ACTRIMS 2023: RRMS treatment may ‘give patients a better choice’

New data from a Phase 2 clinical trial testing vidofludimus calcium, Immunic Therapeutics’ novel oral treatment candidate for relapsing-remitting multiple sclerosis (RRMS), show promising safety and efficacy, according to the company’s chief medical officer.

The therapy was found to safely reduce brain lesions and prevent disability progression in most people with RRMS, the data from the EMPhASIS Phase 2 trial and its open-label extension show, said Andreas Muehler, MD, also a co-founder of Immunic.

For a population that often faces a choice between efficacy or safety when it comes to selecting a disease-modifying therapy, vidofludimus calcium may prove an effective medication for multiple sclerosis (MS) — and one that may have a better safety profile than most currently approved drugs, Muehler said in an interview with Multiple Sclerosis News Today that took place during the recent Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2023, held in San Diego and virtually.

This is “a new category of oral drugs” for MS patients that is “convenient, safe, and [with] robust efficacy,” Muehler said.

Vidofludimus calcium may be particularly good at slowing disability

Previously known as IMU-838, vidofludimus calcium is an oral medication designed to reduce MS activity and progression. It works by interfering with the normal metabolism of immune cells known to drive inflammation and nerve cell death in people with the disease.

After preclinical investigations showed the therapy suppressed immune cells as expected, Immunic launched the EMPhASIS Phase 2 trial (NCT03846219) to test the medication’s safety and efficacy in people with RRMS.

In the trial, 268 adults were randomly assigned to receive 10, 30, or 45 mg of vidofludimus calcium or a placebo, taken orally once per day for 24 weeks, or about six months. After completing that part, most participants opted to join an ongoing open-label extension (OLE) phase, in which all are receiving vidofludimus calcium for up to 9.5 years.

The study’s main goal was to detect changes in the cumulative number of active lesions — a measure that assesses both lesions with active inflammation and new or enlarging lesions on MRI scans.

This is a metric that says little to patients, Muehler said, noting that people with MS are more concerned with measures like relapse rates and accumulation of disability — gauges that have a discernible impact on their day-to-day life.

To researchers, however, such data can be pivotal: looking at brain lesions enables scientists to see an effect from treatment in a shorter period of time.

That’s because lesions are “much more common” — thus, scientists “don’t need to wait for four years to see a few relapses here and there,” he said. Instead, they can get a sense of how effective the treatment will be on relapse rates.

This is possible because there is a direct correlation between the number of lesions and relapses.

“The more lesions you have, the more possibility you have to have a relapse,” Muehler said.

Results from EMPhASIS indicated that the higher doses of vidofludimus calcium led to significant reductions in the total number of lesions compared with a placebo after six months of treatment. More specifically, the 30 mg dose resulted in 76% fewer lesions than a placebo, and there was a 71% reduction with the highest, 45 mg dose.

Data spanning both EMPhASIS and the open-label extension also suggested that patients had low relapse rates, with only 3% experiencing a relapse in the first year and 6.2% in the first two years.

Still, Muehler emphasized that vidofludimus calcium has properties that “may make it particularly good in disability. … Maybe not as good in relapse as other drugs, but particularly good in disability.”

This is important for patients, who overall are not “solely focused on avoiding one or two relapses in their lifetime,” he said.

“What they’re more concerned with is that, long term, they’re able to live a life, have a social life, have a work life, have a family life, and disability is not interfering with” any of those aspects, Muehler said.

In the main trial, results showed that only 1.6% of patients on vidofludimus calcium experienced confirmed disability worsening (CDW), defined as an increase in Expanded Disability Status Scale (EDSS) scores that is sustained for at least 12 or 24 weeks.

In contrast, 3.7% of patients on a placebo experienced both 12-week CDW and 24-week CDW in the first six months.

Now, data presented at ACTRIMS showed that the slowing in disability accumulation continued to be observed in the extension phase, after a follow-up period ranging from 2-4 years for all participants.

After all patients had been followed for one year in the OLE, the majority had not experienced sustained disability accumulation — 97.6% were free of 24-week CDW. Moreover, the rate of no progressors, namely those without such disability accumulation, remained high after two years (94.5%).

The proportion of patients experiencing 24-week disability progression after two years in the OLE was 5.5%, which compares favorably to historical data from trials testing other approved MS drugs, Muehler noted.

For example, the rates of disability progression after two years were higher than 6% in trials testing the high-efficacy medications Ocrevus (ocrelizumab) and Kesimpta (ofatumumab), and higher than 9% on trials of Aubagio (teriflunomide), an approved treatment that targets the same molecule as vidofludimus calcium.

The findings were “very important to us,” Muehler said. “We really thought that this is the main need for patients nowadays.”

He added that while there’s a lot of emphasis on relapse activity in clinical trials, “the effectiveness of a drug should really be measured in long-term disability.”

The identical Phase 3 trials ENSURE-1 (NCT05134441) and ENSURE-2 (NCT05201638) are now underway globally to confirm the benefits of vidofludimus calcium in adults with RRMS and active secondary progressive MS patients.

Each trial is recruiting about 1,050 patients, who will receive the 30 mg dose for 72 weeks, or about 15 months. Participants will then be invited to join an open-label extension lasting up to eight years.

The trials’ main goal is to determine whether vidofludimus calcium can reduce relapse rates, but disability progression and lesions also will be evaluated as secondary measures.

Same target as Aubagio, but ‘similar to placebo’ in terms of side effects

To eliminate immune cells involved in MS attacks, vidofludimus calcium was designed to target the dihydroorotate dehydrogenase (DHODH) enzyme, which is required for the production of specific RNA and DNA building blocks called pyrimidines.

Pyrimidines are unique in that they are usually recycled and not newly produced in the body.

“When you have a growing cell, it’s just using over and over again the same pyrimidines,” Muehler said.

But there are “very special situations where [cells] need so many [pyrimidines] that … recycling is never enough,” Muehler said. In that case, cells can produce their own pyrimidines by turning on a specific molecular pathway that requires DHODH.

The body only needs to activate pyrimidine production in a few circumstances. One of these instances is when immune cells become very active, as happens in autoimmune conditions like MS.

Thus, by blocking DHODH, vidofludimus calcium can essentially starve the overactive immune cells of these building blocks and reduce the production of RNA and DNA molecules in these cells, which will ultimately result in “an immune-suppressive or immunomodulatory action,” Muehler said.

According to the researcher, there’s a few reasons why this mechanism might be beneficial in MS. The first is its selective effect.

While vidofludimus calcium can enter all cells in the body, it only exerts an effect on the immune cells that drive autoimmunity, leaving healthy cells alone.

“The other immune cells that you need to fight bacteria or infections and so forth, they’re completely intact,” Muehler noted.

That’s a significant benefit of targeting DHODH, according to Muehler.

“You don’t want a full immunosuppression because it leads to all kinds of side effects,” he said, noting that most other immune-suppressing drugs for MS “have a relatively wide immunosuppression.”

In addition to its selectivity, vidofludimus calcium also has a “broad antiviral effect,” stemming from the fact that virus-infected cells also need a lot of pyrimidines to make more viruses and continue to spread the infection.

Those antiviral properties may be useful to MS patients, in light of evidence linking the Epstein-Barr virus (EBV) to MS onset and progression. Those properties also may mean that vidofludimus calcium could avoid progressive multifocal leukoencephalopathy (PML), a serious viral infection in the brain that comes as a rare side effect of some MS treatments.

Such benefits have been observed with Aubagio, an approved oral MS therapy that also works to inhibit DHODH. The medication is one of the only MS treatments that has not led to any PML problems, “and I think this likely is the same for [vidofludimus calcium] because it also has this mechanism,” Muehler said.

However, Muehler believes that’s where the safety similarities between Aubagio and vidofludimus calcium end.

“Most of the oral drugs that are in the market … they’re the same,” Muehler said, noting that Aubagio is no exception. “They have a slew of side effects that interfere with the patient’s life, and … about the same effect on relapse reduction” and other measures.

But Immunic wanted to “give patients a better choice,” he said. “We really wanted a drug that was very different, that had a “a side effect profile that was similar to placebo.” The goal is that “patients don’t notice that they’re taking the drug.”

I think patients sometimes want to make the choice to have a drug that maybe doesn’t have as much risk as other drugs.

The reason vidofludimus calcium may be able to provide such a promising safety profile is because it is more specific for DHODH. Aubagio, on the other hand, also targets another family of enzymes called kinases.

Targeting those kinases contributes to a number of side effects associated with Aubagio, but doesn’t seem to offer any additional efficacy. Compared with vidofludimus calcium’s 76% reduction in brain lesions at its 30 mg dose, Aubagio was associated with about a 61% lesion reduction in clinical trials, according to Muehler.

”In a lot of ways we don’t like to compare us with Aubagio … because it’s really not representative of what the DHODH inhibitors should look like in terms of safety,” Muehler notes.

The company sees vidofludimus calcium as a new category of oral MS drugs. While it offers comparable lesion reductions to other approved oral MS therapies, it will likely have a safety profile similar to that seen with glatiramer acetate, a less effective MS treatment sold as Copaxone, with generics available.

“I think patients sometimes want to make the choice to have a drug that maybe doesn’t have as much risk as other drugs,” Muehler said. Immunic hopes to offer patients who are more cautious “better efficacy for the same risk level that glatiramer acetate has.”

Vidofludimus calcium shows potential in progressive MS

Immunic believes that vidofludimus calcium also may be a promising treatment candidate for progressive forms of MS, in which disability continues to accumulate even in the absence of relapses.

While “the hypothesis for most MS experts is that maybe inflammation doesn’t play a huge role … in progressive MS,” Muehler believes the treatment’s antiviral effects could benefit this patient group.

In light of recent evidence suggesting that EBV reactivation in MS patients might be central to disease processes, vidofludimus calcium would be “very well-suited to fight EBV-related disability worsening,” Muehler said.

Researchers also have identified another action of vidofludimus calcium, unrelated to DHODH activity, that “helps nerve cells to survive if they’re attacked.” That neuroprotective effect could help preserve nerve cells and prevent disease progression.

“We’re hoping that with our broader effect — both anti-EBV and neuroprotective effect — we can show an effect in progressive MS patients,” he said.

The CALLIPER Phase 2 trial (NCT05054140) is now investigating vidofludimus calcium’s effects in up to 450 people with primary or secondary progressive MS who experienced no relapses in the previous two years. The trial is continuing to recruit patients at sites in the U.S., Canada, and Europe.

An interim analysis focusing on biomarkers of disease progression is expected in the second half of this year, Muehler said. Later analyses will focus on brain volume changes and disability progression.

Interim analyses for the ENSURE trials likely will come at the end of 2024, but the timing for that analysis is “a little bit more unpredictable,” because it can only be done after a certain number of relapses occur.

“This [interim analysis] will give us … some initial signal whether the study is on track” to show a significant effect in terms of efficacy, Muehler said. But he noted that a regulatory application for vidofludimus calcium’s approval in relapsing forms of MS will require a full data readout.

For that, “we have to wait until the end of 2025 or early 2026,” he said.

Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the ACTRIMS Forum 2023 Feb. 23–25. Go here to see the latest stories from the conference. Follow along on Facebook, Twitter, and Instagram for live updates using the hashtag #actrims2023.