Two-year treatment with temelimab reduced brain atrophy, or shrinkage, preserved myelin, and reduced disease progression in patients with relapsing-remitting multiple sclerosis (RRMS), according to findings from an extension study of a Phase 2b clinical trial.

Temelimab, previously known as GNbAC1, is a monoclonal antibody that neutralizes the MS-associated human endogenous retroviruses envelope protein, or pHERV-Env, particularly found in active lesions in people with MS. This protein induces an immune response that potentially impairs the repair of myelin — the protective layer around nerve fibers that is deteriorated in MS patients.

The treatment candidate, developed by GeNeuro, was designed to block inflammation and restore myelin. Its development results from more than 25 years of research into human endogenous retroviruses, a family of viruses inserted into the human genome. Some of these retroviruses are associated with autoimmune diseases.

The Servier-funded, two-year Phase 2b extension study (NCT03239860), called ANGEL-MS, evaluated the safety and efficacy of monthly intravenous (into-the-vein) injections with temelimab, and included 94% of the 219 participants who had completed the 12-month primary trial, named CHANGE-MS (NCT02782858). Patients entering ANGEL-MS continued receiving the same dose of temelimab they were receiving at the end of CHANGE-MS.

Patients’ brain atrophy was assessed through magnetic resonance imaging (MRI) in two areas of the brain called the cortex — involved in functions such as memory and motor control — and thalamus — which relays sensory and motor signals to the cortex. Researchers also assessed the maintenance of myelin integrity through the magnetization transfer ratio, whose decline is associated with myelin nerve fiber loss.

The team compared the original temelimab dose groups in CHANGE-MS — 6, 12, and 18 mg/kg — to patients on placebo for six months and then on temelimab for the last six months in CHANGE-MS.

Despite the study’s early termination due to Servier’s decision to end its partnership with GeNeuro, all participants were seen at end-of-study visits. Across the two studies, 154 RRMS patients received temelimab for at least 96 weeks.

Evaluations of disease progression revealed dose-response effects for the first time, the company noted, as the 18 mg/kg dose of temelimab (the highest dose tested) had a positive effect on MRI measures linked to MS disease progression. This was reflected in a lower proportion of patients with confirmed disease progression at 12 weeks, as determined by the Expanded Disability Status Scale (EDSS), or by a 20% worsening in the 25-foot timed walk test.

Subsequent analyses, regardless of length of treatment or body weight, confirmed the dose-dependent clinical effects.

Treatment with 18 mg/kg temelimab induced a reduction in brain atrophy — 42% relative reduction in the cortex, and 43% in the thalamus — and also maintenance in myelin integrity, shown by improvements in magnetization transfer ratio values.

These benefits confirmed and extended the results seen at both 24 and 48 weeks in CHANGE-MS trial.

“We are extremely pleased with this data, which clearly confirm the robust and consistent effects of temelimab on key MRI markers of neuroprotection, and we are excited by the early signs of clinical benefit,” Jesús Martin-Garcia, CEO of Switzerland-based GeNeuro, said in a press release. “The results of ANGEL-MS confirm the potential of temelimab to act against disease progression, the largest unmet medical need in this indication.”

Temelimab was also well-tolerated by patients, with no dose-limiting safety signals.

“These results are remarkable, and they are coherent with temelimab’s novel mode of action seeking to stop the activation of the brain’s innate immunity and restoring the myelin repair system,” said Hans-Peter Hartung, the study’s lead investigator and chairman of the department of neurology of the University Hospital Düsseldorf in Germany. “It offers promise to treat progressive patients with low inflammatory activity, and could have potential synergies with existing anti-inflammatory drugs in relapsing MS patients.”

GeNeuro cautions that although these results are encouraging, the limited number of participants and the fact that they had the relapsing form of MS precludes making definitive conclusions.

In September 2018, GeNeuro announced it had reacquired worldwide rights to develop and market temelimab from Servier.