Results from the CHANGE-MS phase 2b study of GNbAC1 have shown that GNbAC1 administration has a significant, consistent positive impact on key neuroprotective markers known to be linked to disease progression.
GNbAC1 is a monoclonal antibody designed to neutralise a pathogenic protein encoded by a member of the Human endogenous retroviruses (HERV-W) family. HERVs are ancestral, retroviral DNA insertions in the human genome, thought to account for up to 8% of the total DNA. The pHERV-W protein is thought to be a causal factor in the development of multiple sclerosis (MS), Type 1 diabetes and Chronic inflammatory demyelinating polyneuropathy.
This is the first time that the benefits of a treatment targeting endogenous retrovirus protein has been shown in a clinical trial.
270 patients took part in the study, which was conducted in 12 European countries. MRI showed a coherent neuroprotective benefit on brain atrophy. Benefits were seen in cortical and thalamic atrophy, with relative volume loss reductions of 31% and 72% respectively between the highest dose of 18 mg/kg and the control group, with statistically significant dose-relationship for both.
Whole brain atrophy revealed a 29% relative reduction in brain volume loss over 12 months for the highest dose versus the control group, with a trend in dose- relationship.
In addition, the number of T1 hypo-intense lesion (black holes, a marker of permanent tissue destruction in the brain) of at least 14mm volume was reduced by 63% at the end of the study in the 18mg/kg versus control group.
The benefit in Magnetisation Transfer Ratio (MTR) signal of 18mg/kg relative to the placebo at six months remained stable versus the control group over the second period of the trial, in both normal appearing white matter and cerebral cortical bands, consistent with a potential benefit on remyelination.
For most MRI measures of neuroinflammation, all groups improved from Month six to Month 12, however there was no significant separation between treatment groups. The trend seen in post-hoc analyses at six months on neuroinflammatory markers, after the primary endpoint of reducing the total number of cerebral Gadolinium-enhancing lesions as measured by MRI was not met and did not translate into a relevant result at 12 months.
No organ-class related toxicity and no dose dependent adverse events were observed. GNbAC1 continued to show an excellent tolerability profile throughout the study.
Prof Hans-Peter Hartung, chairman of the Department of Neurology of the University Hospital Düsseldorf and Lead Investigator of the study said: “What is impressive is the consistency of the effect already observed at one year across all these key markers of neurodegeneration, and that this effect appears to be independent from an anti-inflammatory action.”
“These positive effects are very promising and may open new doors towards addressing the key unmet medical need of disease progression in MS,” he added.
Achieving these positive Phase 2b results through the neutralisation of pathogenic HERV-W protein supports its causal role in the neurodegenerative mechanisms of MS. GNbAC1 may provide a safe treatment option against neurodegeneration unrelated to inflammation in all forms of the disease, a major objective that is not addressed by currently available MS treatments.
Source: MS-UK 26/03/18