significantly reduced annualised relapse rates (ARR) and disability progression in patients with RMS; teriflunomide 7 mg also significantly reduced ARR. Post-hoc analyses of TEMSO showed that both doses of teriflunomide reduced annualised rates of relapses with neurological sequelae and relapses requiring healthcare resources; these results were replicated for teriflunomide 14 mg in TOWER. Pooled data from TEMSO and TOWER are presented.

Methods: TEMSO and TOWER were phase 3, randomised, double-blind, placebo-controlled, parallel-group studies conducted in patients with RMS. Five relapse outcomes were analysed in the pooled modified intent-to-treat populations (N=2251): relapses with sequelae defined by increase in Expanded Disability Status Scale (EDSS) score/Functional Score (FS) 30 days post-relapse; relapses with sequelae defined by investigator; relapses leading to hospitalisation, relapses treated with iv corticosteroids; and severe relapses as defined by Panitch (EVIDENCE study). Adjusted annualised rates for each relapse outcome were derived using a Poisson model with robust error variance, with treatment, study, baseline EDSS strata and region as covariates. 

Results: Compared with placebo, teriflunomide significantly reduced annualised rates of: relapses with sequelae defined by EDSS/FS by 36.4% (14 mg; P<0.001) and 31.4% (7 mg; P<0.001); relapses with sequelae defined by the investigator by 53.1% (14 mg; P<0.001) and 20.4% (7 mg; P=0.046); and relapses leading to hospitalisation by 45.5% (14 mg; P<0.001) and 25.5% (7 mg; P=0.02). Teriflunomide 14 mg and 7 mg had a significant beneficial effect on relapses requiring iv corticosteroids with a decrease of 34.5% (14 mg) and 25.4% (7 mg); P<0.001, both doses. Teriflunomide 14 mg significantly reduced severe relapses (defined by Panitch) by 45% (P<0.001; 7 mg NS).

Conclusion: Teriflunomide significantly reduced occurrence of severe relapses, including relapses with sequelae and relapses requiring healthcare resources in this pooled data set. This post-hoc analysis replicates the results from the individual TEMSO and TOWER studies, and indicates that teriflunomide may reduce relapse-related healthcare costs.

Commentary on abstract P 1095

In the phase 3 TEMSO and TOWER studies, teriflunomide 14 mg significantly reduced ARR and the risk of 12-week confirmed disability progression, while the 7 mg dose also significantly reduced ARR in both studies. A post-hoc analysis of the pooled TEMSO and TOWER studies was done to provide an estimate of the treatment effects of teriflunomide on relapse outcomes across a larger population sample. Results showed that both doses of teriflunomide significantly reduced ARR with sequelae-EDSS, relapses with sequelae defined by the investigator, relapses leading to hospitalization, and relapses requiring IV corticosteroids. The higher dose of the drug also reduced severe relapses. Compared with placebo, the significant treatment effect of teriflunomide on relapses with sequelae-EDSS was maintained across all time points for the 14 mg dose and the overall trend was maintained for the 7 mg dose. Investigators concluded that 14 mg teriflunomide significantly reduced the occurrence of severe relapses including those with sequelae as well as relapses requiring healthcare resources and as such, may reduce relapse-related healthcare costs. A significant effect from the 7 mg dose of the drug was also observed on some outcomes but the overall effect was less pronounced than that seen with the higher dose.

Questions and answers with Dr. Richard Macdonell, Director of Neurology, Austin Health, Heidelberg, Australia

Q: What difference do you think it might make to MS patients to be able to choose an oral agent over an injectable preparation?

A: The major advantage for MS patients is that an oral agent should lead to better compliance. Studies have shown that because of AEs and the mechanics of continually having to take an injectable preparation, most patients only remain on treatment for 18 to 24 months. Given the chronic nature of MS, it is important that patients remain on treatment for many years and an oral option should make it easier for patients to comply and achieve the best possible outcomes.

Q:  Is there much of a difference in the AE profile between the 14 mg and the 7 mg dose, given that the higher dose of teriflunomide was more effective in preventing relapses, especially severe relapses?

A: The difference in the side effect profile between the 14 and the 7 mg dose is not significant but in most countries, only the 14 mg dose has been licensed. Side effects with teriflunomide are generally manageable.  The one that has been most problematic has been brittle hair and hair falling out from a brush. The hair loss issue tends to settle after about 9 months providing patients are prepared to put up with it for that length of time. The occasional patient may develop some mild nausea or diarrhea and occasionally abnormal liver function tests do lead to discontinuation of the medication.

Q: In which patients or patient groups do you feel teriflunomide might be best indicated?

A: Teriflunomide might be best indicated in women who are not planning on having any more children and have instituted effective contraception or who are postmenopausal. Because of issues with compliance, males are more likely to be suited to an oral medication such as teriflunomide rather than injectable therapies.  And patients doing well on injectable therapies but who are suffering from treatment fatigue and who are injecting irregularly are another group where teriflunomide may play a role. Because of potential teratogenic effects, I would tend to avoid using it as the first option in young women who are thinking about pregnancy at some point in the future. Nor would teriflunomide be first-choice in a patient with highly active disease.