Diroximel fumarate (DRF) in patients with relapsing–remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study

Naismith, Robert T.; Wolinsky, Jerry S.; Wundes, Annette; LaGanke, Christopher; Arnold, Douglas L.; Obradović, Dragana; Freedman, Mark S.; Gudesblatt, Mark; Ziemssen, Tjalf; Kandinov, Boris; Bidollari, Ilda; Lopez-Bresnahan, Maria; Nangia, Narinder; Rezendes, David; Yang, Lili; Chen, Hailu; Liu, Shifang; Hanna, Jerome; Miller, Catherine; Leigh-Pemberton, Richard

doi:10.1177/1352458519881761

Cited by 50 publications

(68 citation statements)

References 19 publications

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“…Interestingly, the rates of investigator-assessed GI AEs and discontinuations because of GI AEs reported for DRFand DMF-treated patients were consistent with rates in the ongoing EVOLVE-MS-1 study, as well as with rates in the pivotal DEFINE and CONFIRM studies, though the trials cannot be directly compared [4,5,14]. The incidence of flushing, though numerically lower with DRF than DMF in this study, was generally consistent with rates reported in phase III studies with DRF and DMF [4,5,14]. However, as the focus of EVOLVE-MS-2 was GI tolerability, we did not evaluate and cannot assess the impact of flushing on patients in the study.…”

Section: Discussionsupporting

confidence: 55%

“…The distinct chemical structure of DRF is hypothesized to elicit less irritation in the GI tract than DMF through lower production of methanol (a GI-irritating promoiety), and less reactivity with pre-systemic off-target proteins or receptors [13]. Interim findings from the ongoing, multicenter, 2-year, prospective, single-arm, open-label DRF phase III EVOLVE-MS-1 study have demonstrated a low rate (~ 31%) of GI AEs when considered within the context of those reported in separate clinical trials and real-world effectiveness studies of DMF [9,10,14]. Notably, < 1% of patients in the EVOLVE-MS-1 study discontinued DRF treatment because of GI AEs [14].…”

Section: Methodsmentioning

confidence: 99%

“…Interim findings from the ongoing, multicenter, 2-year, prospective, single-arm, open-label DRF phase III EVOLVE-MS-1 study have demonstrated a low rate (~ 31%) of GI AEs when considered within the context of those reported in separate clinical trials and real-world effectiveness studies of DMF [9,10,14]. Notably, < 1% of patients in the EVOLVE-MS-1 study discontinued DRF treatment because of GI AEs [14]. However, it is challenging to make any conclusions about differences in the GI tolerability profile between DRF and DMF in the absence of head-to-head data.…”

Section: Methodsmentioning

confidence: 99%

“…After the initial 120 patients, the subsequently randomized patients (i.e., part B) were enrolled, bringing the overall planned population to 500 patients. Patients who completed the 5-week treatment period were eligible to enroll in the EVOLVE-MS-1 (Clini-calTrials.gov [NCT02634307]) long-term, open-label, DRF safety study [14].…”

Section: Methodsmentioning

confidence: 99%

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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

et al. 2020

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Background Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile. Objectives The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing-remitting multiple sclerosis. Methods EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing-remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability. Results DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39-0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%). Conclusions DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events. Clinical Trials Registration ClinicalTrials.gov (NCT03093324). Maria Lopez-Bresnahan and David Rezendes: Employees of Alkermes Inc. during the time the research and analyses were conducted.

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Section: Discussionsupporting

confidence: 55%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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

et al. 2020

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“…For example, Alkermes, Inc. has developed diroximel fumarate (DRF), also known as ALKS8700, a novel MMF prodrug. Importantly, this new formulation has been shown to yield bioequivalent levels of MMF at the cellular level when compared directly to DMF (Figure 1) [108] while interacting less with off-target proteins and therefore producing fewer unwanted side effects [109]. Indeed, interim findings from EVOLVE-MS-1 and EVOLVE-MS-2 which demonstrate that DRF has a favorable safety and efficacy profile and is well-tolerated in MS patients [108,110].…”

Section: Safety Profilementioning

confidence: 99%

Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation: A Promising Emerging Approach with Broad Potential

Jadeja¹,

Powell²,

Martin³

2020

Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications

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The medicinal benefit of salts of fumaric acid and its esters (FAE), known as fumarates (mono and dimethyl fumarate), was realized many years ago. Early on, FAE were derived from plants and mushrooms (e.g., Fumaria officinalis, Boletus fomentarius var. pseudo-igniarius). The FAE containing formulation Fumaderm ® was licensed in Germany for the treatment of psoriasis in 1994. Recently, a clinical formulation of dimethyl fumarate known as BG12 (Tecfidera) was approved for use in the United States, New Zealand, Australia, European Union, Switzerland, and Canada for the treatment of multiple sclerosis. Others and we have assessed the potential benefit of FAE in a number of disease conditions that are diverse with respect to etiology but unified with regard to the involvement of inflammation and oxidative stress. Hence, a FAE-based drug with robust anti-oxidative and anti-inflammatory effects that is already US-FDA approved is a perfect contender for repurposing and rapid clinical implementation for their management. There is a burgeoning literature on the use of FAE in the prevention and treatment of diseases, other than psoriasis and MS, in which oxidative stress and/or inflammation are prominent. This chapter highlights critical information gleaned from these studies, exposes lacunae of potential importance, and provides related perspectives.Keywords: fumaric acid esters, oxidative stress, Nrf2, antioxidant Drug Repurposing Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation:… DOI: http://dx.doi.org/10.5772/intechopen.91915 in which oxidative stress and/or inflammation are prominent. The present review highlights critical information gleaned from these studies and exposes and provides perspectives on lacunae of potential importance. Pharmacokinetics of fumaric acid estersDimethyl fumarate (PubChem CID: 637568), described as a "white crystalline compound with a fruit-like taste" [19], is a dimethyl ester of fumaric acid with the official chemical name of trans-1,2-ethylene carboxylic acid dimethyl ester [20]. Because of its rapid degradation by intestinal esterase, DMF does not cross the intestinal wall in significant amounts [21]. Thus, because of its short-lived activity, evidence of direct, sustained anti-inflammatory or antioxidant effects derived directly from DMF is limited [22]. Instead, monomethyl fumarate (MMF; PubChem CID: 21721168), the product of DMF metabolism by intestinal esterase, is said to be the main active metabolite [23]. This is confirmed by pharmacokinetic studies that demonstrate following oral DMF intake, serum concentrations of MMF peak within 2-2.5 h and its half-life is approximately 1 h [24]. Further, the ingestion of DMF along with a high fat/high-calorie diet was found to interfere with intestinal absorption, delaying the systemic peak of MMF significantly [16,17]. Following doses of delayed-release DMF of up to 240 mg, the mean C max of MMF in healthy human subjects was 1.43 μg/ml with a corresponding MMF area under the curve of 2.41 μg h/ml. ...

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Multiple Sclerosis

Pitts

Dyckman

2021

Burger's Medicinal Chemistry and Drug Discovery

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Several new medicines have been approved or entered development for the treatment of Multiple Sclerosis (MS) in the past few years. The sphingosine‐1‐phosphate (S1P) modulator fingolimod was the first FDA approved oral disease modifying therapy for MS, and it has inspired a number of additional agents directed at this clinically validated target. Fumarates (e.g. dimethyl fumarate), dihydroorotate dehydrogenase inhibitors (e.g. teriflunomide) and other agents which decrease lymphocyte proliferation (e.g. cladribine) represent additional clinically validated therapeutic approaches. While the mechanisms of action for these new agents may not be fully defined, they have demonstrated a good degree of efficacy in the treatment of relapsing forms of MS. It is of interest to note that biologic agents which target CD20 on B cells have also shown significant efficacy in the treatment of MS. This, in turn, has spurred MS clinical trials with Bruton's Tyrosine Kinase (BTK) inhibitors, which also act on B cell pathways. The introduction of each of these newer agents still requires careful consideration of the risk–benefit for individual patients, but has also set a higher bar in the treatment of MS for subsequent agents, as evidenced by the discontinuation of several agents in late stage clinical trials. This higher bar has also pushed some historic agents to second or third line agents. This speaks to an overall advancement in the treatment of MS, and provides hope for further advances in therapeutic options.

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Diroximel fumarate (DRF) in patients with relapsing–remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study

Cited by 50 publications

References 19 publications

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

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

Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation: A Promising Emerging Approach with Broad Potential

Multiple Sclerosis

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