Vidofludimus Calcium (IMU-838): Targeting DHODH
Vidofludimus calcium (IMU-838) is a small molecule investigational drug under development as an oral tablet formulation for the treatment of multiple sclerosis, or MS, including relapsing multiple sclerosis, or RMS, and progressive multiple sclerosis, or PMS, as well as primary sclerosis cholangitis, or PSC, and other chronic inflammatory and autoimmune diseases.
By inhibiting dihydroorotate dehydrogenase, or DHODH, a key enzyme of pyrimidine de novo biosynthesis, highly metabolically activated T and B immune cells experience metabolic stress, which leads to a modulation of their activity and function. Thereby, pro-inflammatory cytokines such as IFNγ, TNFα, IL-17A and IL-17F, produced by activated Th1 and Th17 cells, which represent subtypes of so-called T helper cells, are repressed, and thereby reduce the inflammation associated with MS and other chronic inflammatory diseases. In preclinical studies of vidofludimus, the active moiety of IMU-838, apoptosis (or programmed cell death) was induced in activated T cells, which Immunic believes may also play a crucial role in the activity of the drug by further dampening the inflammatory response.
Immunic believes that a key advantage of DHODH inhibition, in general, is that the sensitivity of specific immune cells to DHODH inhibition correlates with their intracellular metabolic activation state, and therefore may not negatively impact “normal” immune and bone marrow cells.
In animal studies of vidofludimus calcium, animals treated with large doses of the active moiety vidofludimus were shown to lack detrimental effects on bone marrow, supporting the lack of an unspecific anti-proliferative effect regularly seen with many traditional immunomodulators.
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 antiviral effect, which has been observed in various virus infected cells, such as hepatitis C virus infections, cytomegalovirus infections and even hemorrhagic fever-causing viruses, such as Arena virus infections. Treatment with vidofludimus calcium may avoid virus reactivation, one of the major drawbacks of the long-term use of traditional immunomodulators.
DHODH Targeting Leads to Metabolic Stress in Metabolically Activated Cells
This graphic illustrates the above mentioned processes.
In 2017, Immunic completed two phase 1 studies of single or repeated once-daily doses of vidofludimus calcium in healthy volunteers, where Immunic observed results supporting tolerability of repeated daily dosing of up to 50 mg of vidofludimus calcium.
To date, vidofludimus calcium has been tested in more than 1,100 individuals and has shown an attractive pharmacokinetic, safety and tolerability profile.
Despite many therapies approved and in late-stage development for relapsing forms of multiple sclerosis, there remains a significant unmet need for a safe, oral, well-tolerated, robust anti-inflammatory, with neuroprotective properties that exceeds what is expected from the reduction of inflammation, alone.
Bolstered by excellent clinical data from the phase 2 EMPhASIS trial, Immunic believes that vidofludimus calcium has the potential to demonstrate medically important advantages compared with other treatments, particularly for the early treatment of RMS patients, due to its placebo like safety profile and its robust anti-inflammatory and neuroprotective properties. Vidofludimus calcium could provide RMS patients with a distinctive combination of robust efficacy and favorable safety and tolerability including the following properties:
- The robust MRI lesion suppression of vidofludimus calcium compares favorably to other first-line and oral base medications commercially available for RMS.
- A very low discontinuation rate for vidofludimus calcium-treated RMS patients, substantially below placebo, indicates an encouraging combination of tolerability and efficacy.
- The absence of hepatotoxicity signals and other relevant adverse events leading to discontinuations distinguishes vidofludimus calcium well from other oral RMS treatments.
- A robust decrease in serum neurofilament light chain, a biomarker for axonal damage, was observed for vidofludimus calcium and provides evidence of its potential neuroprotective activity.
On July 1, 2021, Immunic announced U.S. Food and Drug Administration, or FDA, clearance of its Investigational New Drug, or IND, application for the phase 3 ENSURE program of vidofludimus calcium in patients with RMS. The ENSURE program comprises two 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 14 countries, including the United States, Latin America, Central and Eastern Europe, and India. 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 will be run concurrently. The read-out of the first of the phase 3 ENSURE trials is currently targeted for end of 2025.
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 multicenter, randomized, double-blind, placebo-controlled phase 2 CALLIPER trial is intended to run concurrently with and to complement the phase 3 program in RRMS. In particular, CALLIPER is focused on progressive forms of multiple sclerosis, or PMS, and designed to corroborate vidofludimus calcium’s neuroprotective potential, as exemplified by slowing of brain atrophy and delay in disability worsening.
The CALLIPER trial is expected to enroll approximately 450 patients at more than 70 sites in North America, Western, Central and Eastern Europe with patients 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 (EDSS). The current goal is to report data from the interim analysis of the phase 2 CALLIPER trial in the second half of 2023 and to read-out top-line data at the end of 2024.
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.
In addition, the final data also provide evidence of dose-proportional neuroprotective activity. For instance, the baseline adjusted decreases in the biomarker serum neurofilament light chain (NfL) 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.
Immunic is exploring the use of vidofludimus calcium in orphan diseases, such as PSC, that may allow for an accelerated path to commercialization. Immunic continues to explore additional orphan diseases in conjunction with interested investigators.
Investigator-Sponsored Phase 2 Trial of Vidofludimus Calcium in PSC
On February 18, 2021, Immunic announced positive top-line data from its investigator-sponsored proof-of-concept clinical trial of vidofludimus calcium in primary sclerosing cholangitis, or PSC, which was conducted at Mayo Clinic in Arizona and Minnesota, both of which are tertiary referral centers for PSC patients. Data showed a statistically significant decrease in serum alkaline phosphatase levels (p=0.041) in the 11-patient per-protocol population after 24-weeks of treatment, as compared to baseline. Additionally, the primary objective, a clinically relevant reduction of serum alkaline phosphatase higher than 25% without an increase in liver biochemistry of more than 33%, was achieved in 27.3% of the patients in the per-protocol population at week 24, as compared to baseline. Other liver biochemistry parameters evaluated, including aspartate aminotransferase, alanine aminotransferase, and total/direct/indirect bilirubin, remained stable, and IMU-838’s favorable safety and tolerability profile was confirmed in the patient population.
Phase 2 Trial of Vidofludimus Calcium in COVID-19 (CALVID-1 Trial)
ClinicalTrials.gov Identifier: NCT04379271
Although numerous pharmacological interventions are in clinical trials for the treatment of COVID-19 and some have obtained Emergency Use Authorization, clear efficacy has not yet been determined for any of the current COVID-19 therapies.
On February 17, 2021, Immunic announced that vidofludimus calcium has shown evidence of clinical activity in hospitalized patients with moderate COVID-19. This planned main analysis of the Company’s phase 2 CALVID-1 trial was based on data from 204 randomized patients and included top-line clinical efficacy, safety, disease marker, and virology data. A final analysis of the complete randomized patient population of 223, which will comprise data on all endpoints, including subgroup and sensitivity analyses, is expected to be available in the second quarter of 2021.
The data showed clinical activity based on multiple secondary endpoints, including (1) clinically meaningful improvements in time to clinical recovery and time to clinical improvement; (2) an even stronger treatment effect on high-risk patients and those over 65 years of age; (3) an anti-viral effect of vidofludimus calcium on SARS-CoV-2, as observed by viral titers; and (4) a robust anti-inflammatory effect, based on a more effective reduction of C-Reactive Protein in treated patients, as compared to placebo. Vidofludimus calcium was also found to be safe and well-tolerated in hospitalized patients with moderate COVID-19.