Vidofludimus Calcium

Vidofludimus Calcium

Vidofludimus calcium (IMU-838) is a small molecule investigational drug in development as an oral next-generation treatment option for patients with multiple sclerosis, or MS, and other chronic inflammatory and autoimmune diseases.

Vidofludimus Calcium is Targeted to Address Multiple Drivers of Neurodegeneration in MS Patients

Vidofludimus calcium is being tested in several ongoing MS trials, including the twin phase 3 ENSURE trials in relapsing MS and the supportive phase 2 CALLIPER trial in progressive MS. If approved, vidofludimus calcium, with combined neuroprotective, anti-inflammatory, and anti-viral effects, has the potential to be a unique treatment option targeted to the complex pathophysiology of MS.


Direct Neuroprotective Effects

  • Potent Nurr1 activation, involved in protection of relevant neurons from cell death
  • Impact on serum neurofilament light chain, a biomarker for axonal damage
  • Encouraging clinical signals from phase 2 trial on change in EDSS and rates of confirmed disability worsening
  • Potential to target progression independent of relapse activity, or PIRA

Anti-Inflammatory Effects

  • Selectively targets hyperactive immune cells
  • Reduces magnetic resonance imaging lesions
  • Reduces relapses
  • Mechanism already shown to reduce brain atrophy
  • Addressing relapse-associated worsening, or RAW

Anti-Viral Effects

  • Established, broad-spectrum
    anti-viral activity
  • Epstein-Barr virus linked to MS
  • Potent anti-Epstein-Barr virus activity
  • Potential to suppress Epstein-Barr virus-related T cells

Vidofludimus calcium can target various aspects of ‘smoldering’ MS

Multiple publications from 2022[1-5] have highlighted the enhanced understanding of the triggers and ongoing neuronal destruction of MS, namely, that MS is triggered by infection from Epstein-Barr virus, or EBV, followed by cross-reactive antibody production and associated auto-inflammation and neuronal damage.

Preclinical data showed that vidofludimus calcium potently activates the neuroprotective transcription factor nuclear receptor related 1, or 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, or 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.

Immunic believes that the combined mechanisms of vidofludimus calcium are unique in the MS space and support the therapeutic performance shown in the phase 2 EMPhASIS trial in relapsing-remitting MS, or RRMS, 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, or NfL, an important biomarker for axonal damage.

Vidofludimus calcium has an attractive and consistent pharmacokinetic, safety and tolerability profile and has already been exposed to more than 1,800 human subjects and patients, to date.
First-in-Class Nurr1 Activator, Targeting Improvement of Physical Ability of MS Patients

Vidofludimus calcium’s ability to activate the neuroprotective transcription factor Nurr1 is associated with direct neuroprotective properties and may enhance the potential benefit for patients. Nurr1 activation mediates its neuroprotective function by acting in microglia, astrocytes and neurons. In microglia and astrocytes, Nurr1 activation leads to a reduction of pro-inflammatory cytokines and blocks the production of direct neurotoxic agents like reactive oxygen species and nitric oxide. Enhanced Nurr1 activity in neurons mediates neuronal survival and differentiation, as well as improved neurotransmission. Therefore, activation of Nurr1 by vidofludimus calcium may halt neurodegeneration and disability progression in patients suffering from MS and other degenerative diseases.

DHODH 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. By inhibiting DHODH, a key enzyme of pyrimidine de novo biosynthesis, highly metabolically active T and B immune cells experience metabolic stress, which leads to a modulation of their activity and function. By addressing only highly metabolically active immune cells, vidofludimus calcium may reduce focal inflammation in the brain, without impacting normal acting immune cells.

Based on the selectivity toward metabolically activated cells (with a high need for ribonucleic acid and deoxyribonucleic acid production), DHODH inhibition also leads to a direct anti-viral effect, which has been observed in various virus infected cells, such as EBV infections, hepatitis C virus infections, SARS-CoV-2 infections, cytomegalovirus infections and even hemorrhagic fever-causing viruses, such as Arena virus infections. Treatment with vidofludimus calcium may avoid virus infections and reactivations, one of the major drawbacks of the long-term use of traditional immunomodulators. In addition, the blockage of reactivation of EBV could be of highest importance for MS patients, as infection with and reactivation of EBV was brought into connection with disease onset and progression[2, 4, 5].

Efficacy of vidofludimus has been observed in several animal disease models for MS, inflammatory bowel disease, as well as systemic lupus erythematosus and transplant rejection. In 2017, Immunic completed two phase 1 studies of single or repeated once-daily doses of vidofludimus calcium in healthy human subjects, where results supporting tolerability of repeated daily dosing of up to 50 mg of vidofludimus calcium were observed.

Clinical Development of Vidofludimus Calcium

Immunic believes that vidofludimus calcium has the potential to demonstrate medically important advantages versus other treatments, due to its favorable safety profile as well as its neuroprotective, anti-inflammatory, and anti-viral effects observed to date. Vidofludimus calcium could provide MS patients with a distinctive therapy that is uniquely matched to the biological drivers of MS. In clinical trials, to date, it has shown data indicating:

  • A targeted effect on hyperactive immune cells without suppression of normal immune function.
  • Improved rates of confirmed disability worsening.
  • Robust magnetic resonance imaging lesion suppression, comparing favorably to other medications commercially available for relapsing MS, or RMS.
  • A robust decrease in serum NfL, providing evidence of vidofludimus calcium’s potential direct neuroprotective activity.
  • A potent Nurr1 activation, which is involved in protection of relevant neurons from cell death.
  • A very low discontinuation rate for MS patients, substantially below placebo, which indicates an encouraging combination of tolerability and efficacy as well as maintenance of normal quality-of-life.
  • Absence of hepatotoxicity signals and other relevant adverse events leading to discontinuations, which distinguishes vidofludimus calcium from other oral RMS treatments.
  • A broad spectrum anti-viral effect, which may support lowering the rate of viral infections and reactivations, including EBV reactivation, potentially resulting in slowing potential EBV-related neurodegenerative processes.
  • Phase 3 Program of Vidofludimus Calcium in RMS (ENSURE Program) Identifier: NCT05134441 & NCT05201638
    Study Website:

    The ongoing ENSURE program comprises two identical multicenter, randomized, double-blind phase 3 trials designed to evaluate the efficacy, safety and tolerability of vidofludimus calcium versus placebo in RMS patients. Each of the trials, titled ENSURE-1 and ENSURE-2, is expected to enroll approximately 1,050 adult patients with active RMS at more than 100 sites in more than 15 countries, including the United States, India and countries in Latin America, Central and Eastern Europe. Patients will be randomized in a double-blinded fashion to either 30 mg daily doses of vidofludimus calcium or placebo and the primary endpoint for both trials is time to first relapse up to 72 weeks. Key secondary endpoints include volume of new T2-lesions, time to confirmed disability progression, time to sustained clinically relevant changes in cognition, and percentage of whole brain volume change, grey matter volume and white matter volume.

    The ENSURE trials are being run concurrently. Immunic currently expects to report an interim futility analysis of the ENSURE program in late 2024. The read-out of the first of the ENSURE trials is currently anticipated in the second quarter of 2026; and the second ENSURE trial in the second half of 2026.

    Based on vidofludimus calcium’s robust activity in preventing lesion formation in the company’s phase 2 EMPhASIS trial in RRMS, the strong and consistent correlation observed between lesion formation and clinical relapse in third-party clinical trials, and the drug’s robust safety profile to date, Immunic believes that this phase 3 program provides a simple and straightforward path towards potential regulatory approval of vidofludimus calcium in RMS.

  • Phase 2 Trial of Vidofludimus Calcium in PMS (CALLIPER Trial) Identifier: NCT05054140

    The multicenter, randomized, double-blind, placebo-controlled phase 2 CALLIPER trial is intended to run concurrently with and to complement the phase 3 program in RMS. In particular, CALLIPER is focused on progressive forms of MS, or PMS, and is designed to corroborate vidofludimus calcium’s neuroprotective potential, as exemplified by slowing of brain atrophy and delay in disability worsening.

    The CALLIPER trial enrolled 467 patients with primary PMS, or active or non-active secondary PMS at more than 70 sites in North America as well as Western, Central and Eastern Europe. Patients were randomized to either 45 mg daily doses of vidofludimus calcium or placebo in a double-blinded fashion. The trial’s primary endpoint is the annualized rate of percent brain volume change up to 120 weeks. Key secondary endpoints include the annualized rate of change in whole brain atrophy and time to 24-week confirmed disability progression based on the expanded disability status scale, or EDSS. Immunic’s current expectation is to read-out top-line data of the CALLIPER trial in April 2025.

    On October 9, 2023, Immunic announced positive interim data from the CALLIPER trial, showing biomarker evidence that vidofludimus calcium’s activity extends beyond the previously observed anti-inflammatory effects, thereby further reinforcing its neuroprotective potential. The 24-week data from the first half of patients showed improvements in serum NfL, consistent throughout the overall PMS population as well as all sub-analyses.

  • Phase 2 Trial of Vidofludimus Calcium in RRMS (EMPhASIS Trial) Identifier: NCT03846219

    On August 2, 2020, Immunic announced positive top-line data from its phase 2 EMPhASIS trial of vidofludimus calcium in patients with RRMS. The trial achieved statistical significance on all primary and key secondary endpoints, indicating activity in RRMS patients. On September 11, 2020, the company published the full unblinded clinical data set which confirmed and expanded on the previously announced top-line results.

    On February 24, 2022, Immunic published final data for the EMPhASIS trial. In the final data set combining patients from both Cohort 1 (30 mg, 45 mg and placebo) and Cohort 2 (10 mg and placebo), placebo adjusted reductions in gadolinium-enhancing lesions at 24 weeks for the 10 mg, 30 mg, and 45 mg dose groups of vidofludimus calcium were 13%, 78%, and 74%, respectively. The company believes this data provides further corroboration for the selection of the 30 mg dose for the ongoing phase 3 program in RMS.

    The final data also provide evidence of dose-proportional neuroprotective activity. For instance, the baseline adjusted decreases in the biomarker serum neurofilament light chain at 24 weeks for the 10 mg, 30 mg, and 45 mg dose groups of vidofludimus calcium were 9%, 18%, and 26%, respectively, as compared to placebo. The company believes this observation suggests that higher doses, such as 45 mg vidofludimus calcium, may be preferrable in indications where neuroprotective effects are most important, such as in PMS.

    On November 17, 2022, Immunic reported data from the open-label extension phase of the trial showing that long-term open-label treatment with vidofludimus calcium was associated with a low rate of confirmed disability worsening over time, comparing favorably to historical trial data for currently available MS medications.

    The results of study cohort 1, exploring the doses of 30 mg and 45 mg of vidofludimus calcium versus placebo, were published in Annals of Clinical and Translational Neurology in 2022 (Fox RJ, et al. Ann Clin Transl Neurol. 2022;9(7):977-987).

    The extended results of the combined study cohorts 1 and 2  cohort 2 explored the dose of 10 mg of vidofludimus calcium versus placebo  were published in Neurology® Neuroimmunology & Neuroinflammation, an official journal of the American Academy of Neurology in 2024 (Fox RJ, et al. Neurol Neuroimmunol Neuroinflamm. 2024;11(3):e200208).

  1. Lublin FD, et al. How patients with multiple sclerosis acquire disability. Brain. 2022 Sep 14;145(9):3147-3161. Available from:
  2. Bjornevik K. et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 10.1126/science.abj8222 (2022). Available from:
  3. Robinson WH, Steinman L. Epstein-Barr virus and multiple sclerosis. Science. 2022 Jan 21;375(6578):264-265. Available from:
  4. Lanz, T.V., et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 603, 321–327 (2022). Available from:
  5. Schneider-Hohendorf et al. Broader Epstein–Barr virus–specific T cell receptor repertoire in patients with multiple sclerosis. J. Exp. Med. 2022 Vol. 219 No. 11 e20220650. Available from:

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