Potential of Vidofludimus Calcium as a Nurr1 Activator

Andreas Muehler, MD

Earlier this year, prior to the release of the phase 2, open-label data from the EMPhASIS trial (NCT03846219), investigators discovered that vidofludimus calcium has neuroprotective capabilities as an activator of nuclear receptor related 1 (Nurr1). Developed by Immunic, the agent is currently being assessed as a potential treatment for relapsing multiple sclerosis (MS) and progressive MS, a disease with few therapeutic options available. Nurr1, a constitutively active ligand-activated transcription factor predominantly expressed in neurons, has neuroprotective and anti-inflammatory activity and has emerged as an attractive target to treat neurodegenerative pathologies including Alzheimer disease, Parkinson disease, and MS.

Published in the Journal of Medicinal Chemistry, full dose-response characterization of the agent in Gal4 hybrid reporter gene assays on Nurr1 (EC50 = 0.4 [±0.2] um) and the related receptors Nur77 (NR4A1; EC50 = 3.1 [±0.7] um) and NOR1 (NR4A3; EC50 = 2.9 [±0.9] um) revealed considerable Nurr1 agonist potency and preference, which markedly exceeded available Nurr1 activators. In addition, no other dihydroorotate dehydrogenase (DHODH) inhibitor caused activation of Gal4-Nurr1 or flNurr1, thus supporting the effects of vidofludimus calcium as directly mediated by interaction with Nurr1.

Hella Kohlhof, PhD

Following the presentation of the preclinical data at the International Society of Neuroimmunology annual meeting, NeurologyLive® reached out to Immunic to gather more information on the study. Andreas Muehler, MD, chief medical officer, Immunic, and Hella Kohlhof, PhD, chief scientific officer, Immunic, provided answers on the success of the study, and why vidofludimus calcium has potential as a treatment for autoimmune and inflammatory diseases. The duo also answered questions on the knowns and unknowns of Nurr1 activation, and how the therapy would used among other MS disease-modifying therapies if approved.

NeurologyLive®: Can you discuss the mechanism of action of IMU-838 and why we believe it can be a successful therapy?

Andreas Muehler, MD: Vidofludimus calcium is a once-daily, oral small molecule drug. Recently published preclinical data (Vietor et al., Journal of Medicinal Chemistry 2023 66 (9), 6391-6402, published in April 2023) showed that vidofludimus calcium activates the neuroprotective transcription factor nuclear receptor related 1 (Nurr1), which is associated with direct neuroprotective properties and may enhance the potential benefit for patients. Additionally, vidofludimus calcium is a known inhibitor of the enzyme dihydroorotate dehydrogenase (DHODH), which is a key enzyme in the metabolism of overactive immune cells and virus-infected cells. This mechanism is associated with the anti-inflammatory and anti-viral effects of vidofludimus calcium.

We believe that the combined mechanisms of vidofludimus calcium are unique in the MS space and support the therapeutic performance shown in our Phase 2 EMPhASIS trial in relapsing-remitting MS patients, in particular, via data illustrating the potential to reduce magnetic resonance imaging lesions, prevent relapses, reduce the rate of disability progression, and reduce levels of serum neurofilament light chain (NfL), an important biomarker of neuronal death.

What is the significance of being an activator of Nurr1?

Hella Kohlhof, PhD: Nurr1 is a neuroprotective transcription factor and an emerging target in neurodegenerative diseases such as multiple sclerosis or Parkinson’s disease. So far, Nurr1 has been described as an undruggable target, because there has been a lack of potent and selective Nurr1 agonists for sufficient target validation. From what we have now seen in our preclinical models, vidofludimus calcium is among the most potent Nurr1 agonists in literature and, to our knowledge, the only Nurr1 activator in active clinical development. Activation of Nurr1 could be responsible for vidofludimus calcium’s postulated neuroprotective effects and may contribute to the previously reported reduction of confirmed disability worsening events in MS patients.

What are the current knowns and unknowns of Nurr1 and its impact on the central nervous system?

Hella Kohlhof, PhD: Nurr1 is well described for its neuroprotective role in Parkinson’s disease and more and more research is done in multiple sclerosis as well. Nurr1 activation mediates neuronal survival and reduces oxidative stress. In addition, Nurr1 activation increases the dopaminergic neurotransmission. With induction of the brain derived neurotropic factor (BDNF) as a direct target gene of Nurr1 activation, the myelination of neurons is positively impacted. Thereby, BDNF drives the proliferation and differentiation of oligodendrocytes, the cells which are responsible for myelination of neurons. In the motor cortex region of the brain of MS patients, a higher expression of Nurr1 relates to neuronal survival and increased neuronal density, which is expected to correlate to a better functionality of this brain region, impacting planning, control, and execution of voluntary movements. What is not known so far is the impact of Nurr1’s differential cellular expression in astrocytes, microglia, oligodendrocytes and neurons and its localization within the cell (cytosolic vs nucleolar), which may provide further insights into the neuroprotective role via targeting inflammation and neurodegeneration.

Although investigational right now, how would IMU-838 fit into the toolbox of therapies for MS?

Andreas Muehler, MD: Depending on the results of our ongoing clinical trials, we believe that vidofludimus calcium has the potential to demonstrate medically important advantages versus other treatments, due to its favorable safety and tolerability profile as well as its combined anti-inflammatory, anti-viral and neuroprotective properties observed-to-date. Vidofludimus calcium could provide MS patients with a distinctive therapy that is uniquely matched to the biological drivers of MS. In preclinical work and clinical trials, to date, it has shown data indicating:

• A targeted effect on hyperactive immune cells without suppression of normal immune function.
• Robust MRI lesion suppression, comparing favorably to other medications commercially available for RMS.
• An initial signal for improved rates of confirmed disability worsening.
• A robust decrease in serum NfL, a biomarker for axonal damage, providing evidence of vidofludimus calcium’s potential neuroprotective activity.
• A potent activation of the target Nurr1, which is involved in protection of relevant neurons from cell death.
• A low discontinuation rate for vidofludimus calcium-treated RMS patients, substantially below placebo, which indicates an encouraging combination of tolerability and efficacy as well as maintenance of normal quality-of-life.
• Based on exposure in more than 1,400 humans and with treatment durations of up 4 years, we still overserved an absence of hepatotoxicity signals and other relevant adverse events leading to discontinuations, which distinguishes vidofludimus calcium from other oral RMS treatments.
• The broad-spectrum antiviral effect of vidofludimus calcium may support lowering the rate of viral infections and reactivations, including EBV reactivation, potentially resulting in slowing potential EBV-related neurodegenerative processes.

Andreas Muehler, MD: What questions do we still have about IMU-838 that will be answered in the coming years?

In our phase 3 ENSURE program in relapsing MS, vidofludimus calcium should meet the relapse-related primary endpoint and we hope to also see an improvement in confirmed disability worsening in the pooled data of the two Phase 3 trials. In addition, we hope to show an initial signal in effectiveness regarding brain atrophy and biomarkers in one of the subpopulations of progressive MS in our phase 2 CALLIPER trial, thereby expanding vidofludimus calcium’s potential applicability.

REFERENCE
1. Vietor J, Gege C, Stiller T, et al. Development of a potent Nurr1 agonist tool for in vivo applications. J Med Chem. 2023;66(9):6391-6402. doi:10.1021/acs.jmedchem.3c00415