Vidofludimus calcium reduced NfL levels in progressive MS patients

Vidofludimus calcium (IMU-838), an investigational oral therapy being developed by Immunic Therapeutics for all types of multiple sclerosis (MS), has demonstrated neuroprotective effects in people with progressive forms of the disease, interim clinical trial data show.

The experimental therapy was associated with reductions in neurofilament light chain (NfL) levels, a well-established marker of nerve damage, and with smaller increases in another biomarker of damage to nerve-supporting cells compared with a placebo.

The findings come from data of about half of the patients enrolled in the Phase 2 CALLIPER clinical trial (NCT05054140). They are similar to newly announced results in people with relapsing-remitting MS (RRMS), including those without recent inflammatory activity, providing additional evidence that vidofludimus calcium exerts effects in MS patients that go beyond its anti-inflammatory activity.

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“Serum NfL has been consistently shown to capture disease activity and to predict future disability in MS. Vidofludimus calcium shows a separation in serum NfL over placebo in this interim analysis,” Jens Kuhle, MD, PhD, said in an Immunic press release. Kuhle is senior physician at the University Hospital Basel, in Switzerland.

Vidofludimus calcium is designed to slow MS progression by interfering with the metabolism of immune cells that fuel inflammation and cell death in MS. Similar to the older approved therapy Aubagio (teriflunomide), it works by blocking the dihydroorotate dehydrogenase (DHODH) enzyme.

However, the candidate therapy also seems to deploy neuroprotective effects unrelated to DHODH, which are believed to be associated with its ability to activate Nurr1, a protein with neuroprotective and anti-neuroinflammatory activity.

“The clear separation observed in serum NfL for vidofludimus calcium over placebo in the PMS [progressive MS] patient population represents another major step forward for, what potentially could be, a first-in-class Nurr1 activator for MS,” said Daniel Vitt, PhD, CEO and president of Immunic.

The CALLIPER trial is investigating vidofludimus calcium in a total of 467 patients with either primary progressive MS (PPMS) or active or nonactive secondary progressive MS (SPMS).

Participants, who had no evidence of relapses in the past two years, were assigned randomly to vidofludimus calcium (45 mg) or a placebo, given as daily tablets for up to 120 weeks (about 2.5 years).

Those who complete the trial then will have the option to join an open-label extension study, where all will receive vidofludimus calcium for up to eight years.

Main goals of the CALLIPER trial

The trial’s main goal is to evaluate whether vidofludimus calcium can slow the rate of brain shrinkage significantly compared with a placebo over the 120 weeks. Secondary measures include total changes in brain volume after six months, and time to disability progression.

While top-line data from the trial is not expected until April 2025, Immunic conducted an interim biomarker analysis to determine if the treatment is showing signs of slowing nerve cell damage.

The analysis included six-month data from the first half of patients (203 patients) enrolled in the trial and focused more specifically on NfL and glial fibrillar acidic protein (GFAP) levels.

While NfL is used commonly as a marker of nerve cell damage, GFAP is believed to reflect damage to astrocytes — star-shaped cells in the brain that provide support to nerve cells — and to predict disease progression and disability.

Results showed that patients who received vidofludimus calcium experienced a 6.7% reduction in NfL levels after six months of treatment, and a 10.4% reduction after 48 weeks. This contrasted markedly with participants given a placebo, whose NfL levels rose by 15.8% after six months and by 6.4% after 48 weeks.

Notably, reductions in NfL levels were seen across all groups of patients in CALLIPER, including in patients without any recent relapses or activity seen on MRIs.

Pleased with improvements in serum NfL

“We are very pleased to see such strong improvements in serum NfL for vidofludimus calcium over placebo in the overall PMS population of this interim analysis, as well as across all PMS subtypes and in patients with and without disease activity, and with and without MRI activity,” said Andreas Muehler, MD, chief medical officer at Immunic.

“We even saw evidence in non-active SPMS, a population where the medical need for new therapies is high as there is currently no relevant treatment available in the US,” Muehler added.

These findings mimic those seen in RRMS patients in the Phase 2 trial EMPhASIS (NCT03846219), where vidofludimus calcium reduced NfL levels even in a subgroup of patients without clinical or MRI disease activity, while levels of that biomarker increased with a placebo.

In the CALLIPER trial, researchers also found that GFAP levels had smaller increases with vidofludimus calcium than with a placebo. While those in the control group experienced a 4.4% increase in GFAP levels after six months and a 6.4% increase after 48 weeks, the biomarker increased by 3.7% after six months on the experimental therapy and by 2.7% after weeks.

“We were […] excited to see an encouraging early signal with GFAP. This is a newer biomarker which is thought to evolve more slowly and with lower amplitude than NfL, and longer follow-up will hopefully allow us to see even stronger results,” Muehler said.

“Although longer follow-up is needed, the GFAP data set also shows a potential promising early signal. Overall, the interim biomarker data further support vidofludimus calcium’s possible activity beyond an anti-inflammatory effect, which may be related to its potent Nurr1 activation,” Kuhle added.

CALLIPER running parallel with the ENSURE trials

CALLIPER is running parallel with the ENSURE Phase 3 program, where two clinical trials — ENSURE-1 (NCT05134441) and ENSURE-2 (NCT05201638) — are evaluating the safety, tolerability, and effectiveness of the experimental therapy in adults with relapsing forms of MS.

An interim analysis of the ENSURE trials is expected late next year, and top-line data should be released in late 2025.

“If the top-line CALLIPER data, expected in April of 2025, continue to show a neuroprotective effect, we may be able to position vidofludimus calcium as the first oral treatment option for non-active SPMS. Additionally, the drug’s first-in-class ability to activate Nurr1, a known neuroprotective target, should also significantly benefit our ongoing phase 3 ENSURE program in relapsing MS where prevention of disability progression independent of relapse activity (PIRA), serves as a key outcome,” Vitt said.