IMU-838 is a small molecule investigational drug (vidofludimus calcium) under development as an oral tablet formulation for the treatment of relapsing-remitting multiple sclerosis, or RRMS, inflammatory bowel disease, or IBD, and other chronic inflammatory and autoimmune diseases. The company is also investigating IMU-838 as a potential treatment option for coronavirus disease 2019, or COVID-19.
By inhibiting dihydroorotate dehydrogenase (DHODH), a key enzyme of pyrimidine de novo biosynthesis, metabolically activated T and B immune cells experience metabolic stress, and the release of Th1 and Th17 key cytokines including IL-17A, IL-17F and IFNg is inhibited, thereby reducing inflammation. In preclinical studies of vidofludimus, the active moiety and free acid form 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’ bone marrow cells. In animal studies of IMU-838, animals treated with large doses of the active moiety of IMU-838 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, or RNA, and deoxyribonucleic acid, or DNA, production), DHODH inhibition also leads to a direct antiviral effect, which has been demonstrated in various virus infected cells, such as influenza virus infections, cytomegolvirus infections and even hemorrhagic fever-causing viruses, such as Arenavirus. Treatment with IMU-838 may avoid virus reactivation, one of the major drawbacks of the long-term use of traditional immunomodulators. Efficacy of vidofludimus has been observed in several animal disease models for IBD, as well as systemic lupus erythematosus and transplant rejection.
DHODH Targeting Leads to Metabolic Stress in Metabolically Activated Cells
Initial clinical trials were conducted using a free acid formulation of the active moiety of IMU-838, vidofludimus, and an amorphous material. In total, this clinical trial data encompasses more than 250 patients treated with the active moiety, helping generate a safety database to encourage further development of IMU-838. Immunic developed and patented a new specific polymorph of the calcium salt formulation of vidofludimus, IMU-838, which Immunic believes exhibits improved physicochemical and pharmacokinetic properties.
Immunic has used and continues to use its IMU-838 formulation in its drug development activities. In 2017, Immunic completed two phase 1 studies of single or repeated once-daily doses of IMU-838 in healthy volunteers, where Immunic observed results supporting tolerability of repeated daily dosing of up to 50 mg of IMU-838. Importantly, IMU-838 has an attractive pharmacokinetic, safety and tolerability profile and, to date, has already been tested in about 650 individuals.
On August 2, 2020, Immunic announced positive top-line results from its phase 2 EMPhASIS trial of IMU-838 in patients with RRMS, reporting achievement of both primary and key secondary endpoints with high statistical significance, indicating activity for IMU-838 in this indication. The data also supports the previously in other patient populations observed, favorable safety profile of IMU-838. On September 11, 2020, the Company published the full unblinded clinical data set, which confirmed and expanded on the previously announced top-line results.
A second phase 2 study in patients with ulcerative colitis, or UC, is also ongoing, with enrollment initiated in April 2018 and top-line data expected to be available in the first half of 2022. Furthermore, Immunic’s collaboration partner, the Mayo Clinic, has started an investigator-sponsored proof-of-concept clinical trial testing IMU-838 activity in patients with primary sclerosing cholangitis, or PSC. Together with the investigators, Immunic currently expects a potential data readout during the fourth quarter of 2020 using the 18 patients who were enrolled prior to the COVID-19 pandemic.
Although the drug is being studied in these ongoing trials primarily for its anti-inflammatory effect, one of IMU-838’s postulated benefits is a host-based antiviral effect, which may be important in these indications to potentially prevent virus reactivations known to occur with other immunomodulatory therapies. In support, IMU-838’s antiviral activity has previously been demonstrated in vitro against human immunodeficiency virus (HIV), hepatitis C virus (HCV), human cytomegalovirus (hCMV), Arenavirus and Influenza A virus. Given what is known about the natural course of the disease, IMU-838’s combination of antiviral activity against the highly pathogenic severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, and a selective immunomodulatory effect against highly activated immune cells may be a promising profile for the treatment of COVID-19.
IMU-838 has successfully demonstrated preclinical activity against SARS-CoV-2. Specifically, IMU-838 was observed to inhibit replication of clinical isolates of SARS-CoV-2 associated with COVID-19. In cellular assays, IMU-838 demonstrated this antiviral activity at concentrations which are well below the blood concentrations associated with IMU-838 dosing regimens studied in ongoing and previous clinical trials. These positive results have encouraged Immunic to prepare a clinical development program for IMU-838 as a potential treatment option for patients with COVID-19 and potential other, future viral pandemics. A phase 2 study in patients with moderate COVID-19 is ongoing, with enrollment initiated in June 2020 and enrollment of 200 patients completed beginning of November 2020. Top-line data from the main phase 2 efficacy analysis is expected to be available in the first quarter of 2021. An additional investigator-sponsored phase 2 clinical trial of IMU-838 in combination with oseltamivir in patients with moderate-to-severe COVID-19 is ongoing in collaboration with the University Hospitals Coventry and Warwickshire NHS Trust, UK.
Immunic, Inc. Publishes Full Unblinded Clinical Data From Phase 2 EMPhASIS Trial of IMU-838 in Patients With Relapsing-Remitting Multiple Sclerosis and Announces Poster Presentation at the MSVirtual2020
Immunic, Inc. Announces First Patients Enrolled in Investigator-Sponsored Phase 2 Clinical Trial of IMU-838 in Combination with Oseltamivir for the Treatment of Patients with Moderate-to-Severe COVID-19
Immunic, Inc.’s Interim Dosing Analysis of IMU-838 as Part of its Ongoing Phase 2 CALDOSE-1 Study in Patients with Moderate-to-Severe Ulcerative Colitis Establishes Broad, Potentially Safe and Effective Dose Range