Neurology Xagena

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Multiple sclerosis: long-term favorable safety profile sustained in patients treated with Dimethyl fumarate

Five-year results from the ENDORSE phase 3 extension study have shown Dimethyl fumarate ( Tecfidera ) provides strong and sustained efficacy in a broad range of people living with relapsing-remitting multiple sclerosis ( RRMS ). These data were presented at the Sixth Triennial Joint Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis ( ACTRIMS-ECTRIMS ).

Across all patients in the ENDORSE study who received Dimethyl fumarate, including some patients who were treated for up to seven and a half years, the safety profile remained consistent with no new or worsening safety signals.

ENDORSE is a global, dose-blind extension study evaluating the long-term safety and efficacy of Dimethyl fumarate ( 240 mg, dosed twice a day [ BID ] or three times a day [ TID ] ).
Patients who received up to two years of Dimethyl fumarate in the pivotal phase 3 DEFINE and CONFIRM studies continued on the same dose in ENDORSE. Patients who previously received placebo or Glatiramer acetate ( Copaxone; 20 mg subcutaneous daily injection; CONFIRM only ) in DEFINE and CONFIRM were randomized 1:1 to Dimethyl fumarate BID or TID.

At five years ( two years in DEFINE or CONFIRM and three years in ENDORSE ), interim results show that patients who continued on Dimethyl fumarate BID treatment experienced sustained clinical efficacy on relapse and disability progression endpoints as measured by annualized relapse rate ( ARR ) and 24-week Expanded Disability Status Scale ( EDSS ), similar to what was observed after two years in DEFINE and CONFIRM. These patients also maintained a low frequency of brain lesions over five years as measured by new or enlarging T2-hyperintense lesions, new non-enhancing T1-hypointense lesions and gadolinium-enhanced [ Gd+ ] lesions.

An analysis of data from ENDORSE evaluated the long-term efficacy of Dimethyl fumarate in newly diagnosed patients, defined as those diagnosed within one year prior to enrolling in DEFINE or CONFIRM and either disease modifying treatment-naïve or previously treated with corticosteroids alone.
Over the five-year observation period, newly diagnosed patients taking Dimethyl fumarate BID experienced sustained reductions in relapses ( measured by ARR and proportion of patients who relapsed ), disability progression ( measured by 24-week EDSS ) and number of brain lesions.
These effects are similar to the results reported for the overall ENDORSE study population, supporting the consistent efficacy of Dimethyl fumarate in this subpopulation.

Another analysis from ENDORSE evaluated the long-term effects of Dimethyl fumarate on the emerging measure of No Evidence of Disease Activity ( NEDA ) over five years. Patients were assessed annually and were considered to have NEDA if they had: no relapses, no 24-week confirmed disability progression, no Gd+ lesions, and no new or enlarging T2-hyperintense lesions.
Results over five years have shown that the proportion of patients achieving NEDA annually was maintained in patients who continued on Dimethyl fumarate, and was improved in patients who switched from placebo to treatment with Dimethyl fumarate BID in the ENDORSE study.

The safety profile of Dimethyl fumarate observed in ENDORSE was consistent with the favorable findings reported in the DEFINE and CONFIRM studies. There were no new or worsening safety findings observed in patients who continued treatment with Dimethyl fumarate from DEFINE and CONFIRM or in patients who switched to Dimethyl fumarate therapy after the conclusion of the pivotal studies.

All patients in ENDORSE had received treatment with Dimethyl fumarate for at least five years if previously on Dimethyl fumarate in DEFINE or CONFIRM, including some patients who had received Dimethyl fumarate for up to seven and a half years cumulatively. Patients previously on placebo in DEFINE or CONFIRM had received Dimethyl fumarate in ENDORSE for at least three years.

The most common adverse events in patients who switched to Dimethyl fumarate from placebo or Glatiramer were flushing and gastrointestinal events, the incidences of which were generally similar to what was observed in DEFINE and CONFIRM.
In patients continuing on Dimethyl fumarate therapy, the most common adverse events were multiple sclerosis relapse and nasopharyngitis.

In patients continuing on, or new to, Dimethyl fumarate treatment there was no overall increased risk of serious infections ( including opportunistic infections ) or malignancies. There was no overall increased risk of renal dysfunction, urinary events or hepatic adverse events in any treatment group; and mean white blood cell and lymphocyte counts remained stable.

Dimethyl fumarate provides a new approach to treating multiple sclerosis by activating the Nrf2 pathway, although its exact mechanism of action is unknown. This pathway provides a way for cells in the body to defend themselves against inflammation and oxidative stress caused by conditions like multiple sclerosis. ( Xagena )

Source: Biogen Idec, 2014