ClinicSpeak: DMF is neuroprotective; the rationale for the SPMS trial

Are you eligible for the dimethyl fumarate (DMF, Tecfidera) SPMS trial? #ClinicSpeak #MSBlog #MSResearch

"The following animal study in a stroke model shows that DMF (dimethyl fumarate) is neuroprotective. Is this important? I have always made the case for disease-specific and disease non-specific mechanisms. The latter refer to mechanisms that are typically downstream of primary events and can be targeted across many diseases. For example, all diseases associated with nerve cell loss, be it acute as in stroke, or more chronic as in MS have mechanisms that can be targeted to reduce nerve cell loss. The so called programme cell survival pathway that is controlled by the master transcription factor Nrf2 is one such pathway. We have evidence that this pathway is responsible for the neuroprotection that is seen with DMF. This study therefore supports the principle of testing DMF in progressive MS."

The following are more details on the DMF SPMS trial:

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of BG00012 in Delaying Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis

Purpose: The primary objective of the study is to investigate whether treatment with BG00012 (dimethyl fumarate) compared with placebo slows the accumulation of disability not related to relapses in participants with SPMS; The secondary objective of the study is to assess the effect of BG00012 compared with placebo on patient-reported outcomes, brain atrophy, and cognitive function.

Primary Outcome Measures: Time to onset of confirmed progression of disability as measured by worsening on one or more of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW) or 9-Hole Peg Test (9HPT). 

Secondary Outcome Measures: Change from Baseline to 2 years on the 12-Item Multiple Sclerosis Walking Scale (MSWS-12). Change from Baseline to Week 108 in ABILHAND Questionnaire Score. Percentage change from Baseline to Week 108 in whole brain volume. Change from Baseline to Week 108 in cognitive function as measured by the Symbol Digit Modalities Test (SDMT)

Estimated Enrollment: 1170

Study Start Date: May 2015

Estimated Study Completion Date: June 2019

Eligibility: Ages Eligible for Study: 18 Years to 58 Years

Key Inclusion Criteria:

1. Onset of SPMS at least 1 to 2 years prior to randomization. SPMS is defined as relapsing-remitting disease followed by progression of disability independent of or not explained by relapses.
2. Have documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to randomization.
3. Have EDSS score of 3.0 to 6.5, inclusive.
4. Have an multiple sclerosis (MS) Severity Score of 4 or higher.

Key Exclusion Criteria:

1. Have a diagnosis of relapsing remitting multiple sclerosis (RRMS) or primary progressive MS as defined by the revised McDonald criteria.
2. Had a recent clinical relapse (within 3 months) prior to randomization.
3. Uncontrolled intercurrent illness including, but not limited to- ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; serious or acute liver, kidney, or bone marrow dysfunction; uncontrolled diabetes; serious or acute psychiatric illness that would limit compliance with study requirements.

ClinicalTrials.gov identifier: NCT02430532

Epub: Zhao et al. Dimethyl Fumarate Protects Brain From Damage Produced by Intracerebral Hemorrhage by Mechanism Involving Nrf2. Stroke. 2015 May 14. pii: STROKEAHA.115.009398.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) represents a devastating form of stroke for which there is no effective treatment. This preclinical study was designed to evaluate dimethyl fumarate (DMF), a substance recently approved for the treatment of multiple sclerosis, as therapy for ICH. 

HYPOTHESIS: We hypothesized that DMF through activating the master regulator of cellular self-defense responses, transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), would act as effective treatment for ICH-mediated damage.

METHODS: Male rats and mice, including Nrf2 knockouts, were subjected to intracerebral injection of blood (to mimic ICH) and then treated with DMF. Neurological deficit, brain edema, gene induction profile and hematoma resolution were evaluated. Phagocytic functions of primary microglia in culture were used to study hematoma resolution.

RESULTS: Treatment with DMF induced Nrf2-target genes, improved hematoma resolution, reduced brain edema, and ultimately enhanced neurological recovery in rats and wild-type, but not Nrf2 knockout, mice. Most importantly, the treatment of ICH with DMF showed a 24 h window of therapeutic opportunity.

CONCLUSIONS: A clinically relevant dose of DMF demonstrates potent therapeutic efficacy and impressive 24 h therapeutic window of opportunity. This study merits further evaluation of this compound as potential treatment for ICH in humans.

CoI: multiple