Understanding the Mechanism and Therapeutic Potential of Vidofludimus Calcium for Multiple Sclerosis

Despite the availability of more than 20 FDA-approved disease-modifying therapies for multiple sclerosis (MS), unmet needs remain across both relapsing and progressive forms of the disease. While current therapies have substantially improved relapse control, clinicians continue to seek agents that can combine anti-inflammatory activity with neuroprotective effects, particularly for patients with progressive disease or relapse-independent progression.

Vidofludimus calcium, also known as IMU-838, is an investigational, orally administered small molecule currently in late-stage clinical development by Immunic for MS and other chronic inflammatory diseases. The agent was initially developed as a potentially safer and better tolerated oral therapy, but emerging clinical and biomarker findings have suggested a broader dual mechanism involving anti-inflammatory activity and activation of nuclear receptor related 1, also known as Nurr1, a pathway increasingly being explored for its potential role in neuroprotection.

In a recent conversation with NeurologyLive^®, Daniel Vitt, PhD, chief executive officer of Immunic, discussed the rationale behind vidofludimus calcium, the design of the phase 3 ENSURE trials in relapsing MS, and the phase 2 CALLIPER (NCT05054140) data in progressive MS. Vitt also outlined how an oral therapy with potential anti-inflammatory and neuroprotective effects could fit into an already crowded MS treatment landscape.

NeurologyLive: Describe the mechanism of action of vidofludimus calcium, what’s the rationale for studying this agent across multiple forms of MS?

Daniel Vitt, PhD: How did we come to that mode of action, and what’s the story behind it? Initially, the drug was intended to solve another problem when we started clinical development in multiple sclerosis, in RMS, with the EMPhASIS study 6 years ago. The idea was to have an easier-to-use drug, to make it safer and better tolerated, something easy for the treating physician and for the patient.

The idea was to improve on things like teriflunomide (Aubagio), where Aubagio was known to be a good drug and easy to handle, but with all the pharmacokinetic and side effect issues. It was really intended to get rid of the side effects, which are driven by off-target kinase inhibition of Aubagio. We succeeded on that, but going into the clinical studies, we found out that the drug does something unique. It has shown hints of direct neuroprotection in patients, specifically seeing that in interestingly low rates of disability progression on the one hand, and secondly also on biomarkers like NfL, where we have seen a dramatic reduction.

We investigated further, and we found that the drug is the first potent activator of a nuclear receptor called Nurr1. That is interesting because Nurr1 has been known for quite some time, maybe 10 years, to be an attractive target in Parkinson disease and other neurodegenerative diseases. It also showed up as maybe one of the top 3 targets in a genetic test of pregnant MS patients, comparing gene expression data with non-MS patients as the key upregulated protein during pregnancy, therefore correlating with the observed slower progression and reduced inflammation in those patients during pregnancy.

So, we think that makes vidofludimus calcium’s mode of action unique. It is a double strike. On the one hand, we have Nurr1 activation, which we believe is the new thing, and that is really a big differentiator from everything currently in development or on the market.

Can you provide details on the phase 3 ENSURE trials and what those studies are designed to answer?

The studies have 2 main goals. One is to get it approved, and secondly to convince doctors and patients that this is the best choice. For that, we follow the more traditional approach on a study general concept. We have 2 independent big phase 3 studies, each recruiting around 1100 patients, and in total we have enrolled 2221 patients in the 2 studies.

This is a huge set of patients, and it will give us a lot of data that we can use to understand and confirm the activity of the drug. They are 2 twin studies to make sure they are almost similar and to enable pooling of the data for secondary endpoints as well. The primary endpoint of the study is time to first relapse, so it is one of those endpoints you can use for estimating the anti-relapse activity of the drug, which is more correlated with the anti-inflammatory portion of activity.

It is powered to be statistically significant and to give us approval from the regulators. The study also records a lot of other secondary endpoints, and among those are, of course, disability endpoints, like 12-week confirmed disability worsening and more. We do not give full guidance here. We are still in the final process of completing our SAP discussions with the FDA, so this is not finalized right now, but we will have a huge set of secondary endpoints read out from the study as well.

To focus on that second part, the study is also aiming to demonstrate efficacy, but also outstanding safety and tolerability, to really make sure we have an easier tool for treating physicians. Today, current therapies come with a lot of screening requirements and monitoring requirements. I think this treatment, if we confirm what we have seen so far, would change that. You would have an easy pick here, and together with the Nurr1 activation and the neuroprotective features of the drug, I think it may open a new tool in the toolbox of physicians for relapsing MS immediately, also preventing relapse-independent progression of patients, so PIRA as one of the key targets here.

That is related to the data we have seen in our progressive MS study last year, because that was the clinical continuation of our Nurr1 hypothesis and transformation of the more biological hypothesis into a clinical data set.

What considerations went into the patient population and study design for ENSURE?

Baseline characteristics are almost the same as with every other bigger phase 3 study recently performed. I think we did 2 things that are important to mention. We stratified for baseline age and EDSS score to make sure we balance the study between the groups on that activity, because these may be the main characteristics of disease activity.

We are trying to make sure that we have balanced disease activity in the study and in the country mix we are using. From the rest, I think it is comparable to what other studies have done. We are advised by the same experts as everybody else, so we really want to make sure it is comparable to other studies that have been performed recently.

Can you break down the phase 2 CALLIPER study, and the major findings clinicians should take away?

CALLIPER is a phase 2 study. Interestingly, it turned out that this is maybe the first real big phase 2 study performed in progressive MS at all. This study was aiming to tell us whether the Nurr1 activation translates into a clinical disability benefit.

It was a pretty good study, a pretty information-rich study, and it is difficult to just say this is the number 1 endpoint. What impressed us most was that we saw a very strong reduction of disability progression: in total, 24% in the overall CALLIPER study. In the PPMS population, it was 31%, and in nonactive SPMS it was 20%.

That by itself is pretty good already, but it gets even better if you stratify the patients and look for those patients who do not have gadolinium lesions at baseline. If you separate those inflammatory patients and just look at those more or less currently untreatable patients without active inflammation at baseline, we see an average for the total study of 33.7% reduction of 24-week confirmed disability progression. In PPMS, it was 34%, and in nonactive SPMS it was 30%.

That is, I think, the most important overall endpoint of the study because it really shows us the drug goes beyond what current drugs can do. This is not related to just an anti-inflammatory effect, but really an effect where patients benefit when the inflammatory part of the disease has cooled down over time.

Going further into the analysis, and just recently reported at one of the conferences, I think it was at ECTRIMS, we also showed that the drug has a quite remarkable level of confirmed disability improvement. On the 24-week CDI, we saw a 2.4-fold likelihood to benefit on CDI for the active versus placebo patients, so a hazard ratio of 2.4. In the PPMS population, it was 2.8. That is something really great, something really mind-blowing for me, and it underlines the unique biology of the molecule and the ability of the drug to improve the situation in patients where the inflammatory situation has cooled off.

If approved, how could vidofludimus calcium change the MS treatment landscape?

It will offer doctors an additional tool with a different profile, and I think the strengths are threefold. One is safety and tolerability, so easy to use and not running into the typical risks of current drugs and the additional work to do with these.

Secondly, clearly a solid reduction of inflammation as an oral, easy-to-use treatment, specifically with an absence of infection risk increase. That means, for example, if you pretreat a patient with an anti-CD20 and there is a situation where there is an acute infection and you need to switch the patient to a different therapy, this would be a perfect choice and the perfect solution for that.

Thirdly, of course, targeting direct neuroprotection. That is something that is relevant for progressive MS patients, for all progressive MS patients, but I think it is also something of interest for relapsing MS patients going forward. Specifically, for example, if you are newly diagnosed and have such a nice safety and tolerability profile, I think it could really deserve to be an early treatment as well, because patients can handle it easily and do not have the risk of hidden progression at an early stage of disease. So I think that could be the treatment of choice from the oral world.

Transcript edited for clarity.