MS Drugs Delay Conversion to Secondary Progressive Disease

November 07, 2017

PARIS — The various disease-modifying therapies now available for the treatment of multiple sclerosis (MS) delay the conversion from the relapsing-remitting form to the secondary progressive form of the disease, a new study suggests.

"Our results suggest that secondary progressive MS is — at least partially — a consequence of early inflammation, and the risk of conversion from relapsing-remitting to secondary progressive disease is modifiable over 5 years with existing therapies," said lead author of the study, Will Brown, MD, University of Cambridge, United Kingdom. 

The study also showed that the delay to conversion is greater with high-efficacy therapies, alemtuzumab and natalizumab, than with interferons/glatiramer acetate, and that all the treatments studied were more effective in delaying conversion if started earlier in the disease course.

"My take-home message is that all of these drugs have an influence on conversion and the greatest effect is seen with higher-efficacy treatment and early treatment," Dr Brown commented to Medscape Medical News.   

"This information is reassuring and should add into what we already know about how treatment reduces relapse rate and disability progression," he added. "This then needs to be considered with all the other factors that come into play when choosing a therapy, including safety, disease activity, and patient preference."

The study was presented here at the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting.

Dr Brown explained that the available disease-modifying therapies for MS do not the slow secondary progressive form of the disease once it has begun and randomized trials have not followed patients long enough to see an effect of drug therapies on conversion from the relapsing-remitting form to the secondary progressive form.

"Thus, despite its enormous consequences, conversion to secondary progressive MS has not been well studied as a trial endpoint. There have been a few previous observational studies that have tried to look at this and one post hoc analysis, but these have been largely limited to the early treatments (β-interferon/glatiramer acetate ) and have found conflicting results, probably because they have used varying methods."

"Therefore, the extent to which secondary progressive MS reflects early inflammation and whether the drug therapies used in the relapsing-remitting phase actually slow the time to conversion have remained unclear," he added.

To look at this issue further, Dr Brown and colleagues analyzed information from MSBase — the largest database of patients with MS worldwide, with more than 50,000 patients included — as well as two other patient cohorts, with patients followed for up to 18 years.

Dr Brown explained that one of the biggest problems with previous studies was that they have used different definitions of secondary progressive MS. 

"MSBase investigators have recently examined hundreds of definitions of secondary progressive MS in more than 17,000 patients and have shown that the one that has the best performance required an EDSS [Expanded Disability Status Scale] increase based on baseline EDSS score in the absence of a relapse, confirmed after 3 months, with a minimum EDSS of 4," he said. "Using this validated definition, we aimed to examine whether various drugs influenced conversion of relapsing-remitting MS to secondary progressive MS in patients taking a single therapy, and if the potency of these drugs and also early versus late treatment influenced this risk." 

The researchers examined data on the β-interferons and glatiramer acetate as well as higher-efficacy therapies: fingolimod, natalizumab, and alemtuzumab.

They identified patients treated with one of these drugs for at least 4 years (only patients who had ever taken a single drug therapy were included) and propensity-matched each patient to untreated patients from a historical cohort and to patients taking other disease-modifying treatments.

To minimize differences between patients, propensity scores were used to match patients according to sex plus baseline age, annualized-relapse rate, EDSS score, and disease duration. To avoid bias caused by lower-efficacy drug groups being used in milder disease through exclusion of patients having taken multiple drugs (such as treatment escalators), patients receiving the lower-efficacy drugs were limited to those followed up before higher-efficacy drugs became available in 2006.

Results showed that all the drugs examined significantly reduced the proportion of patients converting to secondary progressive MS.  

The individual hazard ratios (HR) for were each drug were as follows: 

  • β-Interferons/glatiramer acetate HR, 0.31 (P < .001); median on-treatment follow-up, 7.9 years;

  • Fingolimod HR, 0.23 (P < .001); median on-treatment follow-up, 4.6 years;

  • Natalizumab HR, 0.50 (P = .001); median on-treatment follow-up, 4.9 years; and

  • Alemtuzumab HR, 0.60 (P = .01); median on-treatment follow-up, 7.2 years.

With matching between the treated cohorts, conversion to secondary progressive MS did not significantly differ between alemtuzumab and natalizumab recipients, so these two groups were combined as "high-efficacy therapies" (n = 118) and matched and compared to patients receiving β-interferon or glatiramer acetate (n = 236).  Results of this analysis showed that high-efficacy therapies conferred greater protection against conversion to secondary progressive MS than did interferon or glatiramer acetate (HR, 0.65 [P = .038]; follow-up, 5.7 years).

Another analysis showed that patients treated with β-interferon or glatiramer acetate within 5 years of their first relapse had a significant advantage over those treated more than 5 years since their first relapse. After up to 18 years of follow-up, 33% of patients who started treatment within 5 years of their first relapse had converted to secondary progressive MS vs 58% of those who began treatment later than 5 years.  

The same patterns were seen with each of the higher-efficacy therapies.

On the question of whether secondary progressive disease is being delayed or actually being prevented by drug treatment, Dr Brown said, "We can't answer this for sure as we need even longer-term follow-up." However, he presented data to suggest that early treatment was staving off conversion long term.

"When we look at untreated patients vs β-interferon/glatiramer acetate started within 5 years of first relapse, the lines mapping conversion rates are getting further apart all the way out to 15 years' duration. But when we look at those patients starting treatment after 5 years, there is only a transient benefit, and after 12 years, lines start to come together, and by 14 years they cross," he said.

More Effective Therapies Better Early?

In another presentation based on data from MSBase registry and propensity matching of patients receiving various therapies, Tomas Kalincik, MD, University of Melbourne, Australia, reported that the differences in annualized relapse rate reduction seen between the more effective therapies — fingolimod, natalizumab, and alemtuzumab — and the β-interferons/glatiramer acetate group diminished with time, age, and higher disability levels.

"We are saying high-efficacy therapies are more effective when they are used early," Dr Kalincik told Medscape Medical News.

"Both this study and the analysis presented by Dr Brown on conversion to secondary progressive MS are suggesting that we should think about treating patients with the more highly efficacious treatments earlier rather than later in the disease course," he said. 

 The MSBase registry is supported by the independent MSBase Foundation Ltd, a health-related charity incorporated in Melbourne, Australia. Dr Brown reports travel expenses for attending conferences or teaching courses from Novartis, Biogen, and Sanofi Genzyme. Dr Kalincik served on scientific advisory boards for Roche, Genzyme-Sanofi, Novartis, Merck, and Biogen and the steering committee for Brain Atrophy Initiative by Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Genzyme-Sanofi, Teva, BioCSL, and Merck; and received research support from Biogen.

7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting. Abstracts 128 and 231. Presented October 27, 2017.

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