Prospective Evaluation of De-Escalation From antiCD-20 Therapies to Dimethyl Fumarate (Tecfidera) or Diroximel Fumarate (Vumerity)

Ten patients >18 years of age with a minimum of 2 years of MS disease stability (no relapse or new magnetic resonance imaging lesions) and at least one year of experience on an anti-CD20 agent prior to initiating de-escalation with diroximel fumarate (Vumerity®) or dimethyl fumarate (Tecfidera®) will be followed for 24 months post de-escalation. To account for screen failures and withdrawals, up to 15 may be enrolled.

• Vumerity (Drug): Titration starting with 231 mg twice a day, orally, for 7 days (per United States Product information). Then continue with 462 mg orally (administered as two 231 mg capsules) twice a day.
• Tecfidera (Drug): Titration will start with 120mg twice a day, orally, for 7 days (per United States product information) and then continue with 240mg twice a day orally.

Primary outcomes

• Components of No Evidence of Disease Activity (NEDA-3) components (of which are no relapse activity, no MRI disease activity and no confirmed disability progression). [From baseline to 24 months]: Number of subjects not meeting NEDA defined as: 1. Evidence of Relapse activity - collected via monthly phone calls and study visits. OR 2. MRI disease activity - presence of new lesions (T2 or Gd enhancing) on scans done at baseline, months 12 and 24. OR 3. 6 months Confirmed Disability progression (CDP6): measured by EDSS done at baseline and every 6 months. CDP6 is defined as an increase in EDSS score of ≥1.5 if baseline EDSS was 0; or ≥1.0 points if baseline EDSS was ≥0.5-≤5; or by ≥0.5 points if baseline EDSS ≥6, sustained over two consecutive visits for ≥6 months. The time with NEDA (primary outcome) will be described using product-limit estimates (Kaplan-Meier plots). With 20 patients, if there is no evidence of disease activity in any patients in 24 months, we are 90% confident that the true rate is below 17%. Similarly with 1, 2, and 3 patients with observable disease activity in 24 months, the true rates are between 0.1-25%, 1-32% and 3-38% respectively.

Secondary outcomes

• Neurofilament light levels [From baseline to 24 Months]: Neurofilament light levels: Neurofilament light chain is a biomarker of neuroaxonal injury measured in serum or plasma. Unit: pg/mL (picograms per milliliter). Range: Continuous, with higher values indicating greater neuroaxonal damage.
• Brain parenchymal volume loss (using Icometrix) [From baseline to 24 Months]: Brain parenchymal volume loss (using iCOMETRIX): Volume is quantified from serial MRI scans using the FDA-cleared iCOMETRIX (icobrain) software platform. Unit: Percentage change in brain parenchymal volume from baseline. Range: Continuous Negative values indicate brain volume loss; larger negative percentages reflect greater tissue loss.
• Multiple Sclerosis Functional Composite (MSFC) [From baseline to 24 Months]: Assessment of MS-related disability that evaluates ambulation (Timed 25-Foot Walk), upper extremity function (9-Hole Peg Test), and cognitive processing speed. Continuous composite score calculated as the mean of standardized z-scores from the three component tests. Positive scores indicate better function and negative scores indicate worse function.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Diagnosed with relapsing forms of MS
* > 18 years of age at the time of initiation of de-escalation
* No evidence of new inflammatory disease activity (no new T2/contrast enhancing lesions, absence of relapses) for at least two years prior to de-escalation
* Have had multiple sclerosis related symptoms at least 3 years prior to baseline visit.
* Taking an anti-CD20 therapy most recently as a DMT continuously for at least one year (have received at least 2 courses) prior to de-escalation.
* Are 6-12 months from their last anti-CD20 infusion
* Willing to follow the protocol
* Able to undergo a brain MRI without anesthesia

Exclusion Criteria:

* Any progression of neurological symptoms in the year prior to the screening visit that would be consistent with progressive MS.
* Use of any non-FDA-approved DMT or systemic corticosteroids in the last 2 years. (Note: Use of inhaled or topical steroids are not an exclusion criteria. Also, use of oral steroids for no greater than 14 days given for a non-MS condition is not exclusionary).
* IgG levels <300 mg/dL
* lymphocytes <800 cells/mm3
* EDSS >6.5
* Is considering pregnancy at the screening visit
* Prior use of alemtuzumab, mitoxantrone, cyclophosphamide, methotrexate, cyclosporine or any experimental MS treatment in the last 5 years.
* Prior allergy to Vumerity
* Other significant medical or psychiatric illness, if uncontrolled. Examples: uncontrolled hypertension, uncontrolled diabetes, uncontrolled asthma, uncontrolled depression
* Cancers other than basal cell skin cancers within the last 5 years
* Unable to give informed consent or follow the protocol.
* Unable to undergo brain MRI.
* History of other chronic neurological illnesses that might mimic MS with chronic or intermittent symptoms (i.e. ALS, myasthenia gravis, chronic neuropathy, etc.)

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• Enrique Alvarez, MD/PhD, Principal investigator, University of Colorado, Denver