Temelimab Proves Safe at Highest Dose for Multiple Sclerosis in Phase 2 Topline Data

Data from the ProTEct-MS trial (NCT04480307) suggest that temelimab is safe and well-tolerated in patients with relapsing MS also treated with rituximab, and data were consistent with prior findings. More analysis will be necessary to define an optimal dose.

GeNeuro has announced the topline results of its phase 2 ProTEct-MS clinical trial (NCT04480307) of temelimab in patients with relapsing multiple sclerosis (MS) who were treated with rituximab and in whom disability worsened without relapse. The data show that the higher doses of the therapy—up to 54 mg/kg—met the primary end point, displaying a strong safety and tolerability profile.1

The primary outcome measure was the occurrence an adverse event (AE) over 48 weeks of treatment. In that time, no patients reported treatment-related discontinuations, nor any serious or severe treatment-related AEs. There were similarly no differences in the clinical or laboratory safety data. The findings suggest that there is no upfront evidence of a dose effect for any of the doses assessed (18, 36 and 54 mg/kg doses) compared with placebo. Additional data from ProTEct-MS and its earlier trials will require further analysis to define the optimal dose for future temelimab trials, according to GeNeuro.

"The fact that we here prove the feasibility and potential added benefit of combining two therapies with different modes of action, is very encouraging," Fredrik Piehl, MD, PhD, professor of neurology and senior physician, Karolinska Institutet, and principal investigator of the study, said in a statement.1 "Fighting neurodegeneration that drives long-term multiple sclerosis disability is the critical unmet need with current treatment options, and we are pleased to see that the study corroborates findings of previous studies with temelimab."

Efficacy data, which were included in the secondary and exploratory measures, showed positive trends on key parameters of neurodegeneration as measured by MRI, which were observed in a patient population that had been treated for at least 1 year with rituximab. Previously, temelimab had been used as a monotherapy in trials.

The ProTEct-MS study sample size included 41 patients with relapsing MS, and while this size was too small to demonstrate statistical evidence of treatment effects, GeNeuro noted that the analyses showed a favorable impact of temelimab with regard to the preservation of neocortical anatomy and myelin integrity. This effect size was deemed to be comparable in magnitude to what had been observed in the CHANGE-MS (NCT02782858) and ANGEL-MS (NCT03239860) trials.

"First, the first interpretable results in this second phase study 2 of temelimab in MS are congruent to those of CHANGE/ANGEL-MS, where an effect on preservation of brain structures had been observed," David Leppert, MD, chief medical officer, GeNeuro, told NeurologyLive®. "Second, results support the concept of combination therapy with a high-efficacy anti-inflammatory drug like rituximab and a neuroprotective compound, temelimab, towards a next stage of MS therapy, with higher long-term efficacy by targeting both inflammation and neurodegeneration."

Leppert said that GeNeuro was "impressed by the congruency of MRI results," saying that they are suggestive of the "neuroprotective capacity of temelimab for cortical structures," which was displayed in measurements of cortical thickness. He added that the company was additionally impressed by "improvement on whole brain and thalamic atrophy."

The combination of temelimab and rituximab was shown to protect against loss of cortical thickness by more than 50% relative to rituximab alone, and cortical tissue integrity, measured by magnetization transfer saturation, was improved for those treated with temelimab, which GeNeuro noted potentially reflects evidence of remyelination.

"Our key objective with ProTEct-MS was to show that temelimab could bring additional benefits on key markers of neurodegeneration in a population of MS patients already treated with a highly-effective anti-inflammatory drug. This objective has been met, as the data show the synergistic potential of targeting neurodegeneration on top of inflammation," Jesús Martin-Garcia, CEO, GeNeuro said in a statement.1 "GeNeuro will now resume discussions with regulatory authorities and with potential partners to define the best development path combining temelimab and anti-neuroinflammatory treatments to bring the synergistic benefits of temelimab to patients."

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Previously, in the phase 2b CHANGE-MS trial and its long-term extension, ANGEL-MS, temelimab did not meet the primary end point of reduction of the cumulative number of gadolinium-enhancing T1 lesions at 24 weeks, which the authors wrote “failed to show an effect on features of acute inflammation.” The results of the extension trial were presented at the 2019 European Committee for Treatment and Research in MS annual meeting by Hans-Peter Hartung, MD, PhD.2 Although it failed to meet this primary outcome, Hartung et al noted that “the results provide preliminary MRI evidence that temelimab could exert an antineurodegenerative effect based on measures of brain atrophy, myelin integrity, and the number of chronic T1 hypointense lesions.”3

ANGEL-MS included 219 patients (94.8%) who had completed the first 48 weeks of CHANGE-MS. Altogether, 75 patients enrolled to receive monthly IV infusions of temelimab 6 mg/kg, 68 patients to receive 12 mg/kg, and 77 patients to receive 18 mg/kg. In the combined study periods, 18-mg/kg temelimab was associated with a 42% (P = .058) reduction in the atrophy rate of the cerebral cortex for those treated compared with controls. The reduction in the rate of atrophy of the thalamus was 43% (P = .038). In the 25-foot walk test, only 2.4% of patients the 18-mg/kg arm worsened 20% or more from baseline (P = .03), compared with 10.2% in the control group. The 12-mg/kg and 6-mg/kg groups reported worsening of by 20% or more in 23.1% and 13.3% of patients, respectively, in the 25-foot walk test.2

"We would like to thank all the study participants for their time and commitment to this important research effort, especially in the difficult circumstances of the pandemic during the past 2 years. We are also very grateful for the Karolinska Institutet’s Academic Specialist Center team whose dedication and commitment made this study possible," Leppert added in a statement.1

REFERENCES
1. ProTEct-MS Phase 2 Trial Confirms Safety of Higher Doses of Temelimab and Synergistic Potential to Address Neurodegeneration on Top of Anti-inflammatory Treatment in Multiple Sclerosis. News release. GeNeuro. March 21, 2022. Accessed March 21, 2022. https://www.yahoo.com/now/protect-ms-phase-2-trial-063000521.html
2. Hartung HP, Cree B, Derfuss T, et al. Neuroprotective effects of temelimab in relapsing-remitting MS patients extend to 96 weeks. Presented at: ECTRIMS; September 11-13, 2019; Stockholm, Sweden. Abstract P1379. http://www.geneuro.com/data/news/P1379-Ectrims-2019.pdf
3. Hartung HP, Derfuss T, Cree BAC, et al. Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study. Mult Scler J. 2022;28(3):429-440. doi:10.1177/1352458521102499