#ECTRIMS2018 — As Siponimod Awaits FDA Decision, Mouse Work Helps in Understanding Benefits Seen in SPMS

Mouse studies of siponimod — a potential progressive multiple sclerosis (MS) treatment that’s up for approval in the U.S. and EU — were among presentations given by Novartis at the 34th European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held Oct. 10-12 in Berlin.

Animal work might seem an odd entry at a major science conference, especially when the investigative treatment it concerns has gone through a pivotal Phase 3 trial and is under regulatory review.

But siponimod is pioneering, said Dan Bar-Zohar, MD, global head of neuroscience development at Novartis, regardless of whatever is decided by the U.S. Food and Drug Administration (FDA) in March, and the European Medicines Agency (EMA) possibly in December 2019. He spoke in an interview with Multiple Sclerosis News Today at the conference.

Dan Bar-Zohar, global head of neuroscience development at Novartis. Photo credit: MS News Today.

It’s “the first disease modifying therapy … that has shown for a first time efficacy in a very typical secondary progressive MS population,” Bar-Zohar said, referring to results from the Phase 3 EXPAND study (NCT01665144) that compared oral siponimod, at 2 mg a day, with a placebo in 1,651 secondary progressive MS (SPMS) patients with moderate to severe disability across 31 countries.

Results — previously reported — showed a confirmed 21% lower rate of  disability progression in treated patients at three months, and 26% at six months, Bar-Zohar said. But equally important, they did so in people more representative of the SPMS population — those starting treatment in their 40s and 50s, not 30s, with low relapse rates, and mean EDSS scores (disability scale) “of 5.4, not 2.4,” he added. Of note, the higher the EDSS score, the worse the patient’s disability level.

“Now, the fact that we’re talking about secondary progressive MS, and the complexity of secondary progressive MS, make us extremely keen to understand the mechanism of action of the drug, particularly when it comes to its central effects,” he said.

“We are trying to build a story around, and understand, what this molecule — siponimod — does inside the central nervous system, which is relevant to the very remarkable efficacy we’ve seen in secondary progressive MS,” Bar-Zohar added.

Building that understanding is where the animal work comes in, allowing researchers to see effects on brain and spinal tissue in ways impossible in patients. It’s not perfect, due to differences in translating results in the EAE mouse model to people, but it helps to explain the “changes in brain volume loss” seen in trial patients, Bar-Zohar said.

From EXPAND and an earlier Phase 2 trial in relapsing-remitting MS patients called BOLD (NCT01185821), scientists know that siponimod’s key mechanism of action is in reducing the inflammation that drives MS progression.

Specifically, it works by blocking the activity of two sphingosine-1-phosphate (S1P) receptors (S1P1 and S1P5) on the surface of immune cells, preventing aggressive lymphocytes from moving into the central nervous system — the brain and spinal cord — stopping them from causing inflammation and damage to the myelin sheath (the protective coat surrounding neurons that is damaged and lost in MS).

But siponimod has also shown potential to work by supporting remyelination, through its ability — again demonstrated in mouse studies — to penetrate the brain and affect a receptor, called S1P5, that’s found on  oligodendrocytes. These are a type of glial cell responsible for the production of myelin.

Its neuroprotective potential was the focus of the animal work shown in Berlin, which looked at siponimod’s effect on brain-derived neurotrophic factor (BDNF), a protein that works to support neuronal survival and new nerve cell growth and differentiation. As such, it is key to synaptic plasticity and cognition.

Findings, released in the presentation “Siponimod increases brain-derived neurotrophic factor (BDNF) levels in the brain of EAE mice,” looked at BDNF levels in mice treated at peak disease activity compared with a control group. Treatment showed a “unique potential” to “induce long-term release of neurotrophic BDNF in the midbrain,” with a final 10- to 15-fold increase in the factor’s levels reported.

Mice treated with fingolimod (Gilenya, Novartis) as a comparator showed an initial increase in BDNF levels in the brain, but these changes were not sustained.

“Now, I need to be a little cautious, because these are animal models,” Bar-Zahar said, but these results do offer “small evidences that accumulate” and help make sense of  “the effect that we see” in patients.

Cognitive benefit, assessed as an improvement in processing speed using the Symbol Digit Modalities Test (SDMT), was recorded in SPMS patients given siponimod in EXPAND. Results showed that the treatment could reduce cognitive decline in these patients. 

The FDA and EMA applications are purely for siponimod as an SPMS treatment, and Novartis has no plans to test this treatment further in those with relapsing-remitting disease, Bar-Zohar said.

Rather, he said, the entire reason for conducting the Phase 2 BOLD study was to judge siponimod against established markers of relapsing-remitting disease — markers that still “unfortunately, even today” don’t really exist for people with SPMS. That earlier study, which opened in 2010, established efficacy, safety — with safety continuing to be supported in EXPAND data now out at six years — and a dose for the Phase 3 trial.

“The huge unmet need is secondary progressive MS,” Bar-Zohar concluded. “So we moved it to secondary progressive MS, and we aspire to have it approved for secondary progressive MS pending the discussions with the health authorities.”