More Evidence Supports Early Start to Therapy in MS

Pauline Anderson

August 11, 2016

More evidence supports the benefit of starting interferon β-1b therapy as soon as possible after onset of multiple sclerosis (MS) symptoms.

The 11-year follow-up of patients enrolled in the BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment) trial shows that early vs delayed treatment reduced the risk for conversion to clinically definite MS (CDMS) by 33.0% and decreased relapse rate, especially early in the disease.

"Up to now, there have been several studies including BENEFIT showing short-term benefits of early treatment, but the question was, does this still pay off 11 years later," said lead author Ludwig Kappos, MD, professor and chair of neurology, University Hospital, Basel, Switzerland.

"This is the first study with complete enough follow-up, and long enough follow-up, to answer that question."

Dr Ludwig Kappos

The new results, which include additional outcomes, such as employment status and resource use, were published online August 10 in Neurology.

In the phase 3 multicenter BENEFIT trial, 468 patients with clinically isolated syndrome (CIS), which means a first acute or subacute episode of neurologic dysfunction highly suggestive of MS, were randomly assigned to immediate treatment or delayed treatment.

The immediate treatment group (n = 292) received interferon β-1b, 250 μg, administered subcutaneously every other day. The delayed treatment group (n = 176) initially received placebo.

After conversion to CDMS or up to 2 years (a mean of 1.5 years), all patients could have treatment with interferon β-1b or another or no disease-modifying therapy.

The 5-year BENEFIT trial and its 8-year extension showed improved outcomes in patients who initiated treatment immediately after CIS compared with those who started treatment after their second clinical event or up to 2 years. These studies showed delays in conversion to CDMS and reduction in the annualized relapse rate (ARR), but only a small change in mean Expanded Disability Status Scale (EDSS) score in both treatment groups.

Long-Term Follow-up

Of the original 468 patients, 59.4% were included in the 11-year follow-up study. This newest analysis found that the risk for conversion to CDMS was still reduced for patients in the early treatment group compared with those in the delayed treatment group (hazard ratio [HR], 0.670; 95% confidence interval [CI], 0.526 - 0.854; P = .0012).

Time to CDMS was shorter in the delayed-treatment group as well as time to first relapse (HR, 0.655; 95% CI, 0.517 - 0.830; P = .0005). Risk for a first relapse was reduced by 34% in the early treatment group compared with the delayed treatment group.

The overall ARR during the 11-year study was lower in the early treatment than in the delayed treatment group, resulting in a 19.1% reduction in risk for relapse (risk ratio [RR], 0.8094; 95% CI, 0.7090 - 0.9242; P = .0018).

The overall lower ARR in patients with earlier treatment appeared to be driven mainly by differences in the first year of the core study. However, write the authors, "it is intriguing" that in the early treatment group, ARR remained lower in all but 2 of the follow-up years — when treatment with interferon β-1b was available to both groups.

The "burning question," said Dr Kappos, is whether this outcome would have been even better with a more effective drug than interferon.

The new study provides Class IV evidence that time to CDMS was prolonged. Dr Kappos noted that the evidence grade would have been higher had there been a continuous control group.

For the Paced Auditory Serial Addition Test-3, a measure of cognitive dysfunction in MS, data were available at baseline and at year 11 for 222 patients.

During the entire study period, total scores, adjusted for baseline score, were higher in the early treatment group. However, processing speed did not differ, as measured by the Symbol Digit Modalities Test, which, Dr Kappos pointed out, was done only during follow-up. Thus, it was not possible to adjust for baseline results.

EDSS scores also did not differ between treatment groups, with scores of participants remaining low and stable. By year 11, 69.8% of patients were fully ambulatory, with minor or no signs of disability (EDSS score <3.0).

As well, the groups had similar healthcare resource utilization. And overall, 73.4% of all patients were still employed, compared with 81.3% at study start.

Relative Stability

These stable results compare favorably with outcomes reported in natural history cohorts (in many cases, patients not receiving treatment). A possible explanation for this relative stability, said Dr Kappos, is that both groups can be considered to have received treatment relatively early.

"This shows that even if you delay treatment by 1.5 years, you still seem to have a positive impact on the disease," said Dr Kappos. "I think it's important that patients who are newly diagnosed with clinical isolated syndrome or very early MS have this perspective."

He noted that while some patients may expect "a catastrophe" following their first symptoms, the delayed treatment group in this study had a relatively good outcome, with a first-generation drug that is only partially effective.

A smaller proportion of patients in the early treatment group (4.5% vs 8.3%) developed secondary progressive MS, but this was not significant (P = .4857), possibly because of the small number of events.

The frequency and type of adverse events in study patients were consistent with those known to be associated with interferon β-1b.

The study suggests that there may be advantages in some areas but not in others. Individual patients must decide on what approach to pursue, said Dr Kappos, who estimates that about 70% of patients with early MS symptoms choose immediate treatment.

The authors stressed that a factor that may be critical to interpreting the new data is the uncontrolled nature of treatment after the placebo-controlled phase.

The researchers are planning another BENEFIT follow-up at year 15.

Retention Rate

For authors of an accompanying editorial, the high retention rate was one of the study's strengths. Other strengths, said Brian C. Healy, PhD, Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Boston, Massachusetts, and Brian G. Weinshenker, MD, Department of Neurology, Mayo Clinic, Rochester, Minnesota, were the similarities between participants in this study and the original sample and between the two treatment groups in this most recent analysis.

"Since BENEFIT 11 participants are comparable to those in the original trial, the results from this study would likely be unchanged had all participants contributed. Furthermore, since the treatment groups who are compared in BENEFIT 11 are balanced as in the original trial, it seems unlikely that the treatment group differences are driven solely by differential dropout between the 2 treatment arms."

However, unidentified biases could influence interpretation of the results, they said.

Despite the study's "excellent design and analysis," comparisons of outcomes in these patients with natural history studies "must be considered cautiously," write Dr Healy and Dr Weinshenker.

With new MS therapeutic options, obtaining long-term outcome information on patients taking different agents at different points in time "will be necessary to determine the best practices for managing recently diagnosed patients at what is emerging to be a critical point in their disease course," they conclude.

The study was supported by Bayer HealthCare Pharmaceuticals. Dr Kappos' institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support the following: steering committee/ consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems AG; and grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. Dr Healy is on the Biogen Worldwide Medical Biostatistics Multiple Sclerosis Advisory Board and has received grant support from Genzyme, Merck Serono, Novartis, and Verily Life Sciences. Dr Weinshenker is a member of the data safety monitoring board for Novartis and Mitsubishi and an adjudication committee for MedImmune. He was supported by Alexion for attendance at a scientific meeting. He receives royalties from RSR Ltd and from Oxford University for a patent for neuromyelitis optica IgG for diagnosis of neuromyelitis optica.

Neurology. Published online August 10, 2016. Abstract Editorial

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