Immunic, Inc

1200 Avenue of the Americas, Suite 200
New York, NY 10036, USA

Phone: +49 89 2080 477 00
Email: info@imux.com

Immunic AG

Lochhamer Schlag 21
82166 Gräfelfing, Germany

Phone: +49 89 2080 477 00
Email: info@imux.com

IMU-838

IMU-838: Targeting DHODH

IMU-838 is a small molecule investigational drug 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.

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 IBD, 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 in IBD 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 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 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 IMU-838 may avoid virus reactivation, one of the major drawbacks of the long-term use of traditional immunomodulators in IBD patients.

DHODH Targeting Leads to Metabolic Stress in Metabolically Activated Cells

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.

To date, IMU-838 has been tested in more than 800 individuals and has shown an attractive pharmacokinetic, safety and tolerability profile.

IMU-838 in Relapsing-Remitting Multiple Sclerosis (RRMS)

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 IMU-838 has the potential to demonstrate medically important advantages compared with other treatments, particularly for the early treatment of RRMS patients, due to its placebo like safety profile and its robust anti-inflammatory and neuroprotective properties. IMU-838 could provide RRMS patients with a distinctive combination of robust efficacy and favorable safety and tolerability including the following properties:

  • The robust MRI lesion suppression of IMU-838 compares favorably to other first-line and oral base medications commercially available for RRMS.
  • A very low discontinuation rate for IMU-838-treated RRMS 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 IMU-838 well from other oral RRMS treatments.
  • A robust decrease in serum neurofilament light chain, a biomarker for axonal damage, was observed for IMU-838 and provides evidence of IMU-838’s potential neuroprotective activity.

 

Phase 3 Program of IMU-838 in RRMS (ENSURE Program)

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 IMU-838 in patients with RRMS. The ENSURE program comprises two multicenter, randomized, double-blind phase 3 trials designed to evaluate the efficacy, safety, and tolerability of IMU-838 versus placebo in RRMS 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 IMU-838 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, with dosing of the first patient expected in the second half of 2021.

Based on IMU-838’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 IMU-838 in RRMS.

 

Phase 2 Trial of IMU-838 in PMS (CALLIPER Trial)

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 IMU-838’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 IMU-838 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 first patient has been enrolled in September 2021.

 

Phase 2 Trial of IMU-838 in RRMS (EMPhASIS Trial)

On August 2, 2020, Immunic announced positive top-line data from its phase 2 EMPhASIS trial of IMU-838 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 April 15, 2021, Immunic announced an interim analysis of the additional 10 mg Cohort 2 of the EMPhASIS trial confirming IMU-838’s dose response in RRMS and supporting phase 3 dose selection. Previously published data from Cohort 1, together with the Cohort 2 data, confirmed that 30 mg once daily IMU-838 is the most appropriate dose for the company’s phase 3 program in RRMS.

IMU-838 in Ulcerative Colitis (UC)

IMU-838 is being developed as a new treatment option for patients with moderate to severe UC who have failed current therapies and are now candidates for therapy with biologics. If approved, Immunic believes that IMU-838 has the potential to be a first-in-class DHODH inhibitor in this indication.
The company’s CALDOSE-1 trial is a phase 2b, dose-finding, multicenter, double-blind, placebo-controlled study being conducted in more than 100 study centers throughout 14 countries, including the United States and countries in Western, Central and Eastern Europe. Recruitment is expected to be completed in the second half of 2021 and top-line data is expected to be available in the first half of 2022.

IMU-838 in COVID-19

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 IMU-838 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 IMU-838 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. IMU-838 was also found to be safe and well-tolerated in hospitalized patients with moderate COVID-19.

IMU-838 in Primary Sclerosing Cholangitis (PSC)

Immunic is exploring the use of IMU-838 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.
On February 18, 2021, Immunic announced positive top-line data from its investigator-sponsored proof-of-concept clinical trial of IMU-838 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.

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