Experimental MS therapy vidofludimus calcium triggers Nurr1 protein
In doing so, the oral anti-inflammatory med exhibits neuroprotective effects
Vidofludimus calcium (IMU-838), an investigational multiple sclerosis (MS) therapy with promising results in clinical trials, may exert neuroprotective effects by activating a protein called Nurr1, according to newly published preclinical data.
The observed actions on Nurr1 are in addition to the therapy’s known role as an inhibitor of the dihydroorotate dehydrogenase (DHODH) enzyme, which is involved in the activity of immune cells that drive MS inflammation.
According to its developer, Immunic Therapeutics, the new findings back the company’s position that vidofludimus calcium is not only anti-inflammatory, but also neuroprotective, and thus has potential to prevent neurodegeneration and disability accumulation for people with all forms of MS.
The study, “Development of a Potent Nurr1 Agonist Tool for In Vivo Applications,” was published in the Journal of Medicinal Chemistry.
Vidofludimus calcium is an oral medication that works to interfere with the normal metabolism of immune cells that drive inflammation and cell death in MS. It does so through inhibition of the DHODH enzyme, a mechanism also used by Aubagio (teriflunomide), an oral therapy approved for relapsing forms of MS.
The benefits of vidofludimus calcium in a relapsing MS patient population were observed in the placebo-controlled Phase 2 trial EMPhASIS (NCT03846219), which enrolled 268 people with relapsing-remitting MS (RRMS).
Results from the trial indicated that daily oral treatment with the therapy (30 or 45 mg) for six months led to significant reductions in total brain lesions relative to patients given a placebo.
Most participants then joined the trial’s open-label extension phase, in which all are receiving the experimental therapy for up to 9.5 years. After two years in the extension phase, data showed that most patients — 94.5% — had not experienced a sustained disability accumulation, and few patients had experienced a relapse.
Notably, data from EMPhASIS indicated that vidofludimus calcium reduced levels of neurofilament light chain (NfL), a biomarker of nerve cell damage, indicating it could have neuroprotective effects. But the exact mechanism driving neuroprotection was not well understood.
“The neuroprotective properties of vidofludimus calcium were already identified in our phase 2 EMPhASIS trial … where the trial data showed encouraging clinical signals regarding prevention of confirmed disability worsening as well as a remarkable reduction of the biomarker neurofilament light chain,” Hella Kohlhof, PhD, chief scientific officer of Immunic, said in a press release.
Therapeutic target for other diseases
Nuclear receptor related 1 (Nurr1) is a transcription factor, a type of protein that regulates the activity of genes to make them more or less active. The protein is found mostly in nerve cells, where it has neuroprotective and anti-neuroinflammatory activity. As such, it is an emerging therapeutic target for neurodegenerative diseases such as MS, Parkinson’s, and Alzheimer’s diseases.
In the study, researchers at Immunic and at the Ludwig-Maximilians-Universität, in Germany, demonstrated that vidofludimus calcium is a potent agonist (activator) of Nurr1 in cells without activating other molecules with a similar structure.
Using the findings, the researchers then developed a new, highly selective Nurr1 activator that could influence Nurr1-related gene activity in nerve support cells and had favorable pharmacological properties in rats.
“From what we have now seen in our preclinical models, vidofludimus calcium and structurally related molecules are among the most potent Nurr1 agonists in literature,” said Daniel Merk, PhD, of the Ludwig-Maximilians-University Munich and the study’s corresponding author.
Immunic now has submitted a new application to patent the findings in the U.S. and European Union.
“The preclinical data confirming vidofludimus calcium as a potent Nurr1 activator is another exciting milestone for our lead development program as it suggests that Nurr1 may be responsible for the drug’s postulated neuroprotective effects,” said Daniel Vitt, PhD, CEO and president of Immunic.
Now, “further studies will have to evaluate whether Nurr1-mediated effects contribute to the therapeutic benefit from [vidofludimus calcium] in MS,” the researchers wrote.
The CALLIPER clinical trial
The ongoing placebo-controlled CALLIPER Phase 2 trial (NCT05054140) is now seeking to confirm the neuroprotective potential of the medication in people with progressive forms of MS.
The trial is recruiting up to 450 people with primary progressive MS or secondary progressive MS (SPMS) without evidence of relapses in the past two years, at sites in the U.S. and Europe.
Interim biomarker analyses, which will include measurements of NfL, are expected from CALLIPER later this year.
Meanwhile, two identical Phase 3 trials — ENSURE-1 (NCT05134441) and ENSURE-2 (NCT05201638) — are seeking to confirm the benefits of vidofludimus calcium in relapsing forms of MS. Both ENSURE-1 and ENSURE-2 are enrolling patients with RRMS and active SPMS at sites worldwide, and interim analyses are expected late next year.