Featured Interviewee

Daniel H. Selchen, MD, FRCPC
Daniel H. Selchen, MD, FRCPC
St. Michael’s Hospital
Toronto, Ontario

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Educational Objectives

  • Describe the benefits and risks of current, new, and emerging agents for MS and how this translates into individualising therapy
  • Identify where emerging oral therapies will fit into MS treatment algorithms based on their safety and efficacy profiles

“Things are getting both better and more confusing [in multiple sclerosis (MS) treatment],” says Daniel H. Selchen, MD, FRCPC, head of the Division of Neurology at St. Michael’s Hospital in Toronto, Ontario. “We have more treatments now than we did a few years ago, and we’re going to have several new ones probably in the next couple of years. So, I think that would be the strongest argument for the need for some guidance, in terms of whom to treat and with what.”

Here, Dr. Selchen offers his clinical perspective on how available and emerging agents may fit into the MS treatment algorithm based on clinical data presented at the 63rd Annual Meeting of the American Academy of Neurology (AAN 2011).

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CDMS: clinically definite multiple sclerosis (MS).
Martinelli V et al. The 63rd Annual Meeting of the American Academy of Neurology (AAN 2011). Poster PD6.006.

Treating Clinically Isolated Syndrome: Which Therapies Delay Disease Progression?

Current clinical opinion encourages early intervention with disease-modifying therapies (DMTs) to delay disease progression and optimise long-term outcomes in MS.1 Thus, in patients with clinically isolated syndrome (CIS), early treatment can reduce progression to clinically definite MS (CDMS),1 as shown by data presented at AAN 2011.

“All 4 of the drugs that have been around for a while—the 3 beta-interferons [IFNβs] and glatiramer acetate [GA]—have evidence for efficacy in CIS,” says Dr. Selchen. “At AAN 2011, the 5-year data from the PreCISe trial with GA were presented.”2 In this randomised, controlled trial (RCT), patients with CIS (N = 481) received either GA or placebo for 36 months, unless a second attack occurred that established the diagnosis of CDMS. This was followed by a 2-year open-label phase with GA treatment. Over 5 years, 80 (32.9%) patients in the early GA group developed CDMS, compared with 118 (49.5%) in the delayed treatment group, amounting to a risk reduction of 41.1% (HR, 0.589; 95% CI, 0.437-0.795; P = .0005; Figure 1).2 “This essentially shows very comparable results to previous trials: The CHAMPS3 and CHAMPIONS4 trials with IFNβ-1a, and the BENEFIT5 trial with IFNβ-1b.”

“So, all of those agents are in play for the treatment of CIS. And there are CIS trials going on with several of the oral agents, [namely cladribine and fingolimod], but we don’t have results yet.” So the question now becomes about individualising treatment choice, explains Dr. Selchen. “Essentially, the discussion with regard to CIS [therapy options] will be very similar to the discussion with regard to relapsing-remitting MS [RRMS]. The only difference is that in patients with much earlier disease, the issue of side effects and tolerability will probably be even more important.”

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AE: adverse event; DMT: disease-modifying therapy; EDSS: expanded disability status scale; GA: glatiramer acetate; IFN: interferon; IM: intramuscular; MRI: magnetic resonance imaging; SC: subcutaneous; SD: standard deviation.
Gobbi C et al. AAN 2011. Poster P06.047.

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ARR: annualised relapse rate.
Comi G. AAN 2011. Oral Laquinimod Reduced Relapse Rate and Delayed Progression of Disability in ALLEGRO, a Placebo-Controlled Phase III Trial for Relapsing-Remitting Multiple Sclerosis. Oral Presentation.

Treating Less Active MS: Balancing Safety With Patient Considerations

The same safety concerns are factored in the selection of first-line therapy for patients with less active MS. “The drug that moves out of the equation at this point is natalizumab because of the risk profile. So, any of the IFNβs and GA are legitimate considerations; in terms of efficacy, it doesn’t really make any difference.” Dr. Selchen notes that similar efficacy among the 3 IFNβs and GA in reducing MS relapse rates and progression of disability was shown in the SAME study (N = 480), discussed at AAN 2011.6 “The decision therefore hinges on side-effect profile and tolerability [Table 1].”

Dr. Selchen comments that “the major question is what to do with fingolimod: In Canada, it has been specifically labelled as a second-line agent, but I strongly suspect there will be some off-label use of the drug in first-line.” This may be the case in patients who are needle-phobes, for instance. “I tell these patients that the drug works and that the 2-year safety profile is really quite good, but we don’t have any data on long-term safety. And when you have this discussion, there are some who become concerned about the longer-term safety, and some who are prepared to take their chances.”

In addition to tailoring treatment to patient preferences, other patient characteristics weigh in on agent selection in the first-line setting, such as patients' intention to become pregnant. “In a patient who wants to get pregnant relatively soon, I would be inclined to avoid fingolimod, because there is some teratogenicity evidence in animals, and we don’t have the same experience that we have with the IFNβs and GA.7 And I would avoid natalizumab because of the possibility of a rebound right at the point where the patient is getting pregnant.”

Upcoming oral agents may also increase treatment convenience in patients with less active disease. “I suspect that over the next few years, in MS treatment, we’re going to gradually move away from the injectables and that we’re going to see oral drugs that have modest efficacy, but a good safety and tolerability profile, become major first-line agents. The drugs that immediately spring to mind—pending more data—are laquinimod and teriflunomide.”

Results from a phase 3 trial with laquinimod, the ALLEGRO study (N = 1,106), were reported at AAN 2011 by Comi and colleagues.8 Laquinimod showed a statistically significant 23% reduction in the annualised relapse rate (ARR; P = .0024), and a 36% reduction in the expanded disability status scale (EDSS; P = .0122), compared with placebo, in patients with RRMS (Figure 2).

In a late-breaking news session, lead author Giancarlo Comi, MD, further noted that patients in the therapeutic arm also had a 33% reduction in brain atrophy9 compared with placebo (P < .0001). In terms of safety, while more patients in the treatment group had elevated ALT levels compared with placebo (6.9% vs 2.7% respectively, RR = 2.6),8 Dr. Comi pointed out that these increases were temporary, reversible, and did not lead to any signs of liver problems.9

“The results are somewhat similar to the current first-line agents, in terms of relapse rate reduction and [magnetic resonance imaging (MRI)] outcomes,” comments Dr. Selchen. “I think probably the most exciting thing about the laquinimod trial is actually the safety profile: The drug appears to be very safe, certainly in the short-term, and very well tolerated.”

Findings from the TEMSO study, a phase 3 trial with teriflunomide, were also presented at AAN 2011.10 In patients with relapsing MS (N = 1,088), teriflunomide reduced ARR by 31.2% and 31.5% with the 7-mg and 14-mg dose respectively, compared with placebo (P < .001 for both doses vs placebo). “But the major presentation actually was about a subgroup analysis from TEMSO, which suggested that the drug appeared to be efficacious regardless of gender, disease activity, or duration of disease—none of the subgroups behaved differently in a significant way,”11 says Dr. Selchen. The drug also appears to have a favourable safety profile.

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Bhan V et al. AAN 2011. Poster P01.196.

Treating Highly Active MS: Incorporating New Agents Into the Algorithm

Tailoring treatment in patients with highly active disease—defined as ≥2 disabling relapses in the previous year and an active MRI scan—is perhaps more challenging. “All of the currently available agents are legitimate as first-line therapy in this patient population, [but] response to all of them is unpredictable,” explains Dr. Selchen. “There are data suggesting that some patients with very active disease will respond to the IFNβs and GA. Therefore, overall, I think this becomes a question of degree of disease severity—if I saw a patient with extremely active disease, with multiple relapses and a hot MRI after relapses, I might actually start them on natalizumab as first-line therapy.”

Data on natalizumab’s efficacy in the real-world setting were presented at AAN 2011 by Bhan and colleagues. The researchers looked at response to natalizumab in patients (N = 266) who had an inadequate response or were intolerant to first-line DMT, and treatment-naïve patients with aggressive disease. The drug resulted in an 82% reduction in ARR (P < .0001; Figure 3), and a nonsignificant 6% reduction in the EDSS (P = NS).12 “They got very much the same sorts of efficacy results as the pivotal trials with natalizumab, and that corresponds to my experience.” Nonetheless, the risk of progressive multifocal leukoencephalopathy (PML) with natalizumab must be taken into consideration. “I think a risk of PML between 1 in 500 and 1 in 1,000 is acceptable in a patient with very aggressive MS where there is a 1 in 3 or 1 in 4 risk of losing their mobility in a relatively short period of time. So it is really a question of patient selection.”

Separate presentations from AAN 2011 examined the efficacies of the new agents in patients with high disease activity. “There are data from the TRANSFORMS trial and TRANSFORMS extension suggesting that patients with more active disease respond well to fingolimod and in an ongoing fashion.13 Although not yet approved, new data with cladribine in the CLARITY trial also suggest that in patients who have failed with other agents, the drug is quite efficacious.”14 Data from the TEMSO trial, presented at AAN 2011, indicate that teriflunomide may also be useful in this setting. “The data suggest that patients with more aggressive disease respond equally well to that drug, as patients with more mild disease.11 But from what we know at this time, this wouldn’t be my first choice in patients with highly active disease, so [of the new agents], fingolimod maybe, and cladribine, if it was available,” says Dr. Selchen.

Induction Therapy: A Potential Strategy for Patients With Highly Active MS From the Onset
“Patients who present with a relatively aggressive disease course from the onset, in theory, would be logical candidates for induction therapy, where we hit them hard initially with a more potent agent for a short period of time, and then follow-up with one of the safer agents. But we need more data.”

This hypothesis was explored in a small study (N = 40) discussed at AAN 2011, where patients received 12 to 18 months of natalizumab therapy and then were switched to GA.15 “The majority of patients got a good clinical result after the switchover, with an ARR of about 0.42 and no significant safety issues.” Cladribine might also be a good option as induction therapy in patients with aggressive disease, Dr. Selchen adds, “since you can get a very dramatic effect that may last a while with a short course of therapy.”

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Managing Breakthrough Disease: Switching to Other Agents

A switch in treatment may also be an effective strategy for managing breakthrough disease. “For patients with significant breakthrough disease on either IFNβs or GA, we essentially now have 3 choices in Canada: 1) If they’re on IFNβ, put them on GA, and if they’re on GA, put them on an IFNβ; 2) Switch to fingolimod; and 3) Switch to natalizumab. I think all of these strategies are reasonable.” Because these drugs work in different ways, patients who don’t respond to one drug may respond to another. “There’s been data for a long time that suggest that no matter what agent you switch to, if you switch patients who aren’t doing well, there’s a significant possibility that they are going to improve.”

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The safety aspect of the oral agents may very well determine their position in the treatment algorithm, as Dr. Selchen points out. “I think we may end up—and this is speculation—with 2 tiers of oral agents: Drugs that are somewhat more efficacious (eg, fingolimod and cladribine) but which, because of mechanism of action, may present some concerns about long-term safety; and drugs that have more modest efficacy (eg, laquinimod and teriflunomide), but potentially less safety concerns.”

Dr. Selchen summarises his opinion on which agents to use, when: “I think for CIS, we now have 4 good choices, which is really all of the currently available injectable agents [IFNβs and GA]; for first-line treatment, again, all of the currently available agents are appropriate and in my opinion, fingolimod is an option in patients who won’t take injectables. I will occasionally, but rarely, use natalizumab as the front-line agent, and I suspect that if and when they become available, laquinimod and teriflunomide will be first-line agents. For patients with breakthrough disease, we know that natalizumab works in this population, and I think both fingolimod and cladribine are also promising agents for breakthrough disease.”

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  1. Gold R et al. Ther Adv Neur Disord. 2010;3:351-367.
  2. Martinelli V et al. 63rd Annual Meeting of the American Academy of Neurology (AAN 2011). Poster PD6.006.
  3. Jacobs LD et al. N Engl J Med. 2000;343:898-904.
  4. Kinkel RP et al. Neurology. 2006;66:678-684.
  5. Kappos L et al. Neurology. 2006;67:1242-1249.
  6. Gobbi C et al. AAN 2011. Poster P06.047
  7. Hellwig K et al. AAN 2011. Abstract S20.002.
  8. Comi G. AAN 2011. Oral Laquinimod Reduced Relapse Rate and Delayed Progression of Disability in ALLEGRO, a Placebo-Controlled Phase III Trial for Relapsing-Remitting Multiple Sclerosis. Oral Presentation.
  9. Comi G. AAN 2011. Late Breaking News Session on “Oral Laquinimod Reduced Relapse Rate and Delayed Progression of Disability in ALLEGRO, a Placebo-Controlled Phase III Trial for Relapsing-Remitting Multiple Sclerosis.”
  10. Miller A et al. AAN 2011. Abstract S41.002.
  11. Miller A et al. AAN 2011. Abstract PD6.001.
  12. Bhan V et al. AAN 2011. Poster P01.196.
  13. Cohen J et al. AAN 2011. Poster P04.195.
  14. Cook S et al. AAN 2011. Abstract P04.197.
  15. Rossi S et al. AAN 2011. Poster PD6.005.

This activity is supported by an educational grant from Teva Neuroscience Canada.

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