BERLIN — Final results of a phase 2 study of the novel antiretroviral protein monoclonal antibody GnbAC1 (GeNeuro and Servier) in multiple sclerosis (MS) have included some interesting findings.
Although the drug does not appear to have much anti-inflammatory activity, there were consistent benefits on other MRI measures of disease progression and antineurodegenerative effects seen in patients with nonactive disease.
"This is a small study, so we have to be cautious, but several different markers are showing some improvement," said Frederik Barkhof, MD, PhD, University College London, United Kingdom, who presented the latest results from the study at the recent 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018.
"The anti-inflammatory activity is very modest, so it is not going to be further developed as an anti-inflammatory agent in MS, but these results suggest that it could be considered for further development as a neuroprotectant — maybe in progressive MS populations," he added.
The antibody is directed against a human retroviral protein thought to play a role in the MS disease process. Human endogenous retroviruses (HERVs) are present in a latent form in the human genome. In patients with MS, 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 causing activation of proinflammatory macrophages and inhibiting remyelination of neurons.
The humanized IgG4 monoclonal antibody GNbAC1 binds to the HERV-W envelope protein and has shown inhibitory activity against HERV-W-mediated pathogenicity, both in vitro and in animal models of MS.
The phase 2 CHANGE-MS study randomly assigned 270 patients with relapsing remitting multiple sclerosis to receive either GNbAC1 (at doses of 6, 12, or 18 mg/kg) or placebo via monthly IV infusion for 24 weeks. The patients who received placebo were then randomly assigned to receive one of the three GNbAC1 doses. All patients were followed for another 24 weeks.
The primary results, presented at last year's ECTRIMS meeting in Paris, did did not show a significant effect of GnbAC1 on the primary endpoint, which was the number of gadolinium-enhancing lesions seen on monthly brain MRI scans from weeks 12 to 24 vs placebo.
However, a post hoc analysis suggested the antibody may have an anti-inflammatory effect in patients with active MS when used 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.
Results at 48 weeks, presented at this year's ECTRIMS meeting, showed a nonsignificant reduction in new T2 lesions in the original highest-dose GnbAC1 group vs the original group that received placebo (mean, 3.83 vs 4.49; P = .480). But there was a significant 63% reduction in new T1 black holes (mean, 0.28 vs 0.75; P = .014).
In addition, in the highest-dose group, there was a reduction in central nervous system loss in comparison with the original group that received placebo. This was "particularly dramatic" in the thalamus, Barkhof reported.
Table. CNS Volume: Median Percentage Reduction at Week 48
|Region||18 mg/kg Dose||Original Placebo||Relative Reduction||P Value for Dose Response|
There was also an improvement in magnetization transfer ratio (an indicator of possible better prognosis) in normal-appearing white matter and in the cerebral cortex in the highest-dose group.
No serious problems regarding safety or tolerability were seen.
"These results should allow for future studies with increased doses of GnbAC1 and/or in combination with other disease-modifying therapies in nonactive progressive MS populations," Barkhof concluded.
Co-chair of the ECTRIMS session at which the study was presented, Ariel Miller, MD, Carmel Medical Center, Haifa, Israel, described the study as "very interesting."
"Any new mechanisms for new drugs in development are exciting," he commented.
The CHANGE-MS study was sponsored by GeNeuro. Dr Barkhof has served as the central MRI reader for several pharmaceutical company–sponsored clinical trials.
34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018. Abstract 143, presented October 11, 2018.
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Cite this: 'Interesting' Latest Results With Antiretroviral Antibody in MS - Medscape - Oct 30, 2018.