Low Temelimab Doses in RRMS Trial Among Reasons for Poor Results

Low doses selected and underlying inflammatory disease may have confounded the ability of temelimab to significantly affect neuroinflammation in a Phase 2 trial in relapsing-remitting multiple sclerosis (RRMS) patients.

GeNeuro‘s investigational MS therapy did, however, show other evidence of clinical benefit that supports its continued development, researchers reported. Their recently published analysis of that trial explores these issues.

That analysis, “Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study,” was published in the Multiple Sclerosis Journal.

A Phase 2 study that concluded in 2017, CHANGE-MS (NCT02782858) failed to achieve its main goal of reducing the number of active MRI brain lesions. But participants who moved into its long-term extension study, ANGEL-MS (NCT03239860), showed signs of reduced brain atrophy (shrinkage), preserved myelin, and slower disease progression — all secondary trial goals.

“The study was not powered for these secondary and exploratory endpoints,” the investigators wrote, “and while many of the MRI outcomes were not, or only marginally, statistically significant, they were consistent.”

A key limitation identified in the analysis was the possibility that participants’ inflammatory disease activity could have masked temelimab’s neuroprotective effects at the 6, 12, or 18 mg/kg doses given. The researchers described the maximum 18 mg/kg dose as “conservative.”

In addition to the signs of clinical benefit observed in CHANGE-MS and ANGEL-MS, temelimab proved safe and well-tolerated.

Temelimab- and placebo-treated patients showed no difference in adverse events throughout the core treatment period. Two treatment-related adverse side effects took place in the open-label extension period. One death occurred, which was considered unrelated to treatment.

“Modern MS therapies are very effective at reducing relapse activity but have little effect on the long-term course of disability,” David Leppert, MD, GeNeuro’s chief medical officer, said in a press release.

“CHANGE-MS and ANGEL-MS have demonstrated that temelimab administration is safe and showed evidence of radiological signs of anti-neurodegenerative effects at 18 mg/kg in patients, so it is important to define the optimal dose in preparation for Phase 3,” Leppert added.

Higher doses of up to 54 mg/kg are now being assessed in the ongoing Phase 2 ProTEct-MS trial (NCT04480307). This study is evaluating the pharmacological effects of administering temelimab to people with relapsing forms of MS, who experience disease progression following rituximab treatment. Results are expected early next year.

Temelimab is a monoclonal antibody designed to prevent inflammation and damage to the myelin coat that insulates nerve cells by specifically targeting the envelope protein (Env) of the human endogenous retrovirus W (HERV-W; formerly referred to as MSRV Env). This family of viruses is found throughout the human genome, where it is “silent,” meaning it is rarely transcribed into an active viral molecule. HERV activation is seen as a potential cause of MS.

The CHANGE-MS and ANGEL-MS studies assessed temelimab’s safety and efficacy at improving markers of inflammation and neurodegeneration detected by MRI among 270 adults with RRMS.

Trial participants were randomized to either monthly intravenous infusion treatment with temelimab at 6, 12, or 18 mg/kg, or to a placebo, for 24 weeks. Placebo-group patients were then randomized to one of the three temelimab doses for the remaining 24 weeks, while those initially on treatment continued at their assigned dose.

Most (92%) who completed CHANGE-MS opted to continue in the ANGEL-MS long-term safety study.

“Publication of the results from the CHANGE-MS Phase 2 study and its 48-week ANGEL-MS extension confirms the potential of temelimab in MS through a new mechanism of action targeting specifically neurodegeneration,” Hans-Peter Hartung, MD, PhD, principal investigator of both studies.

“This was a first-in-class ambitious exploratory Phase 2,” Hartung added, “and its promising results show the importance of pursuing novel paths to achieve progress against the remaining medical need of tackling disability progression in MS.”