Novel Drug Safe, Effective in Relapsing MS: 2-Year Data

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NATIONAL HARBOR, Maryland — Evobrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor for relapsing multiple sclerosis (RMS), is relatively safe and effective over the long-term, new research suggests.

Results from the longest follow-up of any BTK inhibitor drug for MS to-date show efficacy over 2½ years in slowing neurodegeneration in the disease.

In addition, “extended experience with evobrutinib did not result in any unexpected side effects that [were observed in] the initial trial,” co-investigator Jerry S. Wolinsky, MD, emeritus professor in neurology at McGovern Medical School, University of Texas Health Science Center at Houston, told Medscape Medical News.

“The effects on reducing relapse activity of the higher doses used were repeated in the open label extension as participants were switched to the 75 mg daily oral dose. When all participants were placed on 75 mg twice daily dose, it was well-tolerated and no new issues were seen,” he added.

The findings were presented here at the Consortium of Multiple Sclerosis Centers (CMSC) 2022 Annual Meeting.

Longest, Largest Study

Initially developed for cancer, BTK inhibitors are highly anticipated drugs in MS because of their ability to provide a more targeted approach in inhibiting the overreactive B cell responses that drive inflammation without directly affecting T cells or healthy B cells, which can occur with other anti-CD20 drugs.

“The mechanisms of action of evobrutinib and other BTK inhibitors are attractive in that they affect both B-cells and microglial cells in manners that might suggest that they could be similar or perhaps better than the anti-CD20 monoclonal antibodies,” Wolinsky said.

Earlier data from the ongoing phase 2 trial on evobrutinib has been promising. As reported by Medscape Medical News, data published in the New England Journal of Medicine in 2019 showed the oral drug was well-tolerated and was associated with reductions in acute and chronic inflammation and reduced T1 gadolinium-enhancing lesions in RMS vs placebo at week 24.

The ongoing study, said to be the largest phase 2 study of any BTK inhibitor in MS and the longest study at 2.5 years, included 267 patients with RMS or secondary progressive MS.

The study started with a 48-week, double-blind period in which patients were randomly assigned to receive evobrutinib as an oral tablet at either 25 mg or 75 mg once daily; 75 mg twice daily, or open-label dimethyl fumarate (DMF; 240 mg twice-daily); or placebo. At week 24, there was a switch to evobrutinib 25 mg once daily.

After the 48-week period, 213 of the 267 participants (80%) chose to enter the open-label extension. They received evobrutinib 75 mg once daily for a median of about 48 weeks, then received 75 mg twice daily.

Among the 267 participants, 164 (61%) completed more than 132 weeks of the open-label period.

No Red Flags

In the latest update from the open-label period up to 2.5 years, investigators report the 75 mg twice-daily dose (n = 42) was associated with the lowest annualized relapse rate (ARR). The ARR was 0.12 for patients who had originally received 75 mg once daily in the double-blind period vs an ARR of 0.3 in the placebo group.

Disability, as assessed with the Expanded Disability Status Scale, remained stable up to week 144 in the open label extension in evobrutinib-treated patients.

Importantly, the treatment continued to show relative safety, with treatment-emergent adverse events (TEAEs) reported among 77.5% of patients. TEAEs related to evobrutinib occurred among 27.7%.

There were also six serious TEAEs determined to be treatment related. Severe/opportunistic infections of grade 3 or higher were reported by nine patients (4.2%), with three that were fatal. However, these were not considered to be related to the therapy.

There were also two cases of COVID-19 pneumonia and one case of E coli sepsis, both of which were not considered treatment-related.

Overall, the TEAEs were described as mild or moderate in the open-label extension period, with no dose-dependent increase in TEAEs among patients who switched to evobrutinib 75 mg twice-daily.

At week 120 in the open-label period, most participants had normal Ig levels, including IgG (91%), IgA (88%), and IgM (82%).

At baseline of the open-label period, 13% of patients had low B-cell counts. By week 96, 52% had low B-cell counts, with the remaining 48% showing normal counts.

Elevation of liver enzymes ALT/AST were observed only among those who had received DMF or evobrutinib 25 mg and occurred within 12 weeks of the open-label extension.

Amylase increases, linked to pancreatic damage, occurred in six (2.8%) patients and lipase increases occurred in 24 (11.3%) patients — but without clinical signs and symptoms.

Wolinsky noted that although it is “too early to be sure, there are no unusual safety concerns thus far,” with the drug.

“As MS specialists, we are always interested in novel approaches to control the disease process that might have the potential of better efficacy, safely, or compliance than existing drugs or [to] possibly help to fill in gaps for specific difficult-to-manage cases.

Of course, what are currently attractive possibilities must first be rigorously shown,” Wolinsky said

New Mechanism

Commenting on the study for Medscape Medical News, Anne Cross, MD, Trotter Multiple Sclerosis Center, St. Louis, Missouri, agreed evobrutinib may hold promise for MS.

Cross said she was “excited” about evobrutinib because of the new mechanism of action and the potential to affect both B cells and myeloid cells.

Indications that the drug potentially works in the central nervous system (CNS) are also exciting, especially “the possible benefit of this on ‘sequestered’ inflammation inside CNS,” added Cross, who was not involved in the research.

She noted there are other ongoing studies being conducted “to determine if this may or may not turn out to be the case.”

Although a reversal of damage already done is not likely, the hope is for “reduced or slowed progression due to reduced inflammation sequestered in the CNS, or maybe some other reason,” she said.

Evobrutinib is now currently under evaluation in the phase 3 EVOLUTION RMS 1 and 2 trials, involving more than 1800 adults with RMS.

Crowded Field

Also commenting for Medscape Medical News, Patricia K. Coyle, MD, Department of Neurology, Stony Brook University Medical Center, Stony Brook, New York, noted “there are at least five BTK inhibitors being developed and tested in clinical trials for MS, so it’s becoming a pretty crowded field.”

“We don’t have great data yet showing that these drugs are absolutely going to be effective for MS, although two have had phase 2 trials for relapsing MS that were positive in suppressing MRI lesion activity. So that’s encouraging,” said Coyle, who was not involved with the current research.

She noted the 2½-year open label extension for evobrutinib “is something you absolutely must have with any new agent to see what happens over the long term.” In addition, the data from the extension was “reassuring,” she said.

A key benefit for evobrutinib over existing RMS therapies is that it’s an oral drug, as opposed to the infusions or subcutaneous injections required with the three anti-CD20 DMTs, Coyle noted.

“Imagine if you could achieve [efficacy] through an oral regimen that you take daily instead of injecting yourself once a month or going to an infusion center twice a year,” Coyle said.

“I do think that would be an advantage, but the efficacy would have to be viewed as relatively equivalent to the anti-CD20s in relapsing MS,” she added.

The study was funded by EMD Serono Research and Development Institute, Inc. Wolinsky is on the Scientific Advisory Board for the EMD Serono trials and receives compensation for consultation. Cross has received honoraria for consulting or serving on advisory boards for: Biogen, EMD Serono, Genentech (F. Hoffmann-La Roche), Horizon, Janssen (J&J), Jazz Pharmaceuticals, Novartis, and TG Therapeutics. She also conducts contracted research funded by Genentech and by EMD Serono. Coyle reports relationships with Actelion, Accordant, Genentech/Roche, Sanofi Genzyme, Viela Bio, Janssen, NINDS, Novartis, Alkermes, Corrona LLD, MedDay, Biogen, Bristol Myers Squibb, Celgene, Novartis, and GlaxoSmithKline.

Consortium of Multiple Sclerosis Centers (CMSC) 2022 Annual Meeting. Abstract DMT02. Presented June 2, 2022.

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