Antibody for Human Retrovirus May Promote Remyelination in MS

November 02, 2017

PARIS — A monoclonal antibody directed against a human retroviral protein thought to play a role in the multiple sclerosis (MS) disease process did not show a significant effect on the primary endpoint of a new phase 2 study: the number of gadolinium-enhancing (Gd+) lesions seen on monthly brain MRI scans from weeks 12 to 24 vs placebo.   

However, a post hoc analysis suggested the antibody, known as GnbAC1, in development by GeNeuro and Servier, may have an anti-inflammatory effect in active patients at the highest (18 mg/kg) of the three doses tested at week 24. In addition, at the same dose, a "promising" effect on remyelination was observed.

The CHANGE-MS study was presented here at last week's 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting.

"This is a completely novel therapeutic approach to multiple sclerosis directly targeting a potential cause of the disease, which appears to promote remyelination without directly affecting normal immunity," said lead investigator, Hans-Peter Hartung, MD, University Hospital Düsseldorf, Germany. 

"While we failed to show a significant effect on the primary outcome of this study — the number of Gd+ lesions at 6 months — there did appear to be a trend suggesting an effect later in the course," he commented to Medscape Medical News.

"And a particularly interesting observation was that the agent did seem to be associated with remyelination as documented by increased magnetization transfer ratio (MTR) values on MRI. This effect was very robust and encourages us to pursue this approach further."    

He added: "We are continuing to follow patients, and it will be interesting to see what will happen at week 48. Based on the pharmacokinetic data it looks as if maximum concentrations are only reached after 4 months. We may have just missed an effect on Gd+ lesions at 24 weeks. We are also considering a study in secondary progressive MS where the remyelinating properties of this agent could be more obvious."

Novel Approach

Commenting on the study for Medscape Medical News, Jeremy Chataway, MA, PhD, FRCP, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College London, United Kingdom, said, "This is suggestive early work but the higher dose looked encouraging. We need to wait for more data but there has been much interest in the idea of embedded viral genomes as possible causes of MS. This is an interesting and novel therapeutic approach." 

Professor Hartung explained that human endogenous retroviruses (HERVs) are present in a latent form in the human genome, and in patients with MS this one particular retrovirus —- HERV-W (formally known as the MS-associated endogenous retrovirus) — appears to be activated by environmental factors and produces a pathogenic surface envelope protein.

Experimental studies have suggested that this pathogenic envelope protein could contribute to the disease process in MS by acting as a potent agonist of the Toll-like receptor 4 causing activation of proinflammatory macrophages and inhibiting remyelination of neurons.

The CHANGE-MS study, conducted in 12 European countries, randomly assigned 270 patients with relapsing-remitting MS to three different doses of the monoclonal antibody (6, 12, or 18 mg/kg) or placebo, via monthly intravenous infusion for 24 weeks. At week 24, placebo patients were re-randomly assigned to active treatment at one of the three doses for an additional 24 weeks.

Week 24 results were presented at the ECTRIMS-ACTRIMS 2017 meeting.

In the main analysis, the antibody showed no effect on any MRI measure of inflammation from weeks 12 to 24 at any dose, or any effect on clinical measures through 24 weeks.

However, a post hoc analysis on the 121 "active" patients — defined as those who had at least one Gd+ T1 lesion on their baseline brain MRI scan — showed a positive effect at the highest dose of the antibody (18 mg/kg) at week 24 in significantly reducing Gd+ T1 lesions (P = .008).

Similar effects were seen across other MRI measures of neuroinflammation, including new and/or enlarging T2, and combined unique active lesions. The 18-mg/kg dose appeared to consistently numerically outperform both lower doses and placebo across MRI endpoints, Professor Hartung reported.

These results support the hypothesis of a late onset of action of the agent, which could be due to its mode of action through neutralizing a pathogenic protein without directly modulating or suppressing patients' immune systems, as well as to the time taken to reach a therapeutic concentration of the antibody in the brain, he suggested.  

Remyelination was measured by MRI with MTR analyses performed in the normal appearing white matter and cerebral cortex of patients. Recent studies have observed that there is a reduction in MTR signal in these areas in patients with MS versus controls, and that the MTR signal directly correlates to the amount of structural myelin contained within each area, Professor Hartung noted.  

Results showed that at the 18-mg/kg dose of the antibody, the MTR signal increased throughout both the normal-appearing white matter and cerebral cortex, from baseline to week 24, with statistical trends vs placebo (P = .06) in both areas. The 18-mg/kg dose demonstrated an increase of approximately 2 MTR percentage units vs placebo, which Professor Hartung described as a "robust" response.  

All eyes will now be on the 48-week data, which are expected to be available early next year. 

Professor Hartung has received fees for consulting, serving on steering committees and boards, and speaking at symposia from BayerHealthcare, Biogen, GeNeuro, Medimmune, Merck, Novartis, Octapharma, Opexa, Roche, Sanofi Genzyme, and Teva.

7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017. Abstract 279.  Presented October 28, 2017.  

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