Two years ago, NeuroSens concluded its eight-part series on sequencing disease-modifying therapies (DMT) in multiple sclerosis. Expert commentaries were provided by Canadian MS specialists, including Drs. Mark Freedman, Ottawa; Michael Yeung, Calgary; Paul Giacomini, Montreal; Daniel Selchen, Toronto; Jiwon Oh, Toronto; and Marc Girard, Montreal. Each article was accompanied by a reader survey to identify clinicians’ goals of therapy, DMT use and perceptions about the relative benefits and risks of different treatment sequences.
Since that time, the therapeutic landscape has changed with the introduction of new DMTs (ocrelizumab, cladribine, peg-interferon-1a), the withdrawal of another (daclizumab), the availability of treatments for progressive MS (ocrelizumab, siponimod in some countries) and the emergence of new treatment-related adverse effects. So it may be timely to review how sequencing therapies was approached two years ago as a prelude to surveying readers about how they view things now. We would ask that you complete the new sequencing survey and we’ll report on the results later this year.
The view from 2017
The NeuroSens series of surveys ran from November 2016 to December 2017 and included 48 questions about drug mechanisms of action, treatment initiation, response assessment, safety considerations, optimizing therapy and sequencing. The series of articles and accompanying audio roundtable were accessed 3927 times by Canadian neurologists, of whom 171 responded to the surveys.
Drug mechanism of action (MOA): In general, a drug’s MOA was not seen as influencing treatment choice when initiating therapy in patients with RRMS. Most respondents viewed T and B cells as the most important therapeutic targets (rather than either alone). In addition, 28% thought that the immune target changes during the course of MS, a view that appears to be supported by emerging data on compartmentalized inflammatory processes in progressive MS. MOA was seen as more important at the time of switching therapies, which appears to reflect safety concerns and the potential risks of additive or cumulative effects on the immune system with sequenced therapies.
Treatment initiation: The preferred starting therapies among respondents were teriflunomide and dimethyl fumarate, reflecting the beginnings of a shift away from injectable to oral DMTs. About one-half of respondents said that lesion number at first presentation was the main factor identifying those at risk of early disability progression. It should be noted that the MAGNIMS group had stated that pretreatment MRI measures were not predictive of treatment response (Wattjes et al. Nat Rev Neurol 2015;11:597-606) but the guidelines may not have been widely disseminated at the time of the survey.
The choice of treatment among respondents was largely determined by safety and tolerability considerations rather than greater efficacy. The most common approach was to initiate any therapy and plan to switch in the event of breakthrough disease activity. However, subsequent surveys raised questions about whether this strategy is carried out in practice.
Evaluating treatment response: Most respondents (69%) stated that they evaluated treatment response according to clinical (relapses, EDSS) and MRI findings, an approach advocated by the Canadian Treatment Optimization Recommendations (Freedman et al. Can J Neurol Sci 2013;40:307-323). Relapses were most often evaluated every six months, and MRIs were commonly obtained annually in the first few years of treatment.
No evidence of disease activity (NEDA) was not considered to be an achievable or sustainable goal, which reflected the findings from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB) cohort study (Rotstein et al. JAMA Neurol 2015;72:152-158). As a consequence, one-third of respondents stated that they would accept some clinical/radiological worsening if patients were satisfied with their initial therapy.
Overall, 90% of clinicians said they relied on MRI to determine if a patient had stable disease. Most respondents believed that a majority of their patients on an initial therapy remained stable for 2 years (79%) or 3-5 years (66%). It was only after five years on a first-line therapy that 52% of respondents thought that most of their patients would no longer have stable disease. The Catch-22 was that stable disease would be determined with an MRI, but after five years an MRI would only be ordered if the patient were no longer stable. There was a slight preference for escalation for treated patients with breakthrough disease activity: 50% said they would escalate immediately; 40% said they would not change treatments immediately but would await further confirmation of worsening disease; and 10% said they would try a lateral switch. The preferred DMTs for escalation were fingolimod and natalizumab (ocrelizumab and cladribine were not available at the time of the survey).
Sequencing: A lateral switch was the preferred approach for patients with poor tolerability to an initial therapy. The simplest switches were from glatiramer acetate or from DMF whereas switching from teriflunomide or an interferon was seen as more difficult. The safest switches were to teriflunomide, fingolimod and DMF.
The goal of escalation was primarily to increase treatment efficacy, although safety issues remained important. When escalating to a second-line DMT, fingolimod was perceived to be the safest option and the easiest therapy to sequence. The least preferred sequence was a switch from natalizumab to alemtuzumab. The main safety concern was progressive multifocal leukoencephalopathy (PML), followed by equal concerns about lymphopenia, malignancy and infections. The main safety concerns with individual DMTs were opportunistic infections (fingolimod), PML (natalizumab), malignancy and B cell depletion (ocrelizumab) and secondary autoimmunity.