Comparing Reactive Microglia and Astrocytes in Secondary Progressive Multiple Sclerosis

News Network | <b>American Academy of Neurology 2022: Multiple Sclerosis Highlights</b>

Robert Zivadinov, MD, PhD, discusses the design of a novel comparative study assessing the effect of siponimod (Mayzent; Novartis) and ocrelizumab (Ocrevus; Genentech) on microglia and astrocytes in patients with SPMS.

Disclaimer: The American Academy of Neurology requested that all attendees remain masked during the Annual Meeting. This interviewee voluntarily removed their mask for this interview.

Robert Zivadinov, MD, PhD: We are presenting a study, which I think is very innovative in terms of methodology. It's based on imaging microglia in MS between 2 head-to-head, FDA-approved, disease-modifying treatments. First, there have been no previous head-to-head disease-modifying studies that used this type of technology, and second, I don't think that anybody previously did so many different measures to determine the evolution of chronic active lesions in MS. For instance, we are going to use 4 different approaches to determine chronic active lesions. The first will be to do paramagnetic rim lesion measurement using quantitative susceptibility mapping. The second will be to evaluate slowly expanding lesions over time. The third will be to use positron emission tomography—which is another type of imaging—to detect binding in some of these lesions, or perilesional tissue, or normal-appearing white and gray matter, and this is going to use a radiotracer called [F18]-PBR06-PET.

That radiotracer is a TSPO, which means translocator binding benzodiazepine receptor protein, and it's extremely sensitive to detecting microglial activation. This tracer has been developed in collaboration with an entity in Toronto, and I have obtained approval from FDA to use this tracer in this study. It has a very long half- and shelf-life—up to 9 to 10 hours—which really makes it very interesting to be used in multicenter studies, and for the purpose of this study, we are actually shipping this tracer from Toronto to Buffalo, which you can imagine takes about 3 hours, so we still have another 6 to 7 hours to scan more patients or account for a long delay. So really, the multicenter component is an interesting one.

The last marker that we are using is a new contrast agent, which is FDA approved, called Feraheme (Ferumoxytol). It's a drug to be given to patients with certain types of anemia. But that drug, that contrast agent, binds to macrophages and resident microglia and shows contrast-enhancing lesions in the brain, for example, like the gadolinium contrast that we are using for all clinical trials in MS. Feraheme is a USPIO, which stands for ultra-small particle iron oxide. It is a contrast agent that has to be infused, and then 24 hours should elapse so that on the second day, we can see how many enhancing lesions are in those patients. Because of that, we are doing 2 MRI scans, the first on day 1 with gadolinium and clinical routine, and the second with the USPIO on day 2.

With all of that being said, all the patients are going to have clinical cognitive laboratory or CT and other exams at baseline, at 6, 12, 24, and 36 months. The hypothesis—why this study has been started and funded by Novartis Pharmaceuticals—is that drugs like siponimod (which is Mayzent) may have more affinity to inhibit microglia activation than very potent anti-inflammatory drugs like ocrelizumab (which is Ocrevus). That is based on an array of the literature, which is increasing, that shows that Mayzent may cross the blood-brain barrier, enter into the central nervous system, and bind specifically to the SP1 receptor 5, which is important for microglia activation, for oligodendrocyte activity, and for astrocytes. So, certainly, this study is probably of the most sophisticated attempt to prove whether you can stop microglia activation with all these 4 methodologies that I outlined with a very high anti-inflammatory B-cell depleter or with a more microglia-oriented S1P inhibitor that is working on S1P receptor 5.

Transcript edited for clarity.