COPENHAGEN, Denmark — Latest results from the clinical trial program with BG-12 (dimethyl fumarate; Tecfidera, Biogen Idec) suggest sustained clinical efficacy and safety in patients with multiple sclerosis (MS) taking the drug for up to 4 years.

In addition, a separate post hoc analysis of the phase 3 pivotal Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting MS (DEFINE) and Comparator and an Oral Fumarate in Relapsing–Remitting Multiple Sclerosis (CONFIRM) clinical trials shows that BG-12 reduced relapses and disease activity in treatment-naive patients.

The latest long-term results come from the ENDORSE study, an extension phase of the DEFINE and CONFIRM trials.

Commenting on these results for Medscape Medical News, Bernd Kieseier, MD, Heinrich Heine University, Düsseldorf, Germany, who did a talk rounding up meeting highlights including these new results, said, "These are reassuringly meaningful clinical results showing that the effects of BG-12 over 2 years are maintained in the third and fourth year, with no additional safety concerns."

Ralf Gold, MD, St. Josef-Hospital/Ruhr-University in Bochum, Germany, a leading investigator in the extension study, said, "When making MS treatment decisions, we weigh efficacy and safety considerations, so it is encouraging to see that the positive profile of BG-12 observed in the DEFINE and CONFIRM studies has been maintained in the ENDORSE clinical trial to date."

These data were presented at the recent 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Newest Oral Therapy

BG-12 is one of the new oral therapies for multiple sclerosis. It was approved by the US Food and Drug Administration in the United States and is going through the reimbursement process in Australia and Canada.

In Europe, regulatory authorities are still reviewing the drug, with "data exclusivity" discussions ongoing. Biogen told Medscape Medical News that it has strong patent protection for the product, but the company is in discussions with the European authorities on regulatory data protection "to ensure maximum coverage is in place."

Of the 2651 patients who participated in DEFINE and CONFIRM, 1736 were enrolled in ENDORSE. Patients who received BG-12 in the DEFINE or CONFIRM studies continued receiving the drug at the same dosage — twice daily (BID) or 3 times daily (TID) — in ENDORSE. Patients who received placebo in DEFINE or glatiramer acetate (GA) in CONFIRM were randomly assigned to BG-12 BID or TID.

Interim efficacy results at 2 years into ENDORSE suggest efficacy and safety of BG-12 similar to those shown in the DEFINE and CONFIRM studies.

Table 1. ENDORSE Results at 2 Years After Treatment in CONFIRM/DEFINE

Variable BG-12, BID Only BG-12 TID, Only Placebo/BG-12, BID Placebo/BG-12, TID GA/BG-12, BID GA/BG-12, TID
Annual relapse rate 0.142 0.198 0.126 0.138 0.128 0.184
Patients relapsed (%) 36.2 38.0 48.7 49.6 40.9 43.2
Disability progression (%) 15.4 16.8 19.9 21.4 23.1 16.4
Serious adverse drug reactions (%) 18 19 22 15 13 18
Treatment discontinued because of adverse drug reactions (%) 4 6 16 16 14 23

 

Professor Kieseier commented to Medscape Medical News: "The obvious question at the end of a 2-year clinical trial is: 'Will these results be maintained over time?' We can see from these latest results that the benefit has been maintained, and in the patients switched from placebo or glatiramer acetate the annual relapse rate has come down to a similar level as those who were taking BG-12 long-term."

He added: "Of course, it would be nice to have a comparison with placebo long term but this can't be done, so the closest we can get is to follow patients to see if a low level of disease activity continues and that seems to be the case. We are seeing a similar relapse rate in the third and fourth years as we did in the first and second year of BG-12 treatment. That is encouraging."

Professor Kieseier noted that annual relapse rates of 0.1 to 0.2, as seen in ENDORSE, are typical of what is achieved with other long-term effective drug therapies. "We don't have a drug that gets this down to zero," he said.

In terms of safety, no new adverse effects were reported in patients continuing to receive BG-12 in ENDORSE. The most common adverse events in patients who were switched to BG-12 from placebo or GA were flushing and gastrointestinal events, the incidences of which were generally similar to those observed in DEFINE and CONFIRM, Biogen reports. The most common adverse event in patients continuing to receive long-term BG-12 is nasopharyngitis (common cold).

Similar to what was seen in CONFIRM and DEFINE, mean lymphocyte counts in patients who switched to BG-12 in ENDORSE decreased over the first year of treatment and then plateaued. The incidence of lymphocyte counts 0.5 × 109/L was 6% to 8% in the continued BG-12 groups and 5% to 9% in the new-to-BG-12 groups.

 
The driving interest in this drug at the moment is its good efficacy paired with good tolerability, and these results show that this profile continues to be there in the long term. Professor Bernd Kieseier
 

For patients who continued treatment with BG-12, mean lymphocyte counts were generally stable and mean counts remained within normal limits at all time points, the researchers note. They add that there was no overall increased risk for serious infections or malignancies in patients continuing to receive, or new to, BG-12 treatment. And there was no overall increased risk for renal dysfunction or hepatic adverse events in any treatment group.

Asked about the lymphocyte count reduction, Professor Kieseier said, "It is something that needs to be considered, but I don't think it is a major concern. The other drugs also show this effect. But it seems to happen relatively infrequently with BG-12."

He added that BG-12 did not seem to have severe toxicities. "Patients will appreciate that. The driving interest in this drug at the moment is its good efficacy paired with good tolerability, and these results show that this profile continues to be there in the long-term."

MRI results from ENDORSE showed continued that treatment with BG-12 resulted in a low frequency of new/enlarging T2 hyperintense lesions, new nonenhancing T1 hypointense lesions, and gadolinium-positive lesions over 4 years. Patients initially randomly assigned to placebo or GA who then received BG-12 in ENDORSE demonstrated MRI outcomes similar to those observed with BG-12 treatment in the parent studies.

Treatment-Naive Patients

In a separate post hoc analysis from the phase 3 DEFINE and CONFIRM studies of 678 new treatment-naive patients with MS, BG-12 was associated with a 50% reduction in relapse rate compared with placebo. Patients taking BG-12 also had a significantly reduced risk for disability progression and a significant positive effect on MRI outcomes in this patient population.

Table 2. DEFINE/CONFIRM: Results at 2 Years in Treatment-Naive Patients

Variable Placebo BG-12, BID BG-12, TID
Annual relapse rate 0.38 0.17 0.15
Patients relapsed (%) 42.2 21.3 20.5
Patients with disability progression (%) 23.3 7.3 13.5
Mean gadolinium-positive lesions (n) 1.9 0.3 0.2
Mean new/enlarging T2 lesions (n) 20.0 4.0 3.9
Mean T1 hypointense lesions (n) 6.6 2.1 2.0

 

Several researchers involved in these studies are employees of Biogen Idec. Dr. Gold receives honoraria and/or research support from Bayer, Biogen Idec, Merck Serono, Novartis, and Teva. Professor Kieseier has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Health Care, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, sanofi-aventis, and TEVA.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Poster #538, #990, #996, and #1004. Presented October 3 and 4, 2013.

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