Brian Murphy, PhD, is a medical/science writer and educator who has written over 300 resource articles about rare diseases. He holds a BS from Georgia Institute of Technology and a PhD from Case Western Reserve University, both in Biomedical Engineering. After graduation, Brian worked as a clinical neural engineer to help restore movement in spinal cord injured patients by reconnecting their brain to their paralyzed muscles using experimental medical devices. In addition to resource pages, Brian has also authored/co-authored several research articles in journals including The Lancet, Journal of Neural Engineering, and PLOS ONE.
Vumerity
Vumerity (diroximel fumarate) is an oral medication approved for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary progressive MS (SPMS), in adults.1
The treatment was approved by the US Food and Drug Administration (FDA) in October 2019 as a 231 mg pill to be taken twice a day during the initial 7 days for a total daily dose of 462 mg.1 Following the initial week, 2 pills are taken twice a day for a total daily dose of 924 mg during the maintenance period. Temporary dosage reduction to 231 mg twice a day is advised for patients who are not able to tolerate the maintenance dosage.
Vumerity was developed as a collaboration by Alkermes and Biogen.
Mechanism of Action
The exact cause of MS is unknown but patients experience progressive neurodegeneration in the central nervous system (CNS) due to autoimmune inflammation. The inappropriate immune response targets autoantigens on myelin, leading to demyelination and ultimately the loss of nerve cells.2
The exact mechanism of action of Vumerity is not fully known. Vumerity is a modified chemical structure from Tecfidera® (dimethyl fumarate (DMF) ), which metabolizes to form monomethyl fumarate (MMF).3 MMF is believed to have immunomodulatory and neuroprotective effects that act by mediating nuclear factor erythroid-derived 2-related factor (Nrf-2)–dependent and independent pathways.4
Get detailed prescribing information on the Vumerity monograph page on Rare Disease Advisor.
MMF causes a shift toward an anti-inflammatory state in immune cell composition and phenotypes as well as inhibiting the infiltration of immune cells into the CNS.4 Nrf-2 dependent pathways in the CNS decrease astrocyte activation, increase oligodendrocyte survival, increase anti-inflammatory M2 microglia, and increase neuroprotective effects through antioxidant activities.4 MMF can also act in the CNS through hydroxycarboxylic acid receptor-2 (HCAR-2) mediated inhibition of microglia activation and neutrophil infiltration as well as nuclear factor kappa B (NF-κB) suppression of astrocyte activation, reduction in cytokines, and nitric oxide (NO) production.4
Pharmacokinetic analysis of Vumerity and DMF found that 462 mg and 240 mg doses, respectively, yielded similar levels of MMF in patients and they were deemed to be bioequivalent.5 The modified structure of Vumerity has been shown to result in fewer gastrointestinal (GI) adverse events, as well, possibly through lower production of methanol in the gut and lower reactivity with off-target proteins.6
Warnings, Precautions, and Adverse Reactions
Vumerity can lead to a number of serious adverse events including anaphylaxis, angioedema, progressive multifocal leukoencephalopathy, lymphopenia, liver damage, flushing, and may result in serious viral, bacterial, or fungal infections due to its immunosuppressive effects.1
There is inadequate data on the effects of Vumerity on special populations, including children, geriatric patients, and pregnant or breastfeeding mothers. However, animal studies indicate that Vumerity may cause embryofetal developmental problems and death.1
The most common adverse reactions experienced by greater than 10% of patients receiving DMF were flushing, abdominal pain, diarrhea, and nausea.1
Efficacy in Trials and Trial Results
The safety, pharmacokinetics (PK), and GI tolerability of Vumerity were assessed in a number of phase 1 trials in healthy participants,6 including a randomized, double-blind, placebo-controlled clinical trial (NCT02201849). The trial assessed the safety, tolerability, and PK for Vumerity compared to DMF or a placebo in 104 healthy participants.
Following these phase 1 trials, Vumerity has also been investigated in 2 Phase 3 trials in patients with RRMS. The first, called EVOLVE-MS-1 (NCT02634307), is an open-label, single-arm trial where patients will be given Vumerity and monitored for up to 96 weeks. The primary endpoint of the trial is safety and tolerability, with several efficacy endpoints being recorded as well.
Preliminary results, as of March 2018, showed that adverse events were reported in 589 out of the 696 patients enrolled at the time.6 Treatment had been discontinued in 14.9% of patients, with 6.3% of those discontinuations being due to adverse events. Only 5 (0.7%) of those discontinuations were due to GI treatment-emergent adverse events, however. The overall safety and tolerability of Vumerity were similar to those of DMF.
Interim efficacy results showed a significant decrease in the mean number of gadolinium-enhancing (Gd+) lesions detected on T1-weighted MRI scans at week 48.7 Patients also had a low adjusted annualized relapse rate of 0.16 (95% CI: 0.13-0.20). The study has since enrolled 1057 patients and is estimated to conclude in November 2021.
The second phase 3 trial, EVOLVE-MS-2 (NCT03093324), was a randomized, double-blind, head-to-head trial comparing Vumerity with DMF. A total of 504 patients between the ages of 18 and 65 years with RRMS were randomized between the 2 drugs and received at least 1 dose. Patients received either 231 mg of Vumerity or 120 mg of DMF twice daily for the first week, then the doses were doubled to 462 and 240 mg, respectively, for the remaining 4 weeks of the trial. Based on phase 1 bioequivalence studies, patients were instructed to take Vumerity with or without food. The trial concluded in June 2019. Patients who completed the EVOLVE-MS-2 trial were rolled over to continue receiving treatment in the EVOLVE-MS-1 trial.
Results of the study showed that patients receiving Vumerity experienced significantly fewer (rate ratio 0.54, P = 0.0003) days of GI symptoms with scores above 2 on the Individual Gastrointestinal Symptom and Impact Scale (IGISIS).3 The IGISIS is a 0-10 point scale based on a questionnaire designed to rate several factors related to the GI symptoms of nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Another scale, the Global Gastrointestinal Symptom and Impact Scale (GGISIS), also showed lower numbers of days with scores above 2, but the results were not significant. Patients receiving Vumerity also had a lower rate of GI adverse events, 34.8% compared to 49%. Fewer numbers of patients discontinued the study due to GI adverse events compared to DMF (0.8% compared to 4.8%).3
Post hoc analysis of the patient diary entries from the study also showed that GI adverse events were less impactful on daily life and work productivity compared to DMF.8 Patients in the Vumerity group also needed to use fewer other medications to manage concomitant symptoms.8
Based on the results of these clinical trials establishing similar safety and tolerability, along with improved GI symptoms, compared to the already-approved DMF, the FDA approved Vumerity in 2019 for adult patients with relapsing forms of MS.
References
1. Vumerity. Package insert. Biogen; 2021. Accessed June 16, 2021.
2. Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 2011;122(2):155-170. doi:10.1007/s00401-011-0840-0
3. Naismith R, Wundes A, Ziemssen T, et al. Diroximel fumarate demonstrates an improved gastrointestinal tolerability profile compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: results from the randomized, double-blind, phase III
EVOLVE-MS-2 study. CNS Drugs. 2020;34(2):185-196. doi:10.1007/s40263-020-00700-0
4. Yadav SK, Soin D, Ito K, Dhib-Jalbut S. Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis. J Mol Med. 2019;97(4):463-472. doi:10.1007/s00109-019-01761-5
5. Wehr A, Hard M, Yu M, Leigh-Pemberton R, von Moltke L. Relative bioavailability of monomethyl fumarate after administration of ALKS 8700 and dimethyl fumarate in healthy subjects (P1.403). Neurology. 2018;90(15 Supplement). doi:10.1007/s00109-019-01761-5
6. Palte M, Wehr A, Tawa M, et al. Improving the gastrointestinal tolerability of fumaric acid esters: early findings on gastrointestinal events with diroximel fumarate in patients with relapsing-remitting multiple sclerosis from the phase 3, open-label EVOLVE-MS-1 study. Adv Ther. 2019;36(11):3154-3165. doi:10.1007/s12325-019-01085-3
7. Naismith R, Wolinsky J, Wundes A, et al. Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study. Mult Scler. 2020;26(13):1729-1739. doi:10.1177/1352458519881761
8. Wundes A, Wray S, Gold R, et al. Improved gastrointestinal profile with diroximel fumarate is associated with a positive impact on quality of life compared with dimethyl fumarate: results from the randomized, double-blind, phase III EVOLVE-MS-2 study. Ther Adv Neurol Disord. 2021;14:1756286421993999. doi:10.1177/1756286421993999
Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.
