Treating relapsing-remitting multiple sclerosis (RRMS) patients with GeNeuro’s investigational compound GNbAC1 lessened brain atrophy and lesion load and suggested myelin preservation, according to results of a Phase 2b study.
Importantly, monthly intravenous GNbAC1 administration for 48 weeks also had neuroprotective effects in the study’s inactive population, which refers to a group of MS patients with insufficient response to disease-modifying treatments now available.
The research, “Week 48 results from a phase IIb trial of GNbAC1 in patients with relapsing remitting multiple sclerosis (CHANGE-MS; clinical trial assessing the HERV-W Env antagonist GNbAC1 for Efficacy in MS),” was presented at the 34th Congress of the European Committee for Treatment and Research on Multiple Sclerosis (ECTRIMS 2018) recently held in Berlin.
Activation of human endogenous retroviruses (HERVs), commonly found but inactive in the genome, is a possible cause of damage to myelin (the protective layer of nerve fibers) in MS. Its activation leads to the production of a protein called pHERV-envelope protein, or pHERV-Env, which triggers an immune response that potentially impairs remyelination. pHERV-Env has been found in MS brain lesions.
GNbAC1 is an antibody that targets this protein, and is designed to block its pro-inflammatory effects and promote remyelination.
The randomized, double-blind, placebo-controlled CHANGE-MS Phase 2b trial (NCT02782858) included 270 RRMS patients (ages 18 to 55) across 50 clinical centers in 12 European countries. The study was conducted for six months, with an extension period of up to one year. Three GNbAC1 doses — 6, 12 or 18 mg/kg — were used.
Magnetic resonance imaging (MRI) scans at six months showed consistent neuroprotective benefits on brain atrophy, or brain shrinkage. Specifically, the cerebral cortex — a brain area involved in functions such as memory and motor control — and the thalamus — which relays sensory and motor signals to the cortex — showed lessened volume reductions of 31% and 72%, respectively, comparing the highest GNbAC1 dose (18 mg/kg) to controls. A significant dose-response effect was found in both brain areas.
Whole brain atrophy also showed a 29% relative decrease over 12 months, again comparing the highest treatment dose to the control group.
The number of MRI T1 hypointense lesions or black holes (lesions with active inflammation), which indicate permanent tissue destruction in the brain, was also 63% lower at the study’s end in the 18 mg/kg GNbAC1 group compared to placebo.
A measure of brain abnormality called magnetization transfer ratio, whose decline is associated with myelin nerve fiber loss, showed that the signal of 18 mg/kg GNbAC1 was notably conserved across all examined brain areas, indicating myelin preservation. This matched results reported at 24 weeks, the researchers noted.
All treatment groups improved from week 24 to week 48 in most MRI measures of neuroinflammation, although without significant differences between the treatment doses.
GNbAC1 also showed an excellent tolerability profile throughout the study, the scientists said, with no significant safety issues reported.
“At week 48, GNbAC1 18 mg/kg showed robust evidence of efficacy across MRI-based, paraclinical measures of neurodegeneration, potentially predictive of a benefit on disability progression in late-phase MS studies,” the researchers wrote.
“The CHANGE-MS, Phase 2b study showed consistent neuroprotective benefits with GNbAC1,” Hans-Peter Hartung, the trial’s principal investigator, said in a press release. “Importantly, these benefits were prominent in the inactive sub-population of patients in this study, precisely the group of MS patients that are sub-optimally treated with currently available therapies. These results appear to be the outcome of a completely new mechanism of action targeting a cause of MS progression.”
Jesús Martin-Garcia, GeNeuro CEO, added: “These positive Phase 2b results demonstrating the neuroprotective effect of GNbAC1 suggest that it could be used as a single agent on progressive MS populations without active inflammation as well as synergistically with existing anti-inflammation MS drugs.”
The findings, Martin-Garcia said, provide an additional element to the company’s development plans.
Recently, GeNeuro announced it reacquired worldwide rights to commercialize and develop GNbAC1 from Servier.