Diroximel Fumarate Shows Low GI Adverse Events in MS

Nancy A. Melville

June 17, 2019

SEATTLE — The experimental drug diroximel fumarate ([DRF]; Vumerity, Biogen and Alkermes) shows benefits in the treatment of relapsing forms of multiple sclerosis (MS) similar to dimethyl fumarate (Tecfidera, Biogen), but with reductions of the gastrointestinal (GI) and flushing side effects that can occur with the latter drug, interim phase 3 findings suggest.

"With a median of approximately 1 year of treatment in this ongoing study, fewer than 1% of patients discontinued diroximel fumarate due to GI adverse events," the authors reported.

"GI and flushing events were mild to moderate in severity and of short duration in most patients."

The findings are from the ongoing, open-label EVOLVE-MS-1, a single-arm, 96-week clinical trial of oral DRF in patients with relapsing-remitting MS (RRMS). They were presented here at the 2019 Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Less GI Irritation

The novel drug is similar to dimethyl fumarate but with a unique chemical structure that may induce less irritation to the GI tract.

Since both compounds are converted to equal levels of monomethyl fumarate upon oral administration, their safety and efficacy profiles are expected to be similar, the authors say.

In one of the two studies from the trial looking at the key issue of tolerability, the authors reported on interim outcomes of GI events, as well as flushing adverse events among 696 RRMS patients treated with DRF for a median of 59.9 (0.1–98.9) weeks.

Of the patients, 215 (30.9%) experienced GI adverse events, with 8 (1.1%) of the events severe. Fewer than 1% (0.7%) discontinued due to GI adverse events.

"This represents a significant improvement in the barrier to therapy initiation," first author Mark Gudesblatt, MD, of South Shore Neurologic Associates in Patchogue, New York, told Medscape Medical News.

"The complaints over the course of the year are the 'any symptoms' and represent mild, tolerable, and not significant patient reports/concerns that would lead to therapy discontinuation or change."

Among 214 patients experiencing GI adverse events with a complete start date, 60% had events within the first month of treatment, with a median time to onset of 19 (5–83) days.

The adverse events resolved in 89% of patients and the median duration of the symptoms for overall GI events was 7.5 days; for diarrhea, the median duration was 5 (1­–63) days and 4 (1–86) days for nausea.

Flushing or flushing-related adverse events occurred in 44.3% of patients, with only 4 (0.6%) experiencing severe flushing or flushing-related events.

Of those patients, 80% experienced flushing or flushing-related events in the first month of treatment, with a median time of onset of 1 (1­–18) days. The flushing resolved in 74% of patients, with a median duration of symptoms of 3.5 (1­–88) days.

Annual Relapse Rates Reduced

In the second analysis looking at the same cohort, patients were divided into groups of those who were newly diagnosed with MS and initiated on the drug within a year of diagnosis, and those who switched from previous treatment with either interferon beta or glatiramer acetate (IFN/GA).

The annualized relapse rate (ARR) at week 48 of treatment with DRF among 82 newly diagnosed patients had dropped to 0.20, an 82% reduction from the ARR of 1.1 in the 12 months prior to DRF initiation.

And among 361 patients switching from IFN/GA, the ARR meanwhile dropped to 0.19 from 0.6, a 68% reduction.

The estimated proportion of patients with a relapse at week 48 was similar in both subgroups (newly diagnosed, 14%; IFN/GA switchers, 13.4%), the authors reported.

"These rates compare very favorably to all of the medium potency treatments, including oral medications, and represent significant superiority to platform agents [injectables]," Gudesblatt noted.

Reductions in the mean number of gadolinium-enhancing (Gd+) lesions was observed for both the newly diagnosed (baseline, 2.2 vs 0.1 at week 48; 96% reduction; P = .0051; n = 70) as well as IFN/GA switchers (baseline, 1.1 vs 0.4 at week 48; 64% reduction; P < .0001; n = 242).

In the newly diagnosed group, as many as 88.6% of patients had no gadolinium enhancing lesions at week 48 vs 55.7% at baseline, with corresponding rates of 89.3% at week 48 vs 74.8% at baseline for the IFN/GA switchers.

The mean number of new or newly enlarging T2 lesions from baseline to week 48 was 3.0 in the newly diagnosed group and 2.7 among the IFN/GA switchers.

Gudesblatt noted that with multiple MS drugs to choose from, it's hard to predict the role that DRF will take.

"The MS treatment scene is very complex and problematic for choice, sequence, and timing of change," he said. "There is no clear consensus on approach to start, switch, escalate vs induction, and how long to treat and when."  

Commenting on the research, CMSC President Michael K. Racke, MD, noted that the 30% rate of GI events over a year and 1% rate of discontinuations due to GI effects reported with DRF, though not dramatic, are notable.

"These are both modest, but statistically significant, improvements over dimethyl fumarate," he told Medscape Medical News.

"There are some patients who have been unable to tolerate dimethyl fumarate due to GI side effects. While this number is low and usually the effects become less over time, it probably results in some patients discontinuing and shifting to another drug," Racke said.

He noted that outside of the US, clinicians have been able to adjust dosing of dimethyl fumarate in the treatment of psoriasis — a measure that could feasibly help control GI symptoms.

"One of the interesting issues with the use of fumaric acid esters is that in Europe, dosing is much more flexible when used to treat psoriasis than the dosing used to treat MS here in the US," he said.

"The dosing in Europe is a combination of mono methyl and dimethyl fumarate for psoriasis," Racke explained. "The dermatologists titrate the dosing based on the white blood cell count, which can be reduced in some patients, particularly with our one-size-fits-all approach. I really do not know if that lessens GI side effects, but [it is] certainly possible.” 

Racke noted that, in terms of the bigger picture of notoriously high drug costs, the expiration of patents may finally bring about needed change.

"I think when some of the oral agents come off patent, they may gain in usage and popularity because they will be easier to make as an inexpensive product," he said. "This could dramatically affect usage in the future as the costs of these medications are approaching $100,000 per year in some cases."

The study was supported by Biogen and Alkermes. Gudesblatt has been a consultant/speaker for Novartis, Biogen, AbbVie, Genentech, EMD Serono. Racke has previously been involved in some dimethyl fumarate and Alkermes clinical trials, but not within the past 2 years.

Consortium of Multiple Sclerosis Centers (CMSC) 2019 Annual Meeting: Abstracts DXT41 and DXT42. Presented May 30, 2019.

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