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Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis.
Mult Scler Relat Disord. 2020 Aug; 43:102129.MS

Abstract

BACKGROUND

Inhibition of dihydroorotate dehydrogenase (DHODH) is an established mechanism for the treatment of relapsing-remitting multiple sclerosis (RRMS). Currently approved treatments have several shortcomings. Consequently, new and effective treatments with improved safety and convenience profiles are sought after by patients.

OBJECTIVE

To explore the overall profile of vidofludimus for the treatment of RRMS.

METHODS

Preclinical investigations were done exploring the species-dependency of DHODH inhibition of vidofludimus. In addition, the preclinical efficacy in a rat experimental autoimmune encephalomyelitis (EAE) model and the inhibition of cytokine release from activated PBMC were investigated. Pharmacokinetic data were also obtained in a Phase 1 multiple ascending dose trial of the formulation IMU-838 (vidofludimus calcium).

RESULTS

It was shown that vidofludimus is 2.6 times more potent in inhibiting DHO oxidation by human DHODH compared to teriflunomide. Although both compounds increased cell apoptosis, vidofludimus was more efficacious in the inhibition of T-lymphocyte proliferation compared to teriflunomide. The same was also observed for the secretion of IL-17 and IFN-γ. Interestingly, the potency or vidofludimus to inhibit rat or mouse DHODH is 7.5 and 64.4 time lower than the for the human DHODH, respectively. The rat EAE study clearly exhibited a dose-dependent inhibition of cumulative disease scores by vidofludimus. In the multiple ascending dose Phase 1 clinical trial, the serum half-life of about 30 h provides a favorable profile for once daily dosing of IMU-838, with quick dosing to steady state through levels within 5 days and the ability to wash out drug quickly, if required.

CONCLUSIONS

The investigations highlighted that the desired selective immunomodulatory properties can be separated from general antiproliferative effects seen and related adverse events in first-generation DHODH inhibitors. Based on data obtained from a series of pre-clinical as well as phase 1 and phase 2 studies, IMU-838 is a promising next-generation candidate for the oral treatment of RRMS. However, this will need to be confirmed in the currently ongoing Phase 2 study in RRMS patients.

Authors+Show Affiliations

Immunic AG, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany. Electronic address: andreas.muehler@imux.com.Immunic AG, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany.Immunic AG, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany.Immunic AG, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany.Immunic AG, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32428844

Citation

Muehler, Andreas, et al. "Vidofludimus Calcium, a Next Generation DHODH Inhibitor for the Treatment of Relapsing-remitting Multiple Sclerosis." Multiple Sclerosis and Related Disorders, vol. 43, 2020, p. 102129.
Muehler A, Peelen E, Kohlhof H, et al. Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2020;43:102129.
Muehler, A., Peelen, E., Kohlhof, H., Gröppel, M., & Vitt, D. (2020). Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Multiple Sclerosis and Related Disorders, 43, 102129. https://doi.org/10.1016/j.msard.2020.102129
Muehler A, et al. Vidofludimus Calcium, a Next Generation DHODH Inhibitor for the Treatment of Relapsing-remitting Multiple Sclerosis. Mult Scler Relat Disord. 2020;43:102129. PubMed PMID: 32428844.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. AU - Muehler,Andreas, AU - Peelen,Evelyn, AU - Kohlhof,Hella, AU - Gröppel,Manfred, AU - Vitt,Daniel, Y1 - 2020/05/06/ PY - 2019/12/27/received PY - 2020/04/10/revised PY - 2020/04/12/accepted PY - 2020/5/20/pubmed PY - 2020/5/20/medline PY - 2020/5/20/entrez KW - DHODH KW - Drug profil KW - IMU–838 KW - Multiple Sclerosis KW - New oral drug KW - Terifludomide KW - Vidofludimus SP - 102129 EP - 102129 JF - Multiple sclerosis and related disorders JO - Mult Scler Relat Disord VL - 43 N2 - BACKGROUND: Inhibition of dihydroorotate dehydrogenase (DHODH) is an established mechanism for the treatment of relapsing-remitting multiple sclerosis (RRMS). Currently approved treatments have several shortcomings. Consequently, new and effective treatments with improved safety and convenience profiles are sought after by patients. OBJECTIVE: To explore the overall profile of vidofludimus for the treatment of RRMS. METHODS: Preclinical investigations were done exploring the species-dependency of DHODH inhibition of vidofludimus. In addition, the preclinical efficacy in a rat experimental autoimmune encephalomyelitis (EAE) model and the inhibition of cytokine release from activated PBMC were investigated. Pharmacokinetic data were also obtained in a Phase 1 multiple ascending dose trial of the formulation IMU-838 (vidofludimus calcium). RESULTS: It was shown that vidofludimus is 2.6 times more potent in inhibiting DHO oxidation by human DHODH compared to teriflunomide. Although both compounds increased cell apoptosis, vidofludimus was more efficacious in the inhibition of T-lymphocyte proliferation compared to teriflunomide. The same was also observed for the secretion of IL-17 and IFN-γ. Interestingly, the potency or vidofludimus to inhibit rat or mouse DHODH is 7.5 and 64.4 time lower than the for the human DHODH, respectively. The rat EAE study clearly exhibited a dose-dependent inhibition of cumulative disease scores by vidofludimus. In the multiple ascending dose Phase 1 clinical trial, the serum half-life of about 30 h provides a favorable profile for once daily dosing of IMU-838, with quick dosing to steady state through levels within 5 days and the ability to wash out drug quickly, if required. CONCLUSIONS: The investigations highlighted that the desired selective immunomodulatory properties can be separated from general antiproliferative effects seen and related adverse events in first-generation DHODH inhibitors. Based on data obtained from a series of pre-clinical as well as phase 1 and phase 2 studies, IMU-838 is a promising next-generation candidate for the oral treatment of RRMS. However, this will need to be confirmed in the currently ongoing Phase 2 study in RRMS patients. SN - 2211-0356 UR - https://www.unboundmedicine.com/medline/citation/32428844/Vidofludimus_calcium,_a_next_generation_DHODH_inhibitor_for_the_Treatment_of_relapsing-remitting_multiple_sclerosis L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-0348(20)30205-4 DB - PRIME DP - Unbound Medicine ER -
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