GeNeuro and Servier have announced positive results at 12 months from the CHANGE-MS Phase 2b study of GNbAC1, a novel and promising therapeutic approach for the treatment of multiple sclerosis (MS). The data showed that GNbAC1 administration had a significant, consistent positive impact on key neuroprotection markers known to be linked to disease progression. This is the first time that the benefit of a treatment targeting endogenous retrovirus protein is shown in a clinical trial.
In this 270-patient study, 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 control group, with a statistically significant dose-relationship for both (p=0.045 and P=0.014 respectively). 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-relationship2 (p=0.079).
In addition, the number of T1 hypointense lesion (black holes, a marker of permanent tissue destruction in the brain) of at least 14mm3 volume was reduced by 63% (p=0.014) at the end of the study in the 18mg/kg versus control group.
The benefit in Magnetization Transfer Ratio (MTR) signal of 18mg/kg relative to the placebo at 6 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 6 to Month 12, however there was no significant separation between treatment groups. The trend seen in post-hoc analyses at 6 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, 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.
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“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,” noted Prof Hans-Peter Hartung, chairman of the Department of Neurology of the University Hospital Düsseldorf and Lead Investigator of the study. “These positive effects are very promising, and may open new doors towards addressing the key unmet medical need of disease progression in MS.”
“The positive impact of GNbAC1 on neuroprotection markers opens a novel therapeutic perspective for MS, in line with Servier’s ongoing commitment to bringing new, safe and effective treatments to patients. Based on this joint achievement, we will now assess the next development steps with our partner to bring these benefits to patients,” stated Dr. Christian de Bodinat, Director of Servier’s Neuro-psychiatry Centre for Therapeutic Innovation.
“These results are a significant success for GeNeuro as they demonstrate the role played by pathogenic HERV-W protein in patients affected by MS. It supports the concept of altering the neurodegenerative course of MS by treating a causal factor of the disease, as suggested by preclinical research,” stated Jesús Martin-Garcia, CEO of GeNeuro. “These clinical results support GeNeuro’s efforts to develop this approach in other HERV-related diseases such as Type 1 Diabetes, CIDP (Chronic Inflammatory Demyelinating Polyradiculoneuropathy) and Amyotrophic Lateral Sclerosis”.
GNbAC1 is a monoclonal antibody designed to neutralize 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, Type 1 diabetes and CIDP.
GeNeuro is presently conducting a 60-patient Phase IIa with GNbAC1 in T1D with expected top line results in September 2018 and has received an Orphan Drug Designation from the FDA for GNbAC1 in CIDP. In 2017, GeNeuro entered into a research agreement with the US NIH for developing new approaches against pHERV-K protein as a target in the treatment of Amyotrophic Lateral Sclerosis (ALS).
CHANGE-MS Phase 2b study was fully funded through a €362.5 million partnership signed with Servier in 2014, in which Servier is involved in the development and potential commercialization of GNbAC1 in MS in territories ex USA and Japan.
Achieving these positive Phase 2b results through the neutralization 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.
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