IMU-838

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 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

Illustration of IMU-838 processes

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.

 

Phase 3 Program of Vidofludimus Calcium in RMS (ENSURE Program)
ClinicalTrials.gov Identifier: NCT05134441
Study Website: https://ensure-ms.com

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.

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