High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.
High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. "I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck," Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
Consider Baseline Characteristics
In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.
He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. "If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age," Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.
Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.
Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. "Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense," said Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d'Hebron University Hospital in Barcelona.
Switching DMTs
In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.
Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. "Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us," Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. "We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation," said Rotstein, assistant professor of medicine at University of Toronto.
For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.
Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.
When switching to a high-efficacy therapy, it's important to administer any vaccines well in advance to ensure a good immune response.
When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. "But in general, we've observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating," said Rotstein.
A study of timing of relapses after fingolimod washout, carried out by Rotstein's group, found a stark signal. "We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse," she said.
The Case for Induction Therapy
In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed "flipping the pyramid" – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.
"We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies," said Giovannoni, professor of neurology at Queen Mary University of London.
About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. "If you have MS, you've got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you're going to get the majority responding and a few of them will break through," said Giovannoni.
He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. "This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden," said Giovannoni.
Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. "We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera," said Giovannoni.
He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. "The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that's irreversible," said Giovannoni.
He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. "So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS," said Giovannoni.
There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.
"I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn't decide that for them," said Giovannoni.
Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.
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