Vidofludimus Calcium
Vidofludimus Calcium
Vidofludimus Calcium is Targeted to Address Multiple Drivers of Neurodegeneration in MS Patients
Vidofludimus calcium is being tested in ongoing MS trials, including the twin phase 3 ENSURE trials in relapsing MS. Top-line data from the phase 2 CALLIPER trial in progressive MS was reported in April 2025. 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
- Encouraging clinical signals from phase 2 trials on change in EDSS and rates of confirmed disability worsening
- Impact on serum neurofilament light chain, a biomarker for axonal damage
- 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
- 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, and in the phase 2 CALLIPER trial in progressive MS, or PMS.
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.
Immunic believes 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 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.
- A robust decrease in serum NfL, observed in patients with both relapsing MS and progressive MS, 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)
ClinicalTrials.gov Identifier: NCT05134441 & NCT05201638
Study Website: https://www.ensure-ms.com/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 are being 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 time to confirmed disability worsening based on Expanded Disability Status Scale, or EDSS, disability progression, volume of new T2-lesions, 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. Completion 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.
On October 22, 2024, Immunic announced a positive outcome of the non-binding, interim futility analysis of the phase 3 ENSURE program. An unblinded Independent Data Monitoring Committee, or IDMC, confirmed that predetermined futility criteria have not been met and recommended the trials should continue without changes, including no need for a potential upsizing. Immunic has remained blinded during the interim analysis and has not seen any of the data available to the IDMC to make their recommendations.
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)
ClinicalTrials.gov Identifier: NCT05054140
The phase 2 CALLIPER trial is an international, multicenter, randomized, double-blind, placebo-controlled, exploratory phase 2 trial focused on progressive forms of MS, or PMS, and designed to corroborate vidofludimus calcium’s neuroprotective potential.
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.
On April 30, 2025, Immunic announced positive data from the CALLIPER trial. In the overall PMS patient population, vidofludimus calcium reduced the relative risk of 24-week confirmed disability worsening, or 24wCDW, events based on changes in the expanded disability status scale, or EDSS, by 20% compared to placebo. Further analyses by disease subtype demonstrated that vidofludimus calcium was associated with a 30% reduction in the relative risk of 24wCDW events in the primary progressive multiple sclerosis study population compared to placebo and a respective 15% reduction in the non-active secondary progressive multiple sclerosis study population. A consistent reduction of disability worsening was observed in the different subpopulations with or without inflammatory gadolinium-enhanced lesion activity at baseline and during the study. Vidofludimus calcium reduced the relative risk of 24wCDW events in patients without gadolinium-enhancing lesions at baseline by 29% compared to placebo.
While vidofludimus calcium had a modest benefit on the annualized rate of percent brain volume change, vidofludimus calcium substantially reduced the annualized rate of thalamic brain volume loss by 20% in patients with PMS compared to placebo. The total volume of new or enlarging T2 lesions showed a substantial difference between vidofludimus calcium and placebo over time, with vidofludimus calcium decreasing and placebo increasing.
The top-line CALLIPER data set confirmed the favorable safety and tolerability profile of vidofludimus calcium already observed in previous clinical trials. No new safety signals were identified.
CALLIPER enrolled 467 patients at more than 70 sites throughout North America as well as Western, Central and Eastern Europe. Patients, aged 18 to 65 years and without limitation on disease duration, were randomized to either 45 mg daily doses of vidofludimus calcium or placebo and treated for up to 120 weeks. CALLIPER enrolled mainly patients with primary progressive multiple sclerosis (n=152/467) and non-active secondary progressive multiple sclerosis (n=268/467). All patients showed no evidence of relapse in the last 24 months before randomization.
Phase 2 Trial of Vidofludimus Calcium in RRMS (EMPhASIS Trial)
ClinicalTrials.gov 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).
Investigator-Sponsored Phase 2 Trial of Vidofludimus Calcium in Post COVID Syndrome
EudraCT number: 2024-511628-16-00
The phase 2 RAPID_REVIVE (“Randomized Adaptive Assessment of Post COVID Syndrome Treatments_Reducing Inflammatory Activity in Patients with Post COVID Syndrome”) trial is a randomized, placebo-controlled, double-blind, parallel group trial led by Prof. Dr. Maria J.G.T. Vehreschild, Head of the Department of Infectious Diseases at the University Hospital Frankfurt, and sponsored by the Goethe University Frankfurt, which received trial funding via a grant from the German Federal Ministry of Education and Research (BMBF).
The trial, for which Immunic is providing study medication, plans to enroll 376 patients at 11 clinical sites in Germany. Following a 7-day screening period during the initialization phase, patients will be randomized 1:1 to receive either vidofludimus calcium (22.5 mg initiation dose for 7 days, followed by 45 mg for 49 days) or placebo. Thereafter, a response-adaptive randomization procedure will be followed. The trial will also include a 28-day follow-up period. The primary endpoint of the trial is the intra-patient change in physical function as measured by the Short Form-36 Physical Function (SF-36-PF) from baseline to day 56. Secondary endpoints include mental and physical health, intensity of fatigue and incapacitation, severity of mental disorder symptoms, and cognitive function.
In addition to Post COVID readouts, the trial is designed to deliver important data on the activity of vidofludimus calcium suppressing Epstein-Barr virus reactivation and related fatigue symptoms. Third-party research has identified Epstein-Barr virus reactivation as potential cause for Post COVID fatigue. Severe fatigue is also a common and debilitating symptom for multiple sclerosis patients with no effective therapies available. Therefore, the RAPID_REVIVE trial could deliver a potential read-through to Immunic’s multiple sclerosis development program as well.
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