Background: The envelope protein of the human endogenous retrovirus type W (HERV-W ENV) is expressed in chronic active MS lesions. Preclinical models have shown that HERV-W ENV activates microglia, prevents maturation of oligodendrocyte precursor cells, and leads to neuronal death. Following the effects of a B-cell depleting, anti-inflammatory therapy, rituximab (RTX), with temelimab (TML), a humanized, IgG4-κ monoclonal antibody against HERV-W ENV represents a novel therapeutic approach against neurodegenerative features of MS.
Objective: To present safety preclinical results on the interaction of RTX and TML, and the trial design of the ProTEct-MS study.
Design/Methods: Interactions between RTX and TML were studied in vitro in high density-peripheral blood mononuclear cells (PBMCs) and ex-vivo in a whole blood loop system from fresh human blood.
ProTEct-MS is a randomized, double-blind, placebo controlled, parallel group study. Enrolment commenced in 2020/6 and will be completed in 2020/12. Patients with RMS (2017 McDonald criteria) (N=40) being previously treated for ³12 months with RTX are randomized (1:1:1:1) to monthly iv TML (18, 36 or 54mg/kg) and placebo for 48 weeks.
Eligibility criteria: age 18-55 yrs, Expanded Disability Status Scale (EDSS) of 2.5-5.5 at screening; clinical worsening in ³1 neurological domain as assessed by EDSS, 6MWT or T25FW, or cognitive functioning as assessed by SDMT over the last year.
Primary objective: assessment of safety and tolerability of TML
Secondary outcome measures: MRI: change of brain atrophy, lesion volume and magnetization transfer ratio
Results: Co-administration of TML with RTX was overall comparable to vehicle for all blood parameters assessed including cytokine levels of all five donors tested in both in vitro and ex-vivo assays. Co-administration of TML with RTX did not affect the functionality profile of either compound. By September 2020, 25% of patients are expected to be randomized, providing baseline clinical and MRI characteristics.
Conclusions: Preclinical safety experiments of the drug combination showed no evidence against the use of TML following RTX in humans. ProTEct-MS study patients represent a RMS cohort with progression in absence of relapse activity (PIRA,) i.e. whose present clinical condition is stable under RTX therapy, enabling TML's effects on attenuating mechanisms of progression to be measured without interference by acute inflammatory activity.