Sequencing MS therapies – a changing landscape


Comment by Dr. Virender Bhan – Senior neurologist, Burnaby/Vancouver, BC, Canada.

NeuroSens recently posted a survey on sequencing disease-modifying therapies (DMTs) in multiple sclerosis to investigate whether clinicians’ approaches have changed in the past 2-3 years. The current survey was a follow-up to a series of surveys conducted over a one-year period ending in December 2017 that accompanied an 8-part article on sequencing. (For a summary of those results see Are opinions changing on changing therapies in MS?, NeuroSens, October 22, 2019).

The 2019 survey obtained 26 responses over the four-week period. A total of 62% of clinicians had >15 years of experience in treating MS, 15% had 5-10 years’ experience and 23% had < 5 years’ experience. A majority (70%) of clinicians stated that the primary goal of therapy was to reduce long-term disability progression. Few respondents said the goal was to suppress inflammation (15%) or reduce relapses (15%). Improvement in MS symptoms was not a stated goal, consistent with MS treatments as disease-modifying rather than symptomatic therapies.

A majority stated that the goal of immune modulation was to suppress T and B cells (39%) or to target pathogenic lymphocyte subsets (31%), such as Th17 or memory T/B cells. Targeting lymphocyte subsets was not cited in the previous surveys, which may reflect recent studies or a more nuanced view of immunomodulation that has emerged. Few respondents stated that the goal was to suppress B cells only (8%) or to induce a Th1 to Th2 shift (8%). The increasing use of B cell-directed therapies suggests that treatment selection may be influenced by the perceived efficacy of this class of drugs rather than mode of action, or the opinion that B cell suppression has collateral effects on T cell activity. A Th1/Th2 shift represents a more immunomodulatory approach; the low number of responses suggests that this notion has been eclipsed by the current focus on immunosuppression.

Treatment selection
As in the previous surveys, the current preferences when initiating treatment are teriflunomide (39%) and dimethyl fumarate (23%), although many continue to favour interferon-β agents (15%) or glatiramer acetate (15%). This continues the trend to first-line oral therapies and away from injectables. No respondent opted for natalizumab, fingolimod or cladribine as the preferred starting therapy, which likely reflects label restrictions and reimbursement requirements.

In the 2016/2017 surveys, the initial DMT choice was largely determined by safety and tolerability considerations rather than greater efficacy. In the present survey, the reason for preferring a first-line oral DMT was the favourable balance between efficacy and safety (80%). Only 15% stated that safety was more important than efficacy, while 5% said that treatment selection was influenced by patient preference. No respondent said they chose a first-line agent because of tolerability.

For newly-diagnosed patients with aggressive or rapidly-evolving MS, the preferred starting therapies were ocrelizumab (43%) and natalizumab (23%). This is a substantial change from 2017 (ocrelizumab was approved in Canada at the end of the initial survey period). Natalizumab has maintained its usefulness in achieving rapid control of inflammatory disease activity. Other higher-efficacy options, such as cladribine (8%) and alemtuzumab (8%), were generally not preferred. No respondent selected fingolimod in this setting. About 15% of respondents would initiate treatment with a first-line agent, which may reflect label/reimbursement requirements rather than preferences.

For breakthrough disease activity in patients currently on treatment, there has been a significant shift away from fingolimod for escalation: fingolimod was perceived to be the safest option and the easiest therapy to sequence in 2016/2017, whereas it was the preferred escalation agent for only 8% of respondents in 2019. This may be due to the availability of more effective alternatives or a change in the perceived safety of the drug. At present, the preferred DMTs for escalation are ocrelizumab and cladribine (31% each), followed by natalizumab (15%). Only 8% selected alemtuzumab, which may reflect a general trend away from alemtuzumab in recent years. Also noteworthy was that few would opt for a lateral switch (8%), indicating a greater preference for escalation in patients with a suboptimal response to an initial DMT.

Sequencing therapies
The 2019 survey asked about the preferred agents for use before and after a given list of higher-efficacy DMTs to obtain some insight on actual treatment sequences that might be employed in practice. The preferred sequences were:

Cladribine: Preferred use was in patients previously untreated (33%) or after natalizumab (33%). After cladribine was stopped, the preferred next agent was ocrelizumab (60%).

Fingolimod: Preferred use was in patients previously untreated (40%). After fingolimod was discontinued, most would switch to ocrelizumab (70%).

Natalizumab: Would commonly be used after fingolimod (40%). After stopping natalizumab, most would switch to ocrelizumab (63%).

Ocrelizumab: Commonly used in patients previously treated with fingolimod (42%). After discontinuing, many would switch to alemtuzumab (44%).

Alemtuzumab: Often preferred in patients after ocrelizumab (33%). If another therapy were needed, many would switch to ocrelizumab (50%).

The results suggest that clinicians would generally prefer to use oral therapies (cladribine, fingolimod) either in newly-diagnosed patients or early in the treatment course. The preference for a fingolimod-to-natalizumab switch may be due to the evidence base for this sequence; most other sequences have not been studied. Also important is the emergence of ocrelizumab as the preferred agent in many treatment sequences. Respondents provided written-in responses (rather than being provided with a list of options), so it is noteworthy that no respondent considered de-escalation as an option.

When asked to rate their level of concern with various potential side effects, progressive multifocal leukoencephalopathy (PML) was rated highest (mean 3.92 out of 5). It should be noted that a PML case was reported with ocrelizumab when the survey was running (PML reported in patient newly-treated with ocrelizumab, NeuroSens, October 30, 2019). There was also a high level of concern about infection risk (3.82), which may reflect a perceived risk associated with cumulative immunosuppressant exposure or recent case reports of opportunistic infections. There was a low level of concern with manageable (ITP, 2.19) or rare (stroke/arterial dissection, 2.7) adverse events.


Dr. Virender Bhan: The NeuroSens survey results offer an interesting contrast to the findings of over two years ago, a testimony to how rapidly the DMT landscape in Canada is evolving. A majority of respondents felt that the primary goal of DMT is reduction of “long-term disability” and only a few chose suppression of inflammation (new MRI activity and relapses). I find this interesting as the evidence to date suggests that the current DMTs are primarily effective in reducing inflammation and short-term disability progression. The effect on long term disability is not yet established.

Most neurologists stated that the goal of DMTs was to suppress T and B cells or to selectively target pathogenic lymphocyte subsets. This is also a change from before when the mode of action was not an important consideration. The increased use of B cell depleting therapies may account for this emerging nuanced view of immunomodulation and immunosuppression.

The survey results for initiating DMTs indicate increasing use of oral agents, although a minority are still using older injectables. I suspect that this trend will continue. In choosing a DMT, an important consideration for most respondents was the efficacy/safety balance rather than safety/tolerability alone. This represents a significant and welcome change from just over two years ago. Another change from the previous survey is that in newly-diagnosed aggressive MS, ocrelizumab is emerging as the top choice, with very few choosing alemtuzumab, fingolimod or cladribine. Interestingly, natalizumab has retained its position, with one-quarter of respondents opting for it.

A significant (and welcome) shift is in the DMTs considered for breakthrough disease activity, with a majority of neurologists now opting for escalation and only 8% voting for a lateral switch. The most preferred DMTs for escalation were ocrelizumab and cladribine, followed by natalizumab. Very few respondents chose alemtuzumab and fingolimod – representing a significant decline from just over a couple of years ago. In particular, fingolimod has gone from being the “most favoured and easy to use” escalation drug to being the preferred escalation DMT for less than 10% of respondents in the current survey – an interesting trend, especially with several new S1P receptor modulators entering the arena.

In sequencing higher efficacy therapies, the survey results are likely speculative and based on neurologists’ perceptions and experience. This is not surprising as there is currently very little or no evidence in this area. Further, it is unlikely that we will ever have high-quality evidence for higher-efficacy DMT sequencing, although ongoing and future observational studies may help guide us. Meanwhile, neurologists will have to deal with such situations on a case-by-case basis, keeping all the relevant factors in mind and using a logical and rational approach.

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