#MSVirtual2020 – 13-year Data Find Tecfidera Safe, Reduces RRMS Relapses

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Long-term treatment with Tecfidera (dimethyl fumarate) continues to be safe and effective at reducing the frequency of relapses and disability progression in patients with relapsing-remitting multiple sclerosis (RRMS), according to 13-year data from a Phase 3 extension study.

The study findings were presented at MSVirtual2020 by Ralf Gold, MD, PhD, professor and chair of the department of neurology at St. Josef-Hospital, Ruhr University Bochum, in Germany, in an oral presentation titled, “Safety and Efficacy in Patients Treated With Dimethyl Fumarate and Followed For 13 Years: Final Results of ENDORSE.” The 8th joint MS meeting was held online Sept. 11-13.

Marketed by Biogen, Tecfidera is an oral disease-modifying therapy, or DMT, approved as a first-line treatment for relapsing MS in the U.S., Canada, Australia, and Europe.

The medication is thought to lower inflammation and oxidative stress — cell damage caused by high levels of oxidant molecules — in the central nervous system (CNS), comprised of the brain and spinal cord. It works by interfering with a signaling pathway involving Nrf2, a protein that controls the activity of genes that regulate oxidative stress.

Data from two previous Phase 3 trials, DEFINE (NCT00420212) and CONFIRM (NCT00451451), had shown that Tecfidera was superior to a placebo at lowering the frequency of relapses and disease progression in people with RRMS. Each trial spanned two years.

Now, Gold presented final 13-year data from the ENDORSE (NCT00835770) trial. That Phase 3 extension study sought to evaluate the long-term safety and efficacy of Tecfidera in RRMS patients who participated in, and completed, either the DEFINE or CONFIRM trials.

During ENDORSE, all patients received Tecfidera at a dose of 240 mg, either two or three times daily.

In addition to the treatment’s safety, the trial investigators evaluated Tecfidera’s effectiveness at lowering the frequency of MS relapses — assessed by the annualized relapse rate (ARR) — and disability progression, based on patients’ scores on the expanded disability status scale (EDSS).

Earlier data from ENDORSE, presented last year at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), showed Tecfidera reduced the number of MS relapses and halted disability progression in a group of 618 people with RRMS who had been followed for 10 years.

As of the Jan. 23, 2020 cut-off date, a total of 1,736 RRMS patients (mean age of 40 years) had enrolled and received at least one dose of Tecfidera in ENDORSE. Only the subset of 750 patients who were treated with Tecfidera’s current recommended dosage of 240 mg twice daily in the extension study were selected to be included in the final analyses.

After completing two years of treatment in DEFINE or CONFIRM, patients were followed for up to 11 years (median of 6.8 years) in ENDORSE.

In the group of 501 patients who received Tecfidera continuously between trials, the ARR remained low over time, with a mean of 0.20 in the first year and 0.11 in years 9-10.

Meanwhile, among the 249 patients who only received Tecfidera in the ENDORSE trial — and not on DEFINE/CONFIRM — the ARR only started to drop after they began treatment with Tecfidera. The findings showed a mean ARR of 0.33 in the original trials and 0.15 in ENDORSE in years 2-10.

In general, the proportion of participants who remained free of relapses during the extension study was similar among patients who received continuous treatment with Tecfidera (45%) and in those who only started treatment with Tecfidera in ENDORSE (42%).

Likewise, the percentage of patients whose EDSS scores remained equal to 3.5 — corresponding to moderate disability — or lower were similar in both groups on years two and 10 of follow-up. Specifically, the results for year two were 86% versus 82% in those who started Tecfidera in ENDORSE; for year 10, the results were 77% versus 74% in the group treated with Tecfidera only during ENDORSE.

“Overall, it is better to treat [with Tecfidera] early,” Gold said during the presentation.

Further, “these are very good news,” Gold added, “because when I started [working on] neurology three decades ago it was clear that 70% could no longer walk after 10 years of MS, so DMF [Tecfidera] gives new life quality.”

The proportion of participants who had no confirmed disability progression for 24 weeks (six months) over 10 years also was nearly identical in those who were always treated with Tecfidera (72% of patients)  and in those who only started treatment in ENDORSE (73%).

Patients’ walking ability also remained stable throughout the study, as well as patient-reported outcomes regarding quality of life and general health status.

Regarding safety, a total of 551 patients (32%) experienced serious adverse events during follow-up, which were, in most cases, MS relapses and falls. The most common adverse events included a minor throat diease (nasopharyngitis), urinary tract infections, and flushing on the face, neck and chest; these symptoms were, for the most part, only mild to moderate in severity.

A total of 282 patients (16%) discontinued treatment due to adverse events. Other causes for discontinuation included MS relapses, gastrointestinal disorders, and disease progression.

One of the participants developed progressive multifocal leukoencephalopathy (PML), a serious brain infection associated with the John Cunningham virus, during ENDORSE. The incidence of other infections or serious infections was low.

Patients’ total levels of white blood cells dropped in the first 48 weeks of ENDORSE, but then tended to remain stable for the majority of the study. No increased incidence of opportunistic infections, cancer, or shingles was observed.

In conclusion, “the overall risk-benefit ratio of DMF [Tecfidera] remained favorable,” Gold said. “We observed low rates of relapses sustained throughout 10 years of treatment with DMF. Also, the confirmed disability progression was low, and patients generally maintained the ability to walk without disability throughout 10 years of treatment.”

According to Gold, “These long-term safety and efficacy data support DMF as a long-term treatment option for patients with relapsing MS.”

He added that this result “gives our MS patients new hope … that we can stop [the disease] to a significant percentage of patients without major side effects.”

Of note, Gold mentioned that “as of June 30 [2020], DMF is the mostly used of all drugs against MS in the world, [as] more than 475,000 patients have been treated” with this therapy.

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