DTB DTB| |Dimethyl Dimethyl fumarate for relapsing-remitting multiple sclerosis
Downloaded from http://dtb.bmj.com/ on November 15, 2014 - Published by group.bmj.com
DTB CME/CPD* BNF 8.2.4
Dimethyl fumarate for relapsing-remitting multiple sclerosis For many years the only drugs licensed for the treatment of multiple sclerosis (MS) were administered by injection (interferon beta, glatiramer and natalizumab). Recently, three oral drugs have become available. We have previously reviewed the use of fingolimod for highly active relapsing-remitting MS1 and teriflunomide for the management of relapsing-remitting MS in adults.2 Here, we review the evidence for dimethyl fumarate (Tecfidera—Biogen Idec Ltd) for the treatment of adults with relapsing-remitting MS.
Background Multiple sclerosis (MS) is an inflammatory disorder of the brain and spinal cord resulting in damage to myelin and axons. Initially, inflammation is temporary and is followed by some form of remyelination. In the early stages patients may recover from episodes of neurological dysfunction. Around 80% of patients present with an acute episode (clinically isolated syndrome) with further episodes occurring sporadically (usually fewer than 1.5 episodes/ year). Over time persistent symptoms accumulate with only partial recovery from each episode. Eventually, around 65% of patients develop secondary progressive MS and in 20% of cases the illness is progressive from onset. 3
What is dimethyl fumarate? Dimethyl fumarate is the principal fumaric acid ester contained in Fumadermi, which is used in Germany for the treatment of psoriasis.4 Although the exact mechanism of action of dimethyl fumarate in MS is not fully understood, it is thought to involve the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway, which is responsible for mediating cellular response to oxidative stress. 5 The summary of product characteristics (SPC) states that dimethyl fumarate demonstrated anti-inflammatory and immunomodulatory properties in preclinical and clinical studies.6 Dimethyl fumarate was launched in the UK in February 2014 for the treatment of adult patients with relapsing-remitting MS.7 The licensed dose is 120mg twice daily, increased to 240mg twice daily after 7 days. Treatment should be initiated under supervision of a physician experienced in the treatment of MS.6
18–55 years with relapsing-remitting MS, a baseline score of 0–5 on the Expanded Disability Status Scaleii (EDSS), and evidence of disease activity demonstrated by at least one gadoliniumenhancing lesion seen on an MRI scan obtained within 6 weeks prior to randomisation, or at least one clinically documented relapse within the 12 months prior to randomisation. The DEFINE study excluded patients who had been treated with interferon alpha, interferon beta or glatiramer acetate within 3 months of randomisation; the criteria for the CONFIRM study were similar but excluded patients with any previous use of glatiramer acetate. Those who had experienced a relapse or had been treated with a corticosteroid within 50 days of randomisation, and those not stabilised after a relapse, were excluded from both studies. Approximately 40% of patients in the DEFINE study and 29% of patients in the CONFIRM study had received previous treatment with an “approved medication” for MS. All efficacy analyses were performed using the modified intentionto-treat population, including all patients who underwent randomisation and received at least one dose of study drug. The primary outcome measures were the proportion of patients with a relapse at 2 years (DEFINE) and the annualised relapse rate at 2 years (CONFIRM). Relapses were defined as new or recurrent neurological symptoms, not associated with fever or infection, that lasted for at least 24 hours and that were accompanied by new objective neurological findings. The risk of confirmed disability progression, defined as at least a 1-point increase on the EDSS in patients with a baseline score of ≥1 or at least a 1.5-point increase in patients with a baseline score of 0, sustained for 12 weeks, was evaluated in both * DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted, subscribers must sign into DTB with their username and password. All users must also complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ Learning username and password) on every visit. The answers to the multiple choice questions will be freely available on dtb.bmj.com on publication of the next issue of DTB.
Clinical efficacy The licensing submission included two randomised double-blind placebo-controlled phase III studies (DEFINE and CONFIRM),8,9 one of which (CONFIRM)9 used open-label (rater-blinded) glatiramer acetate as a reference comparator. Both trials included adults aged
EDSS scores range from 0 to 10, with higher scores indicating greater disability. An EDSS score of 5 describes a patient who is able to walk without aid or rest for 200m; disability is severe enough to impair full daily activities.16
ii
Not licensed in the UK.
i
dtb.bmj.com
Vol 52 | No 9 | September 2014 | DTB |
105
Downloaded from http://dtb.bmj.com/ on November 15, 2014 - Published by group.bmj.com DTB | Dimethyl fumarate for relapsing-remitting multiple sclerosis
studies as a secondary endpoint.8,9 Although the studies investigated two different dose regimens for dimethyl fumarate, only the results for the dose currently licensed in the UK (240mg twice daily) are presented here. In the DEFINE study, participants were randomised to double-blind treatment with dimethyl fumarate 240mg twice daily (n=410), dimethyl fumarate 240mg three times daily (n=416) or placebo (n=408).8 The proportion of patients with a relapse at 2 years was 27% with twice daily dimethyl fumarate and 46% with placebo (hazard ratio [HR] 0.51, 95% CI 0.40 to 0.66; p
Downloaded from http://dtb.bmj.com/ on November 15, 2014 - Published by group.bmj.com
DTB CME/CPD* BNF 8.2.4
Dimethyl fumarate for relapsing-remitting multiple sclerosis For many years the only drugs licensed for the treatment of multiple sclerosis (MS) were administered by injection (interferon beta, glatiramer and natalizumab). Recently, three oral drugs have become available. We have previously reviewed the use of fingolimod for highly active relapsing-remitting MS1 and teriflunomide for the management of relapsing-remitting MS in adults.2 Here, we review the evidence for dimethyl fumarate (Tecfidera—Biogen Idec Ltd) for the treatment of adults with relapsing-remitting MS.
Background Multiple sclerosis (MS) is an inflammatory disorder of the brain and spinal cord resulting in damage to myelin and axons. Initially, inflammation is temporary and is followed by some form of remyelination. In the early stages patients may recover from episodes of neurological dysfunction. Around 80% of patients present with an acute episode (clinically isolated syndrome) with further episodes occurring sporadically (usually fewer than 1.5 episodes/ year). Over time persistent symptoms accumulate with only partial recovery from each episode. Eventually, around 65% of patients develop secondary progressive MS and in 20% of cases the illness is progressive from onset. 3
What is dimethyl fumarate? Dimethyl fumarate is the principal fumaric acid ester contained in Fumadermi, which is used in Germany for the treatment of psoriasis.4 Although the exact mechanism of action of dimethyl fumarate in MS is not fully understood, it is thought to involve the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway, which is responsible for mediating cellular response to oxidative stress. 5 The summary of product characteristics (SPC) states that dimethyl fumarate demonstrated anti-inflammatory and immunomodulatory properties in preclinical and clinical studies.6 Dimethyl fumarate was launched in the UK in February 2014 for the treatment of adult patients with relapsing-remitting MS.7 The licensed dose is 120mg twice daily, increased to 240mg twice daily after 7 days. Treatment should be initiated under supervision of a physician experienced in the treatment of MS.6
18–55 years with relapsing-remitting MS, a baseline score of 0–5 on the Expanded Disability Status Scaleii (EDSS), and evidence of disease activity demonstrated by at least one gadoliniumenhancing lesion seen on an MRI scan obtained within 6 weeks prior to randomisation, or at least one clinically documented relapse within the 12 months prior to randomisation. The DEFINE study excluded patients who had been treated with interferon alpha, interferon beta or glatiramer acetate within 3 months of randomisation; the criteria for the CONFIRM study were similar but excluded patients with any previous use of glatiramer acetate. Those who had experienced a relapse or had been treated with a corticosteroid within 50 days of randomisation, and those not stabilised after a relapse, were excluded from both studies. Approximately 40% of patients in the DEFINE study and 29% of patients in the CONFIRM study had received previous treatment with an “approved medication” for MS. All efficacy analyses were performed using the modified intentionto-treat population, including all patients who underwent randomisation and received at least one dose of study drug. The primary outcome measures were the proportion of patients with a relapse at 2 years (DEFINE) and the annualised relapse rate at 2 years (CONFIRM). Relapses were defined as new or recurrent neurological symptoms, not associated with fever or infection, that lasted for at least 24 hours and that were accompanied by new objective neurological findings. The risk of confirmed disability progression, defined as at least a 1-point increase on the EDSS in patients with a baseline score of ≥1 or at least a 1.5-point increase in patients with a baseline score of 0, sustained for 12 weeks, was evaluated in both * DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted, subscribers must sign into DTB with their username and password. All users must also complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ Learning username and password) on every visit. The answers to the multiple choice questions will be freely available on dtb.bmj.com on publication of the next issue of DTB.
Clinical efficacy The licensing submission included two randomised double-blind placebo-controlled phase III studies (DEFINE and CONFIRM),8,9 one of which (CONFIRM)9 used open-label (rater-blinded) glatiramer acetate as a reference comparator. Both trials included adults aged
EDSS scores range from 0 to 10, with higher scores indicating greater disability. An EDSS score of 5 describes a patient who is able to walk without aid or rest for 200m; disability is severe enough to impair full daily activities.16
ii
Not licensed in the UK.
i
dtb.bmj.com
Vol 52 | No 9 | September 2014 | DTB |
105
Downloaded from http://dtb.bmj.com/ on November 15, 2014 - Published by group.bmj.com DTB | Dimethyl fumarate for relapsing-remitting multiple sclerosis
studies as a secondary endpoint.8,9 Although the studies investigated two different dose regimens for dimethyl fumarate, only the results for the dose currently licensed in the UK (240mg twice daily) are presented here. In the DEFINE study, participants were randomised to double-blind treatment with dimethyl fumarate 240mg twice daily (n=410), dimethyl fumarate 240mg three times daily (n=416) or placebo (n=408).8 The proportion of patients with a relapse at 2 years was 27% with twice daily dimethyl fumarate and 46% with placebo (hazard ratio [HR] 0.51, 95% CI 0.40 to 0.66; p
